October 2013 – Emergency Medicine Literature of Note

Intracranial Angioplasty, Where Did We Go Wrong?

This week The Lancet published a friendly reminder from the SAMMPRIS investigators warning us that it is a bad idea to go putting stents in places they do not belong. This unintended favor came in the form of the publication of the long term follow-up from the Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis trial online this week in The Lancet.

The SAMMPRIS trial, originally published in the NEJM in 2011 applied the frequently attempted, but rarely accurate mantra,“If it works on the heart then it should work on the brain.” The authors took high risk TIA patients with radiologically confirmed intracranial stenosis and randomized them to “aggressive” medical management or percutaneous transluminal angioplasty and stenting (PTAS). The trial was stopped early because of the exorbitant amount of periprocedural strokes and death among those in the PTAS group. Specifically there was an 8.9% absolute increase in stroke and 1.8% increase in mortality within the first 30 days of enrollment. The authors’ summary of this dramatic failure was that the true benefits and harms could not be assessed at the time of initial publication, as there was not enough data to determine if the long term benefits outweighed these initial harms.

The recent paper is the 2-year follow up of this cohort and specifically addresses these presumed “long term benefits”. The overall occurrence of stroke was 19% in the medically managed group vs 26% in the PTAS group. It is apparent no clinically significant benefit exists especially when considering the devastating early harms. Yet another example of our limited understanding of the pathophysiology of atherosclerotic disease, and the ramifications of introducing thrombogenic objects into already tight spaces.

“Aggressive Medical Treatment With or Without Stenting in High-Risk Patients with Intracranial Artery Stenosis (SAMMPRIS): the Final Results of a Randomized Trial” http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62038-3/fulltext

Nihilism, Emergency Medicine, and the art of doing nothing at emnerd.com and @CaptainBasilEM

Intracranial Angioplasty, Where Did We Go Wrong?

Ischemic Stroke – Shaken, Not Stirred

It’s always mildly entertaining when stroke neurologists flip hats – from espousing the success of tPA to promoting the Next Big Thing. This is when you hear tPA’s greatest proponents admitting “only 20% to 30% of patients have complete recanalization within 2 hours of intravenous tPA” or “one third of those with any recanalization experience reocclusion.”

Ah, sigh.

But, regardless, this study is about the Next Big Thing – which is a transcranial sonothrombolysis helmet. This safety evaluation of 20 patients starts with IV tPA as indicated, and then continues with this operator-independent 2-MHz pulsed-wave ultrasound through a special headband. The theory, of course, is there will be gaseous microbubbles at the site of occlusion that increase efficacy of tPA and further prevent reocclusion. This safety study had a primary endpoint of 10% symptomatic intracranial hemorrhage with a power of 0.80.

Good news! There were no episodes of sICH. But, however, 6 out of 20 (30%) had asymptomatic ICH. And, then, in the ultimate safety outcome – there were 4 deaths resulting from the 14 other serious adverse events. These deaths were mostly progression of cerebral edema and related consequences, and the authors state they were unrelated to the study device.

The first author is on the scientific advisory board for the device manufacturer – which is not disclosed in the text. The second author holds the patent for the device and is Chair of their scientific advisory board. The Texas Board of Regents is the asignee for the patent for the device, and is one of two sponsoring institutions. And, as the authors note, “other limitations include possible selection bias and investigators unblinded to treatment.”

The median NIHSS was 15, so some poor outcomes are to be expected – but, still, I think this is only convincingly safe if you have financial conflicts of interest.

“CLOTBUST-Hands Free – Pilot Safety Study of a Novel Operator-Independent Ultrasound Device in Patients With Acute Ischemic Stroke”
http://www.ncbi.nlm.nih.gov/pubmed/24159060

A Plea For Strep Throat Simplicity

A recent article published in the BMJ delightfully demonstrates that regardless of how we choose to overcomplicate the treatment of acute pharyngitis, our patients will all do just fine. The authors do have to be commended for their ambition as they attempt to supplant the mighty Centor’s claim as the clinical tool to guide antibiotic use. Not as self-aggrandizing as Centor, they named their rule FeverPAIN, an acronym for its five components. Their ambition is even more noteworthy as they endeavored to describe this rule’s derivation, validation, revision, bootstrap validation and clinical implementation all in one paper.

Despite the authors’ attempts to woo us with promises of bootstrapping and stepwise logistic regression, this study was essentially a pragmatic trial examining the effectiveness of three treatment strategies to guide antibiotic utilization in patients with acute pharyngitis. Patients (3 years or older) were randomized into one of three groups, either delayed antibiotics, antibiotics as determined by the FeverPAIN score, or antibiotics as determined FeverPAIN score and a positive rapid antigen test.

Overall all three groups did well. The average duration of symptoms was 4 days. Both the clinical score group and clinical score + antigen test group had on average one day fewer symptoms than the delayed antibiotic group, all while receiving 10% fewer courses of antibiotics. Initially this finding seems counterintuitive. If more antibiotics were given in the delayed antibiotic group, how then did their symptoms last longer than those in the clinical score groups? Unless of course antibiotics played no role in this difference.

Its important to keep in mind that although this was a randomized trial, it was not blinded. Patients in both the clinical score group and the clinical score + antigen group had an experience in which the doctors spent time medically evaluating them and in some cases even running a “test”. Whereas in the delayed antibiotic group the patients had a less fulfilling experience, instructed to go home and a prescription for antibiotics would be waiting for them if they did not improve. Seemingly the prior two groups had a far stronger meaningful response than those in the delayed antibiotic group, demonstrating it is not antibiotics but rather talking to your patients and explaining the expected course of the disease that makes a difference on symptom burden. Interestingly the rapid antigen test added very little to reduction in antibiotic use and had no effect of length of symptoms.

This trial suffers from what is known as the Pollyanna Effect. If everyone will do well regardless of the intervention they receive, then it is almost impossible to show a clinically relevant superiority of one treatment strategy over another. More importantly with the incidence of rheumatic fever being so low it is considered clinically irrelevant. The question is not which of these strategies is most effective for the treatment of acute pharyngitis but rather is any treatment necessary at all?

“Clinical score and rapid antigen detection test to guide antibiotic use for sore throats: randomized controlled trial of PRISM (primary care streptococcal management)”. www.ncbi.nlm.nih.gov/pubmed/24114306

Nihilsm, Emergency Medicine and the art of doing nothing at emnerd.com

A Plea For Strep Throat Simplicity

Nihilsm, Emergency Medicine and the art of doing nothing at emnerd.com

Down-Titrating Antibiotics for HCAP

The 2005 IDSA guidelines for healthcare-associated pneumonia are a little bit broad. If you, a family member, or a pet has e-mailed or read about someone in the hospital, the recommendations are for a full-court press with coverage for multi-drug resistant pathogens.

However, this is clearly inappropriate. The HCAP population is profoundly heterogenous, where patients receiving home wound care are grouped with patients with recent hospitalization and receipt of IV antibiotics. It is clear, then, patients will suffer adverse effects and costs from overly-broad spectrum antibiotic coverage.

This group in Japan developed a decision instrument to guide antibiotic therapy, and prospectively evaluated it in 124 CAP and 321 HCAP patients over a two-year period. Their HCAP stratification is very reasonable: mild disease with 1 additional risk factor for MDR or severe disease with zero risk factors for MDR were treated as CAP. Everyone else received full HCAP coverage, with MRSA and anti-pseudomonal coverage.

A presumptive causative organism was diagnosed in about 50% of CAP and 60% of HCAP. Of the 93 patients an organism isolated in the “low-risk” HCAP category, none had MRSA, and 3 had pseudomonas. In the higher-risk HCAP groups, the low-severity group had 18 of 63 with an MDR pathogen, and the high-severity group had 28 of 56.

It is difficult to conclusively describe the safety of the treating-HCAP-as-CAP strategy, given the lack of a control group and the differences between baseline disease severity. However, on first glance, it seems unlikely this conservative strategy impacts initial treatment failure and mortality rates in a clinical significant fashion. This is an approach I’ve advocated for in the past, and plan to continue based on this addition to the body of evidence for individualized antibiotic selection for HCAP.

“A New Strategy for Healthcare-Associated Pneumonia: A 2-Year Prospective Multicenter Cohort Study Using Risk Factors for Multidrug- Resistant Pathogens to Select Initial Empiric Therapy”
http://www.ncbi.nlm.nih.gov/pubmed/23999080

Direct Vascular Toxicity From PPIs

Proton-pump inhibitors have been the mainstay of many gastroesophageal disorders. 21 million people in the U.S. received a prescription for PPIs in 2009, associated with a cost of $13 billion globally.

Unsurprisingly, there are signals of harm from PPIs that are not completely understood. It is recognized gastric pH is part of the body’s natural immune defense mechanism, and increased pH as a result of PPI use increases susceptibility to infection. Additionally, some concerns have been documented regarding CPY2C19 inhibition, resulting in decreased clopidogrel activity. However, multiple studies also point to increased vascular risk with PPIs that do not significantly inhibit CPY2C19.

These authors further explore the hypothesis the mechanism of PPI vascular risk has nothing to do with CPY2C19. They find, through high-throughput chemical screening, that PPIs directly inhibit dimethylarginine dimethylaminohydrolase (DDAH). This enzyme metabolizes asymmetrical dimethyarginine (ADMA), which is further responsible for inhibiting nitric oxide synthase (NOS). In clinical terms, inhibition of NOS is a bad thing, and consistent with multiple clinical studies demonstrating increased ADMA activity is associated with cardiovascular death.

The in vivo portion of this study is limited by mouse model, but they do show a dose-dependent decrease in tissue nitric oxide associated with omeprazole administration. The end clinical result of this would be increased oxidative stress, reduced vasodilator function, and otherwise impaired vasoprotective mechanisms.

It’s an interesting translational study uncovering a reasonable hypothesis for the recurrent themes of observed PPI harms. It also tailors neatly into the prior clinical trial evidence suggesting PPI use in upper GI bleeding decreases bleeding-related deaths, while increasing non-bleeding deaths, resulting in no net mortality benefit.

The International Consensus and the American College of Gastroenterology guidelines say PPIs “may” be considered prior to endoscopy to downstage lesion severity, while NICE states PPIs should not be offered prior endoscopy for non-variceal UGIB. The most recent Cochrane Review on the topic show no patient-oriented benefits to PPI prior to endoscopy. I think it’s very reasonable to make an individualized decision whether the risks and costs associated with PPI use outweigh the benefits of acute clot stabilization in UGIB.

“Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor Asymmetric Dimethylarginine”
www.ncbi.nlm.nih.gov/pubmed/23825361

What to Make of Esmolol in Septic Shock?

This is the new hotness in critical care discussions – the co-administration of intravenous esmolol to critically ill folks on high-dose vasopressor support in the ICU. It’s a fascinating thought – considering the alpha- and beta-stimulation of norepinephrine necessary to maintain central perfusion, co-administration of a sympatholytic seems self-defeating, in a sense.

However, this may not be the case. There are multiple dose-dependent effects of catecholamines on different tissues, as well as concern the tachycardia resulting from sympathomimetic myocardial stimulation in sepsis results in adverse outcomes. Based on prior observational evidence, these authors performed a randomized, open-label trial of esmolol co-administration in a cohort of critically ill patients on vasopressor support.

They randomized 154 patients with HR >95 and septic shock to esmolol, titrated to a HR between 80 and 94 bpm, vs. usual care. The hemodynamic variables showed, despite the use of esmolol, norepinephrine dosage was not significantly increased in order to maintain MAP. Improvements in stroke volume compensated for a lower heart rate, resulting in non-significantly lower cardiac index. However, what has everyone fascinated – the control group had 90% in-hospital mortality, compared with 67% for the esmolol group. I don’t think anyone disagrees this is statistically significant and clinically important.

There were differences in baseline variables between groups. The etiology of sepsis was substantially tilted towards peritonitis in the esmolol group, with obviously different causative organisms. Lactic acid, base excess levels, and SAPS II scores favored the esmolol group. The lead author and one co-author also have financial conflicts of interest with Baxter, the makers of esmolol (Brevibloc). Financial conflicts, open-label, and the size of the study all make me wary of reproducibility and the magnitude of the effect size.

So, there are problems warranting additional and independent confirmation. That said, the mortality benefit observed in this study is large enough I wouldn’t contest anyone who wanted to go ahead and start trying this in their highest-predicted mortality subset. However, I’d also consent patients/families to this therapy as experimental and prospectively collect data for at least retrospective pre-/post- comparisons.

“Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock A Randomized Clinical Trial”
www.ncbi.nlm.nih.gov/pubmed/24108526

Another Taste of the Future

Putting my Emergency Informatics hat back on for a day, I’d like to highlight another piece of work that brings us, yet again, another step closer to being replaced by computers.

Or, at the minimum, being highly augmented by computers.

There are multitudinous clinical decision instruments available to supplement physician decision-making. However, the general unifying element of most instruments is the necessary requirement of physician input. This interruption of clinical flow reduces acceptability of use, and impedes knowledge translation through the use of these tools.

However, since most clinicians are utilizing Electronic Health Records, we’re already entering the information required for most decision instruments into the patient record. Usually, this is a combination of structured (click click click) and unstructured (type type type) data. Structured data is easy for clinical calculators to work with, but has none of the richness communicated by freely typed narrative. Therefore, clinicians much prefer to utilize typed narrative, at the expense of EHR data quality.

This small experiment out of Cincinnati implemented a natural-language processing and machine-learning automated method to collect information from the EHR. Structured and unstructured data from 2,100 pediatric patients with abdominal pain were analyzed to extract the elements to calculate the Pediatric Appendicitis Score. Appropriateness of the Pediatric Appendicitis Score aside, their method performed reasonably well. It picked up about 87% of the elements of the Score from the record, and was correct when doing so about 86%, as well. However, this was performed retrospectively – and the authors state this processing would still be substantially delayed by hours following the initial encounter.

So, we’re not quite yet at the point where a parallel process monitors system input and provides real-time diagnostic guidance – but, clearly, this is a window into the future. The theory: if an automated process could extract the data required to calculate the score, physicians might be more likely to integrate the score into their practice – and thusly lead to higher quality care through more accurate risk-stratification.

I, for one, welcome our new computer overlords.

“Developing and evaluating an automated appendicitis risk stratification algorithm for pediatric patients in the emergency department”

http://www.ncbi.nlm.nih.gov/pubmed/24130231

Foam, Actually

I chastise JAMA on occasion, but, any article that starts like this is the mark of a truly great academic publisher:

“The lights are low and the music volume is high. As arms and legs sway on a packed dance floor, streams of soapy suds blow down from the ceiling….”

No, it’s not a ‘tween reviewing an illegal high during a rave, it’s a actually CDC surveillance of a spike in eye injuries resulting from “foam parties”. This write-up details an investigation in Collier County, Florida, in which more than 40 patients sought care for eye irritation and pain in a single night. These patients all received ocular inoculation with foam during the course of revelry, and over half were ultimately diagnosed with corneal abrasions. The cause – the highly concentrated chemicals such as sodium lauryl sulfate and other proprietary mixtures similar to those found in soaps and shampoos.

So, beware the foam! (but not the FOAM).

“Party Alert: Here’s Foam in Your Eye”
http://www.ncbi.nlm.nih.gov/pubmed/24129456

“Notes from the Field: Eye Injuries Sustained at a Foam Party — Collier County, Florida 2012”
http://1.usa.gov/1d69xek