Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Randomised double blind placebo controlled trial of prednisolone in children admitted to hospital with respiratory syncytial virus bronchiolitis

van Woensel JB, Wolfs TF, van Aalderen WM, Brand PL, Kimpen JL.

Thorax 1997; 52: 634-637 [abstract]

Reviewed by Al Torres, M.D., M.S., University of Illinois College of Medicine at Peoria

Review posted September 29, 1998

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I. What is being studied?:

The study objective:

To compare oral prednisolone with placebo on the clinical course of children admitted to hospital with RSV bronchiolitis

The study design:

A randomized, double blind controlled trial

The patients included:

54 patients with RSV, 40 non-mechanically ventilated (20 per group), 14 mechanically ventilated (7 per group). RSV had to be confirmed by immunofluorescence test in a child < 2 yrs with clinical picture of bronchiolitis.

The patients excluded:

Patients that had received systemic or inhaled steroids in the previous 2 months were excluded. One patient in the non-ventilated group was intubated on day one and was excluded from the efficacy analysis.

The interventions compared:

Oral prednisolone (1 mg/kg/day divided bid), or identical-appearing placebo once daily, for seven days.

The outcomes evaluated:

In the non-ventilated group, a daily symptom score with a scale of 0 to 12, consisted of 4 items (respiratory rate, presence of wheezing, presence of cyanosis, and use of accessory respiratory muscles) was assigned and the differences assessed by day 3. In the ventilated patients, hospital length of stay and duration of mechanical ventilation were the outcome measures.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Blinded sealed envelopes, the sequence of which was determined by random number tables, were prepared by a blinded pharmacist. Patients were stratified on the basis of weight.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. Hospital discharge was the endpoint of followup, and all patients were accounted for.

Were patients analyzed in the groups to which they were randomized?

Yes. Patients were analyzed as non-ventilated groups (n = 39) and ventilated groups (n = 14), and there were no crossovers. However, one patient from the non-ventilated group (received placebo) was intubated on day one and excluded from efficacy analysis. True intention-to-treat analysis should have included this patient. The different outcome measures for the two groups made this problematic for this one patient (although an additional patient was intubated and mechanically ventilated after three days, and it is not clear what outcome measures were then applied to this patient). A category of "failure" could have been created for the non-ventilated patients to account for those needing mechanical ventilation.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. Identical capsules of placebo and prednisolone dissolved into water were used.

4. Were the groups similar at the start of the trial?

Yes. Differences in age, gender ratio, family history of atopy, high risk (heart disease, BPD, ex-premie), mean IgE, and median symptom score were not significantly different.

To determine whether the effect of treatment was dependent on the severity of symptoms at entry, the authors performed an analysis of variance modeling the effects of treatment, baseline severity score, and their interaction. Neither baseline severity score, nor the interaction term was significant.

5. Aside from the experimental intervention, were the groups treated equally?

Unknown. Other clinical interventions (continuous albuterol, terbutaline, neuromuscular blockade, ipratropium, etc.) were at the discretion of the patients' physicians, and no information is offered regarding comparisons between groups.

III. What were the results?

1. How large was the treatment effect?

Non-ventilated patients: Not large enough to reach statistical significance. In this group, the symptom score (mean, SE) decreased significantly faster in the prednisolone group (-1.2, 0.2 points/day) than it did in the placebo group (-0.6, 0.2) (95% CI for difference -1.2 to -0.1, p = 0.02). Hospital length of stay was one day shorter in the prednisolone group (7.3, 1.2) than in the placebo group (8.3, 0.9), but this was not statistically significant (95% CI for difference, -4.1 to 2.2, p = 0.54).

Ventilated patients: The mean hospital length of stay was significantly shorter in the prednisolone group of ventilated patients (11.0, 0.7) than in the placebo group (17.0, 2.0) (95% CI -10.2 to -1.8, p <0.01). However, due to the skewed distribution of ICU length of stay (i.e., most patients don't stay very long) and outliers (e.g., one patient in the placebo group with BPD died after 3 weeks in the ICU), it would have been helpful to confirm this difference using median LOS (1). There was a nonsignifiant decrease in the duration of mechanical ventilation in treated patients (-1.6 days; 95% CI for difference = -5.8 to 2.7, p = 0.56).

2. How precise was the estimate of the treatment effect?

In non-ventilated patients, the 95% confidence interval for the daily decrease in symptom scores in the prednisolone group shows that the decrease could be as small as 0.1 and as large as 1.2 points per day. For the ventilated patients, the decrease in hospital length of stay in the prednisolone group could be as low as 1.2 days and as high as 11.8 days.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Maybe. The population studied appears similar to many hospitals with bronchiolitis patients. Use of bronchodilators, supplemental oxygen and antibiotics in the groups was not significantly different. The method of ventilation was not standardized. Because the trial was double-blinded, it is less likely that the treatment group received differential types of treatment that might bias the results. The results of this trial must be taken in context with the results of the other 7 trials (2-4,6-8) evaluating the efficacy of steroids for bronchiolitis.

2. Were all clinically important outcomes considered?

No. Although length of stay, duration of mechanical ventilation and symptom scores were compared, there is no information offered about potential complications of prednisolone such as hyperglycemia, gastrointestinal bleeding and immunosuppression that could increase the rate of infections. Use of antibiotics did not differ between the groups.

3. Are the likely treatment benefits worth the potential harms and costs?

If prednisolone does not increase gastrointestinal bleeding and infections, and the benefits are confirmed in multicenter studies, the cost of the medicine is quite low. If length of stay were truly to be reduced, this would probably more than compensate for the small added cost of the medication. It is unclear if the benefit of the drug actually results in a reduction in hospital costs. The treated non-ventilated group had symptom scores improve faster but not length of stay. The ventilated patients did have shorter length of stay but not a significantly shorter duration of mechanical support. The results of this study would be stronger if co-interventions were standardized, including ventilator management. Having explicit criteria for discharge would also make the results more believable.

References

1. Weissman C. Analyzing intensive care unit length of stay data: problems and possible solutions. Crit Care Med 1997;25:1594-1600. [abstract]
2. Dabbous IA, Tkachyk JS, Stamm SJ. A double blind study on the effects of corticosteroids in the treatment of bronchiolitis. Pediatrics 1966;37:477-84. [abstract]
3. Leer JA, Green JL, Heimlich EM, Hyde JS, Moffey HL, Young GA, et al. Corticosteroid treatment in bronchiolitis. A controlled collaborative study in 297 infants and children. Am J Dis Child 1969;117:495-503. [abstract]
4. Springer C, Bar-Yishay E, Uwayyed K, Avital A, Vilozni D, Godfrey S. Corticosteroids do not affect the clinical or physiological status of infants with bronchiolitis. Pediatr Pulmonol 1990;9:181-5. [abstract]
5. Daugbjerg P, Brenoe E, Forchhammer H, et al. A comparison between nebulized terbutaline, nebulized corticosteroid and systemic corticosteroid for acute wheezing in children up to 18 months of age. Acta Paediatr 1993;82:547-551. [abstract]
6. Klassen T, Sutcliffe T, Watters L, Wells G, Allen U, Li M. Dexamethasone in salbutamol-treated inpatients with acute bronchiolitis: A randomized, controlled trial. The Journal of Pediatrics 1997;130:191-196. [abstract] [PedsCCM EBJC Review]
7. De Boeck K, Van der Aa N, Van Lierde S, Corbeel L, Eeckels R. Respiratory syncytial virus bronchiolitis: A double-blind dexamethasone efficacy study. The Journal of Pediatrics 1997;131:919-921. [abstract]
8. Richter H, Seddon P. Early nebulized budesonide in the treatment of bronchiolitis and the prevention of postbronchiolitic wheezing. The Journal of Pediatrics 1998;132:849-853. [abstract]
9. Roosevelt G, Sheehan K, Grupp-Phelan J, Tanz R, Listernick R. Dexamethasone in bronchiolitis: a randomised controlled trial. The Lancet 1996;348:292-295. [abstract] [PedsCCM EBJC Review]

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