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Date: February 6th, 2018

Reference: Foster SJ et al. Oral prednisolone in preschool children with virus-associated wheeze: a prospective, randomised, double-blind, placebo-controlled trial. Lancet January 2018

Guest Skeptic: Dr. Tessa Davis is a Pediatrician specialising in Pediatric Emergency Medicine and currently practicing in a central London hospital. She is also the co-founder of Don’t Forget the Bubbles and on the FeminEM Speaker Bureau.

Case: Tom is a 4-year-old boy who comes into the emergency department with a wheeze following a viral illness. He has been taking salbutamol at home today but he’s still not improving. He has mild work of breathing and a bilateral wheeze. His oxygen saturation is 94% on room air. Tom has no other previous medical history. You start to write up the salbutamol, but should you give him a dose of prednisolone too?

Background: We see “little wheezers” in the emergency department all the time. It is really common during the winter months and often due to a viral infection (1).

There has always been some uncertainty about the benefit of prednisolone for viral wheeze in pre-school children. In 2009, a study by Panickar et al found no positive effect in giving steroids to pre-school children with wheeze (2).

Since then, our practice, and our treatment guidelines, have changed, in spite of questions about the applicability of this study (3,4)

Clinical Question: Does oral prednisolone improve virus-associated wheeze in preschool age children?

Reference:  Foster SJ et al. Oral prednisolone in preschool children with virus-associated wheeze: a prospective, randomised, double-blind, placebo-controlled trial. Lancet January 2018

  • Population: Patients 24 to 72 months of age with a wheeze plus symptoms or signs of a viral upper respiratory tract infection.
    • Exclusions: Oxygen saturations <92% on room air; silent chest; shock or sepsis; previous PICU admission with wheeze; prematurity; other cardiac or respiratory disease; likely alternative diagnosis for the wheeze; or steroid treatment within the preceding 14 days.
  • Intervention: Three-day course of oral prednisolone (1mg/kg once daily).
  • Comparison: Placebo that it looked, smelled, and tasted like the prednisolone.
  • Outcome:
    • Primary: Length of stay in the hospital
    • Secondary: Re-attendance; readmission; salbutamol usage; and residual symptoms after discharge
Dr. Borland and BatDoc

Dr. Borland and BatDoc

Dr. Meredith Borland is the senior author on this publication. She is a paediatric emergency medicine specialist from Perth, Australia and been doing clinical research for a couple of decades. Dr. Meredith is also the director of a tertiary hospital paediatric emergency department. We met at SkiBEEM18 and she agreed to come on the SGEM and discuss her publication.

Authors’ Conclusions: “Oral prednisolone had a clear benefit over placebo at reducing the length of stay in children presenting to a paediatric emergency department with virus–associated wheeze and was well tolerated.”

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. No
  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. Yes
  8. All groups were treated equally except for the intervention. Yes/No. There were 23 patients in the placebo group were given prednisolone later based on clinician judgement. These patients remained in the placebo group for analysis.
  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: They screened 3,727 patients for eligibility with 624 being included in the study. The mean age was 41 months and about 2/3 were male. 

Median length of stay was significantly less in the prednisolone group

  • Primary Outcome:
    • Median LOS: Placebo group was 540 min [IQR 124–971] Prednisolone group 370 min [121–709]
    • The unadjusted ratio of geometric mean for LOS was 0·79 (95% CI 0·64–0·97; p=0·0227) favoring the prednisolone group
      • Note: we are not going to get into subgroup analyses as they are only hypothesis generating.
  • Secondary Outcomes: 
    • Re-Attendance: No difference
    • Re-Admission: No difference
    • Salbutamol Usage: No difference
  • Adverse Events: No serious adverse events were reported.

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Listen to the podcast on iTunes to hear Meredith’s responses to our ten nerdy questions.

1) Selection Bias: There is a possibility of selection bias. Looking at Figure 1 there were more patients who were not included (771) than were included in the study (624). Most of these declined to participate (488) or were not approached to participate (283). You also noted in the manuscript the difficulty with recruitment in view of junior doctor changeover, so they may not have been recruited consecutively. Do we know any more about the patients not recruited and do you think it is possible it could have impacted the results?

2) Baseline Demographics: The baseline demographic factors in each group was incomplete (table 1). You state that there is no clinical difference between the groups, but this is not illustrated using statistical analysis?

3) Blinding: In the methods it said the placebo was “matched for volume, concentration, colour, smell, and taste” of the prednisolone. Did you do a taste-test between the two solutions and could you tell the difference? It would have been easy to ask the parents which group they thought their child was assigned to test for blinding.

4) Pulmonary Score: This has not been validated for patients under five years of age, so the results from this should be questioned as to accuracy (5).

Pulmonary Score

 

5) Taste:  Prednisolone tastes awful and is associated with vomiting. We recently covered a paper comparing dexamethasone to prednisolone for pediatric asthma (SGEM#194: Highway to the Dexamethasone). Did you consider using dexamethasone for these children with a wheeze?

6) Family History or Personal History of Atopy: We found it strange that these things did not affect outcomes in this study. Do you have any idea why?

7) Length of Stay: This was counted as time from drug administration to the time the child could have been discharged. However, time of day for discharge and delays in families arranging transport prevented the children from being discharged at times. Did this have any real effect on in-patient efficacy. If emergency health-care is 24/7/365 and can be accessed at any time does that mean we should be sending people home at any time?

8) Discharged in Four Hours: None of the results were significant in the group of patients who were discharged within four hours. So, would this be relevant to emergency department flow?

9) Changing Outcome: Originally you had dual primary outcomes (there can be only one). This seems like an oxymoron, dual means two and primary means one. It reminded me of terms like jumbo shrimp, fresh frozen and conscious sedation. Then you changed your study post hoc from a non-inferiority trial to a superiority trial. Can you explain why the change and why you picked 10% as what would be considered significantly different?

10) Harm: We must not just consider efficacy but must also consider adverse events and harms. You reported “No serious adverse events were reported during the study or follow-up period”. Like most studies, yours was not powered for harm. One child from each group was reported as being hyperactive but this is something we often associate with steroid usage.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We think the authors’ conclusions of efficacy are stronger than the data supports. While there appears to be a benefit to oral steroids for treating wheeze in children, it is not that clear.

SGEM Bottom Line: In pre-school children presenting with wheeze to the Emergency Department, who have tried and failed using salbutamol at home, early use of oral prednisolone should be considered.

Case Resolution: In view of Tom’s salbutamol use at home, normal oxygen saturations, and pulmonary score of 3, he was given 1mg/kg of oral prednisolone alongside his salbutamol burst treatment. He was able to wean his salbutamol and was discharged eight hours later from the short stay unit.

Dr. Tessa Davis

Dr. Tessa Davis

Clinical Application: This study isn’t going to change what I currently do as I think it supports my intuition that as yet we still don’t have a good diagnostic system for infant and childhood wheeze. A theory which would support both the Panickar and Foster work is that there are different cohorts of children between the age of 1-5 who present with similar symptomatology but for different pathophysiological reasons. The spectrum of bronchiolitis to viral wheeze to asthma is not precise enough to guide the most effective management. If we can’t define the group we are treating how can we adequately assess the response to treatment? What I will be doing is thinking carefully about the diagnosis in patients I see, or are reviewed by me, and asking “Why shouldn’t this patient have steroids?”

What Do I Tell the Parents/Caregivers? I would say to Tommy’s parents that this is a grey area and with patients Tommy’s age we have spent a lot of time debating between ourselves and looking at evidence as to whether steroids will help Tommy. It is not clear cut for him.

Keener Kontest: Last weeks’ winner was Dr. Rijpsma from the Netherlands. They knew Dr. Douglas Prehn was a urologist. Prehn’s sign is described as pain relief when lifting the testicle. It was thought to differentiate between epididymitis and testicular torsion.

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

FOAM logoOther FOAMed:

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. Jartti T, Lehtinen P, Vanto T, et al. .
Pediatr Allergy Immunol 2007; 18: 326–34.
  2. Panickar J, Lakhanpaul M, Lambert PC, et al. Oral prednisolone for preschool children with acute virus-induced wheezing. N Engl J Med 2009; 360: 329–38.
  3. British Thoracic Society, Scottish Intercollegiate Guidelines Network. A national clinical guideline. https://www.brit-thoracic. org.uk/document-library/clinical-information/asthma/btssign- asthma-guideline-2014/ (accessed Dec 3, 2017).
  4. National Asthma Council Australia. The Australian Asthma Handbook, version 1.1. Melbourne, VIC: National Asthma Council Australia, 2015.
  5. Smith SR, Baty JD, Hodge D 3rd. Validation of the pulmonary score: an asthma severity score for children. Acad Emerg Med 2002; 9: 99–104.