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SGEM#194: Highway to the Dexamethasone – For Pediatric Asthma Exacerbations

SGEM#194: Highway to the Dexamethasone – For Pediatric Asthma Exacerbations

Podcast Link: SGEM194

Date: November 9th, 2017

Reference: 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. Ann Emerg Med 2016

Guest Skeptic: Dr. Michael Falk is a Pediatric Emergency Medicine provider who works at Harlem Hospital Center in New York and Children’s National Medical Center in Washington, DC.  He was Director of Emergency Department Simulation and the Co-Fellowship Director at ST Luke’s-Roosevelt Hospital in New York and is a Best Evidence in Emergency Medicine (BEEM) presenter and author. This episode is based upon a BEEM critical review.

Case: A four-year old male who is a known asthmatic presents to the emergency department with an asthma exacerbation. He has been sick with an upper respiratory infection for the last two days. He is getting worse despite his mother giving albuterol every four hours. You order three treatments with albuterol and atrovent and you ask the medical student who is with you, which would be the best steroid to give to this patient by mouth and why?

Background: Untill recently prednisolone have been the standard of care for oral steroids used in the treatment of an asthma exacerbation.  But this medication has a bitter taste which can make it very hard to administer to a younger child.  Also, it is associated with a significant amount of vomiting and this is one of the leading reasons for treatment failure for outpatient asthma [1].

Dexamethasone has been wildly used for a number of pediatric conditions including croup [2], has a longer half-life [3] and is much better tolerated than prednisolone.

There have been a number of recent studies that have compared prednisolone to dexamethasone for outpatient treatment of asthma. A systematic review and meta-analysis demonstrated a single or two-dose regimen of dexamethasone is as effective as a 5-day course of prednisone/prednisolone with less vomiting in the dexamethasone group [4].

The Canadian Guidelines now include the option of giving oral prednisolone or dexamethasone for moderate asthma [5].

While all these studies have shown that dexamethasone was as good as prednisolone for the treatment of asthma, of the seven randomized control trials that have been done, they all have issues with methodology and utilizing different dose of steroids.

PRAMThis study was designed to address these issues and look at a single dose of dexamethasone compared to three days of prednisolone and all the patients were assessed using the Pediatric Respiratory Assessment Measure (PRAM) to control for some of these variations.

The PRAM has five components and has a maximum total score of 12 points: suprasternal retractions (0 to 2), scalene muscle contraction (0 to 2), air entry (0 to 3), wheezing (0 to 3), and SaO2 (0 to 2).


Clinical Question: Is a single oral dose of dexamethasone non-inferior to three days of prednisolone in treating children who present to the emergency department with an acute exacerbation of asthma?


Reference:  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. Ann Emerg Med 2016

  • Population: All patients between the ages of 2 to 16 with history of asthma presenting to the emergency department with an acute asthma exacerbation.
    • Excluded: Anyone with critical or life-threatening exacerbation; varicella of HSV infection; TB exposure; fevers > 39.5C; steroid use with in the last 4 weeks; those with metabolic disease; or any comorbid condition.
  • Intervention Dexamethasone (DEX) 0.3 mg/kg (max. 12 mg) orally once.
  • Comparison: Prednisolone (PRED) 1 mg/kg per day (max. 40 mg/day) orally for three days.
  • Outcome:
    • Primary: Pediatric Respiratory Assessment Measure (PRAM; range 0 to 12) at day four of treatment.
    • Secondary: Change in PRAM score, PRAM score at emergency department discharge, hospital admission on day one, emergency department length of stay, unscheduled visit to health care provider for respiratory symptoms, readmission to the hospital or additional systemic corticosteroids ≤14 days of study enrollment, vomiting within 30 minutes of study medication, school days and parental workdays missed and days of restricted activity.

Authors’ Conclusions: “In children with acute exacerbations of asthma, a single dose of oral dexamethasone (0.3 mg/kg) is noninferior to a 3-day course of oral prednisolone (1 mg/kg per day) as measured by the mean PRAM score on day 4.”

checklistQuality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. Unsure
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Treating doctors were not blinded, but the assessors were blinded to which group the patients were in. No
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: There were 226 children included in this study with more boys than girls. The mean age was around 6 years.


There was no difference in mean PRAM scores at day four between the dexamethasone and prednisolone groups.


  • Primary Outcome: Mean PRAM 0.91 DEX vs. 0.91 PRED (95% CI -0.35 to -.34)
  • Secondary Outcomes: 
    • Mean PRAM scores at Discharge – No difference between groups
    • Length of Stay in the Emergency Department – No difference between groups (~ four hours)
    • Admission to Hospital – No difference between groups (14.6% vs. 13.1%)
    • Length of Admission – No difference between groups (2.33 days vs. 2.69 days)
    • Return Visits to Health Care Provider – No difference between groups (13.9% vs. 14.2%)
    • Missed School and Missed Work – No differences between groups
    • Further Systemic Steroids – Difference (13.1% vs. 4.2%)
    • Vomiting – Fourteen patients in the prednisolone group vomited (Seven within 30 minutes of the first dose, seven on day two and six on day three). No patients in the dexamethasone group vomited.

Screen Shot 2015-04-25 at 3.11.12 PM

  1. Blinding: This was an open label study. The lack of blinding could have introduced some bias. It would have been better if the participants and providers did not know what treatment they were receiving.
  2. Selection Bias: They do not explicitly state patients were selected consecutively. In addition, some of the exclusion criteria were based on subjective assessment. There were significantly less boys in the dexamethasone group vs the prednisolone group (61% vs 75%). This could have been due to chance or selection bias. It is unclear if this difference in boys vs. girls would have impacted the results.
  3. Prognostic Factors: There were higher rates of an atopic dermatitis, stronger family histories for both atopic dermatitis and asthma, and higher rates of daily usage of salbutamol, in the dexamethasone group.  This might have indicated that this group was sicker than the other group and could have skewed the data to make it less significant when compared to the prednisolone group.
  4. Side Effects: This study showed that the most common side effect, vomiting, was not observed in the dexamethasone group.  Given that vomiting, or not being able to tolerate oral medications, is a very common reason for a patient to fail outpatient asthma care. The lack of vomiting in the dexamethasone group would bias the results away from oral prednisolone.
  5. Treatment Failure: The dexamethasone group had a higher number of treatment failures that required a second course of steroids to address this issue.  But these patients were also older and based on their PRAM scores, were actually sicker than the other patients in the study (this hold true for the prednisolone group as well).  One possible reason for this is that in the UK and Ireland they use a lower dose of dexamethasone (0.3 mg/kg) than we do in the US and Canada (0.6 mg/kg).  But the other studies that were done in the US, using the higher dosing regime, still had similar failure rates.  What has become commonly accepted clinically is for the patients who are sicker to receive a second dose of dexamethasone to take at 48 hours after discharge.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusion.


SGEM Bottom Line: A single dose of dexamethasone is non-inferior to a three-day course of oral prednisolone in the treatment of children with an acute asthma exacerbation presenting to the emergency department.


Case Resolution: The medical student says that he has just finished reading a paper on single dose dexamethasone and that their conclusion was it was just as effective and better tolerated than prednisolone in the pediatric population.  Given that he would give dexamethasone at 0.6 mg/kg and strongly consider a second dose to be given at 48 hours after discharge since the patient is having a moderate asthma exacerbation.

image1

Goose and Maverick

Clinical Application: You should strongly consider using dexamethasone as either a single or two-dose regime for the treatment of asthma in the emergency department rather than the traditional three-day course of oral prednisolone.  If you are giving dexamethasone, it would be wise to consider a second dose to be given at 48 hours after discharge.

What do I tell my patientYour child is having an asthma attack. We used to give three-days of oral steroid medication called prednisolone. The number one side effect of this medicine is vomiting. There is another form of steroids called dexamethasone. It usually only needs to be given once and does not seem to cause vomiting. We often will give a second dose to take two days from now.

Keener Kontest: Last weeks’ winner was Noel Blanco from El Paso, Texas. This a back-to-back win for Noel. He knew that sucrose breaks down to glucose and fructose. 

Listen to the SGEM podcast on iTunes to hear this weeks’ keener question. If you know the answer, then send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed:

  • REBEL EM – Single Dose Dexamethasone or 5 Days of Prednisone in Adult Asthmatics?
  • St. Emlyn’s – Why don’t we use dexamethasone for children’s asthma?

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.


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References:

  1. Lucas-Bouwman ME et al. Crushed prednisolone tablets or oral solution for acute asthma? Arch Dis Child. 2001 Apr;84(4):347-8.
  2. Russell KF, Liang Y, O’Gorman K, et al. Glucocorticoids for croup. Cochrane Database Syst Rev. 2011;(1):CD001955.
  3. Schimmer BP, Parker KL. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill; 2007. p. 1587-612.
  4. Keeney et al. Dexamethasone for Acute Asthma Exacerbations in Children: A Meta-analysis. Pediatrics. 2014 March; 133(3): 493–499.
  5. O Ortiz-Alvarez, A Mikrogianakis; Canadian Paediatric Society, Acute Care Committee. Position Statement: Managing the paediatric patient with an acute asthma exacerbation. Posted: May 1 2012 | Reaffirmed: Jan 30 2017
  • John Cronin

    Hi Ken,

    Many thanks to you and Michael for the excellent review of the study. Hopefully it’ll increase the awareness of dexamethasone as an option for acute asthma exacerbations and help improve the care of these kids.

    We did employ randomization in blocks of 12 as you say, however we didn’t stratify for things like gender, family history or anything else. Hence there was, by chance, a slight difference between the groups. I don’t think gender would have made a difference to outcomes and there was no difference between the 2 groups when we did a subgroup analysis of just males and just females.

    I can understand the confusion regarding consecutive recruitment as we did not explicitly say that in the final version of the paper. However patient were recruited consecutively in the study. It took almost exactly one year to recruit all the patients, which was a good rate of recruitment we felt. We recruited 245 out of 354 potentially eligible presentations. There was a consort diagram included in the study which gave some more detail on this.

    I was glad Dr Falk mentioned about our really excellent follow-up. We found that patients and their parents were really engaged with the study and interested in it. We were surprised ourselves with the fact that almost every single one returned for their day four review. We are in debt to these patients and parents for making this day possible. Just further evidence that studies like this are possible in ED.

    You do mention about the further steroid use in the dexamethasone group being more than that of the prednisolone group. And perhaps the solution as you discussed is a second dose of dexamethasone (kinda like having a wing man!). I should repeat that this study was powered to see a difference in mean PRAM score on Day 4 and there was no difference between the groups. So to really prove whether a second dose is beneficial one would have to do a study of one versus two doses of dexamethasone. (Was there ever a sequel to Topgun?:))

    Thanks again,
    John Cronin

    • Ken Milne

      Thank you John and your team for conducting the research and publishing the study. One wonderful thing about the #FOAMed world is having the lead author respond to a blog critical appraisal. We really appreciate you taking the time to look at our review and comment.

      The clarification on some of the methodology issues were helpful. I hope researchers and editors who read this will consider adding certain elements to the final publications. Just putting in the term “consecutive” for the recruitment of patients eliminates one question we always have.

      Dr. Falk will be responding separately to your comments. He was an excellent guest skeptic and I look forward to having him back on the SGEM.

      If you are conducting another study “Highway to the Dexametha-Zone 2” perhaps some other sites (Canada, Australia, USA) would be interested in participating. Please accept this as a standing invitation to appear on the SGEM to discuss the publication.

      To answer the question at the end of your feedback, yes and no. There has not been a sequel to Top Gun but apparently one is planned to be released in 2019.

      http://www.independent.co.uk/arts-entertainment/films/news/top-gun-2-release-date-maverick-paramount-a7819421.html

      We might have to start another series on the SGEM…movie reviews:)

      Cheers,
      Ken

    • Mike Falk

      Thanks for the feedback and the clarification. I had assumed you did consecutive recruitment but didn’t want to say that and not know. Is asthma not that prevalent in Dublin? We have such high rates in New York, that I assume everywhere else is the same! What is the rate? As mentioned I work in Harlem and see there is actually data that say up to 25% of all children have asthma in our community.

      I would love to see a follow up study to this. I do think that we really need to get some sound data that a 2nd dose does the job and that we are not do some kids a “disservice”. My clinical experience is that adding the 2nd dose is highly effective and reduces “bounce backs” but the problem with assumptions is they can make an “ass” out of you!!

      Perhaps we should do a tale of two cities and asthma as a follow up?

    • Mike Falk
    • Mike Falk

      Here is great graph looking at asthma rates and area in NY city. As you can see it is quite serioulsy overrepresented in the areas with the highest endemic poverty rates (or I can see it knowing the city, sorry). It is really quite a devastating issue here and anything that we can do to improve outcomes and the life of children who suffer from this is great!

      Perhaps we shuld look at replicating or doing similar study here at one of more hospitals!

      https://www.cccnewyork.org/blog/concentrations-of-risk-asthma-and-poor-housing-conditions/

  • Ken Milne
  • Ken Milne

    Theme music for this episode was suggested by Ian Lewins. https://www.youtube.com/watch?v=vwBbrngafl0

  • Ken Milne

    Dr. Damian Roland: What I Learned This Week http://rolobotrambles.com/causeandcure/

  • Kirsty Challen