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A Multicenter, Randomized, Double-Blind, Controlled Trial of Nebulized Epinephrine in Infants with Acute Bronchiolitis

Wainwright C, Altamarino L, Medico-Cirujano et al.

New Engl J Med 2003;349:27-35. [abstract]

Reviewed by Parthak Prodhan MD, Natan Noviski, MD Department of Pediatric Critical Care, Massachusetts General Hospital, Boston, MA

Review posted June 4, 2004

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I. What is being studied?:

The study objective:

To compare the effectiveness of nebulized single-isomer epinephrine compared to treatment with saline placebo in previously well infants hospitalized with acute bronchiolitis.

The study design:

A multi-center, prospective, randomized, double blind, placebo-controlled trial. Infants were recruited when admitted to any of the four Australian hospitals in one season (April 2000 and September 2001) with a clinical diagnosis of bronchiolitis.

The patients included:

All previously well infants (n=194) less than 12 months of age (or less than 12 months of corrected age if they were premature) who were admitted any of four Queensland, Australia, hospitals with a clinical diagnosis of acute bronchiolitis. A diagnosis of acute bronchiolitis was made if the infant had a history of upper respiratory tract infection and clinical findings consistent with bronchiolitis, including wheezing or wheezing with crackles and respiratory distress with chest recession. Of note, infants with chronic neonatal lung disease associated with prematurity were also included.

The patients excluded:

Those not eligible for the study included infants

1. with cardiac disease
2. with clinically significant respiratory disease, such as cystic fibrosis
3. who received corticosteroids in any form within 24 hours before presentation
4. who received bronchodilators within 4 hours before presentation
5. who required ventilatory support before their parents could give consent for their participation in the study

The interventions compared:

Patients were randomized to two treatment strategies: Three 4-ml doses of 1 percent nebulized epinephrine (epinephrine acid tartrate, 1 percent, with sodium metabisulfite and vehicle) or three 4-ml doses of normal saline (chlorobutanol, edetate disodium, sodium chloride, and purified water) administered at four-hour intervals after hospital admission.

The outcomes evaluated:

The two primary outcomes were the length of the hospital (LOS) stay and the time until the infant was ready for discharge.

The secondary outcome measures were the degree of changes in the components of the clinical scores (the degree of change in the respiratory rate, the heart rate, and the respiratory-effort score) before and after nebulization therapy and the time that supplemental oxygen was required.

Detailed clinical histories as per a defined clinical pathway were obtained. A nasopharyngeal-aspiration sample for detection of respiratory syncytial virus was obtained from all patients. Observations at admission included respiratory rate and heart rate while the infant was quiet, temperature, respiratory effort, oxygen saturation while breathing room air, presence or absence of wheezing or crackles on auscultation of the chest, and level of hydration.

The nursing staff recorded the respiratory and heart rates while the patient was quiet, supplemental oxygen requirements, oxygen saturation, respiratory effort (scoring each component as mild, moderate, or severe), and blood pressure just before and 30 and 60 minutes after the delivery of the drug. Observations were made at admission and just before, 30 minutes after, and 60 minutes after each dose.

Ready for discharge was considered if the infant had not received supplemental oxygen for 10 hours, had minimal or no chest recession, and was feeding adequately, without the need for intravenous fluids.

Data on readmission to the hospital in the month after discharge were also collected.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Randomization was performed by the manufacturing pharmacy to one of the two treatment strategies: racemic epinephrine or saline placebo. Patients were stratified according to center in blocks of 50 numbers, so that each block comprised 25 patients randomly assigned to epinephrine and 25 to placebo. Two of the smaller hospitals were regarded as one center for the purpose of stratification. Each patient was assigned the next sequential number for the particular center. There was one bottle of epinephrine or placebo solution per patient randomly assigned to a treatment group, corresponding to the patient''s number.

However, the randomization was not stratified according to the severity of illness. More infants with moderately severe illness and less infants with the highest severity of illness were assigned to epinephrine than to placebo, although these differences did not reach statistical significance.

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

Was followup complete?

Yes. All infants who entered the trial were properly accounted for and attributed at its conclusion. A total of 194 infants were assigned to treatment: 99 to epinephrine and 95 to placebo.

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

Yes. An intention-to-treat analysis was used.

Secondary questions:

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

Yes. All study personnel and participants were blinded to treatment assignment for the duration of the study. All study solutions were identically clear, colorless, and with an odor of chlorobutanol. Equal volumes of solutions were dispensed in amber bottles and were prepared in advance with standard dosing units and were numerically coded for the use of attending physicians, ward nurses, and the study nurses. Epinephrine and placebo were administered by means of standard hospital jet nebulizers through a firmly applied facemask with an oxygen flow of 6 liters per minute. The same types of nebulizer bowls and masks were used throughout the study at each hospital.

However the parents, ward staff, and research nurse for each enrolled patient were not questioned as to which therapy they believed the infant received, and which allocation group patients belonged. The treatment group with racemic epinephrine associated with a higher heart rate compared to the saline group could potentially clue the parents, ward staff, and the research nurse into the type of therapy provided.

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

Yes. There were no significant differences between the groups at randomization in terms of demographic variables, the proportion of infants requiring supplemental oxygen or intravenous fluids, or the proportion of infants whose nasopharyngeal aspirate was positive for respiratory syncytial virus. There were no significant differences at admission between the groups in the duration of wheezing or the duration of coryza.

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

Yes. All infants admitted with bronchiolitis were treated according to the same clinical pathway to ensure consistent care and minimize the variability of the results. The clinical pathway included guidelines for the use and termination of supplemental oxygen and the use of intravenous fluids. The number and method of nebulization's across the groups was similar. Measurements of outcome variables were obtained in a uniform fashion across the groups equally.

Seven infants (3.6 percent) required admission to the intensive care unit, and three (1.5 percent) required ventilatory support. There were no significant differences between the groups in the proportions requiring intensive care (P = 0.23) or ventilatory support (P = 0.08).

Fourteen infants did not receive all three doses of nebulized epinephrine or placebo (10 in the epinephrine group and 4 in the placebo group, P = 0.11). Three infants in the placebo group received antibiotics, as did one in the epinephrine group. No infants received steroid therapy, and two in the placebo group were treated with bronchodilators other than epinephrine when their condition failed to improve.

III. What were the results?

1. How large was the treatment effect?

	Patients	Mean LOS overall (h)	Confidence Interval 95%
Epinephrine	99	58.8	49.4 - 70.0
Placebo (Saline)	95	69.5	59.3 - 81.4

	Patients	Time until ready for discharge (h)	Confidence Interval 95%
Epinephrine	99	46.5	38.3 - 56.5
Placebo (Saline)	95	47.7	39.0 - 58.3

There were no significant overall differences between the treatment groups in evaluation of primary outcomes (the length of the hospital stay (P = 0.16) or the time until the infant was ready for discharge (P = 0.86). The differences between the epinephrine and placebo groups in the length of the hospital stay and the time until ready for discharge were not significant for infants who received no oxygen or oxygen without intravenous fluids (P = 0.06 to P = 0.39).

Among infants who required supplemental oxygen and intravenous fluids, the time until the infant was ready for discharge was significantly longer in the epinephrine group (135.9 hrs, 95% CI 96.9-191.3) than in the placebo group (80.2, 95% CI 62.0-103.5) (P = 0.02). The need for supplemental oxygen at admission had the greatest influence on the score for severity of illness and strongly predicted the length of the hospital stay and the time until the infant was ready for discharge (P < 0.001).

There were no significant changes in secondary outcome measures (the respiratory rate, blood pressure, or respiratory-effort scores) from before each treatment to after each treatment. The heart rate was however significantly increased after each treatment with epinephrine sixty minutes after the last nebulization treatment; the mean heart rate was 151 per minute in the epinephrine group (95% confidence interval, 147 to 156), as compared with 138 per minute in the placebo group (95 % confidence interval 134 to 142; P < 0.001).

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

The authors aimed to detect a difference between the two groups of half a standard deviation in the length of the hospital stay and the time until the infant was ready for discharge at the 1 percent significance level for a two-sided test with 85 percent power; which would require 200 infants, with 100 infants in each group. They enrolled a total of 194 infants, 99 in epinephrine treatment group and 95 to the placebo group. We can calculate the standard deviation of the length of stay to be approximately 50 hours, so this study was only powered to detect a difference of 24 hours. There may well have been a clinically significant difference that is less than 24 hours, and this study would not have been large enough to detect such a difference.

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

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

Yes. The results of this well designed study, which concludes that the use of nebulized epinephrine did not significantly reduce the length of the hospital stay or the time until the infant was ready for discharge among infants admitted to the hospital with bronchiolitis, is timely. There has been much discussion over the last decade regarding the best treatment options for these patients to obtain favorable outcomes. Our experience with treating infants with bronchiolitis compliments the findings of this study in that supportive care until the viral illness runs its course is important irrespective of the use of any type of bronchodilators.

Few of these patients were critically ill and therefore the study results may not be applicable to a sicker cohort usually admitted to pediatric intensive care units. Further, this study investigated single isomer epinephrine rather than the racemic mixture more commonly used in the US.

2. Were all clinically important outcomes considered?

The primary outcome measures (the length of the hospital stay and the time until the infant was ready for discharge) and the secondary outcome measures (degree of change in the respiratory rate, the heart rate, and the respiratory-effort score and the time that supplemental oxygen was required) are clinically relevant endpoints to consider.

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

No. There was no benefit in using three 4-ml doses of 1 percent nebulized single isomer epinephrine as compared to a placebo of three 4-ml doses of normal saline administered at four-hour intervals after hospital admission in previously well infants hospitalized with acute viral bronchiolitis.

The treatment group was associated with a significant effect on the heart rate (mean 151 versus 138 per minute in control group) but non-significant increases in respiratory rates (by about two breaths per minute), increase of about 5 mm Hg in both systolic and diastolic blood pressure 30 minutes after treatment. Further, there was no significant difference between the groups in the change in the respiratory-effort score from before to 60 minutes after each treatment.

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