Enoximone Miracle for Asthma: Science? Advertising? Both?

Potential leaps forward in medical science are noteworthy.  They should be peer-reviewed, disseminated, and developed – and those responsible, rewarded, to be sure.  But, the medical literature is full of grey areas between science and advertising – including routine publication of sponsored trials, to a “Clinical Evidence Synopsis” composed solely by those with COI, to this latest egregious sample.

Enoximone is a phosphodiesterase inhibitor currently in clinical trials for advanced heart failure.  However, the author of this report documents eight cases of its use in the setting of catastrophic status asthmaticus – three of which progressed to respiratory arrest.  After initiation of medical therapy without improvement, the author gave each of these patients one or multiple doses of intravenous enoximone – with profound improvement.  Anecdotally.

This is all very fine, and case reports are an important step in the chain of evidence.  Enoximone very well may be an important future therapy for selected patients with severe bronchospasm.  However, there’s one slight problem with this publication, stemming from the Declaration of Interest by the author (J.B.):

J.B. received lecture fees from the following companies: Carinopharm GmbH, Germany; Carinopharm, UK; Incapharm, Italy; and Devrimed, The Netherlands, distributors of enoximone. J.B. contributed to a syllabus concerning enoximone for which he received a fee from Carinopharm GmbH, Germany. Carinopharm GmbH filed an IP for the use of enoximone in status asthmaticus in which J.B. is named as the inventor, without financial consequence. J.B. is co-founder and shareholder of Advanced Perfusion Diagnostics at Lyon, France.

So, the publication ultimately represents unfettered promotion of a therapy for whom the author has multiple personal financial conflicts of interest.

Science?  Advertising?  Both?

“Emergency treatment of status asthmaticus with enoximone”

Highly-Sensitive, But Not Highly Valuable

There is a great deal of continuing debate raging over the use of “high sensitivity” troponins in the Emergency Department.  But, it’s not the test alone at fault – the responsibility for interpreting and acting upon the results lay with clinicians.  In the era of conventional troponins, the test was a powerful tool to rule-in myocardial infarction.  With high sensitivity troponins, the greater value in the tool is in ruling-out.

However, while much is made of the theoretical beneficial test characteristics of high sensitivity troponins, few have measured actual patient-oriented outcomes.  This group from Valencia, Spain, prospectively evaluated consecutive patients at a single institution as their laboratory switched from a conventional TnI assay to a highly sensitive one.  Comparing 699 consecutive patients from the pre-hsTnI period to 673 consecutive patients in the post-hsTnI … there were too many baseline differences to draw any useful conclusions.

But, in an effort to salvage the paper, the authors perform a propensity-score matching algorithm to balance to cohorts.  Based on these matched cohorts, for which they do not offer much in the way of detail, there were no differences in major adverse cardiac events or death at 6-month follow-up.  Regarding management decisions after the change, they note patients were less likely to undergo non-invasive testing in a chest pain observation unit, but substantially more likely to undergo invasive procedures.

This is just a single-center experience, and their observations are incontrovertibly corrupted by the unfortunate change in patients characteristics across their study periods.  It does, at least, provide some small window into how hsTnI might impact the management pathway for patients presenting with chest pain.

“High-sensitivity versus conventional troponin for management and prognosis assessment of patients with acute chest pain”

Should Paramedics Intubate Out-of-Hospital Cardiac Arrest?

Airway management of out-of-hospital cardiac arrest is a controversial topic.  Most patients transported for OHCA have receive prehospital airway management.  However, attempts at establishing an airway can interrupt compressions, over-ventilation can decrease cerebral perfusion, and delays in airway acquisition impact transport to definitive care.

This study retrospectively evaluates the CARES surveillance group, a multi-site registry from North America, comparing neurologically intact survival after prehospital endotracheal intubation, supraglottic airway, or no advanced airway.  In the unadjusted results, survival rates were 5.4% for intubated patients, 5.2% for supraglottic airway, and 18.6% for no advanced airway.  After statistical adjustments and propensity scores, the authors report the ultimate winner is not attempting an advanced airway – and then endotracheal intubation is superior to supraglottic airway.

But, really, this study tells us nothing.  Even though the authors attempt several methods of statistical adjustment, the likely presence of massive unmeasured confounders invalidates these observations.  There is an entire host of patient-level and situational factors that impact the type of airway attempted, the number of airway attempts, and the aggressiveness of care provided both pre-hospital and in-hospital.  The profound differences in unadjusted outcomes, between those not receiving an advanced airway and those requiring one, paints the most obvious picture of the likely underlying differences in unfavorable physiology at work.

This is hardly the first observational report regarding the impact of prehospital airway management.  And, frankly, we’ve seen enough – this type of retrospective cohort does not hold the answer, unless the registry was specifically designed to answer such questions.  To the authors credit, they do not overstate the level of evidence provided – but an unsophisticated reader might draw the wrong conclusions.

“Airway management and out-of-hospital cardiac arrest outcome in the CARES registry”

Guideline Recommendations Are Written in Dry Erase Marker, Not Stone.

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

Medicine is filled with guidelines, professional recommendations and expert consensus statements. These documents guide clinical practice. In Emergency Medicine, we often rely on non-EM specialty guidelines. For instance, we often state that a patient in whom you consider ACS should get evocative testing (i.e. stress test) within 72 hours of presentation according to the American College of Cardiology/American Heart Association (ACC/AHA) guidelines. As more guidelines and subsequent revisions are released a number of questions arise. Should we adopt the guidelines immediately? If so, which pieces are ready for immediate incorporation into clinical care? At the heart of these questions is the strength and durability of the recommendations.
This article is unique in the question it asked: what is the durability of class I recommendations from the ACC/AHA? The looked at 11 guidelines published between 1998 and 2007 along with revisions to these guidelines from 2006 to 2013. What they found was surprising. Out of 619 original class 1 recommendations, about 80% were retained in subsequent revisions. About 9% were downgraded or reversed and about 11% were omitted.  Not surprisingly, recommendations with multiple randomized studies backing them up tended to stick around (90.5%) but those recommendations supported by opinion only did not (73.7%).
What can we take away from this? First, we shouldn’t adopt recommendations (even level 1) that don’t have good evidence backing them up. Secondly, guidelines should be updated frequently (these authors suggest every 3 to 5 years) to incorporate new evidence that may up or downgrade recommendations. Guideline adherence shouldn’t be used as a performance measure since the recommendations are anything but written in stone. Lastly, this is a further call for our specialty to take the reigns and start writing our own, high-quality guidelines from which we can base clinical practice.
“Durability of Class 1 American College of Cardiology/American Heart Association Clinical Practice Guideline Recommendations”

Stroke MRI in 6-Minutes or Your Money Back

Despite the advances of modern medicine, the non-contrast CT of the brain is a crude tool.  It is especially poor in the setting of acute stroke – infrequently providing helpful diagnostic information, while serving primarily to rule out intracranial hemorrhage.

These authors, however, offer us a glimpse of the MRI of the future – a useful diagnostic test without long delays of image acquisition time.  These authors report on a single-center, convenience sample of patients with acute neurologic deficits who were able to undergo MRI.  They use a 3.0T MRI to acquire DWI, FLAIR, GRE, perfusion, and MRA sequences using a 6-minute protocol on 62 patients, and two radiologists rated image quality as moderate or good 94% or greater for each modality.

The authors also provide two sample cases, one of which being an acutely altered, profoundly disabled patient within the 3-hour window for tPA.  The 6-minute MRI, however, showed heterogeneous perfusion abnormalities more suggestive of seizure, rather than stroke.  After treatment with anti-eplipetics, the patient made a full neurologic recovery.

This series is small enough it’s clearly just a technology pilot.  Additional study regarding diagnostic accuracy and feasbility in the acute setting is necessary, but it would certainly be a vast improvement over the current state of the art.  Considering the present rush to judgement for tPA and the likelihood of overtreatment of stroke mimics, a diagnostic modality that adds to clinical assessment is sorely needed.a

“Six-Minute Magnetic Resonance Imaging Protocol for Evaluation of Acute Ischemic Stroke: Pushing the Boundaries”

No, You Can’t Get Drunk Off Tampons

Yet another bit of YouTube lunacy debunked – the concerning “recent phenomenon” amongst adolescents and young adults to use alternate methods of ethanol absorption to decrease detectability, or increase the rate of intoxication.

Such as “tampons soaked in vodka”.  In the vagina.

So, how viable is this strategy?  A toxicologist from USC investigates this strategy in vitro with a relatively straightforward study – simply measuring the maximum quantity of alcohol that could be absorbed by a tampon prior to insertion.  Commercially available tampons, with the applicator attached, maxed out at 15mL.  Minus the applicator, tampons absorbed up to 31mL – but obviously lost any insertion potential.

Disregarding the likely local irritation and discomfort of this method of administration, 15mL is clearly not enough to result in any appreciable level of intoxication – even assuming complete absorption across the vaginal mucosa, which is another topic of entirely reasonable uncertainty.

Another media-hyped “danger” that clearly isn’t.

“A New Clandestine Route of Ethanol Administration? Volume of Vodka Absorbed in Commercially Available Tampons. An in vitro study”

A Shared Decision-Making Trial … But Fatally Flawed?

Shared decision-making is developing as the proposed solution to many of the problems with resource utilization today.  Rather than embrace “zero miss” practice without properly involving patients as the decision-makers, we are now encouraged to offer the patient choices regarding their diagnostic and treatment decisions.  By sharing the decision – and the risk – I find patients quite amenable to forgoing much low-yield testing.

To that end, a multi-center trial has begun, evaluating the use of shared decision-making in low-risk chest pain.  The trial is based on an information graphic created by the Mayo Clinic, and individualized risk assessment is supported by Jeff Kline’s attribute-matching algorithms.  This is fabulous, from a conceptual standpoint – as shared decision-making is not nearly as feasible without the proper communication tools or best available evidence available at the point of care.

However, there’s an important missing element from the proposed information graphic:

Link to high-resolution version.

The decision tool explains the 45-day risk of myocardial infarction if testing is deferred.  However, the patient-oriented decision is between stress test (or CT coronary angiogram, at the University of Pennsylvania), cardiology follow-up, and primary care follow-up – and the decision aid doesn’t actually address those choices.  It does not describe the relative risks of MI between each option, and, more importantly, it does not describe the risks or benefits of the additional testing offered.  Without information regarding the rates of true positive and false positive test results, the incremental prognostic value of such tests, or the costs associated with additional testing, the patient doesn’t have the appropriate foundational information for their choice.

Conceptually, this is a fantastic trial.  However, I’m not sure the decision-aid has been correctly designed and implemented, with regard to the choices offered.  Indeed, if the poor test characteristics of stress and CTCA in this population were shared with patients, it would probably even show more powerful reductions in resource utilization.

“Effectiveness of the Chest Pain Choice decision aid in emergency department patients with low-risk chest pain: study protocol for a multicenter randomized trial”

Abscess Management in the Era of MRSA

Every so often, it’s good to circle back from the esoteric to the basics, and remind ourselves how to provide the best, evidence-based treatment for some of the most common diseases – in this case, abscesses.

This review in the New England Journal is a reasonable, concise overview of the evidence behind management of cutaneous abscesses, updated for the increasing prevalence of methicillin-resistant Staphylococcus aureus.  And, quite simply, there’s no evidence for any reason yet to panic.  The authors of this article summarize the literature thusly:

  • Incision & drainage is definitive treatment.  Non-complicated disease does not require additional antibiotic treatment, and the incremental benefit – if any – would be single-digit differences in clinical failure.
  • Packing of abscesses is a matter of tradition, and evidence is neither sufficient to conclusively confirm nor refute this practice.
  • Primary closure of abscesses after I&D is reasonable, particularly for larger, exposed, and cosmetically important areas.
  • Antibiotic coverage for primarily cellulitic soft-tissue infections ideally includes both MRSA and streptococcal coverage, but recent evidence showed no advantage to double-coverage.  Clinical trials regarding antibiotic use are ongoing:  NCT00729937 NCT00730028  NCT00729937
  • Wound cultures are not necessary.

One could argue covering such basics in infection and wound management is a sundry affair for a blog frequently covering the cutting edge.  However, current management of such a common condition is so highly variable and frequently low-value, ACEP even made a point to include abscess management in their Choosing Wisely campaign list.

Now, go and do as little harm as possible.

“Management of Skin Abscesses in the Era of Methicillin-Resistant Staphylococcus aureus”

SIRS is Rarely Sepsis

You already knew this – but that hasn’t stopped your hospital from purchasing the “Sepsis Alert” tool for your electronic health record.  Now, you and your nurses get blasted with computerized interruptions every time a patient is tachycardic and has an elevated WBC count.  And, you ignore it – because it’s 1) wrong, or 2) you placed a central line and admitted the patient to the ICU half an hour ago.

But, just how often do these sepsis alerts, based on systemic inflammatory response criteria, fire erroneously?  That is the question asked by this group from Harbor-UCLA and UC Davis.  Using the National Hospital Ambulatory Medical Care Survey from 2007 to 2010, these authors attempted to estimate the frequency of true infection in the setting of SIRS.  Unfortunately, while the NHAMCS set now includes vital signs obtained at triage, it does not include results of tests, such as the WBC.  Therefore, these authors – and this is where the study breaks down a bit – were required to mathematically conjure up a range of estimates for the frequency with which patients would meet the WBC criterion for SIRS.  Based on minimum and maximum estimates, the percentage of Emergency Department visits estimated to have SIRS ranged from 9.7% to 26.0%, and the authors ultimately split the difference at 17.8% for their analysis.

Based on their estimate, there were approximately 66 million visits to Emergency Departments meeting SIRS criteria, and the largest cohort of eventual diagnoses for these patients was indeed infection – but this constituted a mere 26% of all SIRS.  The remaining diagnoses were scattered among trauma, mental disorders, respiratory diseases, and other non-specific, organ-system dysfunction, catch-all ICD-9 codes.  While the interruptions and low specificity of SIRS alert tools are the obvious problem addressed by this study, the other implication is the troubling scope of the problem:  after trauma and infection are excluded, there are approximately 42 million other ED visits that may erroneously trip institutional protocols, costly unnecessary testing, and additional resource utilization targeting sepsis.

This is the sort of decision-support that simply doesn’t add any proven value, and another venue of encroachment into efficient and effective care.

“Epidemiology of the Systemic Inflammatory Response Syndrome (SIRS) in the Emergency Department”

Conclusively Settling Azithromycin’s Cardiac Toxicity Forever

We’ve been obsessed with azithromycin’s cardiovascular effects for quite some time – with some studies showing an increase in events, and other studies using azithromycin as the active agent to decrease coronary events.  Why is it such an issue?  Mostly because azithromycin has become the nonsensical cure-all of eager-to-please primary care physicians for self-limited or viral conditions, let alone the mainstay of treatment for pneumonia.

This latest study comes from a retrospective cohort of Veterans Affairs patients admitted and receiving IDSA guideline-compliant treatment for community-acquired pneumonia.  These authors compared a cohort of patients receiving ß-lactam + azithromycin with any other guideline-compliant therapy, typically fluoroquinolone monotherapy.  They created two propensity-matched cohorts based on known confounders, resulting in comparison groups of 31,863 patients each, with a treatment period spanning 2001 to 2012.

Of these, 1,948 patients exposed to azithromycin had a myocardial infarction recorded within 90 days, compared with 1,523 in the non-azithromycin cohort, for an OR of 1.11 (95% CI 1.03-1.20).  No other cardiovascular disease was increased, and no specific subgroup conferred a higher or lower risk of MI after azithromycin use.  Most of the difference in MI occurred within 30 days of exposure.

However, interestingly, the overall 90-day mortality was 6,582 in the azithromycin cohort, compared with 8,152 in the non-azithromycin cohort, for an OR of 0.73 (95% CI 0.70-0.76).  And, the authors happily run with this mortality advantage – concluding “azithromycin compared with other antibiotics was associated with a lower risk of 90-day mortality (number needed to treat of 21)”.  But, how does a short course of a macrolide antibiotic generate such a profound survival curve that progressively widens months after exposure?  The authors do not provide data on causes of death, nor do they provide much explanation for the observed survival advantage.  Either short-course azithromycin provides a powerful, anti-inflammatory effect with long-term advantage – as implied by the authors – or there’s a problem with the data and the matching.

My vote is for problems with the data.  Propensity matching is only as good as the prognostic importance of variables included in the algorithm, and suffers tremendously when performed on retrospective data not gathered specifically to support such analyses.  Sadly, this study is probably best served to be assigned to the scrap heap of unreliable retrospective observations.

“Association of Azithromycin With Mortality and Cardiovascular Events Among Older Patients Hospitalized With Pneumonia”