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 Use of Albuterol in Hospitalized Infants With Bronchiolitis

Dobson JV, Stephens-Groff SM, McMahon SR, Stemmler MH, Brallier SL, Bay C.

Pediatrics 1998; 101: 361-368. [abstract] [full-text for AAP members]

Reviewed by Kshama Daphtary, MD and Kathleen Meert, MD, Children's Hospital of Michigan

Review posted November 19, 1998

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I. What is being studied?:

The study objective:

To determine whether the use of albuterol by nebulization enhances physiologic or clinical recovery in hospitalized infants with moderate bronchiolitis.

The study design:

Prospective, double-blind, randomized placebo-controlled clinical trial.

The patients included:

All patients less than 24 months of age who were admitted to the pediatric inpatient unit at the Maricopa Medical Center, Phoenix with a first episode of wheezing during the period from November 1995 to March 1996.

Eligibility criteria:

1. age less than 24 months
2. viral bronchiolitis defined as an acute infection of the lower respiratory tract, preceded by or accompanied by fever, and/or rhinitis, tachypnea, expiratory wheezing and increased respiratory effort
3. moderately severe acute bronchiolitis defined as having at least one of the following findings on initial evaluation:

- oxygen saturation on room air < 94 %

- moderate to severe accessory muscle use (clinical score 2)

- moderate to severe wheezing (clinical score 2)

The patients excluded:

1. chronic cardiac disease
2. chronic pulmonary disease
3. significant concurrent illness (sepsis, meningitis, pneumonia, urinary tract infection, gastroenteritis)
4. current gestational age less than 38 weeks,
5. history of wheezing requiring hospitalization or bronchodilators
6. history of bronchodilator therapy before current illness
7. concurrent steroid treatment
8. severe bronchiolitis requiring intensive care:

- mechanical ventilation

- documented apnea

- heart rate > 200/min

- hypercarbia

The interventions compared:

Twenty-three patients received nebulized albuterol (1.25 mg for patients less than 10 kg and 2.5 mg for patients more than 10 kg in normal saline to make a total volume of 3 ml) every 2 hours for the first 24 hours and then every 4 hours for the next 48 hours. Twenty-nine patients received 3 ml of nebulized normal saline every 2 hours for the first 24 hours and every 4 hours for the next 48 hours.

The outcomes evaluated:

Primary endpoints:

1. Improvement in oxygen saturation (SaO2) on room air at 24 hours and maximal improvement in SaO2 during hospitalization were primary endpoints. Oxygen saturation was recorded after equilibration to room air over a 15 minute period immediately before a scheduled study drug administration. This assessment was done at 24 hour intervals.
2. The time required to independently reach 3 separate preestablished discharge criteria:

- SaO2 on room air 94 %

- no or mild wheezing (clinical score < 2)

- no or mild accessory muscle use (clinical score < 2)

The clinical score included separate 0-3 scales for accessory muscle use and wheezing , with 0 representing the least severe and 3 representing the most severe observations.

Secondary endpoints:

1. duration of hospital stay. This was determined by the pediatric inpatient team independent of the study investigators clinical evaluation of severity of illness.
2. adverse outcome measures including

- incidence of cardiovascular side-effects

- deteriorating respiratory status.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, the patients were randomly assigned to receive either albuterol or normal saline. The method of randomization was not specified.

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

Was followup complete?

Follow-up was not complete for all patients. Fifty-eight patients were enrolled in the trial. Three patients were withdrawn from the trial within 24 hours of enrollment because the parents wished not to participate in the study for reasons not specified. These 3 patients were excluded from statistical analysis. Another 3 patients were withdrawn from the study by the pediatric inpatient team because of worsening clinical status. All 3 had been assigned to receive albuterol. They were also excluded from statistical analysis. The removal of these 6 patients may not have affected the results of the study, but an intention-to-treat analysis should have been performed to eliminate any potential bias introduced by these dropouts. The remaining 52 patients were followed up until they were discharged from the hospital.

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

The 6 patients who were withdrawn from the trial were not included in the analysis. The rest of the patients were analyzed in the groups to which they were randomized.

Secondary questions:

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

Yes, the patients, physicians and the respiratory therapists who administered the treatments were blind to the use of albuterol or normal saline. The drugs were prepared in the pharmacy and supplied in identical containers.

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

Yes, the 2 groups had similar baseline characteristics including age, gestational age at birth, gender, weight, viral agent, symptomatology (fever, cough, rhinorrhea, wheezing), duration of symptoms, race, pretreatment with nebulized albuterol, heart rate, oxygen saturation, accessory muscle score and wheeze score. The placebo group had twice as many patients with exposure to smokers and a family history of wheezing, but these differences were not statistically significant.

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

Yes, both groups received oxygen to maintain saturation above 94%, intravenous hydration, nasopharyngeal suctioning and chest physiotherapy. No patient received steroids or other respiratory medications (ipratropium bromide, epinephrine).

III. What were the results?

1. How large was the treatment effect?

Both treatment groups showed an improvement in oxygen saturation on room air over time. Improvement in oxygen saturation was measured as the percentage increase in SaO2 over 3 time intervals (time 0 to 24 hours, time 0 to Max SaO2, and 24 hours to Max SaO2). There was no significant difference in improvement between the 2 groups (p=.86, .48 and .55 respectively for the 3 time intervals).

Table 1. Improvement in % SaO2 on room air over time

	Albuterol	Placebo
Time 0 to 24 hours	1.8% (0.1%-3.6%)	1.6% (0.2%-3.0%)
24 hours to Max SaO2	2.2% (1.3%-3.1%)	1.8% (0.9%-2.8%)
Time 0 to Max SaO2	4.0% (2.6%-%.4%)	3.4% (2.4%-4.5%)

* Figures in parentheses are the 95% confidence intervals.

The other primary outcome measure of the study was the time required to reach 3 preestablished discharge criteria. This was demonstrated by calculating the percentage of patients in each treatment group who did not meet these criteria at 24, 48 and 72 hours. There were no statistical differences in the percentage of patients not meeting discharge criteria at any of these time points.

Table 2. Percentage of patients on albuterol and placebo not meeting the discharge criteria at different time intervals

	Time 0	24 hours	48 hours	72 hours
SaO2 <94% on room air
Albuterol	69.6	43.5	21.7	17.4
Placebo	79.3	37.9	21.1	21.1
Moderate to severe retraction
Albuterol	69.6	26.1	13	13
Placebo	75.9	31	11.6	3.9
Moderate to severe wheezing
Albuterol	56.5	26.1	13	6.5
Placebo	69	34.5	21.6	21.6

The actual length of hospital stay of the 2 groups of patients was compared by comparing the percentage of patients in each group still hospitalized at 48 and 72 hours.

Table 3. Percentage of patients still hospitalized at 48 and 72 hours

	48 hours	72 hours
Albuterol	82.6	47.8
Placebo	75.9	31.0

The relative risk (RR), comparing albuterol to control, of remaining hospitalized at 48 hours is 1.09 and at 72 hours is 1.54. The relative risk reduction (RRR) at 72 hours is -54% which means that albuterol increased the risk of being in hospital at 72 hours by 54%. The absolute risk reduction (ARR) is -0.17.

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

Based on the confidence intervals for the primary outcome variables "improvement in SaO2 at 24 hours, and maximal improvement in SaO2," the data appear precise (Table 1).

The 95% confidence intervals for the relative risk reduction of remaining in hospital at 72 hours (-54%) is -205% to 23% and that for the absolute risk reduction (-0.17) is -43% to 9.5%. The confidence intervals cross zero and this suggests that the differences are not significant.

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

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

Yes and no. The trial was carried out on infants with moderately severe bronchiolitis. The study excluded patients who required intensive care and those with underlying chronic cardiac and pulmonary illness or any significant concurrent illness. It is unlikely that nebulized albuterol will be helpful for treating bronchiolitis in severely ill ICU patients since no beneficial effect was observed in less severely ill patients. On the other hand it may be possible that the patients studied were not "sick enough" for a beneficial effect of albuterol to be observed. Since the spectrum of severity of illness varies from ICU to ICU and since more and more intensivists are also playing a "hospitalist" role, this study may be applicable to those who care for less critically ill children.

2. Were all clinically important outcomes considered?

Yes. Improvement in oxygen saturation and the time needed to fulfill preestablished criteria for discharge based on accessory muscle use and wheezing were the primary outcomes considered. These outcome measures reflect overall improvement in the clinical status and are commonly used in clinical practice. However, one must realize that percentage change in SaO2 may not accurately reflect the magnitude of change in PaO2. The relationship between SaO2 and PaO2 is not linear but depends on the particular location on the oxyhemoglobin dissociation curve.

The actual length of hospital stay was also considered. Although this is a less objective criteria and can be influenced by non-medical factors like social situations, it is good that the authors looked at both, the time to fulfill the objective criteria for discharge and the time they were actually discharged.

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

No. No treatment benefit was seen with the use of nebulized albuterol in children with moderately severe bronchiolitis. No patients in either treatment group showed any clinically significant adverse effects. However 3 patients who were withdrawn from the study had received albuterol and had worsening respiratory status. None of them required mechanical ventilation and all 3 recovered over time. The cost of administering nebulized albuterol for 72 hours was estimated to be $1200 per patient.

Related Reviews

Kellner JD, Ohlsson A, Gadomski AM, Wang EE. Efficacy of bronchodilator therapy in bronchiolitis. A meta-analysis. Arch Pediatr Adolesc Med 1996; 150: 1166-1172. [abstract]

Review, by M. Reloza-Macias

Comments

Submitted 9/17/99:

One problem that the authors did not discuss in the issue of how much of the inhaled medication is deposited in the small airway of these young infants, especially during an acute inflammatory disease of the small airways. Studies have shown that the percentage of the inhaled medication, given by a nebulized or an MDI with mask, is very small in young infants. Thus, the same authors should repeat the study with a much higher inhaled dose, or use an MDI and a spacer with mask. Obviously, their data regarding this "standart:" dose is valid, i.e., there is no better effect in bronchiolitis compared to placebo.

Asher Tal M.D
Soroka University Medical Center, Ben-Gurion Univiversity
Beer-Sheva, Israel

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