Sickle Cell Acute Pain Episodes: Lessons Learned from the Prematurely Halted PECARN STArT Trial

A faces pain-assessment sheet and a prepared syringe on an overbed tray table, with an adolescent patient resting on the stretcher behind, in a pediatric emergency department

Article reviewed: Morris CR, Hatabah D, Korman R, et al. Arginine therapy for sickle cell disease acute pain episodes: the STArT randomized clinical trial. JAMA. Published online August 19, 2026
DOI: 10.1001/jama.2026.13310 | PubMed: PMID 42616542

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

Trial design sidebar

Why the trial stopped early, and why that matters beyond arginine

STArT closed after 76.1% of target enrollment because conditional power for the primary outcome had fallen below 6%, even assuming the full 17-hour effect originally hypothesized. Futility stopping is not a safety signal, and it is not proof of no effect. It means the predicted chance of reaching the primary statistical result was low if enrollment continued, not zero [1].

The primary outcome measure is a possible culprit. Time to crisis resolution correlated with hospital length of stay, which can be shaped as much by institutional opioid discontinuation practice as by drug biology [1,2,7]. US stays have trended shorter over the last 25 years and are now brief: the editorial describes a contemporary median under 72 hours, and PECARN’s MAGiC trial reported a median under 56 hours [1,2,5]. A post hoc recalculation using STArT’s own variance estimates put the required sample size above 900 participants [1]. Morris et al note that phase 3 trials targeting acute sickle cell pain have so far failed to shorten either hospital length of stay or time to crisis resolution [1], despite the study drugs spanning four largely distinct mechanisms: inhaled nitric oxide in 2011 [11], IV magnesium in PECARN’s MAGiC trial in 2015[5], poloxamer 188 in 2021 [12], and rivipansel, an E-selectin antagonist, in 2023 [13]. Arginine is the fifth agent to move nothing on this family of endpoints. The authors now question the outcome measure itself.

Three levers are on the table. The first is to enroll patients with objective organ injury, where the endpoint can be adjudicated on an image or a laboratory value rather than on a clinician’s decision to stop an opioid infusion. Among 54 STArT participants who either had acute chest syndrome at presentation or developed it after randomization, mean time to crisis resolution was 108 hours with arginine versus 184 hours with placebo (29 vs 25 participants; P = 0.16; median difference 34 hours) [4]. Because acute chest syndrome status partly arose after randomization, this exploratory comparison cannot establish a treatment effect. The editorialists note that further detail from this cohort is awaited and would likely be informative [2]. The second is to change the outcome entirely. STArT captured 72-hour and 28-day ED return and rehospitalization as safety outcomes, and the editorialists argue these belong on the efficacy side, because the burden of sickle cell disease acute pain “may reside less in the duration of individual hospitalizations and more in the frequency of readmissions and ED revisits” [2]. The 28-day ED-return rates were 27.1% with arginine and 32.4% with placebo, and at a disease level return visits follow as many as 29% of initial ED encounters, with up to 28% of hospitalized children readmitted within 30 days [1]. The third lever is the design itself: the editorialists raise external control cohorts, or a crossover in which patients serve as their own controls, as ways to cut the participant numbers a conventional trial would need [2].

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

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
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
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
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
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
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
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
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
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
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
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
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
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

By Michelle Lin, MD|2026-08-28T00:00:21-07:00Aug 24, 2026|Heme-Oncology, Pediatrics, Tox & Medications|

PERC-Peds Rule Could Change How Children Are Evaluated for Pulmonary Embolism: A PECARN Study

Pediatric emergency clinician evaluating a child at bedside, no imaging equipment in frame

Article reviewed: 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

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

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.
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.

By Lauren VonHoltz, MD MPH|2026-07-20T21:50:18-07:00Jul 21, 2026|Pediatrics, Pulmonary, Radiology|

What We Still Do Not Know About Pediatric Mental Health Emergencies: PECARN Research Agenda

Adolescent sitting on an emergency department bed seen from behind, with a caregiver and clinician nearby in a calm, dimly lit room

Article reviewed: 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
DOI: 10.1016/j.annemergmed.2026.05.015 | PubMed: PMID 42429726

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

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
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
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.
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
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

By Michelle Lin, MD|2026-07-13T03:11:42-07:00Jul 13, 2026|Pediatrics, Psychiatry|

AZ-SWED Trial: Azithromycin Does Not Improve Preschool Wheezing Outcomes

Pediatric emergency clinician listening to a wheezing toddler's chest with a stethoscope while the child sits on a parent's lap

Article reviewed: 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
DOI: 10.1056/NEJMoa2516505 | PubMed: PMID 42149992

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

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
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
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
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
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
Ducharme FM, Jensen ME, Mendelson MJ, et al. Asthma Flare-up Diary for Young Children to monitor the severity of exacerbations. J Allergy Clin Immunol. 2016;137(3):744-749.e6. PMID: 26341275. doi:10.1016/j.jaci.2015.07.028

By Michelle Lin, MD|2026-06-02T21:43:22-07:00Jun 4, 2026|Infectious Disease, Pediatrics, Pulmonary|

PRoMPT BOLUS: A Landmark PECARN Trial Defining Fluid Choice in Pediatric Sepsis

Two IV fluid bags labeled 0.9% sodium chloride and lactated Ringer's hanging side by side in a pediatric emergency department

Article reviewed: Balamuth F, Weiss SL, Long E, et al; PRoMPT BOLUS Investigators of the PECARN, PERC, and PREDICT Networks. Balanced Fluid or 0.9% Saline in Children Treated for Septic Shock. N Engl J Med. Published online April 24, 2026
DOI: 10.1056/NEJMoa2601969 | PubMed: PMID 42028918

For years, clinicians and researchers have debated a fundamental question in pediatric emergency care: does the type of fluid used in pediatric sepsis resuscitation matter?

The PRoMPT BOLUS trial was designed to answer this question. Conducted across 47 international sites in 5 countries and enrolling more than 9,000 children, this large, pragmatic randomized trial compared 0.9% saline with balanced crystalloids in children treated for suspected septic shock.

The results have just been released. Across a wide range of clinically meaningful outcomes (including kidney injury, mortality, and recovery), there was no difference between fluid types.

Background

Sepsis remains a major global health concern, affecting approximately 50 million people each year, with children accounting for nearly half of these cases. Early fluid resuscitation is a cornerstone of treatment, making the choice of fluid a critical and historically debated decision.

Two primary types of crystalloid fluids are used in practice:

0.9% saline, which contains a higher-than-physiologic chloride concentration
Balanced fluids (such as lactated Ringer’s, Hartmann’s solution and PlasmaLyte), which more closely resemble plasma electrolyte composition

Prior research raised concerns that saline could contribute to metabolic acidosis and kidney injury, while balanced fluids were associated with improved outcomes in some adult and smaller pediatric studies. However, the pediatric literature remained inconsistent, with observational studies reaching conflicting conclusions. As a result, guidelines offered only weak recommendations favoring balanced fluids and called for more definitive trials.

PRoMPT BOLUS was designed to fill this gap.

Study Design

This trial used a pragmatic, randomized design (NS vs. balanced fluids), intentionally embedded into routine clinical care. Pragmatic trials evaluate clinical interventions within typical practice, rather than highly controlled clinical settings. By incorporating fluid randomization without modifying additional aspects of clinical practice, this approach allowed investigators to study fluid choice in real-world conditions across diverse healthcare systems. PRoMPT BOLUS was a collaborative effort across multiple networks including PECARN (Pediatric Emergency Care Applied Research Network), PERC (Pediatric Emergency Research Canada), and PREDICT (Paediatric Research in Emergency Departments International Collaborative).

Children ages 2 months to <18 years were eligible if clinicians suspected sepsis and were planning to treat with more than one fluid bolus for abnormal perfusion consistent with septic shock. They were randomized to receive either balanced fluids or 0.9% saline, with clinicians otherwise managing care as they normally would.

The primary outcome was MAKE30 (Major Adverse Kidney Events within 30 days), a composite that includes mortality, need for renal replacement therapy, or persistent kidney dysfunction at hospital discharge or 30 days, whichever came first.

This pragmatic approach was critical to the study’s success. It allowed for:

High enrollment across multiple international sites
Enrollment at the beginning of sepsis resuscitation so that most early fluid was as randomized
Strong generalizability to everyday clinical practice
Minimal disruption to clinical workflows

Results

Primary Outcome

The primary outcome, MAKE30, occurred at nearly identical rates in both groups:

Balanced fluids: 3.4%
Saline: 3.0%

This difference was neither statistically nor clinically significant. There were also no differences in any of the individual MAKE30 components between treatment groups.

Secondary and Safety Outcomes

Similarly, there were no meaningful differences in:

Mortality
Hospital length of stay
Hospital-free days (median of 23 days in both groups)
Safety events such as thrombosis or cerebral edema

Together, these findings strongly support the conclusion that both fluids are equally safe and effective.

Biochemical Differences

Although there were measurable and statistically significant biochemical differences between groups (such as higher rates of hyperchloremia and hypernatremia with saline and hyperlactatemia with balanced fluids), these changes did not translate into clinically meaningful outcomes.

Subgroup Analyses

Subgroup analyses across patient characteristics, illness severity, and total fluid volume showed no differences in outcomes. While there was a non-significant trend suggesting potential benefit of balanced fluids in the most severely ill patients, the study was not powered to confirm this finding.

Major Findings

The results of PRoMPT BOLUS can be distilled into several key conclusions:

Both 0.9% saline and balanced fluids are safe and effective for treatment of children with suspected septic shock
Fluid type does not influence major clinical outcomes, including mortality or kidney injury
Biochemical differences exist between fluid choices, but did not translate to differences in clinical outcomes

Importantly, while the study cannot fully exclude a benefit of balanced fluids in the sickest patients, it provides strong evidence that for children presenting to the ED with suspected sepsis, either fluid is an appropriate choice.

Clinical Implications

These findings have immediate and meaningful implications for clinical practice.

First, they simplify decision-making. Clinicians can focus on timely recognition and treatment of children with suspected sepsis, and engage in fluid resuscitation with fluids that make sense for the clinical scenario.

Second, the results support flexibility in care. Fluid choice can now be guided by:

Availability
Medication compatibility
Patient-specific factors (e.g., electrolyte abnormalities, underlying conditions)

Limitations

While the study is robust, several limitations should be considered.

The overall incidence of MAKE30 was lower than expected (~3% vs. an anticipated ~6%), which may reflect a less severely ill population than initially projected. This could limit the ability to detect small differences between groups.

Additionally, although subgroup analyses suggested a possible benefit of balanced fluids in more severely ill patients, the study was not powered to draw definitive conclusions in this population.

Bottom Line

The PRoMPT BOLUS trial provides the strongest evidence to date addressing fluid choice in children presenting to the ED with suspected sepsis. Both 0.9% saline and balanced crystalloids are safe and effective for resuscitation in children with suspected septic shock.

References

Balamuth F, Weiss SL, Long E, et al; PRoMPT BOLUS Investigators of the PECARN, PERC, and PREDICT Networks. Balanced Fluid or 0.9% Saline in Children Treated for Septic Shock. N Engl J Med. Published online April 24, 2026. doi:10.1056/NEJMoa2601969

By Lauren VonHoltz, MD MPH|2026-05-04T21:19:59-07:00May 7, 2026|Critical Care/ Resus, Pediatrics|

Who Gets Mistriaged? Disparities in Pediatric Behavioral Health ED Triage | A PECARN multicenter analysis

mistriaging of pediatric mental health conditions with ESI
A 14-year-old Hispanic girl presents to the Emergency Department with her mother for suicidal ideation after a conflict at home. The girl is quiet and cooperative. Her mother, who speaks primarily Spanish, is trying to explain the situation. The nurse assigns an ESI level 2, the same score given to nearly every child who walks through the door with a behavioral health complaint. But does that score accurately capture this patient’s needs?

A new multicenter PECARN study published this week in JAMA Network Open takes a close look at triage accuracy for pediatric behavioral health ED visits. The findings: mistriaging errors are common, and they are not equally distributed [1].

Hoffmann et al. analyzed 78,411 ED visits by children aged 5 to 17 with behavioral health chief concerns across 15 PECARN Registry EDs from 2021 to 2023 [1]. They classified each visit as appropriately triaged, overtriaged, or undertriaged using vital signs, Glasgow Coma Scale, pain scores, emergency medication use, resource utilization, and disposition. Of the 74,564 visits with complete data:

57% were overtriaged
34% were appropriately triaged
8.5% were undertriaged

How ESI Handles Behavioral Health

The Emergency Severity Index (ESI) is used in over 90% of US EDs [2]. It sorts patients into 5 acuity levels. Level 1 is for patients needing lifesaving interventions. Level 2 is for high-risk situations, confused patients, or those in severe pain. Levels 3 through 5 are based on anticipated resource needs. In this study, 83.5% of all behavioral health visits were triaged as ESI level 2.

To assess triage accuracy, the authors compared each child’s assigned ESI level against what actually happened during their visit.

Overtriage

Overtriage means a child was assigned a higher acuity score than their clinical course supported. For a child assigned ESI level 2, overtriage was defined as meeting ALL of the following [1]:

Stable vital signs within 2 hours of arrival (heart rate and respiratory rate not high risk for age, SpO2 ≥93% or not recorded)
Pain score <7 (or not recorded)
GCS of 15 (or not recorded)
No emergency medications during the visit

In other words, the triage nurse predicted high acuity, but the visit didn’t bear that out.

Undertriage

Undertriage means the opposite: a child was assigned a lower acuity score than their clinical course warranted. For example, a child triaged as ESI level 4 (expected to need 1 resource) who ended up being admitted, needing emergency medications, or using multiple resources. The triage nurse underestimated how sick the child was or how much care they would need.

Undertriage Disproportionately Affects Minority Children and Spanish-Speaking Families

The most concerning equity finding was in undertriage.

After adjusting for clinical and visit characteristics, undertriage was significantly more likely for Hispanic children (AOR 1.46), non-Hispanic Black children (AOR 1.28), and children whose families preferred Spanish (AOR 1.31), all compared to non-Hispanic White and English-speaking patients [1]. The authors point to implicit clinician bias, systemic racism, and underutilization of professional interpreters as likely contributors.

The safety implications are real. Children whose acuity is underestimated may face longer waits, miss time-sensitive interventions, or leave the ED without being seen despite elevated risk.

Overtriage Was Common

More than half of all visits (57%) were overtriaged [1]. These children received a higher acuity triage score than their clinical course supported.

The strongest predictor was age. Children aged 5-9 had over 4-fold higher adjusted odds of overtriage compared to those aged 10-14 (AOR 4.43), possibly because younger children have a limited ability to communicate their symptoms and needs.

To a lesser degree, non-Hispanic Black children also had higher adjusted odds of overtriage compared to non-Hispanic White children (AOR 1.17). The authors cite research on adultification, the tendency to perceive Black youth as older or more threatening than they are, as a potential contributor. This means Black children in this study were more likely to be both undertriaged and overtriaged compared to White children. The errors are not unidirectional. They likely reflect different biases operating at different points in care.

Take Home Points

The ESI has limited ability to differentiate pediatric behavioral health presentations. In this study, 83.5% of behavioral health visits were triaged as ESI level 2.
UNDERTRIAGE was more likely for Hispanic children (AOR 1.46), non-Hispanic Black children (AOR 1.28), and Spanish-speaking families (AOR 1.31), raising concerns about missed acuity in these groups.
OVERTRIAGE occurred in 57% of visits, driven most strongly by younger age (AOR 4.43 for ages 5 to 9) and to a lesser degree by non-Hispanic Black race (AOR 1.17).

References

Hoffmann JA, Foster AA, Rojas CR, et al. Overtriage and undertriage of children presenting to the emergency department for behavioral health. JAMA Netw Open. 2026;9(3):e263042. Full text
McHugh M, Tanabe P, McClelland M, Khare RK. More patients are triaged using the Emergency Severity Index than any other triage acuity system in the United States. Acad Emerg Med. 2012;19(1):106-109. doi:10.1111/j.1553-2712.2011.01240.x

By Michelle Lin, MD|2026-03-28T19:43:20-07:00Mar 28, 2026|Pediatrics, Psychiatry|

From Collision to Clarity: PECARN cervical spine injury prediction rule for injured children

PECARN cervical spine injury prediction tool featured image (adapted from Midjourney)

For years, adult literature has provided clear guidelines for cervical spine imaging through the NEXUS and Canadian C-spine Rule (CCR) tools. These have been invaluable in helping clinicians decide when to image the neck in trauma patients. Similarly, the Pediatric Emergency Care Applied Research Network (PECARN) has developed robust tools for assessing blunt head trauma in children. However, until now, there has been a gap in guidance for clinicians managing pediatric patients at risk for cervical spine injuries.

Case Scenario: What would you do?

A 10-year-old boy presents to the emergency department (ED) after a high-speed motor vehicle collision. He complains of neck pain and is reluctant to move his head. The child’s mother is extremely worried, fearing the worst after witnessing the collision.

The Problem

Cervical spine injuries in children, while uncommon, can be devastating if not identified and treated promptly. Emergency physicians often face the challenge of deciding whether to proceed with imaging, given the potential risks associated with ionizing radiation from CT scans. The lack of clear guidelines specifically tailored for pediatric patients has historically led to either overuse of imaging, with its associated risks, or underuse, with the risk of missed injuries.

PECARN Cervical Spine Injury Prediction Rule

On June 4, 2024, Lancet published “PECARN prediction rule for cervical spine imaging of children presenting to the emergency department with blunt trauma: a multicentre prospective observational study.” This study proposes a new clinical prediction rule to guide imaging decisions for pediatric cervical spine injuries.

The study enrolled 22,430 children, aged 0–17 years, presenting with blunt trauma across 18 PECARN-affiliated ED in the US. About half were in the derivation and half in the validation cohort. The researchers derived and validated a clinical prediction rule using data from these children, which identified key risk factors for cervical spine injury, divided into high-risk and non-negligible (intermediate) risk factors.

High Risk (>12.1% risk of injury) -> Consider CT

Altered mental status (GCS 3-8 or AVPU = U)
Abnormal airway
Breathing
Circulation findings
Focal neurological deficits

Intermediate Risk (2.8% risk of injury) -> Consider X-Rays

Neck pain or midline neck tenderness
Mental status: GCS 9-14, AVPU = V or P, or other signs of altered mental status
Substantial head or torso injury

Definition on Cervical Spine Injury

Fractures or ligamentous injuries of the cervical spine
Cervical intraspinal hemorrhage
Cerebral artery injury
Cervical spinal cord injury, including
- Changes in the cervical spinal cord on MRI
- Cervical spinal cord injury without radiographic association

PECARN Cervical Spine Injury Prediction Tool (Download full sized PDF at PECARN site)

The prediction rule had strong test characteristics with 94.3% sensitivity and 99.9% negative predictive value, indicating that it can reliably identify children who do not need imaging, thus avoiding unnecessary radiation exposure. This evidence-based approach to pediatric trauma care would have reduced the number of CT scans by more than 50% without missing clinically relevant injuries.

Case Example Resolution

Using the PECARN cervical spine injury prediction rule, the attending physician evaluates the boy and finds that he does not exhibit any high-risk factors. However, because he reports neck pain and has midline neck tenderness on exam (intermediate risk), the rule recommends that the cervical spine can not be clinically cleared. It also suggests plain x-rays and not a CT scan. This differs from the adult population whereby CT scan imaging is often the first choice for diagnostic testing.

The x-rays reveal no evidence of cervical spine injury, and the boy is cleared with instructions for follow-up care. This approach not only alleviated the mother’s anxiety but also avoided unnecessary radiation exposure for the child.

Reference

Leonard JC, Harding M, Cook LJ, et al. PECARN prediction rule for cervical spine imaging of children presenting to the emergency department with blunt trauma: a multicentre prospective observational study. Lancet Child Adolesc Health. 2024;8(7):482-490. doi:10.1016/S2352-4642(24)00104-4. PMID 38843852

By Michelle Lin, MD|2026-01-08T21:25:20-08:00Jun 10, 2024|Pediatrics, Radiology, Trauma|