A child with sickle cell disease arrives in your emergency department (ED) in an acute pain episode. In one of the largest US pediatric trials of a treatment for acute sickle cell pain, how long that crisis lasted varied far more between hospitals than it did between the study drug and placebo.

The PECARN STArT trial randomized 274 children and young adults with sickle cell acute pain episodes to IV arginine or saline placebo at 10 US children’s hospitals. Arginine, which targets the nitric oxide depletion that drives vaso-occlusion, did not shorten time to crisis resolution, and the trial was halted early for futility [1]. The more useful numbers are in site-level data. Median time to crisis resolution varied by as much as 61 hours between participating hospitals, and mean total parenteral opioid by as much as 3.0 mg/kg of based on morphine-equivalent calculations [1,3]. These are observational site differences. They may reflect analgesia and opioid-discontinuation practice, patient mix, and other institutional factors that the analyses can not distinguish.

Study Design

STArT was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted (2021-2024). Patients aged 3 to 21 years with sickle cell disease who presented to the ED with acute pain requiring parenteral opioids and hospital admission were randomized within 12 hours of their first IV opioid dose. Arginine was given as a 200 mg/kg loading dose followed by 100 mg/kg every 8 hours until discharge. Of 274 patients randomized, 271 received study drug, 129 arginine and 142 placebo. The primary outcome was time to crisis resolution, the interval from first study drug delivery to the last dose of parenteral opioid, and it is the outcome the US Food and Drug Administration prefers for regulatory approval in this population [1].

Results

Median time to crisis resolution was 60.8 hours with arginine versus 65.8 hours with placebo, an absolute difference of 7.2 hours favoring arginine with a confidence interval spanning benefit in either direction (95% CI, -21.6 to 35.9 hours). Total parenteral opioid use, pain scores, and hospital length of stay were similar between groups, and the arginine effect on time to crisis resolution did not differ significantly by chronic pain status. Serious adverse events did not differ and there were no deaths [1].

Three descriptive findings arose from the collected data:

• Site variation. Median time to crisis resolution differed by up to 61 hours across the 10 hospitals, and mean total parenteral opioid by up to 3.0 mg/kg [1,3].
• Delay to study drug. Study drug arrived a median of 8 hours after the first ED dose of IV opioid, and only 50.4% of participants had sought care within 24 hours of pain onset [1]. In 23 of 271 treated participants the last IV opioid had already been given before study drug arrived, producing a primary outcome of zero hours.
• Chronic pain prevalence. 41% of participants met criteria for chronic sickle cell pain, including 34% of children younger than 12 years [1]. A single triage pain score means something different in a child who already has pain 15 or more days a month.

Build an Expedited Pain Plan in the Emergency Department

It is unclear why the wide variation in time to pain crisis resolution. The study was not designed to untangle the reasons, but in theory the causes are likely multifactorial and include: patient mix, underlying chronic pain, time spent in pain before arrival, institutional practices, and individual practitioner analgesia practices. That last one is something that you can act on today.

An expedited pain plan for a sickle cell acute pain episode

Consider administering intranasal fentanyl at triage, if  IV opioids are not readily available.

The American Society of Hematology 2020 recommendation is to assess the patient and administer analgesia within 1 hour of ED arrival, with reassessment every 30 to 60 minutes. It is a strong recommendation on low-certainty evidence [8].

Two cross-sectional PECARN studies describe what meeting those targets looks like. In a PECARN Registry analysis of 9233 ED visits for uncomplicated sickle cell pain at 12 children’s hospitals, a first opioid dose within 60 minutes of arrival was associated with lower odds of hospitalization (OR 0.84; 95% CI, 0.75-0.95). That association held even when the second dose fell outside 30 minutes (OR 0.85), and with a timely first dose the odds fell stepwise as the second-dose interval shortened: 0.78 within 60 minutes, 0.70 within 45, and 0.62 within 30 (95% CI, 0.52-0.75) [9]. Separately, among 400 children at 20 academic pediatric EDs in the US and Canada, only 19% received intranasal fentanyl, and those who did had nearly ninefold higher adjusted odds of discharge from the ED (adjusted OR 8.99; 95% CI, 2.81-30.56; P < .001) [10].

Both studies are cross-sectional and neither establishes causality. Timeliness of the first dose is the more robust of the two signals, since it survived a late second dose.

Not All Pain is the Same

The STArT study enrolled acute pain episodes, defined by pain severe enough to need parenteral opioids. However, arginine specifically targets vaso-occlusion pain. The accompanying JAMA editorial argued that these are not the same thing: the term acute pain episode has become operationally synonymous with vaso-occlusive episode, yet acute pain in sickle cell disease also arises from neuropathic mechanisms, central sensitization, and musculoskeletal injury [2]. A trial that heterogeneously enrolls all of them dilutes the study population. Notably, 41% of the study participants had underlying chronic pain [1].

Can We Narrow the Patient Inclusion Criteria?

The editorial accompanying STArT argues for enrolling a more narrow subset of patients, focusing on objective markers rather than pain severity [2]:

• Hypoxemia, worrisome for acute chest syndrome
• Very high LDH with thrombocytopenia, reported in a small retrospective adult series as suggesting a severe vaso-occlusive subtype that prompted consideration of early intervention [6]
• Acute kidney injury or acute liver injury, used the way organ dysfunction defines severity in sepsis trials

Bottom Line

• Arginine is not ready. Nothing in this STArT trial displaces supportive care, NSAIDs, and opioids for a sickle cell acute pain episode.
• The 61-hour spread between hospitals was more than three times the trial’s originally hypothesized 17-hour treatment difference. How your department assesses and treats pain is part of what that spread reflects.
• The American Society of Hematology recommends giving an analgesic dose within the first hour of ED arrival. Consider intranasal fentanyl at triage, while awaiting IV access.

References

1. Morris CR, Hatabah D, Korman R, et al; Pediatric Emergency Care Applied Research Network (PECARN). Arginine therapy for sickle cell disease acute pain episodes: the STArT randomized clinical trial. JAMA. Published online August 19, 2026. PMID: 42616542. doi:10.1001/jama.2026.13310
2. Anum SJ, Kanter J. Arginine treatment and sickle cell disease pain: a great STArT, but a hard end point. JAMA. Published online August 19, 2026. PMID: 42616535. doi:10.1001/jama.2026.14849
3. Rees CA, Hatabah D, Korman R, et al; PECARN. Hospital variations in time-to-crisis-resolution among children and adolescents with sickle cell disease. Am J Hematol. 2026;101(1):206-212. PMID: 41190764. doi:10.1002/ajh.70129
4. Morris CR, Ahmad F, Airewele G, et al. Sickle cell disease treatment with arginine therapy (STArT): results of a phase-3 randomized controlled trial. Blood. 2025;146(suppl 1):616. doi:10.1182/blood-2025-616
5. Brousseau DC, Scott JP, Badaki-Makun O, et al. A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children. Blood. 2015;126(14):1651-1657. PMID: 26232172. doi:10.1182/blood-2015-05-647107
6. Gardner K, Thein SL. Super-elevated LDH and thrombocytopenia are markers of a severe subtype of vaso-occlusive crisis in sickle cell disease. Am J Hematol. 2015;90(10):E206-E207. PMID: 26205137. doi:10.1002/ajh.24126
7. Ataga KI. The challenge of clinical end points in sickle cell disease. Blood. 2023;142(24):2047-2054. PMID: 37890140. doi:10.1182/blood.2023021220
8. Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4(12):2656-2701. PMID: 32559294. doi:10.1182/bloodadvances.2020001851
9. Gwarzo I, Coleman KD, McKinley K, et al. Opioid timeliness in the emergency department and hospitalizations for acute sickle cell pain. JAMA Pediatr. 2025;179(11):1194-1202. PMID: 40892426. doi:10.1001/jamapediatrics.2025.2967
10. Rees CA, Brousseau DC, Ahmad FA, et al; SCD Arginine Study Group and PECARN. Intranasal fentanyl and discharge from the emergency department among children with sickle cell disease and vaso-occlusive pain: a multicenter pediatric emergency medicine perspective. Am J Hematol. 2023;98(4):620-627. PMID: 36606705. doi:10.1002/ajh.26837
11. Gladwin MT, Kato GJ, Weiner D, et al; DeNOVO Investigators. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA. 2011;305(9):893-902. PMID: 21364138. doi:10.1001/jama.2011.235
12. Casella JF, Barton BA, Kanter J, et al. Effect of poloxamer 188 vs placebo on painful vaso-occlusive episodes in children and adults with sickle cell disease: a randomized clinical trial. JAMA. 2021;325(15):1513-1523. PMID: 33877274. doi:10.1001/jama.2021.3414
13. Dampier CD, Telen MJ, Wun T, et al; RESET Investigators. A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis. Blood. 2023;141(2):168-179. PMID: 35981565. doi:10.1182/blood.2022015797

A 69-year-old woman presents to the emergency department (ED) after 2 falls at home. She tripped on a rug overnight, felt dizzy as she tried to get up, and fell again. She struck her head but has no pain from it. Her chief complaint is right shoulder pain, and she reports frequent shoulder dislocations in the past. An x-ray shows an acute comminuted, non-displaced fracture of the humeral neck with involvement of the greater tuberosity.

Initial management is immobilization in a sling for 1-3 weeks, and the evidence supports nonoperative treatment for most proximal humerus fractures [1,2]. A collar and cuff sling is an appropriate management plan to allow the elbow to hang free, so gravity applies gentle traction that helps maintain fracture alignment. However, what if your ED does not stock such a sling?

Trick of the Trade

Build a collar and cuff sling from 2 Posey soft limb holders, the padded wrist restraints most EDs already stock. In our case, this improvised collar and cuff sling provided adequate support to the wrist and a cushion for the patient’s neck.

Materials

2 Posey soft limb holders:

• Use one complete holder.
• Use only the padding from the second holder.

Top padding from full Posey holder for the wrist; bottom padding from second Posey holder for neck collar

Steps

• Wrap one cuff around the wrist of the injured arm.
• Remove the padding from the second cuff, and thread that padding onto the long strap of the first cuff.
• Pass the strap behind the patient’s neck. Slide the padding along the strap until it cushions the back of the neck. This is the collar.
• Adjust the strap length so the elbow rests at 90 degrees with the wrist slightly above the elbow, and secure the buckle.
• Improvised collar and cuff sling made from a Posey soft limb holder, worn with the elbow at 90 degrees and the wrist supported

Improvised collar and cuff setup

Tips

• Application of the padded neck collar is important, because the Posey strap is often thin, flat, and coarse. It can dig into the neck once it carries the weight of an arm over the next 1-3 weeks.
• Support the wrist only and allow the elbow to hang to gravity. This axial traction helps to maintain fracture alignment.

Interested in More?

For a collar and cuff improvised with the neck strap from a shoulder immobilizer, plus other common ED splinting techniques, see SplintER Series: Common ED Splint Techniques 104.

References

1. Handoll HH, Elliott J, Thillemann TM, Aluko P, Brorson S. Interventions for treating proximal humeral fractures in adults. Cochrane Database Syst Rev. 2022;6(6):CD000434. doi: 10.1002/14651858.CD000434.pub5
2. Rangan A, Handoll H, Brealey S, et al. Surgical vs nonsurgical treatment of adults with displaced fractures of the proximal humerus: the PROFHER randomized clinical trial. JAMA. 2015;313(10):1037-1047. doi: 10.1001/jama.2015.1629

Welcome to the AIR ACS Cardiology Module! After carefully reviewing all relevant posts in the past 11 months from the top 50 sites of the Digital Impact Factor [1], the ALiEM AIR Team is proud to present the highest quality online content related to ACS cardiology emergencies in the Emergency Department. 5 blog posts met our standard of online excellence and were approved for residency training by the AIR Series Board. More specifically, we identified 1 AIR and 4 Honorable Mentions. We recommend programs give 3 hours of III credit for this module.

AIR Stamp of Approval and Honorable Mentions

In an effort to truly emphasize the highest quality posts, we have 2 subsets of recommended resources. The AIR stamp of approval is awarded only to posts scoring above a strict scoring cut-off of ≥30 points (out of 35 total), based on our scoring instrument. The other subset is for “Honorable Mention” posts. These posts have been flagged by and agreed upon by AIR Board members as worthwhile, accurate, unbiased, and appropriately referenced despite an average score.

Highlighted Quality Posts: ACS Cardiology 2026

(AIR = Approved Instructional Resource; HM = Honorable Mention)

If you have any questions or comments on the AIR series, or this AIR module, please contact us!

Pulmonary embolism (PE) in children is uncommon, but delayed or missed diagnosis can have serious consequences. Despite this, there is relatively little evidence to guide clinician evaluation of suspected pediatric PE. There are no validated pediatric PE rule-out strategies and adult diagnostic pathways have not been prospectively tested in children.

PECARN sought to change that with their recently published study – BEEPER: Bedside Exclusion of Pulmonary Embolism without Radiation in Children [1]. The investigators developed a rule that safely excluded PE in low-risk children.

Study Objective

The goal of BEEPER was to prospectively evaluate whether the Pulmonary Embolism Rule-out Criteria adapted for children (PERC-Peds) could safely exclude pulmonary embolism in children without the need for laboratory testing or imaging.

What is PERC-Peds?

PERC-Peds was adapted from the adult Pulmonary Embolism Rule-out Criteria (PERC), a well-established adult clinical decision rule used to exclude PE in low-risk patients without additional testing [2]. Using retrospective pediatric data, investigators modified the adult PERC rule to create the pediatric version. A child was considered PERC-Peds negative only if ALL of the following were true:

• Clinician gestalt pretest probability <15%
• No prior PE or proximal DVT
• No surgery requiring intubation within 30 days
• No current estrogen use
• No hemoptysis
• Heart rate always:
  • <100 beats/min if older than 12 years
  • <120 beats/min if 12 years or younger
• Oxygen saturation consistently >94%
• No suspected DVT

Study Design

A Large, Prospective, Multicenter PECARN Study

BEEPER was a multicenter, prospective observational diagnostic accuracy study conducted across 21 emergency departments within PECARN (the Pediatric Emergency Care Applied Research Network).

Inclusion Criteria:

• 4–17 years old, AND
• had suspected PE or proximal DVT prompting clinicians to:
  • order diagnostic testing, OR
  • strongly consider PE in the differential diagnosis

Eligible diagnostic testing included:

• D-dimer
• CT pulmonary angiography (CTPA)
• V/Q scan
• MRI angiography
• Other pulmonary vascular imaging

All testing decisions remained entirely at clinician discretion.

Outcome Definition

The outcome was venous thromboembolism (VTE), including:

• image-confirmed pulmonary embolism, OR
• proximal DVT (above knee or elbow)

Results

Enrollment

• 4,039 children enrolled, 3,988 had analyzable data

Prevalence of Disease

Overall:

• 254 children (6.3%) had PE and/or proximal DVT

Breakdown:

• Isolated proximal DVT: 76
• Both PE and proximal DVT: 56
• Isolated PE: 122

Performance of PERC-Peds

The PERC-Peds rule demonstrated extremely high diagnostic sensitivity.

Diagnostic Accuracy

• Sensitivity: 99.6% (95% CI 97.8–99.9%)
• Specificity: 19.6% (95% CI 18.4–21.0%)
• False negative rate: 0.1% (95% CI 0–0.75%)
• Negative predictive value: 99.9%

There was only ONE false negative. These findings suggest that PERC-Peds can safely exclude PE in a subset of low-risk children without additional laboratory testing or imaging.

D-Dimer Findings

BEEPER also provided the first large prospective evaluation of D-dimer performance in children undergoing PE evaluation. Clinicians ordered D-dimer testing in approximately 75–79% of enrolled children. Using a standardized threshold of 500 ng/mL:

• Sensitivity: 88.8%
• Specificity: 61.9%
• False negative rate: 1.2–1.4%

These data support the use of D-dimer as part of a sequential diagnostic strategy in pediatric PE evaluation for those children who fail PERC-Peds.

PERC-Peds + D-Dimer Sequential Strategy

One of the most clinically important findings was the potential value of combining:

• PERC-Peds
• followed by D-dimer if PERC-Peds failed

This sequential strategy would have:

• safely excluded PE in 54.7% of enrolled children,
• excluded PE in 69% of children who had D-dimer ordered,
• maintained an acceptable false negative rate of 1.0% (95% CI 0.6–1.5%),
• estimated reduction in CT pulmonary angiography use by approximately 18.5%.

Putting PERC-Peds in Context

The PERC-Peds rule performed well compared to the regularly utilized adult PERC rule. Adult PERC studies [2] typically show sensitivities around 95% with false negative rates below 2%, while in BEEPER, the sensitivity approached 100% with an exceptionally low false negative rate. Just as importantly, this is the first prospective study to support a bedside rule-out strategy for PE in children: offering a potential pathway to safely reduce unnecessary CT scans and radiation exposure in low-risk patients. BEEPER also lays the groundwork for a more standardized pediatric PE evaluation approach, where clinicians could use PERC-Peds first, followed by D-dimer testing when needed, reserving imaging for children at higher risk.

What’s Next?

While BEEPER represents a major step forward in pediatric PE diagnosis, the study also highlights important limitations and unanswered questions. PERC-Peds demonstrated high sensitivity, but relatively low specificity: meaning many children will still fail the rule, and indiscriminate use could potentially increase testing. Importantly, BEEPER was an observational diagnostic study, meaning it did not evaluate outcomes from the implementation of a clinical decision rule.

BEEPER provides the foundation for a new era of pediatric PE evaluation research. Future studies will likely focus on implementation science: understanding whether use of PERC-Peds changes clinician behavior, safely reduces imaging, and can be integrated into real-world emergency department workflows. Investigators also envision future diagnostic algorithms that combine PERC-Peds with D-dimer testing to reserve imaging for children at highest risk, potentially reducing unnecessary radiation exposure in a meaningful number of patients. Additional work can evaluate performance across different clinical settings, refine the gestalt component of the rule, and explore integration into electronic health record decision support tools. Taken together, BEEPER fills one of the most important evidence gaps in pediatric emergency medicine and represents the first major step toward safer, more standardized, and evidence-based pediatric PE evaluation.

References

1. Ellison AM, Kuppermann N, Shihabuddin BS, et al. PERC-Peds rule for bedside exclusion of pulmonary embolism without radiation in children in the USA (BEEPER): a multicentre, prospective, observational, diagnostic accuracy study. Lancet Respir Med. Published online July 2026. doi:10.1016/S2213-2600(26)00086-X.
2. Kline JA, Courtney DM, Kabrhel C, et al. Prospective multicenter evaluation of the pulmonary embolism rule-out criteria. J Thromb Haemost. 2008;6(5):772-780. doi:10.1111/j.1538-7836.2008.02944.x. PMID: 18318689.

Every emergency physician knows these moments. A 10-year-old with autism is escalating in a hallway bed, and nobody can say which de-escalation approach or which medication is safest for him. A 15-year-old is boarding for a third night after a suicide attempt, receiving no active treatment while she waits for a psychiatric bed. A charge nurse asks whether universal suicide screening is worth the workflow disruption. These are routine clinical decisions, and for most of them the pediatric evidence simply does not exist.

A new consensus statement from the PECARN Mental Health Working Group, A Research Agenda for Acute Pediatric Mental and Behavioral Health Emergencies, published in Annals of Emergency Medicine, maps where those evidence gaps are and which ones matter most [1]. The panel reached consensus on 51 research priorities, 31 of them top tier. Read as a whole, the agenda is an unusually honest inventory of how much of current pediatric behavioral health emergency care runs on extrapolation and local habit.

Background

One in 6 US children has a mental or behavioral health condition, and nearly half receive no treatment from a mental health professional [2]. The ED has become the de facto safety net: visits for self-harm and harm to others have risen substantially over the past decade, boarding times have stretched, and in 2021 the American Academy of Pediatrics, the American Academy of Child and Adolescent Psychiatry, and the Children’s Hospital Association jointly declared a national emergency in child and adolescent mental health [3]. What has not kept pace is the evidence for what emergency clinicians should actually do during these visits.

How the Agenda Was Built

The working group used a modified Delphi process with 23 expert partners: 4 parents and 1 young adult with lived experience of pediatric mental health emergency care, general and pediatric emergency physicians, emergency nurses, child and adolescent psychiatrists with emergency expertise, ED social workers, out-of-hospital and EMS-fellowship-trained clinicians, and a research funder. Across 3 survey rounds, 76 literature-informed candidate priorities were modified, expanded, and rated on need and urgency, research impact, and family centeredness. The prespecified retention criteria required agreement from both the family representative group and the clinician and funder group, so family voices could not be outvoted. The result: 51 consensus priorities sorted into 3 tiers.

Where the Gaps Are

Suicide prevention dominates

Suicide prevention questions account for 42% of the top tier. The panel wants to know which suicide risk screening tool best predicts real outcomes such as return visits, attempts, and deaths, including in neurodivergent children and non-English speakers; what universal screening does to those outcomes; and whether safety planning, with or without structured follow-up calls, actually increases mental health follow-up and reduces future attempts in youth. The contrast with adult evidence is striking. In adults, the multicenter ED-SAFE trial showed that universal screening plus a brief intervention reduced post-discharge suicidal behavior [4]. The pediatric equivalent has never been done. The panel also prioritized a practical lethal-means question: which safety devices, from medication lock boxes to firearm safes, do caregivers actually prefer and use after the ED visit?

Agitation: everything is still an open question

Which de-escalation methods best reduce medication use, restraint use, and staff injuries, and how does that differ by age, developmental stage, culture, language, and trauma history? Which medications are safest and most effective, for which children? What works for children with neurodevelopmental disorders such as autism spectrum disorder, who face a higher risk of pharmacologic and physical restraint? None of these have comparative evidence today, even though documented racial disparities in restraint application make the stakes plain [1].

Boarding and ED care

Top-tier questions include whether brief therapy delivered in the ED during boarding improves symptoms, shortens length of stay, and lowers admission rates, and whether home-based care is a safe and acceptable alternative to hospitalization. The panel also flagged care in rural and low-resource EDs, where most of these children are actually seen.

Before and after the ED

Out-of-hospital priorities center on training first responders in de-escalation and trauma-informed care and on testing novel response models, including mental health co-response teams and alternative destinations. A single-county pilot of direct EMS transport to a psychiatric emergency facility found that roughly 2 in 5 encounters met criteria for direct transport, with only 0.5% requiring secondary ED transfer within 24 hours [5]. On the back end, the agenda targets the high-risk post-discharge window: what actually gets youth to mental health care after they leave, and whether stepped-care models using telehealth reduce return visits and future attempts.

Clinical Implications

Nothing in a research agenda changes tomorrow’s orders, and this post will not pretend otherwise. The value for a practicing clinician is different. First, the agenda names how thin the floor is under common practices: medication choice for acute agitation in children, for example, is largely extrapolated from adult psychiatry. Knowing where evidence is absent should make us slower to treat local protocol as settled science. Second, this document signals where PECARN and federal funders will direct pediatric emergency mental health research over the next 5 to 10 years, which is useful for anyone building a QI program, a research career, or a departmental protocol they would prefer not to rewrite twice. Third, the top-tier questions double as an audit checklist: if your ED cannot say how often it restrains children, whether safety planning happens before discharge, or what its mental health boarding times are, the agenda is a reasonable place to start measuring.

One limitation deserves mention because the authors themselves flag it: no expert partners identified as Black or Hispanic, a notable gap given the documented racial disparities in restraint use and in behavioral health triage that PECARN’s own work has described.

Bottom Line

PECARN’s consensus research agenda distills the pediatric mental and behavioral health emergency evidence gap into 51 prioritized questions, with suicide prevention accounting for 42% of the top tier. It will not change your practice today. It tells you something more uncomfortable and more useful: for most of what we do during pediatric behavioral health visits, from de-escalation to safety planning to boarding care, the evidence base has not been written yet, and this is the field’s official to-do list for writing it.

References

1. Hoffmann JA, Foster AA, Krass P, et al. A research agenda for acute pediatric mental and behavioral health emergencies. Ann Emerg Med. Published online July 10, 2026. PMID: 42429726. doi:10.1016/j.annemergmed.2026.05.015
2. Bitsko RH, Claussen AH, Lichstein J, et al. Mental health surveillance among children – United States, 2013-2019. MMWR Suppl. 2022;71(2):1-42. PMID: 35202359. doi:10.15585/mmwr.su7102a1
3. American Academy of Pediatrics, American Academy of Child and Adolescent Psychiatry, Children’s Hospital Association. AAP-AACAP-CHA declaration of a national emergency in child and adolescent mental health. 2021.
4. Miller IW, Camargo CA Jr, Arias SA, et al. Suicide prevention in an emergency department population: the ED-SAFE study. JAMA Psychiatry. 2017;74(6):563-570. PMID: 28456130. doi:10.1001/jamapsychiatry.2017.0678
5. Glomb NW, Trivedi T, Grupp-Phelan J, et al. Safety of a prehospital emergency medical services protocol for an alternative destination for pediatric behavioral emergencies in Alameda County. J Am Coll Emerg Physicians Open. 2023;4(2):e12930. PMID: 37051504. doi:10.1002/emp2.12930

Preschool wheezing is one of the most common pediatric ED presentations, and reaching for azithromycin can be tempting. Rhinovirus is the virus most often detected in these episodes, but pathogenic bacteria are commonly found in the nasopharynx of affected children, and some earlier outpatient data suggested that early antibiotic therapy might blunt severity.

The AZ-SWED trial (Azithromycin Therapy in Preschoolers with a Severe Wheezing Episode Diagnosed at the Emergency Department), published in the New England Journal of Medicine, tested this directly in the ED. The trial was stopped early for futility [1].

Study Design

Denninghoff et al enrolled 840 children aged 18-59 months presenting with moderate-to-severe wheezing across eight PECARN emergency departments. The age range was chosen to target preschool-aged children before a clear asthma diagnosis is typically established, the population in whom antibiotic benefit has been most often hypothesized and in whom practice variation is greatest. Children were randomized to either a 5-day course of azithromycin or a matching placebo, with all participants also receiving standard care at the treating clinician’s discretion, including bronchodilators and corticosteroids.

Because prior research raised the possibility that bacterial co-colonization might identify a subgroup most likely to benefit from antibiotics [2-5], the trial pre-specified separate analyses for children with and without detectable nasopharyngeal Streptococcus pneumoniae, Moraxella catarrhalis, or Haemophilus influenzae, the three organisms most commonly implicated in respiratory illness in this age group. This let the investigators test whether the bacteria-positive children benefit, rather than leaving it as a post hoc question.

The primary outcome was symptom severity over 5 days, measured using the Asthma Flare-up Diary for Young Children (ADYC), a validated 17-item caregiver-reported instrument in which each symptom is scored from 1 (best) to 7 (worst) [6]. Secondary outcomes included ED and hospital length of stay and return ED visits or hospitalizations within 72 hours [1].

Results

Azithromycin provided no clinical benefit over placebo, regardless of bacterial detection status.

ADYC symptom scores over 5 days were similar between groups in children with detectable nasopharyngeal bacteria (p = 0.70) and in those without (p = 0.69). There were no meaningful differences in length of stay or in return visits or hospitalizations.

Rhinovirus was the most commonly detected virus, identified in 72.5% of participants. Pathogenic bacteria were detected on nasopharyngeal swab in 62% of children overall. Azithromycin did clear nasopharyngeal bacteria more effectively than placebo (58.7% vs 11.4%), confirming that the drug was biologically active. That microbiologic effect, however, did not translate to clinical improvement on any outcome measured.

Clinical Implications

This is a large, ED-based randomized trial, and it argues against routine antibiotic use in preschool wheezing. Up to a quarter of children hospitalized for wheezing currently receive antibiotics, which likely reflects the same uncertainty the trial set out to address. The bacteria detected in the nasopharynx do not appear to drive the acute wheezing episode in these children, and treating them does not change how the children do.

The dissociation between bacterial clearance and clinical outcomes is itself informative. The fact that azithromycin reliably eradicated nasopharyngeal bacteria without any detectable clinical signal suggests that these organisms are bystanders rather than drivers of the acute episode, at least in most preschool wheezers. This has implications beyond this trial: it cautions against using bacterial detection alone as a rationale for antibiotic prescribing in this age group.

Bottom Line

Routine azithromycin has no role in the management of preschool wheezing, even in children with detectable nasopharyngeal bacteria. Bronchodilators and corticosteroids where appropriate remain the mainstays of care, and these data give clinicians another reason to hold antibiotics in this group.

References

1. Denninghoff KR, Casper TC, Zorc JJ, et al. Azithromycin for Preschoolers with Wheezing in the Emergency Department. N Engl J Med. Published online May 18, 2026. PMID: 42149992. doi:10.1056/NEJMoa2516505
2. Bisgaard H, Hermansen MN, Buchvald F, et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007;357(15):1487-1495. PMID: 17928596. doi:10.1056/NEJMoa052632
3. Bacharier LB, Guilbert TW, Mauger DT, et al. Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial. JAMA. 2015;314(19):2034-2044. PMID: 26575060. doi:10.1001/jama.2015.13896
4. Stokholm J, Chawes BL, Vissing NH, et al. Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4(1):19-26. PMID: 26704020. doi:10.1016/S2213-2600(15)00500-7
5. Mandhane PJ, Paredes Zambrano de Silbernagel P, Aung YN, et al. Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: a placebo-controlled randomized trial. PLoS One. 2017;12(8):e0182411. PMID: 28771627. doi:10.1371/journal.pone.0182411
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