Category: Pediatrics

What are Children’s Lives Worth (to Save)?

This article regarding the cost of upgrading emergency departments to be “ready” for sick children has been bouncing around in the background since its publication, with some initial lay press coverage.

The general concept here is obviously laudable and the culmination of at least a decade of hard work from these authors and the team involved – with the ultimate goal of ensuring each emergency department in the country is capable of caring for critically unwell children. The gist of this most recent publication builds upon their prior work to, effectively, estimate the overall cost (~$200M) of improving “pediatric readiness”. Using that total cost, they then translate this into humanizing terms by referencing the total cost per child it might require in different states, and the number of pediatric lives saved annually.

As can be readily gleaned from this sort of thought experiment, these estimates rely upon a nested set of foundational assumptions, all of which are touched upon by prior work by this group. There are surveys of subsets of emergency departments regarding “readiness“, which involve questions such as the presence of pediatric-sized airway devices and staff dedicated to upkeep of various pediatric support. Then, they use these data and salary estimates to come up with the institutional costs of readiness. Then, they have another set of work looking at the odds ratios for increased poor outcomes at departments whose “readiness” is in the lowest percentiles, and this work is extrapolated to determine the lives saved.

Each of these pieces of work, in isolation, is reasonable, but represents a bit of a house of cards. The likelihood of imprecision is magnified as the estimates are combined. For example, how direct is the correlation between “readiness” based on certain equipment and pediatric survival, if the ED in question is a critical access hospital with low annual census? Is the cost of true clinical readiness just a part-time FTE of a nurse, or should it realistically involve the costs of skill upkeep for nurses and physicians with education or simulation?

I suspect, overall, these data understate the costs and overstate the return on investment. That said, this is still critical work even just to describe the landscape and take a stab at the scope of funding required. Likely, the best next step would be to target specific profiles of institutions, and specific types of investment, where such investment is likely to have the highest yield – as a first step on the journey towards universal readiness.

“State and National Estimates of the Cost of Emergency Department Pediatric Readiness and Lives Saved”
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2825748

The End of Respiratory Season Hell?

Every year, we have our peak of respiratory viruses – traditionally influenza, respiratory syncytial virus, and their accompanying lessor demons. These are each awful, of course, in their own way from a patient- and parent-oriented standpoint, but they’re also quite awful at the population level, overburdening limited pediatric and emergency department resources. RSV, in particular, is a vicious scourge of young and vulnerable infants.

The story told here – sponsored by Sanofi – is one of nirsevimab, a monoclonal antibody protein featured last year in the NEJM. Nirsevimab is the evolution of palivizumab, previously approved and used as a multi-injection prophylaxis scheme for the highest-risk infants. The generally established advantages of nirsevimab over palivizumab are higher and longer levels of neutralizing antibodies, requiring only a single injection rather than a multi-dose course. Nirsevimab has been recommended by the Advisory Committee on Immunization Practices for infants in the U.S. since August 2023.

These data give us a wee look at what happens to a country that adopts such a practice of wide immunization with nirsevimab – Spain! These authors compare the burden of lower respiratory tract infections and bronchiolitis admissions at 15 pediatric emergency departments across 2018 to 2024, with 2023-24 being the first season where nirsevimab was in wide usage. Most regions used a strategy in which nirsevimab was provided to new births during RSV season, as well as other young infants born prior to the onset of the season. The two “COVID seasons” of 2020-21 and 2021-22 were excluded from their comparisons.

Generally speaking, the administration of nirsevimab diminished lower respiratory tract infection presentations, bronchiolitis presentations, and bronchiolitis admission by approximately 60% as compared to prior years. The overall effect of these reductions in bronchiolitis presentations had the net effect of decreasing all presentations to the ED by about 20%. I suspect virtually every emergency department and PICU out there would prefer this sort of an experience each winter.

The catch: nirsevimab costs ~USD$500 per dose. The initial ACIP cost-effectiveness evaluations were based on the assumption nirsevimab would be priced at ~$300 a dose, at which point it was considered cost-effective. Obviously, $500 is more than $300 – and thus it becomes a robust debate which infants should be offered nirsevimab with many inputs, assumptions, and remaining uncertainties. The promise is certainly out there, however, of dramatically improved respiratory virus seasons for those working in the emergency department.

“Nirsevimab and Acute Bronchiolitis Episodes in Pediatric Emergency Departments”
https://publications.aap.org/pediatrics/article/doi/10.1542/peds.2024-066584/199339/Nirsevimab-and-Acute-Bronchiolitis-Episodes-in

In: Dexamethasone, Out: Prednisone

Move over ketamine and TXA, there’s another medication gradually approaching do-it-all darling status in Emergency Medicine: dexamethasone.

Sore throats?

Croup?

Headaches?

Non-specific aches?

Well, yes to all of the above, in the appropriate clinical context –

But, most prominently, as featured in this brief report, for asthma – particularly childhood asthma.

It’s NHAMCS – so it is representative data being transformed into rough weighted estimates – between 2010-2021, but we see its use increasing from 3.5% of asthma visits to 17.3% – and the rates are over double that in children.

A heartening trend for a simpler administration and adherence strategy – and non-inferior, overall, while entirely reasonable to judiciously select a higher-risk patient in whom it might be plausible to prescribe prednisone/prednisolone instead.

“Trends in dexamethasone treatment for asthma in U.S. emergency departments”
https://onlinelibrary.wiley.com/doi/full/10.1111/acem.14997

Pediatric C-Spine Injury Risk Factors

It would seem the Pediatric Emergency Care Applied Research Network (PECARN) is gearing up to develop another decision instrument – this time for cervical spine injuries.

This is a prospective, observational study of 4,091 pediatric blunt trauma patients across four pediatric level-1 trauma centers, surveying treating providers about the presence or absence of factors suspected to be implicated with cervical spine injuries. The factors were selected based on previous studies, as well as those suspected as having potential physiologic plausibility and good interrater reliability. The stated purpose – to ultimately develop a decision instrument akin to their prior work for clinically important minor head injury.

Overall, the prevalence of a cervical spine injury – vertebral fractures, ligamentous injury, intraspinal hemorrhage, or spinal cord injury – was 1.8%. The vast majority of patients in their cohort (78.2%) underwent some sort of imaging, although only 15.8% underwent CT. The most predictive items identified are those already typically considered: diving injuries, axial loading injuries, clotheslining, loss of consciousness (including intubation), neck pain, altered mental status (frequently associated with obvious head injuries), limited range of motion, focal neurologic deficits, and substantial torso and thoracic injuries. Of the 74 patients with CSI in their cohort, effectively only one would have been missed by a decision instrument based on these factors – a fall from 10 feet whose symptoms localized to the thoracic spine, and had a C7 burst with T2-T4 compression fractures. Obviously, this was not missed clinically – again revealing the role of clinical judgment outside of any decision instrument.

The most interesting tidbit, leading into the most substantial implications for generalizability, is their note regarding “high-risk MVC”. They comment previous case-control studies determined both predisposing conditions (e.g., congenital abnormalities of the cervical spine) and high-risk MVC were identified as risk factors, whereas in this study they were not. They discuss the low prevalence in their cohort of those with predisposing conditions, and, conversely, the high prevalence of high-risk mechanisms, to justify their lack of multivariate effect on predicting CSI. Even though they did not fall out as predictive elements in this cohort, a future prediction model intended for general use may yet include such features. As such, these data ought not be fully relied upon to downgrade those potential risk factors.

“Cervical Spine Injury Risk Factors in Children With Blunt Trauma”
https://pediatrics.aappublications.org/content/early/2019/06/18/peds.2018-3221

Yet Another Febrile Infant Rule

The Holy Grail in the evaluation of infants of less than 60 days remains safe discharge without a lumbar puncture. Boston, Philadelphia, Rochester, Step-by-Step and others have tried to achieve this noble goal over the years. And now, the Febrile Young Infant Research Collaborative has tossed their hat into the ring.

In this retrospective query of their Pediatric Health Information System and other electronic medical records, these authors identified 181 non-ill appearing patients across 11 Emergency Departments with invasive bacterial infection, defined as bacteremia in either blood or cerebrospinal fluid. Using 362 matched controls as a comparison cohort, these authors used the typical logistic regression route to tease out the strongest predictors of IBI – age in days, observed temperature, absolute neutrophil count, and urinalysis result. Subsequently, they condensed the continuous variables into cut-offs maximizing area under the curve. These cut-offs were then incorporated into a scoring system based on the strength of their adjusted odds ratio, and then the final output was validated on the derivation set using k-fold cross-validation with 10 sets.

The final result using their best cumulative score cut-off: sensitivity of 98.8% (95% CI 95.7-99.9) with 31.3% specificity. The two cases missed were that of a 3-day old and a 40-day old otherwise afebrile in the ED with normal UA and an ANC <5185. The authors ultimately conclude their score, if validated, may have best value as a one-way prediction tool primarily to reduce current routine invasive testing, owing to its poor specificity. Certainly, I agree it does not have much value in those who might otherwise not undergo testing; a more specific risk score may be better, if not clinician gestalt.

The other tidbit I might mention is whether there could be value in incorporating time-of-onset of fever into their evaluation. We’ve seen in other studies a few of the fallouts with regard to sensitivity of IBI stem from recency of illness onset, and it may be falsely reassuring to find a normal ANC early in an illness course. Furthermore, these authors do not specifically mention whether the lack of fever in the ED could have been associated with prehospital antipyretic use. Finally, their data collection does not appear to incorporate respiratory swab results; readily available respiratory viral panel results may also prove useful in ruling out IBI.

While these data are certainly alluring, considering the desire to avoid invasive procedures in young infants, substantial prospective work is still likely required.

As a sad aside, the authors state:

However, these criteria were developed >25 years ago, and the epidemiology of serious bacterial infections has changed considerably since that time.

Unfortunately, as vaccination frequency continues to decline, even since patients were enrolled for this study, our “modern” cohort may better begin to resemble that of 25 years ago.

“A Prediction Model to Identify Febrile Infants ≤60 Days at Low Risk of
Invasive Bacterial Infection”

https://www.ncbi.nlm.nih.gov/pubmed/31167938

Levetiracetam vs. Phenytoin

The epic, classic showdown from time immemorial: new vs. old.

But, more specifically, these are two trials set to determine relative utility of each in pediatric seizures, vying for the coveted “second-line” therapy recommendation once benzodiazepines have failed. The thought and hope is, of course, the newer agent – levetiracetam – is at least as efficatious, if not moreso, as it can be infused more quickly. The authors then propose levetiracetam is associated with fewer long-term adverse effects and medication interactions during oral maintenance, and, as such, allows for convenient continuation after intravenous initiation.

Generally speaking, these two trials are very similar – both open-label trials randomizing pediatric patients with ongoing seizures, both analyzing about 250 patients … and both demonstrating effectively similar results by different routes. EcLiPSE, interestingly, was designed as a superiority trial, with a primary outcome of time from randomization to seizure cessation. Median time to seizure cessation not statistically different at 35 minutes for fosphenytoin and 45 minutes for levetiracetam, with similar numbers of treatment failures for additional anticonvulsants or intubation. In ConSEPT, the primary outcome was cessation of seizure activity within 5 minutes of the end of the infusion, and here results favored phenytoin at 60% versus 50% for levetiracetam.

Effectively, however, the sample sizes are small enough, the types of patients heterogenous enough, and the differences small enough, the Bayesian interpretation is probably a wash. These are both fine second-line options, but these trials do not provide any data supporting levetiracetam as a superior option.

“Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30724-X/fulltext

“Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30722-6/fulltext

A Brief BRUE Follow-Up

The “apparent life-threatening event” has long since been replaced by the “brief resolved unexplained event – an event occurring in an infant <1 year of age with:

  • Cyanosis or pallor
  • Absent, decreased or irregular breathing
  • Marked changes in tone
  • Altered level of responsiveness.

This is just a brief, single-center, retrospective chart review identifying children hospitalized for BRUE and their outcomes up to 5 years. These authors identified 120 hospitalized infants under one year of age meeting criteria for BRUE, and performed telephone follow-up at least 6 months after the event. Most children hospitalized were less than 1 month of age, and about half were hospitalized for apnea or breathing issues. Of the 87 they were able to contact, none had died or developed chronic medical illness, 71 had developed normally, and the remainder developed either a global or verbal developmental delay.

This is a small sample, to be sure, but these data suggest children hospitalized for BRUE are not specifically at risk for long-term poor neurologic or cardiac outcomes above the baseline population level.

“Long-Term Follow-Up of Infants After a Brief Resolved Unexplained Event–Related Hospitalization”

https://www.ncbi.nlm.nih.gov/pubmed/30951030

Rochester v. Philadelphia, Pediatric Edition

It’s a little tough for Rochester to go head-to-head against Philadelphia – with apologies to the Americans, Red Wings, Rhinos, Knighthawks, and Razorsharks. The playing field of … the playing field … is just on another level in Philadelphia. The playing field of febrile infants, however, is another matter.

This small study re-analyzed prospective data from 135 febrile children ≤60 days of age with documented invasive bacterial illness, and applied the Rochester and modified Philadelphia criteria for risk-stratification. IBI was defined as having a positive blood or CSF culture, if obtained. In this small sample, both Rochester and Philadelphia were 100% sensitive for all cases of meningitis in infants greater than 28 days of age, but each missed similar numbers of those with bacteremia. A comparison for those below 28 days is frankly irrelevant, as the modified Philadelphia criteria specifically applies only to those >28 days of life – so, yes, it is comically 100% sensitive and 0% specific in neonates. The Rochester criteria, which does not mandate CSF, if applied to those ≤28 days, would have missed two cases of meningitis, and is therefore not suitable for use.

The takeaway here is not so much which criteria is superior to the other – the elements of each are virtually identical. Moreso, it is the recognition that each is about 83% sensitive, and all children in this age range evaluated in the ED and discharged will require close follow-up for re-evaluation of clinical status.

“Risk Stratification of Febrile Infants ≤60 Days Old Without Routine Lumbar Puncture”
https://www.ncbi.nlm.nih.gov/pubmed/30425130

Did You Miss … CATCH2?

We’ve talked about the PECARN vs. CATCH vs. CHALICE cage-match before. PECARN has been the subject of multiple sub-investigations, but CHALICE has been neglected and gone to seed. CATCH, on the other hand, has a sequel.

What’s new in CATCH2? Vomiting!

Adding to the original 4 + 3 item list, these authors conducted a new multi-center study comprised of 4,060 children with minor head injury. The stated purpose was to prospectively evaluate CATCH, with a secondary plan to improve performance if found to be deficient – and, although it is not explicitly stated, it appears these authors anticipated the missing link to be inclusion of vomiting.

Only 23 children in their cohort required neurosurgical intervention, while 197 had any brain injury on CT. The original CATCH had sensitivity of 97.5% and specificity of 59.6% for any brain injury, while adding “≥4 episodes of vomiting” increased sensitivity to 99.5% and decreased specificity to 47.8%. Sensitivity of CATCH2 was 100% for any cases requiring neurosurgical intervention, although confidence intervals are obviously wide, given the paucity of events.

So, another entrant arrives to the pediatric head injury decision-instrument sweepstakes. Interestingly enough, these instruments were created because of concerns of CT overuse – up to 53% in 2005! – as cited by these authors. With CATCH2, the CT ordering rate would be 55%. This is both greater than the 34% rate witnessed in this study, and vastly greater than the 8% seen in Australian and New Zealand, although with different entry criteria. It would seem to me these instruments are rather making the problem worse, rather than better ….

“Validation and refinement of a clinical decision rule for the use of computed tomography in children with minor head injury in the emergency department”
http://www.cmaj.ca/content/190/27/E816

The Probiotic Hoax?

The concept of probiotic therapy is a compelling one: under duress from illness or adverse effects from medications, the gastrointestinal biome becomes altered. Orally repleting this biome to restore “normal balance” ought to improve morbidity. Sounds good, right?  Unfortunately, plausibility is not the same as practical efficacy.

Other indications or specific contexts notwithstanding, this multi-center trial shows probiotics confer no advantage for progression of gastroenteritis in children. These authors conducted a randomized, double-blinded trial in six pediatric Emergency Departments in Canada, including 886 children presenting with fewer than 72 hours of infectious diarrheal symptoms. They each received a 5-day course of either Lactobacillus rhamnosus R0011 and L. helveticus R0052 or placebo. Short answer: about 25% of each cohort progressed to moderate-to-severe gastroenteritis, and the duration of diarrhea was a little over two days, regardless.

The authors note “5 out of 12 leading guidelines endorse the use of probiotics”, although it does not appear they have a citation regarding how many dentists would recommend.  While these data do not generalize to all indications, nor potentially all possible probiotic formulations, these data certainly tilt the board away from “potentially useful” towards “probably not useful”.  Adverse events were common and similar between groups, so probiotics are unlikely to be harmful in a population with normal baseline health status – but you might as well just visualize your money concurrently swirling along down the toilet.

“Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis”

https://www.nejm.org/doi/full/10.1056/NEJMoa1802597