The HSV Meningitis Question

This is one of those questions that always crops up when evaluating an infant for sepsis and meningitis – should we test and/or empirically cover for herpes simplex virus infection? Just how frequently is this diagnosis made?

The answers, as described in this retrospective, multi-center study, are complex. First, the basics: 26,533 total encounters analyzed, with 112 children ultimately diagnosed with HSV meningitis. Then, it’s basically chaos. The percent of patients whose CSF was tested for HSV ranged from 12.5% to 70.9% across hospitals included, along with empiric coverage with acyclovir ranging from 4.2% to 53.0%. Rates of positive HSV results were unrelated to overall institutional testing or empiric acyclovir coverage rates, excepting in the sense that HSV infection was more frequent in younger infants – and younger infants were more likely to be tested and empirically treated, in general.  A handful of patients with ultimate diagnoses of HSV meningitis were not treated or tested initially, and were found on a subsequent visit.

The authors go into some detail regarding the questionable value of empiric treatment, citing a number needed to treat of 152 for infants 0-28 days and an NNT of 583 for infants from 29-60 days. Generally speaking, these authors agree with a prior cost-effectiveness analysis recommending waiting for the initial CSF cell count, and empirically treating those with a CSF pleocytosis. Consequently, these authors would therefore recommend testing only those ultimately treated empirically – but this is naturally a pragmatic consideration, rather than a statistically modeled balance between sensitivity and specificity.

There are a few more nuances within the paper with regard to their gold standard for diagnosis of HSV meningitis, limitations with regard to selection of patients undergoing testing, and generalizability from these tertiary referral settings, but it is still generally an interesting snapshot of data. Unfortunately, their ultimate conclusion is still back at square one – reiterating a call for specific clinical and laboratory data to help guide clinicians in selecting patients for HSV testing and empiric treatment. In the meantime, we’ll just keep doing our best to differentiate the ill child at the bedside based on gestalt and the culture of our practice setting.

“Herpes Simplex Virus Infection in Infants Undergoing Meningitis Evaluation”

Treatment Failure, or is Treatment the Failure?

Acute respiratory tract infections – otitis media, streptococcal pharyngitis, and sinusitis – comprise virtually a laundry list for antibiotic overuse in self-limited conditions. Certainly, a subset of each of these conditions are true bacterial infections and, again, a subset of these have their resolution hastened by antibiotics – and, finally, a subset of those would have clinically important worsening if antibiotics were not used. Conversely, the harms of antibiotics are generally well-recognized,though not necessarily routinely appreciated in clinical practice.

This patient-centered outcomes study, with both retrospective and prospective portions, enrolled children diagnosed with the aforementioned “acute respiratory tract infections” and evaluated outcomes differences between those receiving “narrow-spectrum” antibiotics and those receiving “broad-spectrum antibiotics”. Before even delving into their results, let’s go straight to this quote from the limitations:

Because children were identified based on clinician diagnosis plus an antibiotic prescription to identify bacterial acute respiratory tract infections, some children likely had viral infections.

“Some children likely had viral infections” is a strong contender for understatement of the year.

So, with untold numbers of viral infections included, it should be no surprise these authors found no difference in “treatment failure” between narrow-spectrum and broad-spectrum antibiotics. Nor, in their prospective portion, did they identify any statistically difference in surrogates for wellness, such as missed school, symptom resolution, or pediatric quality of life. However, adverse events were higher (35.6% vs. 25.1%, p < 0.001) in the broad-spectrum antibiotic cohort, and this accompanied smaller, but consistent, differences favoring narrow-spectrum antibiotics on those wellness measures.

So, the takeaway: broad-spectrum antibiotics conferred no advantage, only harms. If you’re using antibiotics (unnecessarily), use the cheapest, most benign ones possible.

“Association of Broad- vs Narrow-Spectrum Antibiotics With Treatment Failure, Adverse Events, and Quality of Life in Children With Acute Respiratory Tract Infections”

Why Are Children Dizzy?

Vertigo presentations in adults are nearly always benign – with cerebral ischemia generally the most worrisome diagnosis in the differential. But, what about children? With a much lower risk for stroke, but also spared the other decay and decrepitude of aging, ought we be more or less concerned?

The short answer: mostly no. However, the etiologies of pediatric vertigo are almost certainly different.

In this short systematic review comprised of 24 studies and 2,726 children, the vast majority of cases resulted from generally benign etiologies. The most common diagnosis was ascribed to “vestibular migraine”, at about a quarter of the cases, followed by a smattering of peripheral vertigo and labyrinthitis-spectrum disorders. Not until diagnostic prevalence approached ~1% of cases did the most serious underlying etiologies begin to manifest, with central nervous system tumors, demyleninating disease, and ototoxic medication effects at the top of the lists of infrequent findings.

The limitations of this analysis include lack of generalizability to the Emergency Department, as several of the included articles are drawn from outpatient subspecialty case series review. A reasonable takeaway from these data, at least, as in adults, is serious underlying etiologies are very infrequently, and isolated vertigo need not be particularly worrisome absent other important neurologic findings.

“The Differential Diagnosis of Vertigo in Children: A Systematic Review of 2726 Cases”

And, The Safest Pediatric Sedation Drug Is …


This ought not surprise virtually anyone, considering the vast body of experience physicians have performing safe, effective procedural sedation with ketamine. However, medicine is prone to its dogmatic confirmation bias, so I applaud these authors for this important report.

This is a prospective, observational, multi-center cohort specifically evaluating all episodes of procedural sedation for serious adverse events and important interventions. These authors recorded medication cocktails used for sedation, any adjunctive use of medication, the procedure performed, fasting status, and underlying health risks, and then tracked the outcomes of each procedure performed.

Ultimately, they included 6,295 children and sedation events in this study. The most commonly used sedation medications were ketamine, propofol, and combinations of ketamine, propofol, and fentanyl. Serious events were rare, occurring in about 1% of sedations – and, likewise, so were important interventions. Furthermore, the vast majority of events and interventions were simply temporary use of positive pressure ventilation in response to periods of apnea. Importantly, no patients required intubation or unplanned hospital admission. Oxygen desaturation was tracked separately from serious events and, along with vomiting, occurred in approximately 5% of sedation procedures.

With regard to other contributing factors to serious events or interventions, any deviation from ketamine monotherapy increased such risks. Whether it be combining ketamine with another opiate or benzodiazepine, or whether propofol were used alone or in combination, all increased the risk of serious events a small absolute amount over the baseline. Several figures included in the manuscript describe the various risk factors associated with serious outcomes with generally predictable associations, including increased risks with periprocedural opiate use, and decreased vomiting when ketamine were excluded.

Overall, even though the short answer to the question posed in the title is “ketamine”, the slightly longer answer is “any choice is probably fine”. Even though the relative risks are increased, the absolute risks are small – and the severity of interventions required, despite their labeling, were essentially benign.

“Risk Factors for Adverse Events in Emergency Department Procedural Sedation for Children”

Morphine Not a Good Adjunct For Pediatric Pain

Treating acute musculoskeletal pain in the Emergency Department is a common occurrence – and even on the docket as a time-to-analgesia quality measure. Where we frequently see failures and delays, however, are in children, with much written regarding oligoanalgesia and the dragging of feet before any sort of pain management. Furthermore, adults are frequently managed with opiate therapy, which, despite its various pitfalls, may be considered to stand above the commonly used ibuprofen and acetaminophen monotherapy in children.

So, does it work better to combine an oral non-steroidal analgesic with opiate therapy in children? Or, perhaps, is even an opiate alone better with regard to adverse effects? That is the question asked by this three-arm, double-blinded, placebo-controlled, randomized trial. Children with painful musculoskeletal injuries were randomized either ti 10mg/kg oral ibuprofen, 0.2mg/kg oral morphine, or the combination of both.

The winner is: not children. With 91 analyzed in the ibuprofen-only arm, 188 in the morphine-only arm, and 177 in the combination arm, there were no reliable differences between analgesia between groups. More disappointingly, the average pain score on the visual analogue scale was ~60mm across all groups, and no group improved more than 20mm within an hour. The authors considered a VAS score of <30mm at 60 minutes to represent adequate pain control, and less than a third from each group achieved this. There were no serious adverse events in any group, but 20% of those receiving morphine complained of mild adverse events, mostly nausea and abdominal pain, compared with 7% of the ibuprofen-only arm.

So, still at square one for oral analgesia – but, at least, this negative trial helps inform our avoidance of the intervention tested here.

“Oral Analgesics Utilization for Children With Musculoskeletal Injury (OUCH Trial): An RCT”

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”

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”

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”

No Pictures of Poop Needed

I like this article – not because of any specific quality improvement reason relating to their intervention, but because it reminded me of something of which I perform too many.

It’s an easy trap to fall into, the – “well, let’s just see how much poop is in there” for diagnostic reassurance and to help persuade the family you’re doing relevant testing in the Emergency Department. However, here are the relevant passages from their introduction:

In a 2014 clinical guideline, the North American and European Societies of Pediatric Gastroenterology, Hepatology, and Nutrition found that the evidence supports not performing an AXR to diagnose functional constipation.


Recent studies showed that AXRs performed in the ED for constipation resulted in increased return visits to the ED for the same problem.

I feel some solace in knowing that 50 to 70% of ED visits for constipation may include an abdominal radiograph as part of their workflow – meaning I’m just, at least, part of the herd.

So, regardless of the point of their article – that a plan-do-act cycle of education and provider feedback successfully cut their rate of radiography from 60% to 20% – this is yet another misleading and/or unnecessary test to delete from our practice routine.

“Reducing Unnecessary Imaging for Patients With Constipation in the Pediatric Emergency Department.”

What Does a Sepsis Alert Gain You?

The Electronic Health Record is no longer simply that – a recording of events and clinical documentation.  Decision-support has, for good or ill, morphed it into a digital nanny vehicle for all manner of burdensome nagging.  Many systems have implemented a “sepsis alert”, typically based off vital signs collected at initial assessment. The very reasonable goal is early detection of sepsis, and early initiation of appropriately directed therapy. The downside, unfortunately, is such alerts are rarely true positives for severe sepsis in broadest sense – alerts far outnumber the instances in a change of clinical practice results in a change in outcome.

So, what to make of this:

This study describes a before-and-after performance of a quality improvement intervention to reduce missed diagnoses of sepsis, part of which was introduction of a triage-based EHR alert. These alerts fired during initial assessment based on abnormal vital signs and the presence of high-risk features. The article describes baseline characteristics for a pre-intervention phase of 86,037 Emergency Department visits, and then a post-intervention phase of 96,472 visits. During the post-intervention phase, there were 1,112 electronic sepsis alerts, 265 of which resulted in initiation of sepsis protocol after attending physician consultation.  The authors, generally, report fewer missed or delayed diagnoses during the post-intervention period.

But, the evidence underpinning conclusions from these data – as relating to improvements in clinical care or outcomes, or even the magnitude of process improvement highlighted in the tweet above – is fraught. The alert here is reported as having a sensitivity of 86.2%, and routine clinical practice picked up nearly all of the remaining cases that were alert negative.  The combined sensitivity is reported to be 99.4%.  Then, the specificity appears to be excellent, at 99.1% – but, for such an infrequent diagnosis, even using their most generous classification for true positives, the false alerts outnumbered the true alerts nearly 3 to 1.

And, that classification scheme is the crux of determining the value of this approach. The primary outcome was defined as either treatment on the ED sepsis protocol or pediatric ICU care for sepsis. Clearly, part of the primary outcome is directly contaminated by the intervention – an alert encouraging use of a protocol will increase initiation, regardless of appropriateness. This will not impact sensitivity, but will effectively increase specificity and directly inflate PPV.

This led, importantly, for the authors to include a sensitivity analysis looking at their primary outcome. This analysis looks at the differences in overall performance if stricter rules for a primary outcome might be entertained. These analyses evaluate the predictive value of the protocol if true positives are restricted to those eventually requiring vasoactive agents or pediatric ICU care – and, unsurprisingly, even this small decline in specificity results in dramatic drops in PPV – down to 2.4% for the alert alone.

This number better matches the face validity we’re most familiar with for these simplistic alerts – the vast majority triggered have no chance of impacting clinical care and improving outcomes. It should further be recognized the effect size of early recognition and intervention for sepsis is real, but quite small – and becomes even smaller when the definition broadens to cases of lower severity. With nearly 100,000 ED visits in both the pre-intervention and post-intervention periods, there is no detectable effect on ICU admission or mortality. Finally, the authors focus on their “hit rate” of 1:4 in their discussion – but, I think it is more likely the number of alerts fired for each each case of reduced morbidity or mortality is on the order of hundreds, or possibly thousands.

Ultimately, the reported and publicized magnitude of the improvement in clinical practice likely represents more smoke and mirrors than objective improvements in patient outcomes, and in the zero-sum game of ED time and resources, these sorts of alerts and protocols may represent important subtractions from the care of other patients.

“Improving Recognition of Pediatric Severe Sepsis in the Emergency Department: Contributions of a Vital Sign–Based Electronic Alert and Bedside Clinician Identification”