0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Article |

Pharmacologic Treatment of Bronchiolitis in Infants and Children:  A Systematic Review FREE

Valerie J. King, MD, MPH; Meera Viswanathan, PhD; W. Clayton Bordley, MD, MPH; Anne M. Jackman, MSW; Sonya F. Sutton, BSPH; Kathleen N. Lohr, PhD; Timothy S. Carey, MD, MPH
[+] Author Affiliations

Not Available


Arch Pediatr Adolesc Med. 2004;158(2):127-137. doi:10.1001/archpedi.158.2.127.
Text Size: A A A
Published online

Background  Bronchiolitis is the most common lower respiratory tract infection in infants. Up to 3% of all children in their first year of life are hospitalized with bronchiolitis. Bronchodilators and corticosteroids are commonly used treatments, but little consensus exists about optimal management strategies.

Objective  To conduct a systematic review of the effectiveness of commonly used treatments for bronchiolitis in infants and children.

Data Sources  We searched MEDLINE and the Cochrane Controlled Trials Register for references to randomized controlled trials of bronchiolitis treatment published since 1980.

Study Selection  Randomized controlled trials of interventions for bronchiolitis in infants and children were included if they were published in English between 1980 and November 2002 and had a minimum sample size of 10.

Data Extraction  We abstracted data on characteristics of the study population, interventions used, and results of studies meeting entry criteria into evidence tables and analyzed them by drug category.

Data Synthesis  Interventions were grouped by drug category and qualitatively synthesized.

Results  Of 797 abstracts identified in the literature search, we included 54 randomized controlled trials. This review includes 44 studies of the most common interventions: epinephrine (n = 8), β2-agonist bronchodilators (n = 13), corticosteroids (n = 13), and ribavirin (n = 10). Studies were, in general, underpowered to detect statistically significant outcome differences between study groups. Few studies collected data on outcomes that are of great importance to parents and clinicians, such as the need for and duration of hospitalization.

Conclusions  Overall, little evidence supports a routine role for any of these drugs in treating patients with bronchiolitis. A sufficiently large, well-designed pragmatic trial of the commonly used interventions for bronchiolitis is needed to determine the most effective treatment strategies for managing this condition.

Bronchiolitis is the most common lower respiratory tract infection in infants. Each year, 21% of North American infants develop lower respiratory tract disease, although most infants and young children experience only a mild form of bronchiolitis. However, up to 3% of all children in their first year of life are hospitalized with bronchiolitis. Respiratory syncytial virus (RSV) is responsible for 70% of all bronchiolitis cases and for 80% to 100% of cases in winter months. Parainfluenza, adenovirus, and influenza account for most of the remaining cases.1

Bronchiolitis-associated hospitalizations have increased considerably since 1980.2 Among children 1 year or younger, annual bronchiolitis hospitalization rates increased from 12.9 per 1000 in 1980 to 31.2 per 1000 in 1996. Although infant hospitalization rates for bronchiolitis increased substantially between 1988 and 1996, hospitalization rates for other lower respiratory tract diseases did not vary extensively. The percentage of hospitalizations for lower respiratory tract illnesses associated with bronchiolitis among children younger than 1 year increased from 22.2% in 1980 to 47.4% in 1996.3

Treatments for bronchiolitis can be categorized as specific or symptomatic. The only known specific treatment is aerosolized ribavirin, an antiviral agent for bronchiolitis caused by RSV. Among the popular symptomatic treatments are bronchodilators and corticosteroids. Little consensus exists about the best management strategies for this common disease, and, thus, care varies substantially across settings and countries.46

Given the conflicting practices in diagnosing, treating, and preventing RSV, a systematic review of the evidence on the management of bronchiolitis was of particular concern to the American Academy of Pediatrics (AAP) and the American Academy of Family Physicians, which nominated the topic for the Agency for Healthcare Research and Quality Evidence-based Practice Program. The Agency for Healthcare Research and Quality chose the Research Triangle Institute International–University of North Carolina Evidence-based Practice Center to develop an evidence report on this issue, including the diagnosis, treatment, and prophylaxis of bronchiolitis and the cost-effectiveness of prophylaxis in moderately premature infants (32-35 weeks' gestation) and in all premature infants with comorbidities.7 The AAP, the American Academy of Family Physicians, health plans, and other groups may use this evidence report as a basis for guidance on the optimal management of bronchiolitis. This article presents the systematic review of the effectiveness of commonly used pharmacologic treatments for bronchiolitis; a companion article presents the results concerning diagnosis.8

To design a detailed search of the scientific literature, we sought the advice of a technical expert advisory group and developed specific key clinical questions and a search strategy about the overall issue of the efficacy of various therapies for bronchiolitis in young children. Primary outcomes of interest were mortality, morbidities related to the acute episode (hypoxia) and to possible long-term sequelae (recurrent respiratory problems), and use of health services, such as the need for and length of hospitalization. Table 1 provides the inclusion and exclusion criteria used to select articles for review.

Table Graphic Jump LocationTable 1. Inclusion and Exclusion Criteria for Studies of the Treatment of Bronchiolitis in Infants and Children

We searched MEDLINE and the Cochrane Collaboration's Database of Controlled Clinical Trials. Table 2 details the search terms used for the MEDLINE searches; we included existing meta-analyses to examine their lists of included and excluded studies. We conducted hand searches of the reference lists of relevant included articles to ensure that we did not miss key studies. In addition, we consulted with the technical expert advisory group about any studies that were under way but not yet published. The search was last updated November 25, 2002, and it contains all abstracts entered into MEDLINE until that date. Two more recently published studies (both of nebulized epinephrine) identified during the review process for this article were also included.

Table Graphic Jump LocationTable 2. Medical Subject Heading Terms for the MEDLINE Literature Search on the Treatment of Bronchiolitis in Infants and Children

Trained abstractors completed detailed data collection forms for each included study; 1 of us (M.V.) summarized these results in evidence tables. Senior study personnel (V.J.K. and C.B.) performed data integrity checks by reviewing the articles a second time against the evidence tables. They also rated the quality of each study on a 4-category scale (poor, fair, good, and excellent) based on randomized controlled trial (RCT) quality criteria that included factors such as adequacy of randomization, concealment of allocation, masking of study personnel and patients or parents, and statistical analysis.9 Disagreements in either abstraction or quality rating were adjudicated by senior authors (V.J.K., M.V., C.B., and A.M.J.) in consultation with subject area or method experts as required.

Our a priori analytic framework set priorities on outcomes based on their clinical relevance to key study questions. Specifically, we presented outcomes such as length of hospitalization or need for more intensive therapies as primary study outcomes in the full evidence report; in assessing effectiveness of therapies, we gave these outcomes priority over physiologic measures such as respiratory rate or composite clinical scores. The summary tables in this article similarly give priority to these key primary outcomes.

We identified 797 abstracts from the entire systematic review of the diagnosis, treatment, and prophylaxis of bronchiolitis in infants and children7; 54 met the inclusion criteria for treatment of bronchiolitis. Including 2 additional studies published during the review process, this article focuses on 44 studies (and an additional 2 articles reporting on long-term follow-up of included studies) of commonly used interventions; major classes of pharmacologic agents include epinephrine, β2-agonist bronchodilators (albuterol and salbutamol), corticosteroids, and ribavirin. Most of these agents can be given by various routes of administration. For example, we found studies of corticosteroids used by inhalation, parenterally, and orally.

We also identified RCTs of several unusual therapies, including RSV immunoglobulin as a treatment rather than as a prophylactic agent,10,11 interferon,12 inhaled helium-oxygen gas,13 Chinese herbs,14 surfactant,15 nebulized furosemide,16 and nebulized recombinant human deoxyribonuclease.17 These interventions are either novel or not in common use in US settings, so we did not include them in this review. A complete review of all interventions studied can be found in the full evidence report7 that forms the basis for this article, available from the Agency for Healthcare Research and Quality (http://www.ahrq.gov/clinic/evrptfiles.htm#bronch).

Most studies in this field are relatively small; few reported a priori sample size calculations or post hoc power analyses. Study quality was generally adequate: 7 studies were rated as excellent, 20 as good, 15 as fair, and 2 as poor. We did not exclude studies on the basis of quality.

Few studies reported outcomes that were prespecified as being of the greatest salience and of primary interest to clinicians and parents, such as need for hospitalization, length of hospital stay, need for more intensive supportive therapies, and development of long-term symptoms. Most studies reported outcomes based on (1) short-term changes in a clinical scoring system; (2) individual measures of physiologic status, such as heart rate, respiratory rate, or oxygen saturation; or (3) physical examination findings, such as retractions and wheezing. The range of clinical scoring systems that we encountered among these studies can be found in the full report,7 but most are a composite of physiologic and physical examination variables.

Table 3, Table 4, Table 5, and Table 6, specific to a category of drug, generally report on results (differences between groups) that were statistically significant at P<.05; we also noted findings of no difference if they were of clinical interest. Studies are ordered alphabetically by first author; outcomes listed first are duration of hospitalization or similar outcomes, followed by clinical scores or individual clinical measures.

Table Graphic Jump LocationTable 3. Bronchiolitis Treatment Trials: Epinephrine
Table Graphic Jump LocationTable 4. Bronchiolitis Treatment Trials: β2-Agonist Bronchodilators
Table Graphic Jump LocationTable 5. Bronchiolitis Treatment Trials: Corticosteroids
Table Graphic Jump LocationTable 6. Bronchiolitis Treatment Trials: Ribavirin
EPINEPHRINE

Nebulized epinephrine has been compared with placebo and 2 nebulized β-2-agonist bronchodilators, salbutamol and albuterol, in 8 RCTs (Table 3).1825 The total number of children studied in these trials was 660.

Few results favoring nebulized epinephrine emerged, and most outcomes reported were short term. Of 5 trials that examined duration of hospitalization, 220,22 noted either shorter hospitalization or fewer admissions in the epinephrine (vs salbutamol) group. Five studies1820,22,23 commented on changes in clinical scores measured at various times. Three studies reported better clinical scores immediately after initial treatment compared with placebo19 and salbutamol,18,22 but the study18 that collected data at 24 and 36 hours did not see a persistent improvement. Four research groups19,20,22,24 commented on oxygen saturation; 3 found short-term differences of unclear clinical significance: 1 at 15 minutes of treatment (but not at 30, 45, or 60 minutes),19 1 at 60 minutes (but not at 30 or 90 minutes),20 and 1 at 60 minutes.22 One trial24 reported that respiratory rates were lower in the epinephrine group.

Six studies reported adverse effects: short-term pallor in the epinephrine groups in 2 studies19,20 and increased heart rates with epinephrine use in 4 studies.18,21,22,25

β2-AGONIST BRONCHODILATORS

We included 13 studies2638 of various bronchodilator agents for the treatment of bronchiolitis; most had multiple treatment arms (Table 4). Of these studies, 11 used salbutamol or albuterol in at least one treatment arm compared with saline placebo, nebulized saline placebo, or unspecified placebo or control. Four studies28,32,36,38 did comparisons with nebulized ipratropium bromide, and 230,31 with oral salbutamol or albuterol. One study27 was of salbutamol administered via a metered dose inhaler (MDI) compared with oral salbutamol.

These studies reported results for a total of 956 patients. Two studies34,37 mentioned sample size calculations; numbers of children assigned to any particular study arm were generally small. Outcomes studied were largely surrogate measures, such as change in clinical severity score, and were primarily short term in nature. Differences in agents, doses, delivery systems, settings, and outcomes limit overall comparisons.

Seven trials examined a primary outcome measure related to need for or length of hospitalization; none reported significance differences between groups. Of 12 studies with a saline placebo comparison, 326,34,35 demonstrated improvements in various types of clinical measures in the short term (30 to 60 minutes after treatment) for patients receiving nebulized bronchodilator therapy and 138 demonstrated worse scores.

Six studies did not report on adverse events associated with treatments. Symptoms such as increased heart rate and temporarily decreased oxygen saturation consistent with the known adverse effects of treatment with β2-agonist agents were reported in the remaining 7 studies.

Nebulized ipratropium bromide, an anticholinergic bronchodilator, in combination with salbutamol has been compared with either drug alone and placebo in two 4-arm studies.28,38 Another team32 compared nebulized ipratropium bromide to nebulized salbutamol in a nebulized saline controlled trial, and a fourth group36 compared nebulized ipratropium bromide plus albuterol with albuterol plus saline placebo. Duration of hospitalization and changes in clinical scores were studied in both trials involving salbutamol, but neither type of outcome measure demonstrated significant differences among the comparison groups.28,32,38 One trial38 showed improved mean oxygen saturation for the combination of ipratropium bromide plus salbutamol vs either ipratropium bromide or salbutamol used as single agents, but no significant differences emerged when the combination was compared with placebo. Respiratory rates did not differ significantly between the groups that received albuterol plus saline placebo vs ipratropium bromide plus albuterol.36

CORTICOSTEROIDS

In all, we included 5 studies3942,44 of oral corticosteroids (273 patients) (one additional article43 was a 5-year follow-up of a prednisolone vs placebo trial), 2 studies45,46 of parenteral corticosteroids (147 patients), and 6 studies4752 of inhaled corticosteroids (492 patients). One study39 compared oral prednisone with placebo. Three studies40,43,44 compared oral prednisolone with placebo and allowed additional supportive treatments that could include bronchodilators. The use of oral dexamethasone vs placebo was the subject of 2 RCTs.41,42 Both studies45,46 of parenteral corticosteroids used dexamethasone vs placebo. Five of the 6 inhaled corticosteroid studies4751 used budesonide, and the sixth study52 used a fluticasone propionate MDI (Table 5).

Many of the inhaled and oral corticosteroid studies evaluated longer-term outcomes, such as persistent cough or wheezing, weeks to years after the initial bronchiolitis episode. Most studies were small; none included a power analysis. As with the previous medications, comparisons among these studies are limited by the variety of drugs, dosages, durations of treatment, co-interventions, and populations studied.

Oral Corticosteroids

Four oral corticosteroid studies39,41,42,44 reported either rates or duration of hospitalization. Rates of hospitalization for patients in the emergency department were lower in 1 study42 using dexamethasone. A second study44 using prednisolone showed a decreased length of stay in ventilated patients only; no difference was seen in nonventilated patients. In contrast, no difference was seen in duration of hospitalization in a second study41 of oral dexamethasone. In addition, 1 study39 found higher rates of hospitalization among children who received oral prednisone. The study40 of prednisolone plus nebulized albuterol reported that clinical scores improved at 2 days for the treatment group vs the placebo plus albuterol group, but these differences were not demonstrated at 3 or 6 days. The 5-year follow-up study43 of prednisolone vs placebo did not demonstrate any long-term differences in transient, persistent, or late-onset wheezing.

Parenteral Corticosteroids

Neither intravenous dexamethasone45 nor intramuscular dexamethasone against placebo46 showed differences between the study groups for outcomes such as duration of hospitalization or time to resolution of clinical symptoms.

Inhaled Corticosteroids

We included 6 studies of inhaled corticosteroids: 5 using budesonide in either a nebulized or an MDI form4751 and 1 using a fluticasone proprionate MDI.52 These studies were, on average, of lower quality than the oral and parenteral corticosteroid studies. Treatments were continued for 2 weeks to 3 months, and outcome measurements were reported for correspondingly longer intervals than for most of the previous categories of agents.

One budesonide study49 demonstrated less need for asthma inhalational therapy 2 years after study entry for the group that used budesonide for 2 months compared with the group that used it for 7 days and the usual treatment control group. No other budesonide studies47,48,50,51 showed significant improvements for the treatment group.

Of concern, 2 of these studies found longer term clinical worsening of symptoms in the inhaled budesonide group, measured either as wheeze or cough at 1 year48 or hospital readmission in the 6 months after study entry for respiratory problems.51 The small study52 of a fluticasone proprionate MDI used for 3 months vs placebo showed a decrease in episodes of night coughing at 36 weeks after study entry in the treatment group but did not demonstrate differences in overall cough or wheezing symptoms at 3, 6, 12, or 24 weeks.

Adverse Events

Four of the oral39,41,42 and parenteral45 corticosteroid studies did not report adverse events as an outcome. Jitteriness related to the dose of albuterol used with oral prednisolone was reported in 1 child.40 The study51 that measured growth rates among children who were receiving inhaled corticosteroids did not find any significant differences. Half of the inhaled corticosteroid studies did not include adverse events in their reported outcomes.47,49,50 Oral candidiasis was reported as an adverse effect in 2 children in the fluticasone proprionate group.52

RIBAVIRIN

We located 10 RCTs of ribavirin for more severe RSV bronchiolitis5360,62,63 and a long-term follow-up from 1 of these 10 studies.61 The total number of patients in the primary studies was 320, and the overall quality was low, with half of the primary studies rated as fair or poor. Five studies55,56,59,62,63 reported on our primary outcomes of interest, such as days of hospitalization, length of time that a child required more intensive supportive interventions, and duration of illness. Four of these studies55,56,59,63 found no significant differences with ribavirin treatment compared with saline placebo. The study62 that did find differences in duration of mechanical ventilation and hospitalization favoring ribavirin used sterile water in the placebo arm. This study has been criticized for use of a sterile water placebo, which can induce bronchospasm, making the ribavirin treatment seem more effective.64 Six of 10 studies53,55,57,58,60,63 reported items that we classified as secondary outcomes, such as clinical symptoms and clinical scores. Differences favoring ribavirin were found for hours to improvement in cough and crepitations but not for wheezing or improved feeding in 1 study.53 Illness severity scores were better in the ribavirin group compared with the water placebo group on days 1 and 4 but not on days 2 and 3 of treatment in another study.57 Similarly, another study63 found better clinical scores in the ribavirin group compared with the saline placebo group on day 3 but not on days 1 and 2 of treatment. Three of the 6 studies55,58,60 reporting secondary outcomes did not find significant differences between the groups.

The long-term follow-up study61 found fewer children with greater than 2 episodes of wheezing during years 1 through 6 after ribavirin treatment but no significant differences in occurrence of overall respiratory illnesses or symptoms in those 6 years. Another study54 measured outcomes such as number of episodes of reactive airway disease and lower and upper respiratory disease in a 1-year follow-up period after use of ribavirin vs usual treatment and found fewer episodes of each in the ribavirin group. Aside from patient withdrawals in 2 studies56,59 for respiratory compromise, eyelid erythema was the only drug-specific adverse event reported in these studies.53 A total of 3 deaths (2 in the ribavirin treatment group and 1 in the water placebo group) were reported in 2 studies55,60; none of these events were believed to be caused by the intervention.

We did not find a substantial and convincing body of evidence to suggest that most treatments used for infants and children with bronchiolitis improve overall clinical outcomes compared with routine supportive therapy. Our results are consistent with previous systematic reviews and meta-analyses on the use of β2-agonist bronchodilators,65,66 corticosteroids,67 and ribavirin.68 We are unaware of any previous review of the use of epinephrine for the treatment of bronchiolitis. Aside from some transient improvements in clinical scores and related measures, we found little evidence to suggest that epinephrine is an effective treatment for bronchiolitis. Although 1 small study20 demonstrated a reduction in the length of hospitalization with nebulized epinephrine use and another22 found a decreased rate of hospital admissions, the weight of evidence does not support the use of nebulized epinephrine.

The widespread use of β2-agonist bronchodilators for bronchiolitis is likely explained by the similarity of symptoms and signs between bronchiolitis and asthma. Two systematic reviews65,66 of bronchiolitis treatment with β2-agonist bronchodilators have been published. Flores and Horwitz65 found no evidence that β2-agonist use either improved oxygenation by a clinically significant amount or reduced admission rates from outpatient and emergency department settings in a meta-analysis that included 8 RCTs. In a Cochrane review, Kellner et al66 examined 20 RCTs and found a statistically significant increase in the proportion of bronchodilator-treated infants who demonstrated an improvement in their clinical scores (odds ratio, 0.29; 95% confidence interval [CI], 0.19-0.45). However, bronchodilator recipients did not show improvement in measures of oxygenation; the difference favored the control population (pooled difference, 0.7; 95% CI, 0.36-1.35). The rate of hospitalization was not significantly reduced in bronchodilator recipients compared with controls (odds ratio, 0.7; 95% CI, 0.36-1.35).

The results of these 2 previous systematic reviews are consistent with our findings. Most studies demonstrated short-term improvements in various clinical scores, but 2 studies also showed worsening hypoxia in children who received a β2-agonist compared with those who received saline placebo. However, we found no significant differences in outcome measures likely to be of greatest importance to clinicians and parents, such as whether a child must be hospitalized and the duration of hospitalization.

Infants with bronchiolitis have been treated with corticosteroids because they are well-known anti-inflammatory agents acting at a multitude of cellular levels.67 Clinicians have considered them for use in infants with acute bronchiolitis partly because of the clear benefits of corticosteroid therapy in children with acute asthma and croup. However, as with inhaled β2-agonists, data supporting the use of corticosteroids are not convincing. Garrison et al67 published a meta-analysis of 6 RCTs of hospitalized infants. Infants who received corticosteroids had a mean length of stay or duration of symptoms that was 0.43 day less than those who received the placebo treatment (95% CI, −0.81 to −0.05 day). The effect size for improvement in mean clinical score was 1.60 (95% CI, −1.92 to −1.28), favoring treatment. They concluded that the combined published studies of the effects of systemic corticosteroids on the course of bronchiolitis suggest a statistically significant improvement in clinical symptoms and in duration of hospitalization and symptoms. Although the authors found a positive effect, they excluded several potentially relevant studies, and the clinical significance of an effect size of 1.6 is unclear.

We found inconclusive evidence that systemic corticosteroid therapy may offer a benefit in terms of rates and duration of hospitalization. Of 5 studies reporting this outcome, 2 saw a statistically significant benefit, although in 1 study the improvement was found only in children who required mechanical ventilation. Two studies actually found increased rates of hospitalization in the corticosteroid group. The preponderance of evidence does not favor the use of corticosteroids to decrease hospitalization. Reminiscent of the history of croup research, these studies all used different doses of corticosteroids, and the 1 that showed a convincing positive effect used the highest dose (1 mg/kg per day of dexamethasone).42 These authors did not report adverse effects, and their results have not been duplicated.

Five of 6 inhaled corticosteroid studies collected data on clinical symptoms as an outcome. The studies that used nebulized or MDI corticosteroids did not demonstrate a benefit for either hospitalizations or most symptom scores. With the exception of 1 poor-quality study that showed a decreased need for asthma treatment 2 years after the episode of bronchiolitis in infants given up to 8 weeks of budesonide, we did not find overall evidence that short-term treatment (1-12 weeks) with inhaled corticosteroids was effective. We also found some evidence to suggest that inhaled budesonide may pose harms; 2 small studies48,51 demonstrated longer term worsened clinical outcomes in children who received budesonide.

The 2003 Red Book69 states: "In hospitalized infants with RSV bronchiolitis, corticosteroids are not effective and are not indicated." The findings of individual studies incorporated by this systematic review differ by the particular corticosteroid drug and dose used and by the populations and outcomes studied. Although an updated meta-analysis might be useful, technical difficulties are likely for such an analysis because of the heterogeneity among studies. Given current evidence, systemic corticosteroids do not seem to offer an overall benefit, even when examining surrogate outcomes, such as clinical scores.

Given the promising initial studies of the use of ribavirin in certain infants at high risk of serious RSV disease, the AAP initially endorsed this treatment approach in 1993. However, the AAP modified its recommendation in 1996 from "should be used" to "may be considered" after several subsequent trials showed no significant effect on clinical outcomes. The use of ribavirin is further constrained by its high cost and possible risk to health care personnel who administer it.70 A systematic review of 8 RCTs of ribavirin therapy published by Randolph and Wang68 in 1996 found that ribavirin use does not significantly affect mortality, lower the likelihood of respiratory compromise, or shorten hospitalization. However, statistical power is insufficient to rule out an effect. Our review excluded some studies that Randolph and Wang had included because they did not have an adequate control group or because of inability to assign outcomes to a relevant subset of randomized patients. We did not find evidence that ribavirin use led to consistent or more than transient improvements in clinical outcomes.

The results of this systematic review should be interpreted in light of several important limitations. First, we restricted included studies to those published in English. As a precaution against publication bias, we looked for abstracts in any language at the initial search stage and did not find evidence that limiting our selection to English-language publications missed any RCTs. Second, by limiting our search to the MEDLINE database and Cochrane Controlled Trials Register, we may have missed studies included only in other databases. Publication bias can affect all systematic reviews and meta-analyses. Unpublished and privately published literature is difficult to locate. We asked our technical expert advisory group and peer reviewers for the full evidence report whether they knew of literature we were missing, but we still could have inadvertently overlooked relevant studies. We are grateful to manuscript reviewers for directing our attention to 2 additional studies published after our original evidence report was completed. These 2 methodologically strong studies added substantial numbers to the epinephrine trials and altered our previous conclusions regarding this therapy. The importance of updating systematic reviews when new evidence emerges is underscored.

A third limitation is that this systematic review did not include a formal meta-analysis. Most of the studies found were small and were likely to be underpowered, although most did not include a sample size or power calculation. By statistically combining results of studies that used the same drugs and outcome measures, we might have found more conclusive evidence of whether a drug is an effective treatment for bronchiolitis. However, in most cases, the heterogeneity introduced by study differences (such as specific drug used in the class, dose and duration of therapy, other interventions used as part of routine care, outcomes measured, and population and setting of the study) would make formal meta-analysis inappropriate and misleading.

Further work to determine whether there are enough similar studies for some or all of the drug classes we examined would be useful. On initial inspection, for example, one might conclude that enough studies of nebulized salbutamol vs saline placebo exist to perform a meta-analysis. However, a closer look reveals that few of these studies used comparable outcome measures. Although most reported a composite clinical score, they did not necessarily use the same scoring method, and breaking the scores down into components such as respiratory rate or the presence of wheezing would require the original study data.

Investigators conducting future studies should choose clinically relevant outcomes. Most of the outcomes studied in this literature are short term. Often they were surrogate outcomes, such as oxygen saturation or respiratory rate immediately after treatment. Investigators should concentrate on measuring outcomes that matter to parents, clinicians, and health systems, such as rates of hospitalization or readmission, duration of hospitalization or emergency department care, the need for more intensive services during hospitalization, the costs of care, parental satisfaction with treatment, and development of chronic respiratory symptoms.

Few studies reported adverse events associated with treatments. Determining whether the risks of a particular treatment are sufficient to exclude its clinical use is difficult with current data. Clinicians commonly use interventions such as inhaled bronchodilators, corticosteroids, and epinephrine, for which current evidence of either benefit or harm is insufficient. These drugs are all available as relatively inexpensive generic products and are often used for other indications, such as asthma. Most clinicians consider them to be safe, although our review found evidence of adverse effects for all these classes of drugs. At the very least, the use of ineffective drugs diverts limited health care resources. Future investigations should carefully monitor and report adverse events.

The treatment studies we reviewed were also almost universally underpowered and as such were unable to give clinicians adequate guidance for management of bronchiolitis. However, we believe that all of these types of treatments will continue to be used unless a large pragmatic trial of the most commonly used interventions is mounted. Such a trial, using the most important outcome measures, would need to be large enough to examine each of the interventions not only in the overall population but also in subpopulations of interest, such as infants with more and less severe disease. Given that no optimal best treatment strategy for bronchiolitis currently exists, aside from supportive care, such as hydration and oxygenation, the use of new pharmacologic agents should be studied in well-designed, adequately sized studies. Using placebos in the control groups of these studies, whenever feasible, is appropriate until such time as it is demonstrated that treatments other than supportive care are effective.

The AAP Committee on Infectious Diseases made recommendations about treatment for RSV bronchiolitis in the 2003 Red Book.69 The committee recommends supportive care as needed, including hydration, supplemental oxygen, and mechanical ventilation as the primary treatment modalities for bronchiolitis. On the basis of this systematic review, we find no evidence to disagree with these recommendations.

What This Study Adds

Despite the numerous clinical trials on treatments for bronchiolitis, such as bronchodilators, corticosteroids, and ribavirin, little evidence exists for the effectiveness of any of these interventions, particularly when measured in terms of significant patient-based outcomes. However, most of the studies in this area are not of sufficient size or quality to conclusively rule out the most commonly used treatments in the face of widespread and continued clinician use. This review justifies a large pragmatic clinical trial testing the more common interventions currently used for bronchiolitis.

Corresponding author: Valerie J. King, MD, MPH, Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, 725 Airport Rd, Campus Box 7590, Chapel Hill, NC 27599-7595.

Accepted for publication October 9, 2003.

This study was conducted by the RTI International–University of North Carolina Evidence-based Practice Center under contract 290-97-0011 from the Agency for Healthcare Research and Quality, Rockville, Md. The full study is available at http://www.ahrq.gov/clinic/evrptfiles.htm#bronch.

We thank (1) Marian James, PhD, the Agency for Healthcare Research and Quality Task Order Officer for this project, for her assistance; (2) the following members of the technical expert advisory group, who provided input and advice for the full evidence report on which this article is based: Henry L. Dorkin, MD, director of the Cystic Fibrosis Center, Newton, Mass; Bernard Ewigman, MD, MSPH, School of Medicine, University of Missouri–Columbia; Glenn Flores, MD, Boston University School of Medicine, Boston, Mass; Anne Haddix, PhD, Rollins School of Public Health, Emory University, Atlanta, Ga; Allan S. Lieberthal, MD, Southern California–Permanente Medical Group, Panorama City; Jonathan L. Temte, MD, PhD, Department of Family Medicine, University of Wisconsin, Madison; and Steve Wegner, MD, NC Access Inc, Morrisville, NC; (3) the following colleagues at RTI International: Amanda Honeycutt, PhD, and John Wittenborn, BA, BS, for their work on the cost-effectiveness analysis of the full report; Loraine Monroe for superior secretarial assistance; Nash Herndon, MA, for editing expertise; and Linda Lux, MPA, and Philip Salib, BA, for technical assistance on the project; and (4) the following colleagues at the University of North Carolina at Chapel Hill: Mary Maniscalo, MD, MPH, and Laura Sterling, MD, MPH, for data abstraction; Cheryl Coon, PhD, for methods abstraction; and Joy Harris and Donna Curasi for superior research assistance.

The authors of this article are responsible for its content, including any clinical or treatment recommendations.

Hall  CB Respiratory syncytial virus and parainfluenza virus. N Engl J Med. 2001;3441917- 1928
PubMed Link to Article
Glezen  WPTaber  LHFrank  ALKasel  JA Risk of primary infection and reinfection with respiratory syncytial virus. AJDC. 1986;140543- 546
PubMed
Shay  DKHolman  RCNewman  RDLiu  LLStout  JWAnderson  LJ Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999;2821440- 1446
PubMed Link to Article
Wang  EELaw  BJBoucher  FD  et al.  Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study of admission and management variation in patients hospitalized with respiratory syncytial viral lower respiratory tract infection. J Pediatr. 1996;129390- 395
PubMed Link to Article
Willson  DFHorn  SDHendley  JOSmout  RGassaway  J Effect of practice variation on resource utilization in infants hospitalized for viral lower respiratory illness. Pediatrics. 2001;108851- 855
PubMed Link to Article
Cahill  PFinan  ELoftus  BG Management of bronchiolitis: current practices in Ireland. Ir Med J. 2002;95167- 169
PubMed
Viswanathan  MKing  VBordley  C  et al.  Management of Bronchiolitis in Infants and Children: Evidence Report/Technology Assessment No.69.  Rockville, Md US Dept of Health and Human Services, Agency for Healthcare Research and Quality2003;AHRQ publication 03-E014
Bordley  WCViswanathan  MKing  VJ  et al.  Diagnosis and testing in bronchiolitis: a systematic review. Arch Pediatr Adolesc Med. 2004;158119- 126
Link to Article
West  SLKing  VCarey  TS  et al.  Systems to Rate the Strength of Scientific Evidence: Evidence Report/Technology Assessment No.47.  Rockville, Md Agency for Healthcare Research and Quality2002;AHRQ publication 02-E016
Rodriguez  WJGruber  WCGroothuis  JR  et al.  Respiratory syncytial virus immune globulin treatment of RSV lower respiratory tract infection in previously healthy children. Pediatrics. 1997;100937- 942
PubMed Link to Article
Rodriguez  WJGruber  WCWelliver  RC  et al.  Respiratory syncytial virus (RSV) immune globulin intravenous therapy for RSV lower respiratory tract infection in infants and young children at high risk for severe RSV infections: Respiratory Syncytial Virus Immune Globulin Study Group. Pediatrics. 1997;99454- 461
PubMed Link to Article
Chipps  BESullivan  WFPortnoy  JM Alpha-2A-interferon for treatment of bronchiolitis caused by respiratory syncytial virus. Pediatr Infect Dis J. 1993;12653- 658
PubMed Link to Article
Hollman  GShen  GZeng  L  et al.  Helium-oxygen improves Clinical Asthma Scores in children with acute bronchiolitis. Crit Care Med. 1998;261731- 1736
PubMed Link to Article
Kong  XTFang  HTJiang  GQZhai  SZO'Connell  DLBrewster  DR Treatment of acute bronchiolitis with Chinese herbs. Arch Dis Child. 1993;68468- 471
PubMed Link to Article
Luchetti  MCasiraghi  GValsecchi  RGalassini  EMarraro  G Porcine-derived surfactant treatment of severe bronchiolitis. Acta Anaesthesiol Scand. 1998;42805- 810
PubMed Link to Article
Van Bever  HPDesager  KNPauwels  JHWojciechowski  MVermeire  PA Aerosolized furosemide in wheezy infants: a negative report. Pediatr Pulmonol. 1995;2016- 20
PubMed Link to Article
Nasr  SZStrouse  PJSoskolne  E  et al.  Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis. Chest. 2001;120203- 208
PubMed Link to Article
Bertrand  PAranibar  HCastro  ESanchez  I Efficacy of nebulized epinephrine versus salbutamol in hospitalized infants with bronchiolitis. Pediatr Pulmonol. 2001;31284- 288
PubMed Link to Article
Kristjansson  SLodrup Carlsen  KCWennergren  GStrannegard  ILCarlsen  KH Nebulised racemic adrenaline in the treatment of acute bronchiolitis in infants and toddlers. Arch Dis Child. 1993;69650- 654
PubMed Link to Article
Menon  KSutcliffe  TKlassen  TP A randomized trial comparing the efficacy of epinephrine with salbutamol in the treatment of acute bronchiolitis. J Pediatr. 1995;1261004- 1007
PubMed Link to Article
Patel  HPlatt  RWPekeles  GSDucharme  FM A randomized, controlled trial of the effectiveness of nebulized therapy with epinephrine compared with albuterol and saline in infants hospitalized for acute viral bronchiolitis. J Pediatr. 2002;141818- 824
PubMed Link to Article
Ray  MSSingh  V Comparison of nebulized adrenaline versus salbutamol in wheeze associated respiratory tract infection in infants. Indian Pediatr. 2002;3912- 22
PubMed
Reijonen  TKorppi  MPitkakangas  STenhola  SRemes  K The clinical efficacy of nebulized racemic epinephrine and albuterol in acute bronchiolitis. Arch Pediatr Adolesc Med. 1995;149686- 692
PubMed Link to Article
Sanchez  IDe Koster  JPowell  REWolstein  RChernick  V Effect of racemic epinephrine and salbutamol on clinical score and pulmonary mechanics in infants with bronchiolitis. J Pediatr. 1993;122145- 151
PubMed Link to Article
Wainwright  CLuis Altamirano  M-CCheney  M  et al.  A multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis. N Engl J Med. 2003;34927- 35
PubMed Link to Article
Can  DInan  GYendur  GOral  RGunay  I Salbutamol or mist in acute bronchiolitis. Acta Paediatr Jpn. 1998;40252- 255
PubMed Link to Article
Cengizlier  RSaraclar  YAdalioglu  GTuncer  A Effect of oral and inhaled salbutamol in infants with bronchiolitis. Acta Paediatr Jpn. 1997;3961- 63
PubMed Link to Article
Chowdhury  Dal Howasi  MKhalil  Mal-Frayh  ASChowdhury  SRamia  S The role of bronchodilators in the management of bronchiolitis: a clinical trial. Ann Trop Paediatr. 1995;1577- 84
PubMed
Dobson  JVStephens-Groff  SMMcMahon  SRStemmler  MMBrallier  SLBay  C The use of albuterol in hospitalized infants with bronchiolitis. Pediatrics. 1998;101361- 368
PubMed Link to Article
Gadomski  AMAref  GHel Din  OBel Sawy  IHKhallaf  NBlack  RE Oral versus nebulized albuterol in the management of bronchiolitis in Egypt. J Pediatr. 1994;124131- 138
PubMed Link to Article
Gadomski  AMLichenstein  RHorton  LKing  JKeane  VPermutt  T Efficacy of albuterol in the management of bronchiolitis. Pediatrics. 1994;93907- 912
PubMed
Goh  AChay  OMFoo  ALOng  EK Efficacy of bronchodilators in the treatment of bronchiolitis. Singapore Med J. 1997;38326- 328
PubMed
Ho  LCollis  GLandau  LILe Souef  PN Effect of salbutamol on oxygen saturation in bronchiolitis. Arch Dis Child. 1991;661061- 1064
PubMed Link to Article
Klassen  TPRowe  PCSutcliffe  TRopp  LJMcDowell  IWLi  MM Randomized trial of salbutamol in acute bronchiolitis. J Pediatr. 1991;118807- 811
PubMed Link to Article
Schuh  SCanny  GReisman  JJ  et al.  Nebulized albuterol in acute bronchiolitis. J Pediatr. 1990;117633- 637
PubMed Link to Article
Schuh  SJohnson  DCanny  G  et al.  Efficacy of adding nebulized ipratropium bromide to nebulized albuterol therapy in acute bronchiolitis. Pediatrics. 1992;90920- 923
PubMed
Totapally  BRDemerci  CZureikat  GNolan  B Tidal breathing flow-volume loops in bronchiolitis in infancy: the effect of albuterol. Crit Care. 2002;6160- 165
PubMed Link to Article
Wang  EEMilner  RAllen  UMaj  H Bronchodilators for treatment of mild bronchiolitis: a factorial randomised trial. Arch Dis Child. 1992;67289- 293
PubMed Link to Article
Berger  IArgaman  ZSchwartz  SB  et al.  Efficacy of corticosteroids in acute bronchiolitis: short-term and long-term follow-up. Pediatr Pulmonol. 1998;26162- 166
PubMed Link to Article
Goebel  JEstrada  BQuinonez  JNagji  NSanford  DBoerth  RC Prednisolone plus albuterol versus albuterol alone in mild to moderate bronchiolitis. Clin Pediatr (Phila). 2000;39213- 220
PubMed Link to Article
Klassen  TPSutcliffe  TWatters  LKWells  GAAllen  UDLi  MM Dexamethasone in salbutamol-treated inpatients with acute bronchiolitis: a randomized, controlled trial. J Pediatr. 1997;130191- 196
PubMed Link to Article
Schuh  SCoates  ALBinnie  R  et al.  Efficacy of oral dexamethasone in outpatients with acute bronchiolitis. J Pediatr. 2002;14027- 32
PubMed Link to Article
van Woensel  JBWolfs  TFvan Aalderen  WMBrand  PLKimpen  JL Randomised double blind placebo controlled trial of prednisolone in children admitted to hospital with respiratory syncytial virus bronchiolitis. Thorax. 1997;52634- 637
PubMed Link to Article
van Woensel  JBKimpen  JLSprikkelman  ABOuwehand  Avan Aalderen  WM Long-term effects of prednisolone in the acute phase of bronchiolitis caused by respiratory syncytial virus. Pediatr Pulmonol. 2000;3092- 96
PubMed Link to Article
De Boeck  KVan der Aa  NVan Lierde  SCorbeel  LEeckels  R Respiratory syncytial virus bronchiolitis: a double-blind dexamethasone efficacy study. J Pediatr. 1997;131919- 921
PubMed Link to Article
Roosevelt  GSheehan  KGrupp-Phelan  JTanz  RRListernick  R Dexamethasone in bronchiolitis: a randomised controlled trial. Lancet. 1996;348292- 295
PubMed Link to Article
Cade  ABrownlee  KGConway  SP  et al.  Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis. Arch Dis Child. 2000;82126- 130
PubMed Link to Article
Fox  GFEverard  MLMarsh  MJMilner  AD Randomised controlled trial of budesonide for the prevention of post-bronchiolitis wheezing. Arch Dis Child. 1999;80343- 347
PubMed Link to Article
Kajosaari  MSyvanen  PForars  MJuntunen-Backman  K Inhaled corticosteroids during and after respiratory syncytial virus-bronchiolitis may decrease subsequent asthma. Pediatr Allergy Immunol. 2000;11198- 202
PubMed Link to Article
Reijonen  TKorppi  MKuikka  LRemes  K Anti-inflammatory therapy reduces wheezing after bronchiolitis. Arch Pediatr Adolesc Med. 1996;150512- 517
PubMed Link to Article
Richter  HSeddon  P Early nebulized budesonide in the treatment of bronchiolitis and the prevention of postbronchiolitic wheezing. J Pediatr. 1998;132849- 853
PubMed Link to Article
Wong  JYMoon  SBeardsmore  CO'Callaghan  CSimpson  H No objective benefit from steroids inhaled via a spacer in infants recovering from bronchiolitis. Eur Respir J. 2000;15388- 394
PubMed Link to Article
Barry  WCockburn  FCornall  RPrice  JFSutherland  GVardag  A Ribavirin aerosol for acute bronchiolitis. Arch Dis Child. 1986;61593- 597
PubMed Link to Article
Edell  DKhoshoo  VRoss  GSalter  K Early ribavarin treatment of bronchiolitis: effect on long-term respiratory morbidity. Chest. 2002;122935- 939
PubMed Link to Article
Everard  MLSwarbrick  ARigby  ASMilner  AD The effect of ribavirin to treat previously healthy infants admitted with acute bronchiolitis on acute and chronic respiratory morbidity. Respir Med. 2001;95275- 280
PubMed Link to Article
Guerguerian  AMGauthier  MLebel  MHFarrell  CALacroix  J Ribavirin in ventilated respiratory syncytial virus bronchiolitis: a randomized, placebo-controlled trial. Am J Respir Crit Care Med. 1999;160829- 834
PubMed Link to Article
Hall  CBMcBride  JTWalsh  EE  et al.  Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection: a randomized double-blind study. N Engl J Med. 1983;3081443- 1447
PubMed Link to Article
Janai  HKStutman  HRZaleska  M  et al.  Ribavirin effect on pulmonary function in young infants with respiratory syncytial virus bronchiolitis. Pediatr Infect Dis J. 1993;12214- 218
PubMed Link to Article
Meert  KLSarnaik  APGelmini  MJLieh-Lai  MW Aerosolized ribavirin in mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease: a prospective, double-blind, randomized trial. Crit Care Med. 1994;22566- 572
PubMed Link to Article
Rodriguez  WJKim  HWBrandt  CD  et al.  Aerosolized ribavirin in the treatment of patients with respiratory syncytial virus disease. Pediatr Infect Dis J. 1987;6159- 163
PubMed Link to Article
Rodriguez  WJArrobio  JFink  RKim  HWMilburn  C Prospective follow-up and pulmonary functions from a placebo-controlled randomized trial of ribavirin therapy in respiratory syncytial virus bronchiolitis: Ribavirin Study Group. Arch Pediatr Adolesc Med. 1999;153469- 474
PubMed Link to Article
Smith  DWFrankel  LRMathers  LHTang  ATAriagno  RLProber  CG A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection. N Engl J Med. 1991;32524- 29
PubMed Link to Article
Taber  LHKnight  VGilbert  BE  et al.  Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants. Pediatrics. 1983;72613- 618
PubMed
Moler  FWBandy  KPCuster  JR Ribavirin therapy for acute bronchiolitis: need for appropriate controls [letter]. J Pediatr. 1991;119509- 510
PubMed Link to Article
Flores  GHorwitz  RI Efficacy of beta2-agonists in bronchiolitis: a reappraisal and meta-analysis. Pediatrics. 1997;100233- 239
PubMed Link to Article
Kellner  JDOhlsson  AGadomski  AMWang  EE Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2000;2CD001266
PubMed
Garrison  MMChristakis  DAHarvey  ECummings  PDavis  RL Systemic corticosteroids in infant bronchiolitis: a meta-analysis. Pediatrics. 2000;105E44
PubMed Link to Article
Randolph  AGWang  EE Ribavirin for respiratory syncytial virus lower respiratory tract infection: a systematic overview. Arch Pediatr Adolesc Med. 1996;150942- 947
PubMed Link to Article
American Academy of Pediatrics, Respiratory syncytial virus. Pickering  LKed.2003 Red Book: Report of the Committee on Infectious Diseases 26th ed. Elk Grove Village, Ill American Academy of Pediatrics2003;524
Committee on Infectious Diseases, Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. Pediatrics. 1996;97137- 140
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1. Inclusion and Exclusion Criteria for Studies of the Treatment of Bronchiolitis in Infants and Children
Table Graphic Jump LocationTable 2. Medical Subject Heading Terms for the MEDLINE Literature Search on the Treatment of Bronchiolitis in Infants and Children
Table Graphic Jump LocationTable 3. Bronchiolitis Treatment Trials: Epinephrine
Table Graphic Jump LocationTable 4. Bronchiolitis Treatment Trials: β2-Agonist Bronchodilators
Table Graphic Jump LocationTable 5. Bronchiolitis Treatment Trials: Corticosteroids
Table Graphic Jump LocationTable 6. Bronchiolitis Treatment Trials: Ribavirin

References

Hall  CB Respiratory syncytial virus and parainfluenza virus. N Engl J Med. 2001;3441917- 1928
PubMed Link to Article
Glezen  WPTaber  LHFrank  ALKasel  JA Risk of primary infection and reinfection with respiratory syncytial virus. AJDC. 1986;140543- 546
PubMed
Shay  DKHolman  RCNewman  RDLiu  LLStout  JWAnderson  LJ Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999;2821440- 1446
PubMed Link to Article
Wang  EELaw  BJBoucher  FD  et al.  Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study of admission and management variation in patients hospitalized with respiratory syncytial viral lower respiratory tract infection. J Pediatr. 1996;129390- 395
PubMed Link to Article
Willson  DFHorn  SDHendley  JOSmout  RGassaway  J Effect of practice variation on resource utilization in infants hospitalized for viral lower respiratory illness. Pediatrics. 2001;108851- 855
PubMed Link to Article
Cahill  PFinan  ELoftus  BG Management of bronchiolitis: current practices in Ireland. Ir Med J. 2002;95167- 169
PubMed
Viswanathan  MKing  VBordley  C  et al.  Management of Bronchiolitis in Infants and Children: Evidence Report/Technology Assessment No.69.  Rockville, Md US Dept of Health and Human Services, Agency for Healthcare Research and Quality2003;AHRQ publication 03-E014
Bordley  WCViswanathan  MKing  VJ  et al.  Diagnosis and testing in bronchiolitis: a systematic review. Arch Pediatr Adolesc Med. 2004;158119- 126
Link to Article
West  SLKing  VCarey  TS  et al.  Systems to Rate the Strength of Scientific Evidence: Evidence Report/Technology Assessment No.47.  Rockville, Md Agency for Healthcare Research and Quality2002;AHRQ publication 02-E016
Rodriguez  WJGruber  WCGroothuis  JR  et al.  Respiratory syncytial virus immune globulin treatment of RSV lower respiratory tract infection in previously healthy children. Pediatrics. 1997;100937- 942
PubMed Link to Article
Rodriguez  WJGruber  WCWelliver  RC  et al.  Respiratory syncytial virus (RSV) immune globulin intravenous therapy for RSV lower respiratory tract infection in infants and young children at high risk for severe RSV infections: Respiratory Syncytial Virus Immune Globulin Study Group. Pediatrics. 1997;99454- 461
PubMed Link to Article
Chipps  BESullivan  WFPortnoy  JM Alpha-2A-interferon for treatment of bronchiolitis caused by respiratory syncytial virus. Pediatr Infect Dis J. 1993;12653- 658
PubMed Link to Article
Hollman  GShen  GZeng  L  et al.  Helium-oxygen improves Clinical Asthma Scores in children with acute bronchiolitis. Crit Care Med. 1998;261731- 1736
PubMed Link to Article
Kong  XTFang  HTJiang  GQZhai  SZO'Connell  DLBrewster  DR Treatment of acute bronchiolitis with Chinese herbs. Arch Dis Child. 1993;68468- 471
PubMed Link to Article
Luchetti  MCasiraghi  GValsecchi  RGalassini  EMarraro  G Porcine-derived surfactant treatment of severe bronchiolitis. Acta Anaesthesiol Scand. 1998;42805- 810
PubMed Link to Article
Van Bever  HPDesager  KNPauwels  JHWojciechowski  MVermeire  PA Aerosolized furosemide in wheezy infants: a negative report. Pediatr Pulmonol. 1995;2016- 20
PubMed Link to Article
Nasr  SZStrouse  PJSoskolne  E  et al.  Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis. Chest. 2001;120203- 208
PubMed Link to Article
Bertrand  PAranibar  HCastro  ESanchez  I Efficacy of nebulized epinephrine versus salbutamol in hospitalized infants with bronchiolitis. Pediatr Pulmonol. 2001;31284- 288
PubMed Link to Article
Kristjansson  SLodrup Carlsen  KCWennergren  GStrannegard  ILCarlsen  KH Nebulised racemic adrenaline in the treatment of acute bronchiolitis in infants and toddlers. Arch Dis Child. 1993;69650- 654
PubMed Link to Article
Menon  KSutcliffe  TKlassen  TP A randomized trial comparing the efficacy of epinephrine with salbutamol in the treatment of acute bronchiolitis. J Pediatr. 1995;1261004- 1007
PubMed Link to Article
Patel  HPlatt  RWPekeles  GSDucharme  FM A randomized, controlled trial of the effectiveness of nebulized therapy with epinephrine compared with albuterol and saline in infants hospitalized for acute viral bronchiolitis. J Pediatr. 2002;141818- 824
PubMed Link to Article
Ray  MSSingh  V Comparison of nebulized adrenaline versus salbutamol in wheeze associated respiratory tract infection in infants. Indian Pediatr. 2002;3912- 22
PubMed
Reijonen  TKorppi  MPitkakangas  STenhola  SRemes  K The clinical efficacy of nebulized racemic epinephrine and albuterol in acute bronchiolitis. Arch Pediatr Adolesc Med. 1995;149686- 692
PubMed Link to Article
Sanchez  IDe Koster  JPowell  REWolstein  RChernick  V Effect of racemic epinephrine and salbutamol on clinical score and pulmonary mechanics in infants with bronchiolitis. J Pediatr. 1993;122145- 151
PubMed Link to Article
Wainwright  CLuis Altamirano  M-CCheney  M  et al.  A multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis. N Engl J Med. 2003;34927- 35
PubMed Link to Article
Can  DInan  GYendur  GOral  RGunay  I Salbutamol or mist in acute bronchiolitis. Acta Paediatr Jpn. 1998;40252- 255
PubMed Link to Article
Cengizlier  RSaraclar  YAdalioglu  GTuncer  A Effect of oral and inhaled salbutamol in infants with bronchiolitis. Acta Paediatr Jpn. 1997;3961- 63
PubMed Link to Article
Chowdhury  Dal Howasi  MKhalil  Mal-Frayh  ASChowdhury  SRamia  S The role of bronchodilators in the management of bronchiolitis: a clinical trial. Ann Trop Paediatr. 1995;1577- 84
PubMed
Dobson  JVStephens-Groff  SMMcMahon  SRStemmler  MMBrallier  SLBay  C The use of albuterol in hospitalized infants with bronchiolitis. Pediatrics. 1998;101361- 368
PubMed Link to Article
Gadomski  AMAref  GHel Din  OBel Sawy  IHKhallaf  NBlack  RE Oral versus nebulized albuterol in the management of bronchiolitis in Egypt. J Pediatr. 1994;124131- 138
PubMed Link to Article
Gadomski  AMLichenstein  RHorton  LKing  JKeane  VPermutt  T Efficacy of albuterol in the management of bronchiolitis. Pediatrics. 1994;93907- 912
PubMed
Goh  AChay  OMFoo  ALOng  EK Efficacy of bronchodilators in the treatment of bronchiolitis. Singapore Med J. 1997;38326- 328
PubMed
Ho  LCollis  GLandau  LILe Souef  PN Effect of salbutamol on oxygen saturation in bronchiolitis. Arch Dis Child. 1991;661061- 1064
PubMed Link to Article
Klassen  TPRowe  PCSutcliffe  TRopp  LJMcDowell  IWLi  MM Randomized trial of salbutamol in acute bronchiolitis. J Pediatr. 1991;118807- 811
PubMed Link to Article
Schuh  SCanny  GReisman  JJ  et al.  Nebulized albuterol in acute bronchiolitis. J Pediatr. 1990;117633- 637
PubMed Link to Article
Schuh  SJohnson  DCanny  G  et al.  Efficacy of adding nebulized ipratropium bromide to nebulized albuterol therapy in acute bronchiolitis. Pediatrics. 1992;90920- 923
PubMed
Totapally  BRDemerci  CZureikat  GNolan  B Tidal breathing flow-volume loops in bronchiolitis in infancy: the effect of albuterol. Crit Care. 2002;6160- 165
PubMed Link to Article
Wang  EEMilner  RAllen  UMaj  H Bronchodilators for treatment of mild bronchiolitis: a factorial randomised trial. Arch Dis Child. 1992;67289- 293
PubMed Link to Article
Berger  IArgaman  ZSchwartz  SB  et al.  Efficacy of corticosteroids in acute bronchiolitis: short-term and long-term follow-up. Pediatr Pulmonol. 1998;26162- 166
PubMed Link to Article
Goebel  JEstrada  BQuinonez  JNagji  NSanford  DBoerth  RC Prednisolone plus albuterol versus albuterol alone in mild to moderate bronchiolitis. Clin Pediatr (Phila). 2000;39213- 220
PubMed Link to Article
Klassen  TPSutcliffe  TWatters  LKWells  GAAllen  UDLi  MM Dexamethasone in salbutamol-treated inpatients with acute bronchiolitis: a randomized, controlled trial. J Pediatr. 1997;130191- 196
PubMed Link to Article
Schuh  SCoates  ALBinnie  R  et al.  Efficacy of oral dexamethasone in outpatients with acute bronchiolitis. J Pediatr. 2002;14027- 32
PubMed Link to Article
van Woensel  JBWolfs  TFvan Aalderen  WMBrand  PLKimpen  JL Randomised double blind placebo controlled trial of prednisolone in children admitted to hospital with respiratory syncytial virus bronchiolitis. Thorax. 1997;52634- 637
PubMed Link to Article
van Woensel  JBKimpen  JLSprikkelman  ABOuwehand  Avan Aalderen  WM Long-term effects of prednisolone in the acute phase of bronchiolitis caused by respiratory syncytial virus. Pediatr Pulmonol. 2000;3092- 96
PubMed Link to Article
De Boeck  KVan der Aa  NVan Lierde  SCorbeel  LEeckels  R Respiratory syncytial virus bronchiolitis: a double-blind dexamethasone efficacy study. J Pediatr. 1997;131919- 921
PubMed Link to Article
Roosevelt  GSheehan  KGrupp-Phelan  JTanz  RRListernick  R Dexamethasone in bronchiolitis: a randomised controlled trial. Lancet. 1996;348292- 295
PubMed Link to Article
Cade  ABrownlee  KGConway  SP  et al.  Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis. Arch Dis Child. 2000;82126- 130
PubMed Link to Article
Fox  GFEverard  MLMarsh  MJMilner  AD Randomised controlled trial of budesonide for the prevention of post-bronchiolitis wheezing. Arch Dis Child. 1999;80343- 347
PubMed Link to Article
Kajosaari  MSyvanen  PForars  MJuntunen-Backman  K Inhaled corticosteroids during and after respiratory syncytial virus-bronchiolitis may decrease subsequent asthma. Pediatr Allergy Immunol. 2000;11198- 202
PubMed Link to Article
Reijonen  TKorppi  MKuikka  LRemes  K Anti-inflammatory therapy reduces wheezing after bronchiolitis. Arch Pediatr Adolesc Med. 1996;150512- 517
PubMed Link to Article
Richter  HSeddon  P Early nebulized budesonide in the treatment of bronchiolitis and the prevention of postbronchiolitic wheezing. J Pediatr. 1998;132849- 853
PubMed Link to Article
Wong  JYMoon  SBeardsmore  CO'Callaghan  CSimpson  H No objective benefit from steroids inhaled via a spacer in infants recovering from bronchiolitis. Eur Respir J. 2000;15388- 394
PubMed Link to Article
Barry  WCockburn  FCornall  RPrice  JFSutherland  GVardag  A Ribavirin aerosol for acute bronchiolitis. Arch Dis Child. 1986;61593- 597
PubMed Link to Article
Edell  DKhoshoo  VRoss  GSalter  K Early ribavarin treatment of bronchiolitis: effect on long-term respiratory morbidity. Chest. 2002;122935- 939
PubMed Link to Article
Everard  MLSwarbrick  ARigby  ASMilner  AD The effect of ribavirin to treat previously healthy infants admitted with acute bronchiolitis on acute and chronic respiratory morbidity. Respir Med. 2001;95275- 280
PubMed Link to Article
Guerguerian  AMGauthier  MLebel  MHFarrell  CALacroix  J Ribavirin in ventilated respiratory syncytial virus bronchiolitis: a randomized, placebo-controlled trial. Am J Respir Crit Care Med. 1999;160829- 834
PubMed Link to Article
Hall  CBMcBride  JTWalsh  EE  et al.  Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection: a randomized double-blind study. N Engl J Med. 1983;3081443- 1447
PubMed Link to Article
Janai  HKStutman  HRZaleska  M  et al.  Ribavirin effect on pulmonary function in young infants with respiratory syncytial virus bronchiolitis. Pediatr Infect Dis J. 1993;12214- 218
PubMed Link to Article
Meert  KLSarnaik  APGelmini  MJLieh-Lai  MW Aerosolized ribavirin in mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease: a prospective, double-blind, randomized trial. Crit Care Med. 1994;22566- 572
PubMed Link to Article
Rodriguez  WJKim  HWBrandt  CD  et al.  Aerosolized ribavirin in the treatment of patients with respiratory syncytial virus disease. Pediatr Infect Dis J. 1987;6159- 163
PubMed Link to Article
Rodriguez  WJArrobio  JFink  RKim  HWMilburn  C Prospective follow-up and pulmonary functions from a placebo-controlled randomized trial of ribavirin therapy in respiratory syncytial virus bronchiolitis: Ribavirin Study Group. Arch Pediatr Adolesc Med. 1999;153469- 474
PubMed Link to Article
Smith  DWFrankel  LRMathers  LHTang  ATAriagno  RLProber  CG A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection. N Engl J Med. 1991;32524- 29
PubMed Link to Article
Taber  LHKnight  VGilbert  BE  et al.  Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants. Pediatrics. 1983;72613- 618
PubMed
Moler  FWBandy  KPCuster  JR Ribavirin therapy for acute bronchiolitis: need for appropriate controls [letter]. J Pediatr. 1991;119509- 510
PubMed Link to Article
Flores  GHorwitz  RI Efficacy of beta2-agonists in bronchiolitis: a reappraisal and meta-analysis. Pediatrics. 1997;100233- 239
PubMed Link to Article
Kellner  JDOhlsson  AGadomski  AMWang  EE Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2000;2CD001266
PubMed
Garrison  MMChristakis  DAHarvey  ECummings  PDavis  RL Systemic corticosteroids in infant bronchiolitis: a meta-analysis. Pediatrics. 2000;105E44
PubMed Link to Article
Randolph  AGWang  EE Ribavirin for respiratory syncytial virus lower respiratory tract infection: a systematic overview. Arch Pediatr Adolesc Med. 1996;150942- 947
PubMed Link to Article
American Academy of Pediatrics, Respiratory syncytial virus. Pickering  LKed.2003 Red Book: Report of the Committee on Infectious Diseases 26th ed. Elk Grove Village, Ill American Academy of Pediatrics2003;524
Committee on Infectious Diseases, Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. Pediatrics. 1996;97137- 140
PubMed

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 73

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
JAMAevidence.com