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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The effectiveness of glucorticoids in treating croup: meta-analysis

Ausejo M, Saenz A, Pham B, Kellner J, Johnson D, Moher D, Klassen TP

Br Med J 1999; 319: 595-600. [abstract, full-text]

Reviewed by Melchor Sanchez-Mendiola, Hospital Central Militar, Mexico City, Mexico.

Review posted April 4, 2000

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I. Are the results of the study valid?

A. Primary questions:

1. Did the overview address a focused clinical question?

Yes. The meta-analysis tried to answer the question: In pediatric patients with croup (patient population), does the treatment with glucocorticoids (intervention) decrease the severity of the disease (decrease in croup scale, less use of epinephrine, length of stay and rate of hospitalization)[outcome measures]?

2. Were the criteria used to select articles for inclusion appropriate?

Yes, two investigators selected studies as being potentially relevant. All studies retrieved were reviewed independently by two reviewers, and to be eligible for inclusion in the meta-analysis the study had to meet all these requirements: patients with croup, comparison of an intervention with corticoid vs. placebo or other active treatment, clinically relevant outcome measures (croup clinical score, rate of hospitalization and time in the hospital, additional interventions), the treatment assignment had to be randomized. These criteria are satisfactory for the relevant clinical question.

B. Secondary questions:

3. Is it unlikely that important, relevant studies were missed?

Yes. The author's study identification strategy was thorough, searching the most important computerized medical databases (Medline Jan 1966 to Aug 1997, Excerpta Medica and Embase Jan 1974 to Aug 1997) to find all publications examining and exploding glucocorticoid therapy for croup (and with each of the names of the specific corticosteroids) with a previously validated strategy (described in detail in Appendix 1 of the paper at BMJ website extra, not included in the printed version). The search was restricted to randomized controlled trials. The authors also searched the Controlled Trials Register of the Cochrane LIbrary, including studies identified by the Acute Respiratory Infection Review Group of the Cochrane Collaboration by hand searching of key journals, and sent letters to the authors of the trials published in the past five years to identify any other ongoing or unpublished trials. No language restrictions were used.

A few recent studies are not included in the review (one by the authors) because of the date limit for the search (August 1997), that probably do not influence the conclusions, but that add important data regarding the use of steroids in croup (1,2). There are also a couple of recent excellent review articles about croup, one of them by one of the authors of this meta-analysis, that give a good overview of the disease in pediatric patients (3,4). Another important issue is that this particular meta-analysis is being included as one the systematic reviews in the Cochrane Library most recent issue, and as such, is expected to be updated continously as new evidence appears (5).

4. Was the validity of the included studies appraised?

Yes. All selected studies were assessed for methodologic quality by two observers in an independent manner. The quality assessment tool used was the previously validated Jadad scale (6), a five-point scale that evaluates randomization, double-blinding and withdrawals and drop-outs in each study. Concealment of allocation was described, as well as the type of sponsorship of the studies. Interrater agreement between reviewers was measured by intraclass correlation, and the differences were resolved by consensus.

5. Were assessments of studies reproducible?

Yes. Agreement between investigators on inclusion of studies had a weighted kappa score of 0.89, indicating substantial agreement. In regard to quality assessment, the intraclass correlation between two reviewers was 0.63 with the Jadad scale, 0.98 for concealment of allocation, and 1.0 for sponsorship source.

6. Were the results similar from study to study?

No. Tests of homogeneity were performed with chi-square statistic for between study variation. The authors report significant heterogeneity among trials for all estimates of treatment effects. The main outcome measure analyzed was the difference between treatment groups in the mean change from croup score at baseline. In the papers where outcome measures were not directly reported the authors derived outcome measures from cross sectional summaries (e.g., at baseline, 6 and 12 hours). The croup score was not reported consistently in each study, so trial effect sizes were used in the pooled estimates (a treatment effect divided by its measurement variation gives an effect size). The heterogeneity among studies was studied using sensitivity and subgroup analyses on the primary outcome of the change in croup scores from baseline at 6 hours, and it was found to be significant.

Nonetheless, in the graphical representation of the pooled effect sizes of steroid treatment vs. placebo (Fig. 1 in the paper), all estimates of effect are more or less aligned at minus 1 on the left side of the no effect line, which suggests a beneficial effect os steroids in croup. The sensitivity analysis showed that the method of scoring the severity of croup was important, since an effect size of -1.2 (95% CI -1.7, -0.7) was shown with the Westley score, as compared with an effect size 50% smaller when other scores were used (-0.6, 95% CI -1.5, 0.3), a size that was no longer statistically significant, and this may be because the low reliability of these non-validated scores decreased its sensitivity to clinically important changes in the patients' status, or because there was a greater degree of variability.

II. What are the results?

1. What are the overall results of the review?

A total of 97 studies were identified and retrieved, of which 44 were excluded for several reasons (retrospective studies, no control group, were retrospective studies, etc.). Twenty four studies were reviewed (full details of the studies are on the BMJ's website extra). Dexamethasone was evaluated in 17 studies, budesonide in 9, and methylprednisolone in three (a few studied more than one drug). Nineteen studies were controlled with placebo. The mean age of children in the studies ranged from 13 to 45 months. Fourteen trials were done in hospitalized patients, and 10 on outpatients. Trials tended to be small with a median of forty patients. The outcome measure most frequently used was the clinical croup score developed by Westley (7) in 13 studies. Other scoring systems were used in 5 studies, and in six studies no clinical score was reported.

There was a significant improvement in Westley score at 6 hours of 2.8 (95% CI 2.2 to 3.5) for dexamethasone or budesonide vs. 1.0 (95% CI 0.3 to 1.7) for placebo. The pooled standarized effect size was -1.0 (95% CI -1.5 to -0.6) at 6 hours and -1.0 (95% CI -1.6 to -0.4) at 12 hours, but at 24 hours it was not statistically significant (fewer patients were studied at 24 hours, so the absence of significance may be due to low statistical power at this timepoint). A decrease in effect size of -1.0 from baseline was thought by the authors to be a clinically important one. The number needed to treat (NNT) at 6 hours was 7 (95% CI 4 to 50), at 12 hours was 5 (95% CI 1 to 11), and at 24 hours was 8 (95% CI 5 to 33).

No significant increase was found in the use of antibiotics in the treatment group. There was a significant decrease in the use of adrenaline in the steroid group, with a difference in risk of 9% (95% CI -16% to -2%) in the budesonide treated group (NNT was 10), and -12% (95% CI -20% to -4%) in the dexamethasone group (NNT 8). No difference was found in the use of supplemental steroids with either treatment.There was no difference in the rate of intubation and tracheostomy.

There was a decrease in the time spent in the emergency room, with a weighted mean difference of -11 (95% CI -18 to 4) hours, and for inpatients hospital stay was reduced -16 (95% CI -31 to 1) hours, and although the decrease in the rate of hospitalization was not significant (95% CI -16%, -39% to 6%), the direction of the effect was towards effectiveness.

2. How precise were the results?

The 95% confidence interval for comparison of the treatment and placebo groups was statistically significant (did not cross unity) at the 6 hours and 12 hours timepoints (data shown above). The 95% CI for adrenaline use was significant, and those for the time spent in the emergency department , inpatient hospital stay and rate of hospitalization were not.

A publication bias was identified in the study through the use of funnel plots, rank correlation test and a graphical method, and there is the possibility that small studies that showed no effect of steroid treatment in croup were not published. There was a significant correlation between treatment effect and sample size.

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

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

Yes. The type of studies used in the overview reflect clinical practice in pediatrics, and validate this therapeutic intervention that has been very controversial in the last decades. The study population were children with croup of several degrees of severity, the age of the children included in the studies are similar to that found in clinical practice, and most trials were of high metholodogical quality (median Jadad score of 3), so the conclusions seem to be applicable to most clinical situations in children with viral croup. The different steroids used are widely available, and the methodology used is feasible clinically in a wide variety of settings. Because there were small numbers of subjects in each individual study, it is difficult to make definitive recommendations about what steroid to use, and the dose and route of administration, however, it seems that an oral dose of dexamethasone of 0.6 mg/kg should be indicated in children with croup because of its efficacy and safety, and as an option nebulized budesonide or intramuscular dexamethasone.

2. Were all clinically important outcomes considered?

Mostly. The degree of respiratory dysfunction as measured by a clinical tool such as the Westley score (and other scores in other studies) was the main outcome measure, and there was a clinically significant improvement at various timepoints, with NNT of 5 to 7. Besides, other clinically important variables, such as the use of antibiotics, supplemental glucocorticoids, epinephrine treatment, time in the emergency department, inpatient hospital stay, intubation and mechanical ventilation, tracheostomy, and rate of hospitalization were measured and interpreted. A possibly important outcome measure that is not reported is the oxygenation and ventilation status of the patients with more objective measurement tools (pulse oximetry, blood gases in the severe cases), since the only measure of oxygenation reported in the Westley score is the degree of cyanosis and level of consciousness, data that are clinically important, but are nevertheless subjective and have high interobserver variability.

There is no information in the study about other potential complications of croup, such as atelectasis, air leak, pneumonia, pulmonary edema, hospitalization in the pediatric intensive care unit, and if there were children in the studies with so-called "spasmodic croup", which could be a different disease altogether, more sensitive to steroid treatment.

3. Are the benefits worth the harms and costs?

Probably yes. The effect in the outcome measures reported in the meta-analysis are clinically important, and probably would be reflected in a clinically reasonable benefit/harm ratio, however there is no data in the study about corticosteroids adverse effects, which are presumably few in the dosages reported, nor about the rate of complications (if any) in the treatment groups vs. the placebo groups. Besides, there is no specific data in the paper about economic consequences and cost-benefit measurements, which would on face value, appear to be clinically reasonable, since steroid treatment is usually not expensive, is ubiquitous, and most health care personnel are comfortable with their use. More important, any degree of improvement in the time of hospitalization would presumably decrease costs of care in a significant manner, however this is not explicitly demonstrated in the paper.

References

1. Johnson DW, Jacobosn S, Edney PC, Hadfield P, Mundy ME, Schuh S. A comparison of nebulized budesonide, intramuscular dexamethasone, and placebo for moderately severe croup. N Engl J Med 1998, 339:498-503. [abstract]
2. Klassen TP, Craig WR, Moher D, Osmond MH, Pasterkamp H, Sutcliffe T, Watters LK, Rowe PC. Nebulized budesonide and oral dexamethasone for treatment of croup: a randomized controlled trial. JAMA 1998, 279:1629-32. [abstract]
3. Klassen TP. Croup. A Current Perspective. Pediatr Clin North Am 1999, 46:1167-78. [abstract]
4. Geelhoed GC. Croup. Pediatr Pulmonol 1997, 23:370-4. [abstract]
5. Ausejo M, Saenz A, Pham B, Kellner JD, Johnson DW, Moher D, Klassen TP. Glucocorticoids for croup (Cochrane Review). In: The Cochrane Library , Issue 1, 2000. Oxford: Update Software. [abstract]
6. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17:1-12. [abstract]
7. Westley CR, Cotton EK, Brook JG. Nebulized racemic epinephrine by IPPB for the treatment of croup: a double blind study. Am J Dis Child 1978;132:484-7. [abstract]

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