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”
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182411

Enough with the Coughing!

Every Emergency Physician who has worked a night shift knows this all too well – the child brought to the ED in the middle of the night for a cough, keeping the entire family up, and the cough has been going on for weeks.

And, the not-at-all-satisfying answer: “This is pretty normal.”

This is yet another publication describing the natural history of symptoms following an upper respiratory illness. These authors in Australia enrolled children evaluated in the Emergency Department for an upper respiratory infection featuring cough. They enrolled 839 children and attempted to follow them for four weeks after the index visit, as well as through follow-up with a pulmonology specialist if seen for persistent, unresolving cough. Nearly 300 of the initially enrolled cohort was lost to follow-up over the course of the month, but of those who were contacted, two-thirds still had cough at 7 days, and a quarter were still coughing at day 21. Ultimately 171 – or 20.4% – were still coughing at day 28 and eligible for pulmonologist evaluation. Of these, about a third were identified to have a previously undiagnosed underlying chronic respiratory disorder (asthma, bronchiectasis, etc.) and about half were given the diagnosis of persistent bacterial bronchitis.

The general takeaway here is that coughs generally linger – but once a cough has persisted beyond 2-3 weeks, it is reasonable to consider alternative precipitating diagnoses other than the initial URI.

“Chronic cough postacute respiratory illness in children: a cohort study”
https://www.ncbi.nlm.nih.gov/pubmed/28814419

Is 3.3% Really the Avoidable Number?

Much has been made about “avoidable” Emergency Department visits – something, as physicians, we are anecdotally all-too-familiar – but the exact scope of the problem has been difficult to quantify. If it were easy, after all, the range of estimates for avoidable visits would not encompass the spread between 4.8% and 90%.

This is another shot at defining avoidable, this time using a very restrictive definition. An avoidable ED visit occurs when a patient is discharged home, and:

  • No tests are performed
  • No procedures are performed
  • No medications are administered or prescribed

These authors utilize the National Hospital Ambulatory Medical Care Survey (NHAMCS) for years 2005–2011, and find an estimated 3.3% of ED visits met those criteria. The most common discharge diagnoses included those related to alcohol use, back pain, throat pain, upper respiratory symptoms, dental issues, and mental health issues.

But, the true net result of this analysis is, unfortunately, it simply grows our estimate for avoidable ED visits to an even-more-ridiculous range between 3.3% and 90%. This definition lends itself far more to convenience for data analysis than face validity as a surrogate for avoidable. Clearly, a lack of testing or medication administration does not indicate a life- or limb-threatening condition has not been ruled out by expert clinical examination and reasoning. Conversely, ordering a test or administering a medication does not indicate the level of service of an ED was necessary, or the ideal venue for care delivery.

Given the limitations of the data set, this is a reasonable approach to add to the discussion of the types of potentially avoidable ED visits. However, I expect to see this 3.3% number cited frequently in isolation without acknowledging the underlying definitions or methods for derivation.  A better title for this paper?  How about: “ED visits resulting in neither treatment nor testing: a descriptive analysis” – the word “avoidable” should be omitted.

“Avoidable emergency department visits: a starting point”

https://doi.org/10.1093/intqhc/mzx081

Neither Benefit Nor Harm Seen With Oxygen in Myocardial Infarction

We’ve been hanging on to the biological hypothesis of treating ischemia with supplemental oxygen for quite some time – despite some evidence to the contrary with regard to damage from oxygen free radical formation. What’s needed is a large, randomized trial – and so we have DETOX2-AMI, run through the SWEDEHEART trial registry.

This trial randomized individual patients with suspected or known myocardial infarction to continuous oxygen therapy or ambient air.  Patients were excluded from enrollment if they had oxygen saturation below 90% at baseline, or were not Swedish national citizens as necessary for long-term follow-up. These patients actually received fairly vigorous oxygen therapy, far exceeding the typical nasal cannula oxygen we see on patients arriving via EMS – patients randomized to the oxygen arm received 6 liters per minute via face mask for 6 to 12 hours.

Over the 1.5 year trial period, these authors enrolled 6,629 patients, generally evenly matched with regard to baseline clinical characteristics, and 75% of whom ultimately had a final diagnosis of myocardial infarction.  Detailed outcomes, owing to the underlying registry infrastructure, are scant – as compared to the AVOID trial, in which many patients underwent cardiac MRI to evaluate infarct size and ejection fraction. What you get are the hard outcomes: death and rehospitalization with myocardial infarction – and there is no difference, both in the short- or long-term, and in both the intention-to-treat and per-protocol analyses. The authors also include median highest troponin T as a surrogate for infarct severity and morbidity, and there is no difference there, either.

The underlying hypothesis here was to demonstrate a beneficial effect to oxygen in myocardial infarction – defined as a clinically relevant effect size of 20% lower relative risk of death – and that threshold was clearly not met.  There are some small differences with regard to oxygen delivery, as compared to AVOID, with the AVOID trial delivering oxygen at a much higher concentration.  But, effectively, the takeaway from these data is: oxygen just probably doesn’t matter enough to be clinically relevant. There’s no reason to be condescending and militant about taking the oxygen off a patient with myocardial infarction, and likewise it’s reasonable to consider it a wasteful intervention with regard to canistered oxygen supply.

Finally, just for fun, to recap the anachronistic acronym MONA:

Morphine – Possible small harms, as relating to inhibition of antiplatelet agents.
Oxygen – Almost certainly irrelevant with regard to clinical outcomes.
Nitroglycerin – Likely irrelevant with regard to clinical outcomes.
Aspirin – Still good!

“Oxygen Therapy in Suspected Acute Myocardial Infarction”
http://www.nejm.org/doi/full/10.1056/NEJMoa1706222

Steroids, Not Universally Useful For Wheezing

In asthma, steroids are fantastic. The earlier, the better. In bronchiolitis, another wheezing-spectrum illness, mostly probably not. How about the general, ambulatory, viral lower respiratory tract infections with wheezing?

This randomized, controlled trial enrolled patients at family practice clinics in Britain with non-asthmatic wheezing relating to a suspected “chest infection”. Patients received either 40mg of oral prednisolone for five days or matching placebo. The primary outcome was duration of moderately bad or worse cough, as recorded by a patient-reported symptom diary, with secondary outcomes of subsequent antibiotic use, cumulative symptom scores, and quality of life scores, and other resource utilization measures.

These authors enrolled 401 patients, 398 of whom received the study intervention. There were no important differences between enrolled groups at baseline – and, there were no reliable, important differences in measured outcomes, either the primary symptom-related outcome, or any of the secondary outcomes.

The strength of this evidence is not such that it eliminates the possibility of a clinically important benefit for a subgroup of patients, but I consider it practice-changing because there was such little reliable evidence at baseline. I have certainly felt it was reasonable to discharge patients with suspected viral LRTI, wheezing, and bronchospasm on an oral steroid based on a low risk profile and at least a hoped-for, physiologically-justified, benefit. Now, the onus is on a subsequent trial to demonstrate said benefit before resuming such practice.

“Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract Infection”
http://jamanetwork.com/journals/jama/article-abstract/2649201

There Are (Almost) No PEs in Syncope, Actually

Last year, we suffered the ignominy of being presented with evidence implying the Emergency Department was systematically failing to adequately evaluate the underlying etiology of patients with syncope. The PESIT trial demonstrated nearly 1 in 6 patients admitted to the hospital had PE, and, worse, most had obvious clinical manifestations of VTE. This is, despite its publication in the New England Journal of Medicine, still nonsense, and flies in the face of every other reasonable estimate of the prevalence of PE.

This study is yet another reasonable refutation of their inflated estimate: a retrospective, secondary re-analysis of a prospectively-collected syncope data set. This analysis reviewed 348 patients previously enrolled in the Emergency Department with a presenting complaint of syncope, about half of whom were observed or admitted to the hospital. Overall, just two of the original 348 were diagnosed with PE in the ED. None of the patients admitted or observed were diagnosed with PE during their hospitalization, but, in their 30-day follow-up period, three total additional PE diagnoses were made.

Without a systematic process for excluding PE, it is reasonable to suggest these numbers are biased towards under-estimating the diagnosis of PE – although the patients in question with 30-day PE each underwent objective testing during their initial presentation with either D-dimer or CTPA. Regardless, the rate of PE in patients hospitalized with syncope is far below the 1 in 6 prominently reported – and we might do well to expunge it from our collective memory.

“Prevalence of pulmonary embolism in patients presenting to the emergency department with syncope”
https://www.ncbi.nlm.nih.gov/pubmed/28811209

The Impermanence of Non-Operative Appendicitis Management

Novelty is no guarantee of superiority. In the olden days, appendicitis meant: out, damned vestigial worm! In modern times, it gives rise to any number of potential antibiotics-first strategies, under observation or as an outpatient.

But, following resolution of the initial appendicitis symptoms, the appendix persists. And, left to its own devices, the risk of recurrence remains. In the few trials and observational series to date, the risk seems to be on the order of 20-30% at one year.

This study suggests the practical rate outside of controlled trial settings may be even higher. This retrospective review of administrative data from 45 pediatric hospitals examines management and resource utilization relating to appendicitis diagnoses. Over the six year study period, approximately 6% of cases of non-perforated appendicitis were managed non-operatively, a rate that increased 20% over the course of the study period – with most of the increase occurring in the final two years. Compared with those managed operatively, those managed non-operatively had higher rates of advanced imaging (8.9%), Emergency Department visits (11.2%), hospitalizations (43.7%) – and, finally, 46% of those managed non-operatively underwent subsequent appendectomy.

Interestingly, the median time elapsed before subsequent appendectomy was only one day – a result these authors found skewed relating to those who were discharged from the Emergency Department rather than after hospitalization for multiple doses of intravenous antibiotics. These authors also found 14% of those with recurrent appendicitis suffered perforation, a much higher proportion than the ~3% found in previous trials.

It certainly sounds appealing, from a superficial standpoint, to avoid surgery in anyone – least of all children. It is reasonable, however, to suggest the rush to transform practice to elevate non-operative management is unwarranted without better long-term data. Patients may be offered a non-operative management strategy, but only in the context of substantial uncertainty regarding ultimate outcomes, and the non-trivial risk of re-hospitalization for subsequent appendectomy.

“Outcomes of non-operative management of uncomplicated appendicitis”
http://pediatrics.aappublications.org/content/early/2017/05/31/peds.2017-0048

 

More Futility: Apneic Oxygenation?

Here’s another pendulum swing to throw into the gears of medicine – an apparent failure of apneic oxygenation to prevent hypoxemia during intubation in the Emergency Department. Apneic oxygenation – passive oxygenation during periods of periprocedural apnea – seems reasonable in theory, and several observational studies support its use. However, in a randomized, controlled ICU setting – the FELLOW trial – no difference in hypoxemia was detected.

This is the ENDAO trial, in which patients were randomized during ED intubation, with a primary outcome of mean lowest oxygen saturation during or immediately following. These authors prospectively enrolled 206 patients of 262 possible candidates, with 100 in each group ultimately qualifying for their analysis. The two groups were similar with regard to initial oxygen levels, pre-oxygenation levels, and apnea time. Then, regardless of their statistical power calculations and methods, it is fairly clear at basic inspection their outcomes are virtually identical – in mean hypoxemia, SpO2 below 90%, SpO2 below 80%, or with regard to short-term or in-hospital mortality. In the setting in which this trial was performed, there is no evidence to suggest a benefit to apneic oxygenation.

It is reasonable to note all patients included in this study required a pre-oxygenation period of 3 minutes by 100% FiO2 – and that oxygen could be delivered by bag-vale mask, BIPAP, or non-rebreather with flush rate oxygen. These are not necessarily equivalent methods of pre-oxygenation, but, at the least, the techniques were not different between groups (>80% NRB). It is reasonable to suggest passive oxygenation may be more beneficial in those without an adequate pre-oxygenation period, but it would certain be difficult to prospectively test and difficult to anticipate a clinically important effect size.

Adding complexity to any procedure – whether with additional monitoring and alarms or interventions of limited efficacy – adds to the cognitive burden of the healthcare team, and probably has deleterious effects on the most critical aspects of the procedure. It is not clear that apneic oxygenation reliably improves patient-oriented outcomes, and does not represent a mandatory element of rapid-sequence intubation.

“EmergeNcy Department use of Apneic Oxygenation versus usual care during rapid sequence intubation: A randomized controlled trial”
http://onlinelibrary.wiley.com/doi/10.1111/acem.13274/full

The Futility of NSAIDs for Back Pain?

This article filled with reproach for non-steroidal anti-inflammatories was highlighted in a New England Journal of Medicine Journal Watch and on Twitter – a wistful treatise remarking on the general ineffectiveness of pharmacologic analgesics. “Nothing works!” accompanied by a general gnashing of teeth and writhing on invisible flames.

But – does this meta-analysis actually reach such a conclusion? Examine the first few words in their conclusion:

NSAIDs are effective for spinal pain …

Off to a good start! But, the catch:

… but the magnitude of the difference in outcomes between the intervention and placebo groups is not clinically important.

These authors pool the results of 35 randomized, placebo-controlled trials for “spinal pain”, which is to say undifferentiated pain relating anatomically to any part of the spine. These trials comprised 6,065 participants – or, if you do the math, an average of 173 patients per trial, nearly all of them performed over a decade ago. The pooled effects of these trials all favored NSAIDs – but, as the authors mention, the absolute magnitude of effect on pain scales was a the edge of their threshold for clinical significance. The authors defined a difference of 10 points on a 100-point scale as clinically important, but most of their pooled results landed between -7 and -16, favoring NSAIDs over placebo. With these small samples, generally moderate GRADE quality, and moderate to high heterogeneity between the pooled results, there is a lot of fuzziness around their ultimate conclusion.

These authors do many, other, exploratory analyses, and it is reasonable to suggest the limitations inherent to each render any conclusions unreliable. Adverse events, as reported, were similar between groups – excepting for increased gastrointestinal adverse events, most of which were non-serious. The authors report this difference as a relative risk of 2.5 for GI side effects in their comparison, but the absolute differences are on the order of an excess of 1 in 100.

This is probably much ado about nothing. Their perspective is not inaccurate, per se, but these trials do find a consistent benefit to NSAIDs. The value judgment here on clinical effectiveness probably misses the mark, particularly considering these are inexpensive, readily available, with few adverse effects in short-term use. I would probably argue it is easier to defend a position they still have utility in multi-modal pain control regimens, rather than to conclude they be consigned to the rubbish bin.

“Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis”

https://www.ncbi.nlm.nih.gov/pubmed/28153830

 

Predicting Treatment Failure in AOM

Like most infectious diseases, acute otitis media generally breaks down into three cohorts. There are viral infections, for which early antimicrobial therapy is virtually, by definition, unhelpful. Then, there are true bacterial infections – many of which resolve without substantial morbidity regardless of antimicrobial treatment, and those which require antimicrobial therapy to prevent such. The trick, and where modern medicine typically fails miserably, is rapidly predicting into which of these cohorts a patient may fall – a conundrum leading to the epidemic of antibiotic overuse.

This is a secondary analysis of a pediatric AOM trial, first published in the New England Journal of Medicine, looking at which patients were more likely to potentially fail conservative treatment. The intervention arm received amoxicillin/clavulanate, and treatment failure occured in 31.7% of children – vastly favoring the antibiotic arm – 44.9% vs. 18.6%. In theory, this exaggerated treatment effect might help better illuminate any small predictors – but, unfortunately, with only 319 patients, meaningful statistical significance on this data dredge is hard to come by. Worse still, the best predictor of treatment failure (or, really, lack thereof)? A peaked tympanogram (A and C curves) – you know, because we’re all routinely measuring tympanometry. Grossly bulging tympanic membranes were predictive of treatment failure, which has some face validity, at least – but, again, this is as compared between severe, moderate, and mild, which requires pneumatic otoscopy to differentiate.

The question here primarily concerns: can you take away good conclusions from bad data? The magnitude of the treatment effect seen in this trial far exceeded the treatment effect expected from antibiotics in other trials. And, consistent with that questionable generalizability, their findings reflect the stringent criteria determining their diagnosis of AOM. Then, they are relying upon their misguided definition for treatment failure, which relies on otoscopic signs, the same ones that will be colinear with worsened disease on initial examination. Unfortunately, the net result of all of this meandering is essentially no clinically useful insight. Considering the limitations the examination of the screaming ill toddler, more pragmatic approaches are necessary.

“Prognostic Factors for Treatment Failure in Acute Otitis Media”

http://pediatrics.aappublications.org/content/early/2017/08/04/peds.2017-0072