Ryan Radecki

Unlocking the Secrets of Atherosclerotic Plaques

In general, the best way to determine the cause of death is autopsy. Most of our patients, however, aren’t willing to undergo this procedure in order to guide preventative care. Thus, we are left using imprecise predictive instruments to prognosticate and prevent untimely demise.

In the cardiovascular sciences, a large part of what we do is salvage – catheterization, stenting, and cardiovascular care units to minimize myocardial injury after infarction. These authors, however, believe they’ve identified a new paradigm in cardiovascular imaging: identification of individual high-risk atherosclerotic plaques.

In this observational cross-sectional study, the authors enrolled 40 patients immediately following myocardial infarction and 40 patients with known stable angina. All patients underwent combined PET and CT with radioactive tracers. In 37/40 post-MI patients, the culprit lesion had significantly higher radioactive uptake compared with all non-culprit lesions. Extending this observation to the 40 patients with stable angina, 18/40 had lesions associated with similar radioactive tracer uptake compared to background. Patients with these lesions underwent intravascular ultrasound, which confirmed high-risk features such as remodeling, microcalcifications, and necrotic cores.

This is light-years away from being validated, and then being further translated into routine care – but it is quite fascinating work. We’ve bemoaned the limitations of our non-invasive imaging, based on our inability to characterize lesion histology or adequacy of tissue perfusion from varying levels of stenosis, and this is a promising step for guiding management of a subset of high-risk patients.

“18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61754-7/abstract

Gorging Ourselves to Death on Healthcare

This Harvard Business School paper highlights the nonsensical nature of the United States healthcare system – every advance promises one step forward, yet inevitably results two steps backward.

This is a piece of observational operations research regarding radiology turnaround times. If you’re involved in your ED’s throughput initiatives in any fashion, I am certain this has been a recurring issue. Most conversations probably take the form “If only radiology were faster, patients would flow through the department like quicksilver.” So, what happened in a 100,000-visit academic ED and a 60,000-visit community ED when, through process improvement, an “inefficient” gatekeeping step was eliminated?

Initially, at the hospitals observed, ultrasounds were available only by radiologist approval after 5pm on weekdays and on weekends. Scans could be performed as needed from a technician on-call, but this inconvenient step alone added 10-15 minutes to the radiology turnaround time for these patients. After these hospitals added 24/7 technician coverage and eliminated the approval step, two things happened: length of stay for patients receiving an ultrasound on nights and weekends decreased (huzzah), and the number of ultrasounds ordered increased by 11.5% (oh hmm).

Unsurprisingly, as the number of patients receiving ultrasounds increased, the overall average LOS for a patient with an abdominal complaint went up by 26 minutes. And, with the extra ultrasounds for the radiologists to read, turnaround times for non-ultrasound radiology results were increased by 30 minutes. Furthermore, CT use in those same time windows also increased by 4.5%, while general CT use in both departments decreased by 10%. The authors hypothesize incidental findings on ultrasound were prompting subsequent CT use to follow-up suspicious reads, leading to even greater resource utilization. As you would expect, this congestion extended out to the waiting room, with a predicted increase in time-to-room as well.

So – more tests, more costs, longer waits – no detectable effect on outcomes.

‘Merica.

“Increased Speed Equals Increased Wait: The Impact of a Reduction in Emergency Department Ultrasound Order Processing Time”
http://hbswk.hbs.edu/item/7310.html

Glucose and Insulin, Less is More

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

With the recent publication of the AHA updated guidelines on the management of cholesterol and their bafflingly continual support of cholesterol management despite the mounting evidence to the contrary, it is only fitting that we turn our attention to the other surrogate endpoint that has for so long supported the fallacy of cardiovascular health: sugar.

In an article by Mulder et al published in the November 2013 JAMA Internal Medicine, the authors attempt to show the benefit of intensive glucose control following an acute myocardial infarction. This hypothesis has been tested several times and other than its initial go around in DIGAMI-1 has not manifested in any positive outcomes. Despite its disappointing history the authors felt that in this trial, in their hospital, with their protocol they would find success. After all, nowadays, clinical trial success is all in how you define it.

These authors defined success in a variety of surrogate endpoints meant to encapsulate infarct size. Both TnT and CKMB measurements were taken serially throughout the first 72 hours. In addition all patients received rest-gated myocardial perfusion scintigraphy (MPS-SPECT) after 6-weeks to grade the extent of their infarct.

Using their intensive glucose control protocol the authors were successfully able to control blood glucose levels far better than those in the standard therapy group. Though this procedural success did not translate into a difference in infarct size, they did manage to find a clinical and statistical difference in the occurrence of in-hospital death and recurrent MI. Specifically there was a 5% absolute increase in death and MI in those patients receiving intensive insulin therapy. This increase in clinical events cannot be accounted for by episodes of hypoglycemia as in this cohort they were very rare (0.4%).

This trial is in no way definitive, but it is becoming increasingly clear that both in the acute setting and long-term, intensive glucose control does more harm than good. Though elevated glucose levels may be a harbinger of future disease, silencing this messenger does not prevent these foretold events from transpiring.

“Intensive Glucose Regulation in Hyperglycemic Acute Coronary Syndrome: Results of the Randomized BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome-2 (BIOMArCS-2) Glucose Trial”
http://www.ncbi.nlm.nih.gov/pubmed/24018647

Glucose and Insulin, Less is More

Giving Hypothermia the Cold Shoulder

Modern resuscitation has many components – emphasis on pre-hospital CPR, distribution of defibrillators, cardiac catheterization … and hypothermia. And, now we’re not so sure about that last one.

Therapeutic hypothermia is based on two randomized trials, published in 2002, enrolling a grand total of 352 patients. Recommendations include rapid cooling after emergency stabilization to a target temperature between 32° and 34°C, and subsequent adoption of this practice spawned a cottage industry of expensive, specialized cooling devices. But, these temperature targets were always somewhat arbitrary, and the question persisted as to whether lower temperatures in fact conferred a neurologic survival advantage.

Nope.

Enrolling nearly a thousand patients, this randomized trial of out-of-hospital cardiac arrest randomized half to 33°C and half to 36°C. Groups were well-balanced on typically expected features favoring survival – comorbidities, bystander CPR, arrest rhythm, and follow-up treatment. And, after cooling for 24 hours, no difference was detected in early deaths, late deaths, or in any measure of cerebral or functional performance. One impressive feature of this trial is the standardized withdrawal of care criteria, reducing patient heterogeneity through that mechanism.

None of this says “hypothermia doesn’t work”. But, a sense of lacking in terms of a dose-response relationship between hypothermia and neurologic survival causes some concern. Why did we observe such profound benefit in the early trials? Erroneous rejection of the null hypothesis due to poor statistical power, unmeasured confounders, or something more sinister? Adding in the pre-hospital hypothermia study from JAMA, both dose-dependent and time-dependent effects are now less certain.

The utility of hypothermia following ischemic insult seems biologically plausible, but, as the editorial comments, perhaps it’s not so much hypothermia as the maintenance of normothermia. Already part of modern post-stroke care, treating and preventing fever improves outcomes – it may simply be the observed benefits are due to intensive antipyresis, rather than hypothermia.

It seems still reasonable to use gentle cooling as a prophylaxis against hyperthermia, but more importantly, it is time, yet again, to reflect on how better evidence refines established practice. Without continuing to recognize the limitations of our knowledge, we must caution ourselves against rushing to generalize implementation from small sample sizes (see: tPA in acute ischemic stroke).

“Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest”
http://www.nejm.org/doi/full/10.1056/NEJMoa1310519

“Temperature Management and Modern Post–Cardiac Arrest Care”
http://www.nejm.org/doi/full/10.1056/NEJMe1312700

tPA for TIA?!

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

Over the last year, the debate over the use of alteplase in acute ischemic stroke has continued to heat up. The issue really boiled over in June after BMJ reporter Jeanne Lenzer wrote a scathing evaluation of clinical guidelines after the publication of the new ACEP Clinical Policy on the use of alteplase in ischemic stroke. Now, to muddy the waters further, enter the discussion of giving alteplase to transient ischemic attacks (TIAs).

That’s right, this week, the American Journal of Emergency Medicine published a case report discussing the administration of alteplase to a patient that the treating physicians agreed had a TIA. Before we get into the article itself, let’s take a stroll back in time to 1995.

On December 14^th, 1995, the NEJM published the NINDS trial and ushered in the era of alteplase for acute ischemic stroke. One of the major exclusions in the study, and one that few have argued with, was “rapidly improving or minor symptoms.” In essence, NINDS sought to exclude patients with TIAs. The reason for this is elegantly stated by Dr. David Liebeskind (UCLA Stroke Center):

“Thrombolysis is not a rational or evidence-based therapeutic option for transient ischemia irrespective of vascular status . . . The prevailing obsession with arterial occlusion has erroneously focused attention on clots rather than ischemia . . . Imaging of occlusion without consideration of clinical details or pahtophysiolgical mechanisms may therefore be misleading.” (Stroke 2010).

From a pathophysiological and outcome standpoint, there is no good reason to administer alteplase to a patient with a TIA regardless of imaging. If the patient has an NIHSS of 0, there is no room for improvement, only harm.

In spite of this, the authors of the above case report recount the story of a 37-year-old woman who presented with a TIA. Her presenting NIHSS was 0. CT angiogram showed a “near total occlusion of the M2 segment of the MCA.” There is no report about the presence of an ischemic penumbra. After the CTA was completed, the patients’ symptoms returned but then rapidly resolved. At this point, the physicians decided to administer alteplase in spite of the absence of symptoms. She was then transferred to a stroke center for consideration of neurointerventional care (a therapy proven not to work. See NEJM March 2013). Interestingly, the authors base their decision to treat on imaging findings but never discuss the resolution of these findings after therapy (i.e. no mention of repeat CTA or MRI/MRA).

What does this tell us about alteplase for TIA? Not much. This is a case report and gives us no information about causality of treatment. It doesn’t even show efficacy of concept because pathophysiologically the idea of giving alteplase to a TIA doesn’t make sense. The authors talk about weighing risks and benefits outside of standard indications and contraindications. But what they have done is give a potentially dangerous, life-threatening medication to a patient with no disability at the time of administration. They have taken on all the risk of the drug without any potential benefit.

What this report really shows is the concept of “indication creep.” Earlier this year, the TREAT task force recommended that patients with rapidly resolving symptoms (but some continued deficit) should be considered for thrombolytic treatment (Stroke 2013). This recommendation wasn’t based on any literature but rather an expert consensus from a meeting sponsored by Genentech (Boehringer-Ingelheim in Europe). This case report is simply the logical extension of an illogical idea: if thrombolytics should be given to a patient with rapidly resolving symptoms, why not give it to one with no symptoms but imaging abnormalities?

The authors conclude by pointing the finger at EM physicians stating that we, “have been historically slow in adopting thrombolytic therapy for CVA.” We haven’t embraced this treatment because we don’t see definitive evidence that it works and we do see the potential harms. A month ago at ACEP, a group of EPs voted 75% to 25% to reconsider the ACEP clinical policy on tPA. The authors go on to suggest that this patient did well and required no further treatments because she received “off-label” thrombolytics. This link violates everything we know about research. Just because something happens after you do something, doesn’t mean the thing you did caused the outcome. Domhnall Brannigan told a wonderful story during his lecture at SMACC last year about a patient who presented with stroke-like symptoms and nausea. Dr. Brannigan gave the patient ondansetron for the nausea and minutes later the patient had resolution of his symptoms. None of us, though, are rushing to give ondansetron for ischemic CVA. The proposition by these authors is just as ludicrous.

“TPA for TIA: The case for “off-label” use of thrombolytics.”
http://www.ajemjournal.com/article/S0735-6757(13)00747-X/fulltext

References

Sobel RM, Wu DT, Hester K, Anda K. tPA for TIA: The case for “off-label” use of thrombolytics. Am J EM 2013; 06 November 2013 (10.1016/j.ajem.2013.10.046

The National Institute of Neurological Disorders and Stroke, rt-PA Stroke Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. NEJM 1995; 333(24): 1581-7.

Liebskind DS. No-Go to tPA for TIA. Stroke 2010; 41(12): 3005-6.

The Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force. Levine SR, Khatri P, Broderick JP, Grotta JC et al. Review, historical context, and clarifications fo the NINDS rt-PA stroke trials exclusion criteria: part 1: rapidly improving stroke symptoms. Stroke 2013; 44: 2500-2505

tPA for TIA?!

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

References

Sobel RM, Wu DT, Hester K, Anda K. tPA for TIA: The case for “off-label” use of thrombolytics. Am J EM 2013; 06 November 2013 (10.1016/j.ajem.2013.10.046

The National Institute of Neurological Disorders and Stroke, rt-PA Stroke Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. NEJM 1995; 333(24): 1581-7.

Liebskind DS. No-Go to tPA for TIA. Stroke 2010; 41(12): 3005-6.

It’s Ultrasound Fightin’ Time

Trauma showdown: pneumothorax. Chest x-ray or ultrasound?

The answer on the surface is pretty clear – unless you delve a little deeper into the precise question asked.

This meta-analysis of head-to-head ultrasound vs. CXR studies for the diagnosis of pneumothorax shows what we all essentially expect: the sensitivity of ultrasound is greatly superior, while specificity is statistically similar. Sensitivities for ultrasound were better for trauma, using the linear (high frequency) probe, and when performed by Emergency Physicians, and ranged from 73% to 85%. CXR sensitivities ranged from 32.6% to 49%, with heterogeneity based on study enrollment methods. Specificities for each were ~99%.

What the study does not address – are these pneumothoracies clinically meaningful? Ultrasound certainly finds more disease, but the newly identified disease will all be closer to the benign end of the spectrum. I guarantee there are patients out there with normal CXR in the setting trauma, who then receive an ultrasound positive for pneumothorax, and are then referred to CT scan and surgical evaluation – would have ultimately been fine. Before we move along to detecting more “disease”, we ought to examine the downstream consequences of missing or detecting these small pneumothoracies.

“Pleural ultrasonography versus chest radiography for the diagnosis of pneumothorax: review of the literature and meta-analysis”
ccforum.com/content/17/5/R208‎

The Curious Story of Diclegis

For no particular reason, I’ve recently become familiarized with the story of Diclegis (Diclectin in this study, and in Canada). For use in pregnancy-induced nausea and vomiting, Diclegis is a delayed-release combination formulation of 10mg each of doxylamine and pyridoxine. It was approved by the FDA in April of 2013, and has rapidly become first-line therapy.

The surprising bit – this is precisely the same drug our mothers took in pregnancy. It was introduced in the 1950s as Bendectin, and it was estimated as many as 30% of pregnant women took this combination pill in the 1970s. However, in the early 1980s, the manufacturer was the target of innumerable lawsuits alleging fetal malformation – and in 1983, voluntarily withdrew the drug from the market. This choice was made solely due to the costs of defending against litigation, and not a reflection of the safety of the drug. The physicians who had published data suggesting fetal risk were eventually discredited, and even the FDA noted in 1999 that Bendectin was not withdrawn for reasons of safety or effectiveness.

So – now it’s back, and, unsurprisingly, it works better than placebo. This manufacturer-sponsored, double-blind, placebo-controlled trial demonstrated improvement with Diclectin in almost every measure. And, 48% of Diclegis users asked for compassionate use of the study drug following conclusion of the study (although, so did 32% of placebo). I’ve also discovered my new favorite disease-severity scoring system: the PUQE Score.

The downside: it costs ~$160 for 30 pills.

A brief perusal of the internet shows doxylamine, a sedating, first-generation antihistamine costs as low as 3 cents per tablet. Pyridoxine, vitamin B6, costs as little as 6 cents per tablet. Diclectin costs ~$5 per tablet. You could pay for Diclegis – after all, it is a special “delayed-release” formulation where doxlyamine reaches peak concentration 6 hours after ingestion. Or, you could do what obstetricians have been telling their patients to do for the last several decades: make your own equivalent dosing from the component medications at a fraction of the cost.

It certainly seems prudent to try the cheaper option, first.

“Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial”
http://www.ncbi.nlm.nih.gov/pubmed/20843504

Houston Resus Podcast

Featuring ACEP Teaching Award recipients Pratik Doshi & Yashwant Chathampally, I’m happy to point the way to a new University of Texas – Houston Emergency Medicine publication: the Houston Resus Podcast.

Another new #FOAMed resource, driven primarily by our resident enthusiasm for teaching and critical care.

The full site is here:
http://www.houstonresus.com

And the iTunes link to the Podcast is:
https://itunes.apple.com/us/podcast/houston-resus-ut-houston-emergency/id685819529