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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A randomized, controlled trial of the effectiveness of nebulized therapy with epinephrine compared with albuterol and saline in infants hospitalized for acute viral bronchiolitis.

Patel H, Platt RW, Pekeles GS, Ducharme FM.

J Pediatr. 2002;141(6):818-24. [abstract]

Reviewed by Rich Lambert MD, Ron Sanders MD, University of Florida, Gainesville

Review posted November 24, 2003

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I. What is being studied?:

The study objective:

The effectiveness of repeated nebulized therapy with epinephrine was compared to treatment with albuterol or saline placebo in previously well infants hospitalized with acute viral bronchiolitis

The study design:

A prospective, double-blinded, randomized placebo-controlled, parallel-group trial. Infants were recruited throughout two successive bronchiolitis seasons (mid November to March; 1998-1999 and 1999-2000) at the time of hospital admission from the emergency department.

The patients included:

All previously well infants aged less than or equal to 12 months with a clinical diagnosis of acute viral bronchiolitis who were hospitalized during the study period because of:

1. Hemoglobin oxygen saturation of less than 95% in room air
2. Poor feeding with or without dehydration
3. Lethargy
4. Sustained tachypnea with a resting respiratory rate of greater or equal to 70 breaths/minute
5. The global impression of need for admission by the attending ED physician.

The patients excluded:

Older than 12 months, had a previous history of wheezing or home bronchodilator use, or if they were directly transferred to the intensive care unit. Additional exclusion criteria included:

1. A gestational age at birth of less than 34 weeks
2. Underlying chronic cardiac or pulmonary disease (e.g. bronchopulmonary dysplasia)
3. Immunocompromised patients
4. History of immunoprophylaxis therapy (i.e. respiratory syncytial virus (RSV) immune globulin or RSV monoclonal antibody therapy).
5. Infants with a parent not fluent in either English or French were also excluded.

The interventions compared:

Patients were randomized to one of three treatment strategies: racemic epinephrine (0.03 ml/kg/dose of a 2.25% solution); albuterol (0.03 ml/kg/dose of a 5 mg/ml solution); or placebo (0.03 ml/kg/dose of 0.9% sodium chloride).

The outcomes evaluated:

Primary study outcome was length of stay (LOS) defined as the time between study entry (which began at the time the consent was signed in the ED after the decision to admit the patient to the ward was made by the attending ED physician) and the actual time that the infant left the in-patient ward, as noted by ward staff.

Secondary outcomes were time from admission until the infant had normal oxygenation (hemoglobin oxygen saturation of ≥95% in room air); adequate fluid intake to meet maintenance requirements (50ml/kg/12 hours); and minimal respiratory distress, indicated by an RDAI (Respiratory Distress Assessment Instrument) score of ≤ 4 (this is a scoring method commonly used in bronchiolitis which is based on a 17 point ordinal scale that assigns points based on wheezing, i.e. expiratory (0-4), inspiratory (0-2), and location of wheeze (0-2), and retractions, i.e. supraclavicular (0-3), intercostals (0-3), and subcostal (0-3)), and minimal requirements of nebulized medication frequency of treatments less often than every 4 hours. A consensus agreement was made between nurse and mother to determine adequate fluid intake for breast fed infants. They also monitored each patient for tachycardia, tremor, and hypertension.

Discharge criteria included: no need for supplemental fluids or oxygen, nebulization not required more often than every 4 hours, and minimal respiratory distress.

Follow-up outcomes: assessed by standardized telephone interview 7 days after hospital discharge including the rates of ED return visits; re-admission to the hospital; admission to the intensive care unit; and return visits to a primary care giver.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Computer generated randomization within blocks of 6 subjects was used to assign patients to one of the three treatment strategies; racemic epinephrine, albuterol or saline placebo.

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

Was followup complete?

Yes. All patients enrolled in the study (including the 10 patients that withdrew) were tracked until discharge for LOS data and received a telephone call 7 days after hospital discharge. Using a standardized telephone interview, follow-up outcome data included rates of emergency department return visits, re-admission to the hospital, admission to the intensive care unit, and return visits to the primary care giver. Data was obtained for all three groups and was similar, i.e., of the 149 patients studied, 93 (62%) had a medical visit in the week post discharge with each group having similar representation (epinephrine 32, albuterol 28, and placebo 33).

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 odorless. Equal volumes of solutions were dispensed in opaque 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.

In addition, the parents, ward staff, and research nurse for each enrolled patient were questioned as to which therapy they believed the infant received, and which allocation group patients belonged. This data was analyzed, and showed no difference in the proportion of correct guesses by treatment group participants.

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

Yes, there were no group differences in baseline characteristics including ethnicity, mean age, gestational age, mode of feeding, passive cigarette exposure, atopic features, and mean duration of symptoms before study enrollment.

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

Yes. The mean number and method of nebulizations across the groups was similar. Supplemental oxygen and fluids were given to all groups equally as based on pre-enrollment criteria. Twice daily measurements of outcome variables were obtained in a uniform fashion across the groups equally.

III. What were the results?

1. How large was the treatment effect?

There was no clinically significant effect between the treatment groups when evaluating either primary outcome (LOS in hours), or secondary outcomes (mean time to normal oxygenation, i.e. O2 sats greater or equal to 95% in room air, mean time to adequate oral intake, mean time to RDAI ≤ 4, and mean time to infrequent nebulizations, i.e. every 4 hours or less).

	Patients	Mean LOS (h) (SD)	Confidence Interval 95%
Epinephrine	50	59.8 (62)	42.3 - 77.3
Albuterol	51	61.4 (54)	46.3 - 76.5
Placebo (Saline)	48	63.3 (47)	49.7 - 76.9

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

The primary outcome was LOS and as mentioned above, there were no differences between the groups. The actual difference as calculated above was only 3.5 hours for the epinephrine group and 1.9 hours for the albuterol group. This is compared to the authors' pre-study goal of a 24 hour decrease in LOS between groups. We agree with the authors' comment about the asymmetric distribution of LOS and appreciate the additional appropriate secondary analyses performed, since using means in this situation may not be the most appropriate measure of comparison. Despite the additional analyses, there were still no differences between groups.

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

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

Yes. Infants affected by bronchiolitis continue to make a major impact on our census in both our pediatric intermediate and intensive care units during the winter season. There has been much discussion over the last decade regarding the best treatment options for these patients to obtain favorable outcomes. While some studies have shown short term improvement using alpha adrenergic agents and bronchodilators, as referenced in this article, there still exists a real paucity of level 1 studies which clearly define an improvement in clinically important endpoints in either outpatient or inpatient settings. Our experience with treating these patients compliments the findings of this study in that supportive care continues to be the gold standard with which to guide patient care.

2. Were all clinically important outcomes considered?

Yes. Decreasing length of stay and reducing potential morbidity to patients by shortening time to important endpoints like mean time to normal oxygenation and infrequent nebulizations are indeed important outcome measurements to consider.

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

No. There was no benefit in using repeated dosing of racemic epinephrine verses albuterol verses placebo. In fact, the mean LOS for the group receiving nebulized saline as a control was not significantly different than either treatment groups. Secondary outcomes revealed similar findings with no statistical significance between groups. Adverse effects included transient tachycardia, mild hypertension, and slight tremor. One patient was transferred to their intensive care unit; however, the reason for transfer was not disclosed. Considering the current lack of quality evidence reflecting a significant clinical improvement in outcome using racemic epinephrine and/or albuterol over supportive care, any potential harm from treatment should be carefully reviewed and considered prior to initiation.

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