Azithromycin Ruins Everything

For some reason – and by “some reason”, I mean extensive evaluation of immunomodulatory properties – there is an obsession with azithromycin use for more than simply its anti-bacterial indications. It has been hypothesized to diminish inflammation and have antiviral properties, and, of course, functions as a floor wax and dessert topping.

This is a randomized, controlled trial of azithromycin versus placebo in pre-school children with acute wheezing as a primary diagnosis. The primary outcome was time to resolution of respiratory symptoms, and secondary outcomes included any use of short-acting beta-agonists, adverse events, and time to any repeat exacerbation of wheezing.  These authors enrolled 300 before funding ran out, and were able to follow-up 222 with completed symptom diaries. Patients were generally similar between the two groups, and over 80% of each cohort had prior episodes of wheezing, and a similar percentage used or was prescribed a beta-agonist at discharge from the Emergency Department.

The winner: nothing and no one. Azithromycin did not improve any outcomes versus placebo, and should not be used for suspected viral wheezing in the hopes of anti-inflammatory symptom improvement until better evidence of benefit emerges.

“Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: A placebo-controlled randomized trial”

No, All Bacteria Do Not Require Antibiotics

The natural world is replete with bacteria.

Humans have existed on this planet for millennia.

In the ages before antibiotics, many humans succumbed to bacterial infections – while, of course, the vast majority survived.

This is not a profoundly reliable observational study, but it does help reinforce this basic concept. This report is a secondary analysis of the GRACE-10 study, which involved primary care patients recruited with a diagnosis of acute cough. The original study was a randomized, placebo-controlled trial for non-specific lower respiratory tract infection, as part of a genomics analysis for evaluation of antibiotic resistance.

This analysis, however, looks solely at the placebo arm, and examines the symptom course and resolution of those who were ultimately diagnosed with a bacterial cause of their LRTI and compares the with those who were not. Of the 834 patients included in their analysis (those with complete symptom diaries), 162 were thought to have a bacteria pathogen based on respiratory culture, nasal swab, or whole blood antibody titers.

S pneumoniae and H influenzae were the most common bacterial pathogens, with most of the remainder the “atypicals” for community-acquired pneumonia. And, at the end of the day: virtually everyone did fine. Patients with a confirmed bacterial pathogen in the setting of their LRTI improved slightly more slowly than those without, had more re-visits in follow-up due to worsening or new symptoms, and a greater percentage were placed on antibiotics in follow-up (12% vs. 6%). The remainder eradicated their bacterial pathogens without antibiotics – you know, the way humans and other contemporary mammals survived for eons.

Now, some of these cases positive for LRTI may be colonization and not pathogenic infection, while some of the negative cases were not diagnosed due to lack of sensitivity. But, regardless, the overall point of this article is probably valid – some bacterial infections will worsen, but in the generally healthy population, a delayed-antibiotic strategy might be valid as an attempt to improve antibiotic stewardship.

“Disease Course of Lower Respiratory Tract Infection With a Bacterial Cause”

The Impending Pulmonary Embolism Apocalypse

After many years of intense effort, our work in recognizing overdiagnosis and over-treatment of pulmonary embolism has been paying off. With the PERC, with adherence to evidence-based guidelines, and with a responsible approach to resource utilization, it is reasonable to suggest we’re making headway into over-investigating this diagnosis.

Prepare for all that hard work to be obliterated.

This is a prospective study of patients admitted to the hospital for syncope, evaluating each in a systematic fashion for the diagnosis of PE. Consecutive admissions with first-time syncope, who were not currently anticoagulated, underwent risk-stratification using Wells score, D-dimer testing if indicated, and ultimately either CT pulmonary angiograms or V/Q scanning. The top-line result, the big scary number you’re likely seeing circulating the medical and lay news: “among 560 patients hospitalized for a first-time fainting episode, one in six had a pulmonary embolism.”

Prepare for perpetual arguments with the admitting hospitalist for the next several eternities: “Could you go ahead an get a CTPA? You know, 17% of patients with syncope have PE.”

I’d like to tell you they’re wrong, and this study is somehow flawed, and you’ll be able to easily refute their assertions. Unfortunately, yes, they are wrong, and this study is flawed – but it won’t make it any easier to prevent the inevitable downstream overuse of CT.

The primary issue here is the almost certain inappropriate generalization of these results to dissimilar clinical settings. During the study period, there were 2,584 patients presenting to the Emergency Department with a final diagnosis of syncope. Of these, 1,867 were deemed to have an obvious or non-serious alternative cause of syncope and were discharged home. Thus, less than a third of ED visits for syncope were admitted, and the admission cohort is quite old – with a median age for admitted patients of 80 (IQR 72-85). There is incomplete descriptive data given regarding their comorbidities, but the authors state admission criteria included “severe coexisting conditions” and “a high probability of cardiac syncope on the basis of the Evaluation of Guidelines in Syncope Study score.” In short, their admission cohort is almost certainly older and more chronically ill than many practice settings.

Then, there are some befuddling features presented that would serve to inflate their overall prevalence estimate. A full 40.2% of those diagnosed with pulmonary embolism had “Clinical signs of deep-vein thrombosis” in their lower extremities, while 45.4% were tachypneic and 33.0% were tachycardic. These clinical features raise important questions regarding the adequacy of the Emergency Department evaluation; if many of these patients with syncope had symptoms suggestive of PE, why wasn’t the diagnosis made in ED? If even only the patients with clinical signs of DVT were evaluated prior to admission, those imaging studies would have had a yield for PE of 65%, and the prevalence number seen in this study would drop from 17.3% to 10.3%. Further evaluation of either patients with tachypnea or tachycardia might have been similarly high-yield, and further reduced the prevalence of PE in admitted patients.

Lastly, any discussion regarding a prevalence study requires mention of the gold-standard for diagnosis. CTPA confirmed the diagnosis of PE in 72 patients in this study. Of these, 24 involved a segmental or sub-segmental pulmonary artery – vessels in which false-positive results typically represent between one-quarter to one-half. Then, V/Q scanning was used to confirm the diagnosis of PE in 24 patients. Of these, the perfusion defect represented between 1% and 25% of the area of both lungs in 12 patients. I am not familiar with the rate of false-positives in the context of small perfusion defects on V/Q, but, undoubtedly a handful of these would be as well.  Add this to the inadequate ED evaluation of these patients, and suddenly we’re looking at only a handful of true-positive occult PE in this elderly, chronically ill cohort with syncope.

My view of this study is that its purported take-home point regarding the prevalence of PE in syncope is grossly misleading, yet this “one in six” statistic is almost guaranteed to go viral among those on the other side of the admission fence.  This study should not change practice – but I fear it almost certainly will.

“Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope”

Prime Time for Dexamethasone in Asthma?

We adore dexamethasone here at EMLoN headquarters.  A pharmacy stocked solely with ketamine, droperidol, and dexamethasone could carry you far in life.  Unfortunately, because of our established bias, the challenge then arises to reconcile the actual results of a trial with what is so desperately wished to be true.

This is a randomized, double-blinded, non-inferiority trial comparing single-dose dexamethasone with five days of prednisone in the treatment of asthma with acute exacerbation.  Single-dose and double-dose dexamethasone protocols have been evaluated in pediatric trials of reasonable size, but data in adults has been lacking.  However, many clinicians – including myself – have assumed generalizability of the pediatric findings to adults, and have been using single-dose dexamethasone protocols for years.

If only one takeaway can be had from this trial, it is: never, ever, skimp on sample size. Far easier said than done, of course, but due to the complex structure and assumptions required for non-inferiority trials, this is a negative trial.  There were 465 subjects randomized – but 89 excluded from analysis as either subsequent admissions or as lost to follow-up.  Of the remaining 376 patients, 9.8% of the prednisone group demonstrated Emergency Department recidivism compared with 12.1% of dexamethasone.  This 2.3% difference between groups, however, suffers a 95% of -4.1 to 8.6%, and exceeds the pre-determined clinically-relevant non-inferiority margin of 8%.

So, unfortunately, we still do not have a precise estimate for the effectiveness difference between a prednisone-based strategy and dexamethasone.  Considering the healthcare burden of asthma in our Emergency Departments, it is somewhat surprising we still have such a paucity of data – as even a small difference in effectiveness may have profound effects on Emergency Department utilization.  In the end, it comes down to where you lay on the spectrum of pre-study odds for non-inferiority or equivalence.  For me, the guarantee of compliance with treatment derived from a single-dose of dexamethasone outweighs the continued uncertainty over its true effectiveness, and this study gives me no cause to change my practice.

“A Randomized Controlled Noninferiority Trial of Single Dose of Oral Dexamethasone Versus 5 Days of Oral Prednisone in Acute Adult Asthma”

Hypoxia & Overtreatment in Bronchiolitis

“Treat the patient, not the number” works for many things in medicine – asymptomatic hypertension, hyperglycemia, and anemia, among others.  However, hypoxia is less frequently dismissed as clinically irrelevant.

And, that perfectly explains the results in this study, which evaluated clinician dependence on oxygen saturation to guide disposition in pediatric bronchiolitis.

Bronchiolitis, a viral process of large airway inflammation, can be challenging to treat.  For the most part, the disease simply must run its course, and it’s a matter of the secondary effects of the infection determining need for admission – work of breathing and hydration status.  Clinicians have been encouraged to accept low oxygen saturations (>90%) in the absence of other sequelae as part of their decision-making process leading to safe discharge home.

But, apparently, we’re still married to “normal” numbers.  In this study, researchers in Ontario randomized patients to the pulse oximeter providing either a true oxygen saturation, or an “altered oxygen saturation” – altered, specifically, to display 3% higher than the true value.  Over four years, 345 patients in respiratory distress with a clinical diagnosis of bronchiolitis met screening criteria, although only 213 agreed to participate.  As you might expect, patients with the true oxygen saturation were much more likely to be hospitalized than the patients with the falsely elevated oxygen saturation – 41% vs 25%.  Patients whose true oxygen saturation was displayed also tended to have increased resource utilization within 72-hours.  Zero adverse patient-oriented outcomes were observed in either group.

This is a small, single-center study, so, strictly speaking, its generalizability is limited.  However, it probably accurately reflects practice in many settings – where hypoxia, independent of more important clinical factors, is inappropriately sufficient cause for admission or observation.  This is a worthy reminder of such a flaw in our practice as respiratory viral season begins to ramp up this fall.

“Effect of Oximetry on Hospitalization in Bronchiolitis: A Randomized Clinical Trial”

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”

Dexamethasone. Think About It.

Many aspects of medicine are simply based on momentum and routine.  One of those routines, in my anecdotal experience, is the use of 5-day courses of steroids for mild/moderate asthma exacerbations.  However, why give multiple doses when one will suffice?  Why not dexamethasone?

Unfortunately, this meta-analysis doesn’t really bring any new knowledge into play.  These authors attempt to pool the results from all the pediatric randomized trials comparing dexamethasone vs. short-course prednisone for the outpatient management of asthma with exacerbation.  No included individual trial showed a relapse rate with dexamethasone significantly worse than prednisone – and, unsurprisingly, the pooled results reflect that same finding.  The only recorded adverse effect – vomiting in the ED or at home – was seen less frequently with dexamethasone, although the overall incidence in both arms was minimal.

But, there are only six trials, most of which are fewer than 100 patients.  These trials are also a mix of oral and intramuscular, single and multiple dose, and dose ranges from 0.3 mg/kg to 1.7 mg/kg (“max 36 mg”!).  There were also methodologic problems with blinding, allocation, and other outcomes issues with each included study.

Based on this low-quality evidence, it would be reasonable to say dexamethasone use is not adequately described in the literature.  It would, likewise, be reasonable to go ahead and make use of dexamethasone in this setting, with the recognition of these limitations.  Personally, I fall on the dexamethasone side of the argument – for children, as well as adults.  When feasible, I use an approximately prednisone-equivalent oral dosing at 0.15 mg/kg up to a maximum dose of 12mg in both populations.

And I would love to see a high-quality trial to settle matter, once and for all.

“Dexamethasone for Acute Asthma Exacerbations in Children: A Meta-analysis”

Outpatient Management of Large Pneumothorax

A guest post by Justin Mazzillo, a community doc in New Hampshire.
“Okay Mr. Smith now that your chest tube is in we’re going to go ahead and discharge you.  Just come back to the Emergency Department if you have any problems.”

That’s pretty much what these investigators set out to do…with a few minor differences. Instead of following the more common practice of aspirate and observe or place a chest tube and admit, the authors’ goal was to demonstrate that patients with large primary and secondary pneumothorax can be managed as outpatients with pigtail catheters. This prospective case series of 132 patients aimed to evaluate the success rate of outpatient management, as well as the one-year recurrence rate, pain medication use, safety and cost of this approach.

Patients who presented to this French hospital with large primary or secondary pneumothoraces had a pigtail catheter placed, were observed for two hours without a confirmatory chest radiograph and then discharged. Patients were seen in follow-up clinic on days 2 and 4 and admitted to the hospital on day 4 if the pneumothorax failed to resolve.

Of the 132 patients, 78% were managed entirely as outpatients. Patients with primary and secondary pneumothoraces had similar success rates, although the latter group was considerably smaller.  Two patients had mechanical catheter issues that were addressed as outpatients on their follow-up visit on day 2. The recurrence rate at one-year was 26%. The average cost of being managed as an outpatient in this study was $926 vs. $4,276 for the conventional inpatient approach.

This seems like an attractive and safe option as health care costs continue to skyrocket and more patients are managed in the ambulatory setting.  
“Ambulatory Management of Large Spontaneous Pneumothorax With Pigtail Catheters”

Another Appeal for Prudent Antibiotics

Bronchitis, deadly scourge of man – at least, considering the quantity of antibiotics prescribed, it must be, right?

Or, the cure is worse than the disease, as these authors seem to demonstrate.  This is a parallel, single-blinded, placebo-controlled trial in 9 primary care centers in Catalonia, Spain, enrolling patients with acute bronchitis.  Non-immunosuppressed patients with a productive cough of less than a week’s duration were randomized to amoxicillin-clavulanic acid, ibuprofen, or placebo for a 10 day course.  The primary outcome was time to cure, with treatment failure and safety outcomes as secondary outcomes.

With approximately 140 patients in each group, the only clinically meaningful significant difference between groups was the incidence of adverse events in the amoxicillin-clavulanic acid group.  These were mostly gastrointestinal events, occurring in 12% of the antibiotic group, compared with 5% of the ibuprofen group and 3% of the placebo group.  Days with cough, treatment failure, and time to overall symptom resolution showed no significant differences between groups.  There was some suggestion of a trend towards benefit from the ibuprofen arm, but this would have to be confirmed in a larger trial.

The main limitation of this article is failure to include a macrolide antibiotic as a comparator, considering the expected bacterial epidemiology of ambulatory respiratory infections.  Regardless, this adds to the body of evidence demonstrating the futility of antibiotics in healthy patients with bronchitis – and I’d expect similar findings even if azithromycin were included.

“Efficacy of anti-inflammatory or antibiotic treatment in patients with non-complicated acute bronchitis and discoloured sputum: randomised placebo controlled trial”

14 Days of Steroids is Too Many Days

Some of the most common practices in Emergency Medicine are only weakly tested or defined – including steroids for acute respiratory illness.  What is the true minimum effective dose?  How many days – 3, 5, 7, or 14?  Burst or taper?  Much of our practice is based on habit and mimicry, along with the general evidence that, despite ourselves, we don’t seem to be doing much harm.

This is the REDUCE trial, a multi-center, randomized, double-blind, non-inferiority comparison between a 5-day and a 14-day course of 40mg oral prednisone for acute COPD exacerbation.  And…it found no difference in the primary outcome measure.  So, then, all’s well.

Except, their outcome measure is utterly bizarre – re-exacerbation within six months?  I cannot fathom how a 1-2 week period of steroids could have any causative association with outcomes more than a handful of half-lives after cessation of treatment.  Perhaps they theorize the short-term steroid exposure is insufficient to avoid long-term damage secondary to the acute inflammation? 

There are also some potentially confounding differences in baseline characteristics.  There were 9% more smokers and 5% more home oxygen in the short-term treatment group – which could favor conventional treatment – but then 4% fewer were on daily steroids during the treatment period and 8% fewer received concurrent antibiotics in the conventional treatment group – which could favor the short-term treatment group.  Some of these differences would have more effect on short-term outcomes, while others would affect long-term outcomes.  I don’t know if there are true clues in the Kaplan-Meier curves they present – because the sample size is small enough these variations might just be occurring due to chance – but it appears there’s a possible hazard towards early re-exacerbation in the 5-day group, followed by regression towards equivalence by six months.

However, these issues aside, their conclusion is probably valid.  Their predefined threshold for non-inferiority was 15% – and they easily cleared that bar.  All the confounders are probably not of significant magnitude to affect the overall result at that threshold – even for shorter, more relevant follow-up time periods.  Additionally, this is otherwise consistent with the other evidence that short-courses of steroids are absolutely acceptable in this context.

Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease”