Introduction
When a child with sickle cell disease (SCD) arrives at the Emergency Department with a pain crisis, families understandably want to know: how long until we can go home? The answer, it turns out, may depend less on patient characteristics and more on the hospital itself and other characteristics like history of chronic pain or how long pain lasted before going to the emergency room.
The STArT (Sickle Cell Disease Treatment with Arginine Therapy) trial was designed to test whether IV arginine could shorten hospitalization time for vaso-occlusive episodes (VOE) [1, 2]. While the trial was stopped early because arginine didn’t seem to effect the time to pain crisis resolution, it became an unexpected success story: with 274 enrolled patients across 10 hospitals, STArT achieved one of the largest pediatric sickle cell pain crisis trial enrollments to date.
This secondary analysis of the 141 patients who received placebo reveals surprising insights about what really drives how long children stay hospitalized—and raises important questions about how we measure success in SCD research [3].
Study Question
What patient and hospital factors present at Emergency Department arrival are associated with longer time-to-crisis-resolution, hospital length of stay, and total intravenous (IV) opioid use in children and young adults with sickle cell VOEs?
Study Design
This was a secondary analysis of 141 patients (ages 3-21 years) randomized to placebo in the STArT phase-3 randomized controlled trial conducted across 10 PECARN sites from 2021-2024.
Key Definitions:
- Time-to-crisis-resolution: Time from study drug delivery to last dose of IV opioids (primary outcome)
- Vaso-occlusive episode: Sickle cell pain crisis requiring IV opioid therapy
- Chronic pain: Patient-reported SCD-related pain on ≥15 days per month for the prior 6 months [4]
Patient characteristics analyzed:
- Age
- Sex
- Genotype
- Number of prior ED visits not resulting in hospitalization
- Fever
- Positive blood cultures
- Acute chest syndrome
- Medication use
- Chronic pain
- Depression
- Duration of current pain before ED arrival
- Prior surgeries
- Enrollment site
Results
The Hospital Variation Story:
This study included all children ages 3-21 with SCD experiencing VOEs severe enough to require IV opioid therapy—essentially, all-comer pain crises presenting to the emergency department.
Time-to-crisis-resolution averaged 77 hours (about 3 days), but this varied dramatically by hospital. Some hospitals discharged children in about 28 hours (just over a day), while others kept children for 142 hours (nearly 6 days). That’s almost a 5-day difference between hospitals.
While the analysis adjusted for patient characteristics like age, sex, genotype, fever, acute chest syndrome at presentation, and other measured factors, this hospital-to-hospital variation remained substantial and was more influential than most individual patient factors in determining how long children stayed hospitalized.
What does this mean? Either some hospitals have practices that safely get children home faster with better pain control, or some hospitals are appropriately keeping higher-risk patients longer—or both. It is also possible that patients continue to experience pain at home, and their pain crisis may not truly be resolved. The study couldn’t definitively answer which, but it clearly shows that where you receive care matters.
What Patient Factors Predicted Longer Stays?
Two patient characteristics stood out as independently associated with longer hospitalizations:
- Children who always get admitted (vs. sometimes being discharged from the ED): stayed about 30 hours longer. Specifically, 82% of these patients required hospitalization at every ED visit.
- Children with prior surgeries (especially gallbladder or spleen removal): stayed about 23 hours longer. This likely reflects more severe disease overall.
Other Factors Worth Noting:
Several additional factors were associated with longer stays, though they overlap with each other:
- Chronic pain (pain ≥15 days/month for past 6 months): 23 hours longer
- Depression: 33 hours longer
- Pain lasting ≥24 hours before coming to the ED: 24 hours longer
- History of positive blood cultures: 34 hours longer
The Surprising Age Pattern:
Previous studies from single hospitals suggested older teens stay longest [2]. This multi-center study found the opposite: younger children (3-4 years) stayed longest (average 103 hours), while older adolescents (16-21 years) had shorter stays (average 68 hours).
While it is established that older children and young adults stay longer in the hospital than younger children, this reversal when moving from a single center to a multicenter trial suggests that length of stay depends heavily on individual hospital practices, regardless of the child’s age.
Caution
- Generalizability: Results reflect practices at 10 academic children’s hospitals participating in a clinical trial. Community hospital patterns may differ.
- Causation vs. Association: We can’t determine whether hospital practices caused the variation or whether unmeasured patient factors differed between sites. The study identified associations, not definitive causes.
- Placebo Group Only: Analysis included only patients randomized to placebo to avoid confounding from the intervention. Results may not reflect all children with pain crises.
- Confounding Factors: Variables like chronic pain, depression, and duration of pain before presentation likely overlap and measure related patient characteristics. The relationship between prior surgeries and longer stays may reflect overall disease severity rather than surgery itself.
- Missing Data: Not all potentially relevant hospital practices were measured (e.g., standardized pain protocols, use of patient-controlled analgesia, early ambulation protocols).
Take Home Message
The STArT trial’s early closure might seem like a setback, but it represents a different kind of success: it generated critical insights about hospital variation, identified high-risk patient populations, challenged our assumptions about age and length of stay, and revealed limitations in current clinical trial endpoints. Most importantly, it demonstrated that multi-center pediatric sickle cell research is feasible—PECARN enrolled 274 patients nearly a year ahead of schedule. These lessons will shape how we design and conduct future trials, ultimately accelerating progress toward better treatments for children experiencing pain crises.
Call To Action
The authors advocate for rethinking study design for future sickle cell VOE trials and the outcome measures used for FDA drug approval [3, 5]:
“Failure to recognize site and patient level factors that contribute to differences in these outcomes may be contributing to suboptimal phase-3 clinical trial results. At a minimum, these differences should be accounted for in the design of future therapeutic trials. Dialog between stakeholders including the FDA, American Society of Hematology, and investigators is urgently needed to identify more ideal outcome measures beyond time-to-crisis-resolution, which is currently the FDA-preferred outcome for orphan drug regulatory approval for acute SCD-VOE.”
Why is this important for patients and caregivers
- Understanding hospital stays for sickle cell pain crises: When your child has a sickle cell pain crisis, the time spent in the hospital can vary dramatically—sometimes by several days—depending on which hospital you visit. This study found that hospital practices may matter as much as your child’s individual condition in determining length of stay.
- What affects how long your child stays:
- Children who almost always need admission (rather than sometimes being treated and sent home) tend to stay longer
- Children who’ve had surgeries like gallbladder or spleen removal tend to stay longer
- The presence or development of acute chest syndrome
- The hospital’s specific practices and approaches can make a difference of 4-5 days in how long children stay
- The good news: This research helps doctors understand that shorter hospital stays may be achievable with better-standardized practices across hospitals. It also helps researchers design better studies to test new treatments for pain crises.
- Questions to ask your care team:
- “What are this hospital’s typical practices for managing pain crises?”
- “Are there ways to manage my child’s pain that might help us go home sooner?”
References
- Rees CA, Brousseau DC, Cohen DM, et al. Sickle Cell Disease Treatment With Arginine Therapy (STArT): Study Protocol for a Phase 3 Randomized Controlled Trial. Trials. 2023;24(1):538. doi:10.1186/s13063-023-07538-z. PMID 37587492
- Morris CR, Hatabah D, Korman R, et al. Arginine Therapy for Pain in Sickle Cell Disease: A Phase-2 Randomized, Placebo-Controlled Trial. Am J Hematol. 2025;100:1119-1131. doi:10.1002/ajh.27692. PMID 40270092
- Rees CA, Hatabah D, Korman R, et al. Hospital Variations in Time-To-Crisis-Resolution Among Children and Adolescents With Sickle Cell Disease. Am J Hematol. Published online November 25, 2025. doi:10.1002/ajh.70129. PMID 41190764
- Dampier C, Palermo TM, Darbari DS, Hassell K, Smith W, Zempsky W. AAPT Diagnostic Criteria for Chronic Sickle Cell Disease Pain. J Pain. 2017;18(5):490-498. doi:10.1016/j.jpain.2016.12.016. PMID 28065813
- 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. doi:10.1182/bloodadvances.2020001851. PMID 32559294
