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Three Part Question

For [children presenting to the Emergency Department with wheeze and who require steroid therapy], is [oral Dexamethasone inferior to oral Prednisolone] in the [management of symptoms]?

Clinical Scenario

A 5 year-old boy presents to the emergency department with an acute exacerbation of asthma, with a tight chest and an oxygen requirement. He is followed up regularly in a paediatric respiratory clinic and is normally on a preventer inhaler. Along with back-to-back mixed nebulisers, you prescribe oral prednisolone, which he vomits 10 minutes later.

The paediatric SHO says she has heard of a recent RCT that shows that a single dose of oral Dexamethasone is as good as 3 days of Prednisolone in the management of acute wheeze and you know from your own experience that oral Dexamethasone is usually well tolerated by kids presenting with croup. Given how often you see children vomit Prednisolone, you ask yourself whether the emergency department should switch to oral Dexamethasone instead for childhood wheeze?

Search Strategy

PubMed/Medline

Search 1: child AND (wheezing[MeSH Terms] OR asthma[MeSH Terms]) AND oral AND (acute OR emergency) AND (prednisolone[MeSH Terms] OR dexamethasone[MeSH Terms])
Search 2: children OR paediatric OR pediatric AND (wheezing[MeSH Terms] OR asthma[MeSH Terms]) AND (prednisone[MeSH Terms] OR prednisolone[MeSH Terms] AND dexamethasone[MeSH Terms])

Search Outcome

Search 1: of 85 papers, 5 relevant RCTs, one observational study, two meta-analyses and one Cochrane review found.
Search 2: of 54 papers, 5 relevant RCTs, two observational studies, one meta-analysis and one Cochrane review found.

Summary of results Studies which compared oral Prednisolone to intramuscular or nebulised Dexamethasone were excluded on the grounds of either causing unnecessary pain or not being readily available/practical

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Qureshi 2001 United States	533 children, 2-18 yrs old, presenting to ED with acute asthma; 2days Dex 0.6mg/kg (max 16mg) vs 5days Pred (load dose 2mg/kg (max 60mg) then 4days 1mg/kg/d (max 60mg))	RCT, non-blinded (2)	Primary: relapse within 10 days	Dex 7.4% vs Pred 6.9% (p=0.84)
			Secondary: hospitalisation rate from ED or after relapse; symptom persistence at 10days; vomiting; parental non compliance; missing school	Similar admission from ED, Dex 11% vs Pred 12%; similar admission after relapse, Dex 20% vs Pred 17% (p=0.84); similar symptom persistence at d10, Dex 22% vs Pred 21%. More exclusion because of vomiting in Pred (3%) vs Dex (0.3%) (p=0.008); more non compliance in Pred (4% vs 0.4%) (p=0.004) and more school absence ≥2d in Pred (19.5% vs 13.2%) (p=0.05)
Greenberg 2008 United States	89 children, 2-18 years-old, presenting to a tertiary PED with asthma exacerbation; 2days Dex 0.6mg/kg vs 5days Pred 2mg/kg	RCT, double-blind, placebo-controlled (3)	Primary: relapse (unscheduled follow-up visit within 10 days)	No significant difference in relapse rate (Dex 16% and Pred 8%, p=0.27)	Study underpowered as new nurse-led protocol meant fewer subjects enrolled.
			Secondary: vomiting in ED	Less vomiting with Dex (10%) than Pred (18%) but not significant (p=0.24)
Altamimi 2006 Canada	110 children, 2-16 years-old, presenting to a tertiary PED with mild/mod asthma exacerbation; 1dose Dex 0.6mg/kg (max 18mg) vs 5days Pred 1mg/kg (max 30mg) BD	RCT, double-blind, placebo-controlled (3)	Primary: no. of days for Patient Self Assessment to return to baseline	Dex 5.21 days versus Pred 5.22 day	New nurse protocol meant fewer subjects enrolled and so did not meet power calculation. Reliant on patient/parental score.
			Secondary: time to discharge; admission rate; salbutamol need	time to discharge 3.5 h (Dex) vs 4.3 h (Pred); admission rate 9% (Dex) vs 13.4% (Pred); no significant difference in no. of salbutamol needed in ED nor at home
Keeney 2014 United States	949 children, <18 years of age, extrapolated from 6 RCTs (including 3 comparing IM Dex to oral Pred)	Meta-analysis (1)	Primary: return visits or hospital readmissions	No difference in relapse rate between the 2 groups at any time point; 5days RR 0.90 (95% CI 0.46-1.78), 10-14days RR 1.14 (95% CI 0.77-1.67), 30days RR 1.20 (95% CI 0.03-56.93)	Meta-analysis dates to before 2 new RCTs and one large observational study. Limited to US studies
			Secondary: vomiting	Reduced vomiting with Dex, both in ED (RR 0.29, 95% CI 0.12–0.69) and at home (RR 0.32, 95% CI 0.14–0.74)
Meyer 2014 United States	949 children, 6 months to 18 years extrapolated from 6 studies (including 3 studies comparing IM Dexamethasone with oral Prednisolone)	Meta-analysis (1)	Primary: unscheduled return visits	No difference (pooled risk difference of 0.02 (95% CI: -0.02 to 0.05) favouring Pred was not significant	Meta-analysis dates to before 2 new RCTs and one large observational study. Limited to US studies
			Secondary: return to baseline	No difference (pooled risk difference of 0.98 (95% CI 0.71-1.35) favouring Dex was not significant
Watnick 2016 United States	13,518 children, 3-17 years-old, presenting to a tertiary PED; Single dose Dex 0.6mg/kg (max 16mg) vs 3-5days of Pred 2mg/kg	Retrospective, observational study (2)	Relapse rates as measured by reattendance within 72hrs	1.28% children given Dex relapsed compared to 2.01% given Pred (p=0.05)	Observational study. Dexamethasone only introduced in 2014, study looked at episodes 2006-2014. 35% patients excluded as did not receive a steroid. Published as a letter.
Parikh 2015 United States	40,257 children, 4-17 years-old, admitted to 42 tertiary children’s hospitals and who received either Dexamethasone or Prednisolone (combinations were excluded)	Multi-centre, retrospective cohort study (3)	Primary: Length of stay	Length of stay ≥3days significantly lower in Dex (5.9%) vs Pred (17%), p=0.002	Observational study. Only 1,166 children (2.9% of cohort) received Dex and dosing regimens not specified
			Secondary: readmission at 7 and 30 days, cost of stay	No difference in readmission rates; reduced costs of stay for Dex group
Paniagua 2017 Spain	590 children, 1-14 years-old, presenting to a tertiary PED; 2days Dex (0.6mg/kg) vs 5days Pred (load dose 1.5mg/kg, then 4 days 1mg/kg)	RCT, non-blinded (2)	Primary: % of patients with asthma symptoms and quality of life at day 7	no difference in symptoms (56.6% Dexamethasone vs 58.3% Prednisolone group) or quality of life score (80 vs 77)
			Secondary: unscheduled returns, admission, adherence, vomiting	No significant difference in admission rate (23.9% vs 21.7%), or in unscheduled returns (4.6% vs 3.3%), or vomiting (2.1% vs 4.4%). Better adherence in Dex group (99.3% vs 96%) p<0.05
Cronin 2016 Republic of Ireland	226 children 2-16yo with asthma/recurrent VIW in tertiary PED; Single dose Dex 0.3mg/kg vs 3days Pred 1mg/kg/day	RCT, open label but PRAM score (Paediatric Respiratory Assessment Measure) assessed by clinician blinded to treatment (2)	Primary: mean PRAM score on d4	No difference in PRAM score
			Secondary: need for further steroids; vomiting; admission; unscheduled return visits within 14d	Less further steroid needed in Pred group (4.2%) vs Dex (13.1%); More vomiting in Pred (14x) vs Dex (0x); No difference in admission rate or no of unscheduled return visits

Comment(s)

Earlier studies comparing oral Dexamethasone to oral Prednisolone have all come from North America where steroid dosing is higher and courses of Prednisolone are typically 5 days instead of the usual 3-day course in Australasia, Ireland and the UK.

Summary of results.

The first RCT by Qureshi et al, which studied high-dose Dexamethasone (0.6mg/kg) for two days against 5 days of Prednisolone, found no difference in relapse rates (returns to the ED) or admissions from ED and had to exclude more children taking Prednisolone as they were more likely to vomit than kids taking Dexamethasone. Non-compliance was more prevalent in children taking Prednisolone than Dexamethasone (4% vs 0.4%). The study was not blinded. Greenberg et al also compared a 2-day course of Dexamethasone versus 5 days of Prednisolone but despite being a double-blinded, placebo-controlled trial, the study had inadequate power, in part due to a new nurse-led protocol at the site for assessing children with wheeze which meant not enough patients were enrolled. The study found no difference in relapse rates. A new nurse-led protocol caused similar problems for Altamimi et al’s study which compared a single dose of oral Dexamethasone with 5 days of oral prednisolone. The study found no difference in return to base-line in patient self-assessment scores or in use of salbutamol inhaler after discharge. Summarising these North American trials (along with the 3 trials comparing IM Dexamethasone with oral Prednisolone), Keeney et al’s meta-analysis found no difference in relapses between the two treatments (relative risk of 1.07 with Prednisolone versus Dexamethasone, CI 0.77-1.50) and found reduced vomiting with Dexamethasone (relative risk 0.29, CI 0.12-0.69). The authors concluded: “Practitioners should consider single or 2-dose regimens of Dexamethasone as a viable alternative to a 5-day course of prednisone/prednisolone.” Another meta-analysis by Meyer et al, who reviewed the same 6 trials, found no difference in unscheduled return physician visits or return to baseline symptoms . A Cochrane review comparing all types of oral corticosteroids for wheeze up until Cronin et al’s study (see below) echoed Keeney et al: “in terms of efficacy, one drug does not appear to be superior to the other”.

Since 2016, there have been four new studies, two of them RCTs and one large retrospective cohort study. Watnick et al’s retrospective observational study showed no difference in re-attendance rates at a US ED but Dexamethasone was only introduced at the hospital in the last year of the eight-year study period and details of the trial were limited in the letter published. Parikh et al’s observational study looked at 40,257 children aged 4-17 years admitted to 42 tertiary children’s hospitals in the US and found a statistically significant reduced length of stay and reduced costs in the children treated with oral Dexamethasone. However, of this large group of children, only 2.9% were treated with Dexamethasone (likely showing continued clinician preference for Prednisolone) and the authors were unable to detail the different dosing regimens. Paniagua et al’s Spanish study replicates earlier US studies in terms of the 2-day 0/6mg/kg/day dosing regimen for Dexamethasone. It was adequately powered and found no difference in symptoms and quality of life score at Day 7 or in admission rates or unscheduled returns. The authors found a significant difference in adherence (better for Dexamethasone). However, the trial was not blinded and the structured interviews on symptoms by telephone could be subject to recall bias. The closest study to Australasian, Irish and UK practice is that of Cronin et al’s RCT comparing a lower single dose of Dexamethasone (0.3mg/kg) versus 3 days of Prednisolone (1mg/kg/day). The study was open label but clinicians re-assessing the children on Day 4 were blinded to the treatment given. Moreover, the assessment is the only trial to use the Paediatric Respiratory Assessment Measure, or PRAM score, a validated clinical score for asthma symptoms in children. The authors found no difference in PRAM score between the two arms at Day 4 and no difference in admission rates or return visits.

Commentary

We are waiting for better epidemiology to tell us what presents to the paediatric emergency department (Mukherjee et al) but a 2012 study at a busy UK PED showed the commonest medical presentation to be breathing difficulties (20.1%) (Sands et al). One study estimates the global prevalence of asthma among 13-14 year-olds and 6-7 year-olds at 14.1% and 11.7% respectively (Mallol et al). In the UK, the mainstay of treatment for acute episodes of childhood asthma assessed as requiring steroids (i.e. not the large cohort of pre-schoolers with viral induced wheeze where we currently avoid steroid therapy) continues to be oral prednisolone (British Thoracic Society Guideline). Dexamethasone has a longer half-life (36-72 hours) and is better tolerated than oral Prednisolone (Aljebab, Hames)) and several of the studies reviewed in this article showed better compliance and less vomiting with oral Dexamethasone. A larger, multi-centre trial to replicate Cronin et al’s findings – that a lower, single dose of oral Dexamethasone is not inferior to Prednisolone based on the PRAM score – would be welcome. But while previous studies may have different age groups and dosing regimens and less reliable outcome measures, single-dose oral Dexamethasone for children presenting with an acute asthma exacerbation is likely non-inferior to oral Prednisolone.

Clinical Bottom Line

Oral Dexamethasone for children presenting with an acute asthma exacerbation is both non-inferior to and better tolerated than oral Prednisolone.

Level of Evidence

Level 1 - Recent well-done systematic review was considered or a study of high quality is available.

References

1. 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.
2. 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.
3. Altamimi S, Robertson G, Jastaniah W, et al. Single-dose oral dexamethasone in the emergency management of children with exacerbations of mild to moderate asthma. Pediatr Emerg Care. 2006 Dec;22(12):786-93.
4. Keeney GE, Gray MP, Morrison AK, et al. Dexamethasone for acute asthma exacerbations in children: a meta-analysis. Pediatrics. 2014 Mar;133(3):493-9.
5. Meyer J, Riese J, Biondi E. Is dexamethasone an effective alternative to oral prednisone in the treatment of pediatric asthma exacerbations? Hosp Pediatr. 2014 May;4(3):172-80.
6. Watnick C, Fabbri D, Arnol D. Single-dose oral dexamethasone is effective in preventing relapse after acute asthma exacerbations. Ann Allergy Asthma Immunol. 2016 Feb;116(2):171-2.
7. Parikh K, Hall M, Mittal V et al. Comparative effectiveness of Dexamethasone versus Prednisone in children hospitalised with asthma. J Pediatr. 2015 Sep;167(3):639-44
8. Paniagua N, Lopez R, Munoz N et al. Randomized trial of Dexamethasone versus Prednisone for children with acute asthma exacerbations. J Pediatr. 2017 Dec;191:190-196.
9. Cronin J, McCoy S, Kennedy U et al. 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.
10. Ducharme FM, Chalut D, Plotnick L, et al. The Pediatric Respiratory Assessment Measure: a valid clinical score for assessing acute asthma severity from toddlers to teenagers. J Pediatr. 2008;152: 476-480;
11. Mukherjee M, Gupta R, Farr et al. On behalf of the Burden and True Cost of Asthma in the UK Research Team. Estimating the incidence, prevalence and true cost of asthma in the UK: secondary analysis of national stand-alone and linked databases in England, Northern Ireland Scotland and Wales a study protocol BMJ open 2014;4:e006647. doi: 10.1136/bmjopen-2014-006647
12. Sands R, Shanmugavadivel D, Stephenson T et al. Medical problems presenting to paediatric emergency departments: 10 years on. EMJ 2012;29:5 379-382.
13. Mallol J, Crane J, von Mutius E, Odhiambo J, Keil U, Stewart A; ISAAC Phase Three Study Group. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three: a global synethesis. Allergol Immunopathol 2013; 41: 73-85 19.
14. British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. (online) [Accessed 21 January 2018 ]
15. Aljebab F, Alanazi M, Choonara I, et al. Observational study on the palatability and tolerability of oral prednisolone and oral dexamethasone in children in Saudi Arabia and the UK. Arch Dis Child 2018;103:83-88.
16. Hames H, Seabrook J, Matsui D et al. A palatability study of a flavoreddexamethasone preparation versus prednisolone liquid in children with asthma exacerbation in a pediatric emergency department. Can J Clin Pharmacol 2008; 15: e95-98.