This is a guest post by Harrison Hayward and Dennis Ren:
Dr. Harrison Hayward is a Pediatric Emergency Medicine fellow at Children’s National Hospital. He finished his General Pediatrics residency at Yale-New Haven Hospital. As an editor and writer of continuing medical education material for the clinical case-sharing app, Figure 1, he enjoys interprofessional learning and is passionate about improving health care delivery to children with complex medical needs.
Dr Dennis Ren is a pediatric emergency medicine physician at Children’s National Hospital and Assistant Professor of Pediatrics and Emergency Medicine at George Washington University School of Medicine in Washington, DC. He is a FOAMed enthusiast and has contributed to outlets such as The Skeptics’ Guide to Emergency Medicine, Don’t Forget the Bubbles, and PedsRAP. His areas of interest include medical education, simulation, interprofessional communication and teamwork, disaster/emergency preparedness.
Perhaps second-dose dex, like second-hand clothes, come easily off and on.
I suppose I’ll stop with the steroid-injected Charles Dickens quotes since the Venn Diagram of emergency medicine providers and people who relish in a Dickens pun must be nearly two distant circles.
What’s the big deal?
Asthma affects about 9% of children in the United States and is a common reason for visits to the emergency department (ED). We all know that guidelines published by the National Asthma Education and Prevention Program (NAEPP) recommend use of systemic corticosteroids for the treatment of acute asthma exacerbations.1 The exact approach to corticosteroid administration can vary widely by provider and institution. Formerly, standard practice per NAEPP recommendations consisted of a 3 to 10-day course of prednisone. We know that medication adherence can be challenging in adults, let alone children.2-3
As such, emerging evidence over the last twenty years has pivoted many providers toward dexamethasone as a practical alternative. Dexamethasone is 5 to 6 times more potent than prednisone and has a half-life of 36 to 72 hours, providing similar clinical results while ameliorating barriers to adherence.4 However, the optimal number of doses of dexamethasone is not clear.
Cronin et al investigated single dose dexamethasone versus 3 days of prednisone for treatment of acute asthma exacerbations and found dexamethasone to be non-inferior,5 showing no difference in return visits, days to symptom resolution, or number of school days missed. Similarly, Qureshi et al and Greenberg et al compared 2 daily doses of dexamethasone with 5 days of prednisone and found no statistically significant difference in relapse or persistence of symptoms after 10 days.6,7 Lastly, Keeney et al conducted a meta-analysis of 6 studies comparing dexamethasone (either 1 or 2 doses) to 3-5 days of prednisone and concluded that dexamethasone was non-inferior as well.8
So the question becomes: In the treatment of mild to moderate acute pediatric asthma exacerbations presenting to the ED, should we give one or two doses of dexamethasone?
The Paper
Martin M, Penque M, Wrotniak B, Qiao H, Territo H. Single-Dose Dexamethasone is not Inferior to 2 Doses in Mild to Moderate Pediatric Asthma Exacerbations in the Emergency Department. Ped Emerg Care. 2022;38(6) 1285-1290. PMID: 35507383
The Methods
This was a single-center, prospective, unblinded, parallel-group, randomized clinical trial.
Patients
They included children aged 2 to 20 years with a known history of asthma, defined as at least one prior episode of wheeze responsive to beta agonists, who presented to their ED between April 2015 and March 2018 with acute mild [Pediatric Asthma Score (PAS) 5-7] to moderate (PAS 8-11) asthma exacerbations. They excluded patients who had severe exacerbations (PAS>11), systemic steroids given in the last two weeks, chronic lung disease, or vomiting of at least two doses of oral steroids in the ED.
Intervention
Patients were block randomized into receiving either a single dose of dexamethasone in the ED, or receiving a first dose in the ED and then a second dose at home the following day that was sent to the pharmacy.
Outcomes
The primary outcome of interest was return visits to either the primary care provider, the ED, or urgent care for persistent or worsening asthma symptoms. Secondary outcomes included length of time that symptoms persisted, missed school days, vomiting, and adverse events like insomnia, mood swings, or appetite changes.
Results
A total of 308 children were randomized into two groups of 154. Ultimately, 141 were enrolled in group 1, which received a single dose of dexamethasone, and 143 in group 2, which received two doses. 25 patients (17.7%) in group 1 were lost to follow-up, as were 27 (18.9%) patients in group 2, resulting in a total of 116 patients analyzed in both groups. The mean age was 7.5 years and 60.2% of patients were male.
They found no statistically significant difference in return visits for persistent or worsening asthma symptoms, reporting a 12.1% (95% CI 6.1-18) vs 10.3% (95% CI 4.8 – 15.8) return rate for patients in group 1 and 2, respectively. A total of 26 patients (11%) returned for persistent or worsening symptoms. Of these patients, eleven returned to the ED. One patient from the single-dose group required admission to the hospital. In the two-dose dexamethasone group, 94 (81%) patients took the second dose.
The authors report “no statistically significant differences between the 2 groups for any of the post-discharge [secondary] outcomes, including days for symptom resolution, number of school days missed, adverse effects, and vomiting since discharge from the ED.”
| Single-Dose Dexamethasone | Two-Dose Dexamethasone | Odds Ratio (95% CI) | |
| Days to symptom resolution, mean (SD) | 2.4 (3.5) | 2.5 (3.4) | 0.974 (0.838-1.132) |
| Patients who missed any school, n (%) | 47 (48.0) | 51 (47.2) | 1.114 (0.613-2.023) |
| % Vomiting | 10 | 4 | 2.424 (0.637-9.228) |
| No adverse effects, n (%) | 71 (61.2) | 83 (71.6) | 0.787 (0.351-1.767) |
Our Thoughts
First, we need to acknowledge that there is no singular gold standard for oral corticosteroid use for mild to moderate pediatric acute asthma exacerbations. As such, any number of individualized variables may exist that determine best approaches for any given patient.
Primary Outcome:
The primary outcome was return visits to the emergency department, urgent care, or primary care doctor for persistent or worsening symptoms. We are not certain if the proportions returning to the ED vs primary care doctor are the same in each group. We are also uncertain as to whether patients required additional medical attention (albuterol treatment, more steroids, etc).
They report no statistically significant difference due to crossing of the 95% confidence intervals, but those intervals are rather wide.
Secondary Outcomes:
One of the secondary outcomes was missing school days. While the authors report, “no statistically significant difference [in]… number of school days missed,” they only report whether patients missed school at all or not. This is an important outcome of interest because the number of missed school days can have a meaningful impact on the family (i.e. parents/caregivers must miss work or find alternative childcare for each school day the patient misses). If receiving two doses of dexamethasone results in less missed school days and less stress for the parents, we would potentially be more inclined to recommend two-dose therapy.
Loss to follow up and Adherence
Fifty-two (18.3%) patients out of the 284 included in the study were lost to phone follow-up. This is a decent proportion of the patients, and it is difficult to know if and how this impacted results.. They also reported 81% adherence to the prescribed second dose in group 2 (they did not verify with the pharmacy that the medication was picked up). Both of these factors make us take the claim of single-dose non-inferiority with a grain of salt.
Unblinded
Finally, lack of blinding introduces bias. The families knew if their child was prescribed a second dose and researchers discovered this as well when they called for follow-up. The authors acknowledge that this was primarily due to a lack of funding. This question of one vs two doses of dexamethasone might be answered more clearly by a funded study that utilizes a placebo.
Given the limitations mentioned, we do not think that this study independently would change any institution’s practice. Like many things with evidence-based medicine, the answer happens to be “It all depends.” The groundwork laid by this study is an important and necessary step toward future blinded, multi-center studies.
On that note, we leave you with one last Charles Dickens quote:
Take nothing on its looks; take everything on evidence. There’s no better rule.
Other FOAMed:
- SGEM #375: Only One vs Two Dose Dexamethasone for Mild to Moderate Pediatric Asthma Exacerbations (https://thesgem.com/2022/09/sgem375-only-one-versus-two-dose-dexamethasone-for-mild-to-moderate-pediatric-asthma-exacerbations/)
- PEM Blog: Why we do what we do: Systematic corticosteroids for acute asthma exacerbations (https://pemcincinnati.com/blog/systemic-corticosteroids-acute-asthma-exacerbations/)
- PEM Morsels: Dexamethasone for Asthma (https://pedemmorsels.com/dexamethasone-asthma/)
- Emergency management of severe asthma
References
- National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138. PMID: 17983880
- Jimmy B, Jose J. Patient medication adherence: measures in daily practice. Oman Med J. 2011 May;26(3):155-9. doi: 10.5001/omj.2011.38. PMID: 22043406; PMCID: PMC3191684.
- Leickly FE, Wade SL, Crain E, Kruszon-Moran D, Wright EC, Evans R 3rd. Self-reported adherence, management behavior, and barriers to care after an emergency department visit by inner city children with asthma. Pediatrics. 1998 May;101(5):E8. doi: 10.1542/peds.101.5.e8. PMID: 9565441.
- Zoorob RJ, Cender D. A different look at corticosteroids. Am Fam Physician. 1998 Aug;58(2):443-50. PMID: 9713398.
- Cronin JJ, McCoy S, Kennedy U, An Fhailí SN, Wakai A, Hayden J, Crispino G, Barrett MJ, Walsh S, O’Sullivan R. A Randomized Trial of Single-Dose Oral Dexamethasone Versus Multidose Prednisolone for Acute Exacerbations of Asthma in Children Who Attend the Emergency Department. Ann Emerg Med. 2016 May;67(5):593-601.e3. doi: 10.1016/j.annemergmed.2015.08.001. Epub 2015 Oct 14. PMID: 26460983.
- Qureshi F, Zaritsky A, Poirier MP. Comparative efficacy of oral dexamethasone versus oral prednisone in acute pediatric asthma. J Pediatr. 2001 Jul;139(1):20-6. doi: 10.1067/mpd.2001.115021. PMID: 11445789.
- Greenberg RA, Kerby G, Roosevelt GE. A comparison of oral dexamethasone with oral prednisone in pediatric asthma exacerbations treated in the emergency department. Clin Pediatr (Phila). 2008 Oct;47(8):817-23. doi: 10.1177/0009922808316988. Epub 2008 May 8. PMID: 18467673.
- Keeney GE, Gray MP, Morrison AK, Levas MN, Kessler EA, Hill GD, Gorelick MH, Jackson JL. Dexamethasone for acute asthma exacerbations in children: a meta-analysis. Pediatrics. 2014 Mar;133(3):493-9. doi: 10.1542/peds.2013-2273. Epub 2014 Feb 10. PMID: 24515516; PMCID: PMC3934336.
Ren, H. A Tale of Two Doses Versus One (Dexamethasone for the Treatment of Mild to Moderate Pediatric Asthma), First10EM, October 17, 2022. Available at:
https://doi.org/10.51684/FIRS.128694
One thought on “A Tale of Two Doses Versus One (Dexamethasone for the Treatment of Mild to Moderate Pediatric Asthma)”
I agree with the conclusion. Also, note that the study design was submitted on february 19th, 2019 to clincialtrials.gov; once the enrollement was over (https://clinicaltrials.gov/ct2/history/NCT02192827). The study description was submitted on april 2015; but the design only in 2019.
Regarding the noninferiority limit of 11 %; I don’t see how we can conclude whether the upper limit of the primary outcome reaches it, given that it is reported using Odds ratio.