Single-dose Dexamethasone: Bursting onto the Scene for Asthma Exacerbations

To treat acute asthma exacerbations in children, how about a single dose of dexamethasone and your done!  Sounds simple, easy, and convenient.  But is it too good to be true?  Early administration of systemic corticosteroids is recommended in national guidelines to treat moderate to severe asthma exacerbations and mild asthma exacerbations that do not respond completely to short-acting β-agonists.¹ The recommended treatment regimen consist of oral prednisone or prednisolone, taken once or twice daily, for five days.¹ However, 5 to 17% of kids vomit the dose of liquid prednisolone depending on the formulation.²  This causes some patients to discontinue prednisolone and less than optimal adherence to asthma pharmacotherapy leads to more emergency department (ED) visits.³  Moreover, at least one in four kids prescribed medications during a pediatric emergency department visit do not get the prescription filled.⁴ Thus, a failure to obtain or continue steroid therapy increases the risk for asthma complications, recurrent ED visits, and health care utilization.⁵ A single dose of dexamethasone — given orally (PO) or intramuscularly (IM) — may be a useful alternative for the treatment of acute asthma exacerbations.  Anecdotally, kids say it tastes better.  And dexamethasone has a much longer duration of effect (72 hours) than prednisolone (36 hours).⁶

A meta-analysis published in Pediatrics sought to determine whether one or two doses of dexamethasone – given PO or IM – was equivalent to a five-day course of PO prednisone or prednisolone for treatment of an acute asthma exacerbation in children.⁷ The primary outcome of interest was unscheduled return visits (clinic visit, ED visit, or hospital admission) for acute asthma exacerbations. Secondary outcomes included vomiting in the ED and at home. Studies were included if they were randomized controlled trials in either an ambulatory or ED setting and compared dexamethasone to either prednisone or prednisolone in children less than 18 years of age. Data were abstracted by four authors and verified by a second author. Study quality was assessed using the Cochrane risk of bias tool, a validated instrument.⁸ In addition, the quality of the included studies was assessed based on the presence of industry sponsorship and whether intent to treat analysis was performed. Two reviewers independently evaluated the included study quality.

Out of 667 studies identified, only six studies met the inclusion criteria.  All six were randomized controlled trials conducted in pediatric emergency departments. Dexamethasone was given as a single IM dose in three studies^9-11, a single PO dose in one study¹², and two PO doses over two days in two studies.^13-14 The mean age of patients in the studies was 53.2 months (or about 4 ½ years old). The majority of patients were boys (63.5%). There were no differences between the dexamethasone groups and the prednisolone/prednisone groups with respect to baseline age, sex, or initial asthma severity score.  Additionally, there was no difference between the treatment groups in terms of improvement in asthma scores during the initial ED visit, number of albuterol treatments received in the ED, post-treatment asthma severity scores, average improvement in asthma scores, or rate of hospitalization during the initial ED visit.

One or two doses of intramuscular or oral dexamethasone are equivalent to a 5-day course of oral prednisolone/prednisone in terms of asthma relapses.  The relative risk (95% CI) of experiencing a relapse in the dexamethasone group vs. the prednisolone/prednisone group at 5, 10-14 and 30 days were 0.90 (0.46 – 1.78), 1.13 (0.77 – 1.67) and 1.20 (0.03 – 56.93), respectively. Patients in the dexamethasone group were less likely to vomit in either the ED (RR 0.29, 95% CI 0.12 – 0.69) or at home (RR 0.32, 95% CI 0.14 – 0.74).

This meta-analysis is currently the most comprehensive evaluation regarding the use of dexamethasone for acute asthma exacerbations.  The number of subjects in the included studies ranged from 15 to 272, with an average of 171. They had similar populations enrolled in the included studies, so the results can likely be generalized to most pediatric asthma patients who visit EDs every year.  The primary outcome of interest being a return visit is a strong choice as this is the ultimate outcome that we are trying to prevent when using systemic steroids. 

There were several limitations to this meta-analysis. All studies included were conducted in EDs and therefore the results may not apply to other settings such as ambulatory care practices or hospitalized patients. Children included in the studies were diagnosed with mild to moderate asthma exacerbations and those with a history of a pediatric intensive care unit admission were excluded in four of the six studies.  Thus, the findings may not be applicable to patients with severe asthma exacerbations.  Also, it is important to note that the endpoint of relapse was not measured at the same time intervals in all included studies. Relapse at 5 days was reported by 4 studies, at 14 days by 3 studies and at 30 days by 1 study. Although there was no statistically significant difference in the relative risk of experiencing relapse at each time point, the RR of relapse at 30 days is solely based on data from one study which enrolled 33 children, and should be interpreted with this in mind. Additionally, vomiting in the ED was reported by 4 studies and vomiting at home was reported by 3 studies.

Among the included studies there was significant variability in the doses of dexamethasone, prednisolone, and prednisone. Dexamethasone doses ranged from 0.3 to 1.7 mg/kg and prednisolone/prednisone doses ranged from 1 to 2 mg/kg. Additionally, there was significant variability in the maximum dose allowed for both dexamethasone and prednisolone. Dexamethasone maximum doses ranged from 15 to 36 mg and prednisolone/prednisone doses ranged from 20 to 100 mg. The NHLBI asthma guidelines recommend using prednisone, prednisolone, or methylprednisolone at a dose of 1-2 mg/kg/day up to a maximum of 60 mg in children.¹ These doses are roughly equal to 0.3mg/kg/day of dexamethasone with a maximum of 9mg.  Four of the six studies included in this analysis used a dexamethasone dose of 0.6mg/kg/day with a maximum of 15 or 16 mg per day. For prednisone/ prednisolone, the majority of patients received 1mg/kg/day.

The authors were unable to compared treatment regimens administered by different routes (PO vs. IM) or perform sub-analyses as the study end points (relapse at 5 days vs. 14 days) varied. The quality of the included studies was poor with five of the six studies scoring less than 4 (out of 8) points using the risk of bias tool. This was due to a lack of blinding in most studies. Also, the first dose of medication in all included studies was given in the ED, therefore ensuring 100% adherence in the dexamethasone groups.  No information was provided regarding adherence in the prednisone/prednisolone groups.

Further studies are needed to determine which dexamethasone route of administration (PO vs. IM vs. IV) is preferred and whether single dose or two dose regimens are equally effective. Also, we need to know more about the adverse effects. The dexamethasone 1 mg/mL oral liquid, which contains 30% alcohol, can cause side effects in kids.  The tablet formulation, which can be crushed, may be preferred. Two randomized controlled trials (NCT00942201 and NCT00973687) that investigated similar interventions and outcomes have been completed per clinicaltrials.gov.  But results are not yet available. One study (NCT02192827) comparing the efficacy of a single dose of oral dexamethasone vs. two doses of dexamethasone in mild and moderate asthma exacerbations in kids is currently recruiting, with an anticipated completion in April 2017.

Optimal adherence to prescribed asthma pharmacotherapy regimens is important and reduces the likelihood of asthma-related ED visits.³ The simplified dosing and lower risk of vomiting make dexamethasone an appealing option.  Although we know that prednisone/prednisolone is effective for acute asthma exacerbations, this is only true if the patient takes it for 5 days.  If the prescription goes unfilled, the likelihood of a return trip to the ED is much higher. Because the meta-analysis and the included studies have several limitations, we believe dexamethasone should be only considered for patients with mild to moderate asthma in whom there are concerns about adherence with a 5-day regimen or who have experienced emesis with previous courses of prednisolone/prednisone.  What do you think?  Should we use single-dose dexamethasone more widely?  Should we consider single dose dexamethasone in asthma action plans too?