A randomized trial of single-dose oral dexamethasone versus multidose prednisolone for acute exacerbations of asthma in children who attend the emergency department

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Cronin JJ, 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". Annals of Emergency Medicine. 2016. 67(5):593-601.
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Clinical Question

In children experiencing an acute exacerbation of asthma, is single dose dexamethasone as safe and effective as 3 days of prednisolone in reducing asthma severity and hospital admission?

Bottom Line

In children with an acute asthma exacerbation, single dose dexamethasone is as effective as multi-dose prednisolone in remitting exacerbation and limiting hospital admission. Conversely, there is a significant difference in adverse events experienced post administration of prednisolone, which can cause vomiting, as opposed to no observed adverse effects after dexamethasone administration. Being a single dose, dexamethasone may also increase patient ease and adherence, however more patients required further steroids within 14 days from the dexamethasone group.

Major Points

Corticosteroids are commonly used for treatment of acute asthma exacerbations.1 The British Guideline on the Management of Asthma recommends the use of oral prednisolone for acute asthma exacerbations because it reduces relapses and subsequent hospital visits.1 Prednisolone treatment requires multiple doses due to its short half-life, while dexamethasone - another similar corticosteroid - only requires a single dose. Use of single dose dexamethasone instead of prednisolone may increase patient compliance.

The study aimed to determine if a single dose of dexamethasone is noninferior to multidose prednisolone through a randomized, open-label trial in patients aged 2-16 years who presented to a tertiary pediatric ED. The trial compared oral dexamethasone (single dose of 0.3 mg/kg) with oral prednisolone (1 mg/kg per day for 3 days). The primary outcome measured was the PRAM score performed on day 4 and the secondary outcomes included requirement for further steroids, adverse events following medication administration, hospital admission, and unscheduled return visits to a healthcare practitioner.

This was the first study performed comparing single-dose dexamethasone to prednisolone as a primary outcome in pediatric patients with an acute asthma exacerbation. An open-label study may have introduced bias and limited the trial’s internal validity. Inconsistency may also be present between the patient-reported and actual compliance. The authors have stated no commercial, financial, or other such relationships exist. Overall the quality of evidence collected is high and should be considered for implementation and further research.

Guidelines

  • National Health Lung and Blood Institute EPR-3 (2007)2
    • Therapy for generalized exacerbations of asthma:
      • Oxygen to relieve hypoxemia
      • SABA (Short-acting Beta Agonists) + inhaled ipratropium bromide in severe exacerbation
      • Systemic corticosteroids (prednisone, methylprednisolone, and prednisolone) in moderate or severe exacerbations or for patients who fail to respond promptly and completely to a SABA 5-10 day course of 1-2 mg/kg/day orally in 2 divided doses (maximum 60 mg/day)
      • IV magnesium sulfate or heliox

Design

  • Randomized, controlled trial, open label, non-inferiority study
  • Randomization design with adequately concealed allocation
  • N = 245
    • Experimental, DEX: N = 123
    • Standard, PRED: N = 122
  • Setting: 1 UK emergency department
  • Enrollment: 2011-2012
  • Analysis: intention-to-treat
  • Primary outcome: remittance of asthma exacerbation by day 4 using PRAM score


Population

Inclusion Criteria

  • Children aged 2 to 16 years
  • Presentation to the ED with acute asthma exacerbation
    • An exacerbation of asthma was defined as acute asthma that prompts ED assessment, with any or all of the following clinical features:
      • Dyspnea
      • Wheeze
      • Acute cough
      • Increased work of breathing
      • Increased requirement for ß2-agonist from baseline use
      • SaO2 less than 95%
  • History of asthma
    • At least 1 previous episode of ß2-agonist-responsive wheeze or a previous diagnosis of asthma, made by a pediatrician or clinician of comparable experience


Exclusion Criteria

Children with:

  • A critical or life threatening asthma exacerbation
  • Active varicella or herpes simplex infection
  • Documented concurrent infection with respiratory syncytial virus
  • Temperature greater than 39.5C
  • Use of oral or intravenous corticosteroids in the previous 4 weeks
  • Concurrent stridor
  • Galactose intolerance
  • Lapp-lactase deficiency or glucose-galactose malabsorption
  • A history of tuberculosis exposure
  • Or significant comorbid disease


Baseline Characteristics

Based on DEX group:

  • Age 5.65 years (mean)
  • Male: 61.8%
    • PRED group contained significantly more males (74.6%)
  • Regularly inhaled corticosteroids: 60.2%

Interventions

  • Randomized to intensive (targeting HbA1c <6%) or standard (HbA1c 7-7.9%) glycemic therapy

    • Then 46% were randomized to intensive (SBP <120) vs. standard (SBP <140) blood pressure therapy
    • Remaining 54% randomized to fenofibrate vs. placebo; all received statin
  • Intensive glycemic control group attended monthly visits for 4 months, then every 2 months, with additional visits and telephone calls as needed
  • Standard therapy group had glycemic control visits every 4 months

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

There was no difference in mean PRAM scores at day 4 between the dexamethasone and prednisolone groups, mean difference = -0.005 (95% CI -0.35 to 0.34)

  • DEX: 0.91 (SD 1.16)
  • PRED: 0.91 (SD 1.52)

Secondary Outcomes

No significant difference in PRAM scores at discharge, mean difference = 0.02 (95% CI -0.39 to 0.43)

  • DEX: 1.01 (SD 1.58)
  • PRED: 0.99 (SD 1.69)

No significant difference in duration of ED stay, mean difference = 0.13 (95% CI -0.63 to 0.71)

  • DEX: 4.31 hours (SD 1.7)
  • PRED: 4.18 hours (SD 2.11)

No significant difference in the number of patients admitted from the ED, in the subsequent length of stay, or in the need for a repeat return to a healthcare provider.

  • Patients discharged and required readmission within 2 weeks:
    • DEX: 3 patients (2.5%)
    • PRED: 1 patient (0.8%)

Children who received further systemic corticosteroids within 14 days of enrollment, absolute difference = 8.9% (95% CI 1.9% to 16.0%)

  • DEX: 16 patients (13.1%)
  • PRED: 5 patients (4.2%)
    • NNH = 11
    • These patients were typically older (mean age = 6.0 years; SD 3.71)
    • Additionally had higher mean PRAM scores (initial PRAM score = 5.43 [SD 2.34], PRAM score at discharge = 3.14 [SD 2.56]; PRAM score at day 4 = 1.48 [SD 1.60])

No significant difference in the number of ß2-agonist inhaler treatments administered in ED, mean difference = -0.01 (95% CI -0.26 to 0.24)

  • DEX: 3.13 (SD 1.00)
  • PRED: 3.14 (SD 1.02)

No significant difference in:

  • Number of days restricted activity
  • Number of school days missed
  • Number of parental workdays missed

Adverse Events

Seven patients vomited within 30 minutes of first dose of prednisolone on day 1, absolute difference = -5.7% (95% CI -9.9% to -1.54%)

  • DEX: none
  • PRED: 7 patients (5.7%)
    • NNH = 17

A total of 14 patients vomited after at least one dose of prednisolone on days 1-3 compared to none in the dexamethasone group.

Criticisms

  • Being an open-label study and knowledge of the intervention may have introduced bias and limited the trial’s internal validity.
  • Significantly more male patients in the prednisolone group raises the possibility of selection bias. However, the interventions studied have no demonstrable sex difference.
  • Inclusion of patients admitted to the hospital in the analysis may be considered a confounding factor. This is determined to not significantly affect the internal validity of the trial because the number of participants in each treatment group in the hospital were similar.
  • Compliance was self-reported meaning there could be some discrepancy with the accuracy of their reporting (inconsistency).

Funding

This study was funded by the National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin in Dublin, Ireland. The authors have stated that no commercial, financial, or other such relationships exist.

Further Reading

1) British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Available at: https://www.brit-thoracic.org.uk/document-library/clinical-information/asthma/btssign-asthma-guideline-2014/. Accessed April 27, 2017.

2) 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):S373-417.