Randomised control trial
Panickar J., et al.Oral Prednisolone for Preschool Children with Acute Virus-Induced Wheezing
The New England Journal of Medicine
January 22, 2009; 329-338
- Submitted by:Catherine Burger - Medical Student, M4
- Institution:Michigan State University College of Human Medicine
- Date submitted:17th August 2009
1
Objectives and hypotheses
1.1
Are the objectives of the study clearly stated?
Yes, The authors first discuss conflicting previous literature assessing the usefulness of systemic corticosteroids in young children with acute viral-induced wheezing and proceed to say "in this study, we assessed the efficacy of a short course of therapy with oral prednisolone in children presenting with virus-induced wheezing." The authors do not clearly state a hypothesis or further describe their objectives.
2
Design
2.1
Is the study design suitable for the objectives
Yes, they performed a randomized, double-blind, placebo-controlled trial.
2.2
Who / what was studied?
Children 10 to 60 months of age, presenting to one of the three study hospitals in the UK, with a clinical diagnosis of viral-induced wheezing were included. Children were either given an age based dose of prednisolone or placebo for 5 days. The study's primary outcome was duration of hospitalization, secondary outcomes included PRAM scores at 4,12 and 24 hours; the total dose of inhaled albuterol during hospitalization; the mean 7 day symptom score, as assessed by a parent or guardian; the mean number of actuations of albuterol given at home during a 7 day period; the time required for the child to be "back to normal"; and hospital readmission for wheezing within a month after discharge.
2.3
Was this the right sample to answer the objectives?
Yes, they studied young children between 10 and 60 months. The excluded children in shock, those with clinical evidence of bacterial sepsis, children with known heart or lung disease, those who were receiving immunosuppressive therapy or had an immunodeficiency, or children who had active varicella infection or had recently been exposed to varicella.
2.4
Is the study large enough to achieve its objectives? Have sample size estimates been performed?
Yes: "we determined the required power for the study from prospectively collected data from 208 preschool children presenting to the University Hospitals of Leicester National Health Service Trust with a physician-diagnosed attack of virus-induced wheezing. We calculated that 350 in each group would give a power in excess of 80% to detect a difference of 5 hours in the geometric mean of duration of hospital stay with a two-sided alpha level of 0.05."
2.5
Were all subjects accounted for?
Yes: 1180 patients assessed for eligibility, 480 not enrolled (162 did not meet eligibility 318 declined), 700 randomized, 13 were dropped (10 were accidentally recruited twice, 3 did not have randomization number properly recorded), 343 were assigned to and included in the prednisolone intention=to-treat analysis, 344 were assigned to and included in the placebo intention-to-treat analysis.
2.6
Were all appropriate outcomes considered?
It appears so, yes: The authors collected data on duration of hospitalization, PRAM scores at 4,12 and 24 hours; the total dose of inhaled albuterol during hospitalization; the mean 7 day symptom score, as assessed by a parent or guardian; the mean number of actuations of albuterol given at home during a 7 day period; the time required for the child to be "back to normal"; and hospital readmission for wheezing within a month after discharge.
2.7
Has ethical approval been obtained if appropriate?
Yes: "The study was approved by the UK National Health Service Multicenter Research Ethics Committee and by local institutional review boards and was approved by the UK national health Services Medicines for Children Research Network."
2.8
Were the patients randomised between treatments?
Yes (see below)
2.9
How was randomisation carried out?
Study numbers were assigned sequentially, and randomization was achieved by generating numerical codes in random permuted blocks of 10. Randomization and packaging of placebo and prednisolone were done by Nova Laboratories with identical packaging and capsules. Randomization codes were locked in a hospital pharmacy until all data entry was complete.
2.10
Are the outcomes clinically relevant?
Yes, they look at length of stay, a validated assessment of the severity of a child's symptoms (PRAM score), parent assessment of symptoms, amount of albuterol use and hospital readmission.
3
Measurement and observation
3.1
Is it clear what was measured, how it was measured and what the outcomes were?
Yes, for example duration of hospital stay was divided into two time periods - the time from enrollment to the time of actual discharge from the hospital and the time from enrollment to the time that the patient was deemed to be "fit for discharge" or signoff for discharge.
3.2
Are the measurements valid?
The PRAM (preschool respiratory assessment measure) assessment has been validated however the parent assessment of "return to normal" or parent assessment of symptom severity have not been validated.
3.3
Are the measurements reliable?
Yes, hospital length of stay, readmission, albuterol use, PRAM scores and parent assessment appear to be good outcome measure for viral-induced asthma.
3.4
Are the measurements reproducible?
Yes, The PRAM assessment is standardized and could be used anywhere, length of stay and albuterol use is commonly recorded during hospital admissions or ED visits as well as readmission.
3.5
Were the patients and the investigators blinded?
Yes, this was a double-blind trial with concealed randomization with identical placebo and prednisolone packaging and capsules and randomization codes were locked until all study data was collected.
4
Presentation of results
4.1
Are the basic data adequately described?
Yes, their primary and secondary outcomes measurements as well as subgroup analysis are all described in the text or tables 2,3, and 4.
4.2
Were groups comparable at baseline?
Yes, not statistically significant differences were found between the two groups. The authors specifically looked at age, sex, previous wheezing, age at first onset of wheezing, coughing or wheezing without a cold in the previous year, conditions previously diagnosed by a physician (such as asthma or eczema), family history of asthma, smokers in household, number of wheezing attacks/ presentations to the hospital in the previous year, fever, previous medications, corticosteroid use in previous year, and baseline PRAM score.
4.3
Are the results presented clearly, objectively and in sufficient detail to enable readers to make their own judgement?
Yes, all data and numbers are presented, clearly labeled and explained.
4.4
Are the results internally consistent, i.e. do the numbers add up properly?
Yes, all groups and subgroups appear consistent.
4.5
Were side effects reported?
No clinically significant adverse events were reported to teh patient safety committee, however in one child in the prednisolone group the parents attributed excess vomiting to the study drug and discontinued the medication.
5
Analysis
5.1
Are the data suitable for analysis?
Yes, it appears their data was properly collected for the outcomes described and statistical comparisons were made as described in the text (see below).
5.2
Are the methods appropriate to the data?
The primary and secondary outcomes described in the methods section appear to correlate well with the data found in the results section.
5.3
Are any statistics correctly performed and interpreted?
Yes, Differences in continuous outcomes between two study groups were assessed by obtaining mean differences with 95% confidence intervals from a linear regression model. The length of stay was also shown graphically with the use of Kaplan-Meier survival estimates.
6
Discussion
6.1
Are the results discussed in relation to existing knowledge on the subject and study objectives?
Yes, the authors compare their results to previous studies that agree and disagree with their results. After a description of the disagreeing studies the authors proceed to highlight differences between their study and the previous studies (such as the authors' use of the PRAM score and the fact that a majority of the children in their study did not have classic atopic asthma phenotype).
6.2
Is the discussion biased?
The discussion does not appear biased since the authors mention their own previous results, conflicting results from other researchers and limitations to their own current study.
7
Interpretation
7.1
Are the authors' conclusions justified by the data?
The data the authors collected and analyzed supports their conclusion that oral prednisolone should not be routinely given to preschool children presenting to the hospital with acute, mild-to-moderate virus-induced wheezing.
7.2
What level of evidence has this paper presented? (using CEBM levels)
This appears to have 1b level of CEBM evidence for a therapy (Individual RCT with narrow Confidence Interval)
7.3
Does this paper help me answer my problem?
Yes, as mentioned previously this paper supports the idea that oral prednisolone should not be routinely given to preschool children presenting to the hospital with acute, mild-to-moderate virus-induced wheezing.
8
Implementation
8.1
Can any necessary change be implemented in practice?
Physicians could consider not routinely giving oral corticosteroids for the presentation of preschoolers to the hospital with virus-induced wheezing but further study of outcomes may be needed before an official clinical recommendation or guideline could be made.
8.2
What aids to implementation exist?
1. Parents often prefer not giving their preschooler medication if not absolutely necessary. 2. Costs could be reduced if the medicine has been given routinely and is no longer needed. 3 Side effects of the medication could possibly be avoided.
8.3
What barriers to implementation exist?
Traditional routine use of corticosteroids for this patient population as well as previous studies showing a possible benefit to these medications may create hesitation in physician and institution practice changes based on this article.