Mpd-196-patel-509-514

RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF ORAL
ALBUTEROL IN INFANTS WITH MILD-TO-MODERATE ACUTE
VIRAL BRONCHIOLITIS
HEMA PATEL, MD, MSC, SERGE GOUIN, MDCM, AND ROBERT W. PLATT, MSC, MS, PHD Objective To determine whether oral albuterol is effective in reducing symptomatology of acute viral bronchiolitis
in infants with mild-to-moderate illness.
Study design In a randomized, double-blind trial, previously well infants were randomized upon discharge from the emergency
department to receive either albuterol (0.1 mg/kg/dose) three times per day or placebo three times per day for 7 days. Daily stan-
dardized telephone interviews were conducted for as long as 14 days. The primary outcome was the time to resolution of illness.
Secondary outcomes included time to normal feeding, normal sleeping, quiet breathing, resolved cough, and coryza.
Results We studied 129 infants (albuterol, n = 64; placebo, n = 65). Baseline characteristics were similar between groups. The
overall mean age was 5.3 months, 60% were male, and 49 of 61 tested infants were positive for respiratory syncytial virus. The
median (95% confidence interval) time to resolution of illness (days) was similar: albuterol, 9.0 (8–13); placebo, 8.0 (7–9); P =
.3) (log-rank test). There were no significant group differences in any secondary outcome. Health care revisit and admission
rates were similar between groups.
Conclusions No significant group differences in either primary or secondary outcomes in infants treated with oral albuterol
versus placebo were found. The widespread use of oral albuterol in this patient group is not recommended. (J Pediatr
2003;142:509-14)
Although acute viral bronchiolitis is the most common lower respiratory tract
condition in infancy,1–3 very little is known about effective therapy for infants withmild-to-moderate respiratory distress, the vast majority of affected infants.
Standard pediatric texts recommend oral bronchodilators in symptomatic infants who donot require hospital admission.4–6 Surveys and pharmacy prescription record databases showthat albuterol (Ventolin, GlaxoSmithKline, Mississauga, Ontario, Canada) is commonlyprescribed to infants with mild-to-moderate bronchiolitis, usually for 5 to 7 days.7 However, there is little evidence to support this widespread practice. To our knowl- the Depar tment of Epidemiology andBiostatistics, McGill University, and the edge, only two trials evaluating the use of oral bronchodilators in bronchiolitis have been published.8,9 Both studies examined the short-term effects (at 30 and 60 minutes) of one dose of oral albuterol and found no difference relative to placebo-treated infants in oxygen bec, Canada.
Supported by the Canadian Association saturation, respiratory rate, or clinical score.8,9 Given the estimated hundreds of thousands of infants receiving oral albuterol in North America each bronchiolitis season, we per- treal Children’s Hospital Research Insti-tute.
formed a randomized controlled trial to assess the effectiveness of this intervention.
Thus, the objective of the study was to determine whether oral albuterol was effec- clinicien with the Fonds de la rechercheen santé du Québec (FRSQ).
tive in reducing the time to resolution of illness (ROI) and specific symptom severity of outpatient infants with mild-to-moderate acute viral bronchiolitis. We hypothesized that infants treated with oral albuterol would have a shorter duration of illness.
Reprint requests: Hema Patel, MD, MSc,FRCPC, Montreal Children’s Hospital,2300 Tupper St, Room A216, Montreal,Quebec, Canada H3H 1P3. E-mail:[email protected].
Respiratory Distress Assessment Instrument dosing units and were numerically coded for the use of thestudy recruitment team. All study personnel and participants Study Design
were blinded to treatment assignment for the duration of the This study was a double-blind, randomized, placebo- study. To evaluate blinding, parents and the research nurse controlled, parallel group trial. It was approved by the Scien- were questioned on the last study day about which therapy tific Review Committee of the Montreal Children’s Hospital Research Institute and by the Montreal Children’s HospitalEthics Review Board.
Procedures
The study medication was administered by using a nee- Study Setting
dle-less syringe that had been labeled at the calculated volume Infants were recruited during three successive bronchi- by the study recruitment team. The first dose of medication olitis seasons (November 1998–March 2001) from the emer- was given in the ED before discharge, and the method of ad- gency department (ED) at our university-affiliated pediatric ministration was taught to the caregiver.
Daily structured telephone interviews with the same caregiver were conducted until the infant had complete symp- Study Participants
tom resolution or for a duration of 14 days, whichever event Eligible infants included all previously well infants (≤12 was earlier. All infants had a final follow-up call 14 days after months old) with a clinical diagnosis of acute viral bronchioli- entering the study. The standardized bilingual interview was tis who were discharged directly home after an ED visit dur- pretested for face validity, clarity, and comprehensiveness. Do- ing the study period. Bronchiolitis was clinically defined as the mains of interest included (1) overall health status of the in- first episode of wheezing in an infant and evidence of an acute fant, (2) adherence with the prescribed therapy, (3) presence respiratory tract infection (coryza or body temperature >38°C and severity of bronchiolitis symptoms, (4) feeding and sleep- rectal or cough). Infants were considered for discharge direct- ing pattern of the infant, (5) return healthcare visits and hos- ly home from the ED if they had (1) adequate hydration, (2) pital admissions, (6) parental life disruptions, and (7) adverse no lethargy, (3) hemoglobin oxygen saturation ≥95% in room air, and (4) mild respiratory distress (respiratory rate ≤70breaths/min, heart rate ≤200 beats/min, and mild accessory Measurements and Outcomes
muscle use). A working telephone and a consistent primary Baseline measures included demographic features, age, caregiver were required for all participating infants.
sex, weight, body temperature, history of atopy in the infant Infants were excluded from the trial if they were older or first degree relatives, passive cigarette smoke exposure, du- than 12 months, had a previous history of wheezing or home ration and symptoms of illness, viral etiology, vital signs, he- bronchodilator use, or required direct hospital admission from moglobin oxygen saturation in quiet rest, and degree of the ED. Infants were also excluded if they had (1) a gestation- respiratory distress. Respiratory distress was measured by al age at birth of <34 weeks, (2) an underlying chronic cardiac using the Respiratory Distress Assessment Instrument or chronic pulmonary disease (eg, bronchopulmonary dyspla- (RDAI), a 17-point categorical score developed by Lowell et sia), (3) immunocompromise, (4) a history of immunoprophy- al.10 This score, which measured wheezing and chest wall re- laxis therapy (ie, respiratory syncytial virus immunoglobulin tractions, was chosen because of its face validity, high inter- or RSV monoclonal antibody therapy), or (5) a parent not flu- rater and intrarater reliability, and discriminative ability.10–15 The primary outcome of interest was the time to ROI, the period from study enrollment to the time that the infant Randomization, Allocation, and Treatment Groups
returned to baseline health status, as determined by the prin- Computer-generated randomization (SAS version 8.0, cipal caregiver. This type of outcome measure has been used using PROC PLAN, SAS Institute, Cary, NC) within blocks in studies of outpatients with viral croup, another common of six subjects was used to assign patients to one of two treat- pediatric respiratory tract infection.16,17 The ROI was select- ment strategies: (1) oral albuterol (0.1 mg/kg/dose) or (2) oral ed as a practical, common-sense reflection of effectiveness of placebo. Infants were treated three times daily for a maximum the intervention. The ROI was scored by using the 4-point of 7 days or until complete resolution of bronchiolitis symp- ordinal scale developed by Cruz et al.16 On this scale, parents toms, whichever event was earlier. Medications were supplied rated the infants’ symptoms globally in one of the following to caregivers on discharge from the ED. Treatment was allo- categories: (1) symptoms worse, (2) symptoms same, (3) cated by the department of pharmacy, with the code for med- symptoms improved, or (4) symptoms resolved.16 The time to ication allocation held by our study pharmacist, who had no symptom resolution—that is, a score of 4—was compared be- Secondary outcomes of interest included duration of Blinding
cough, coryza, noisy breathing, time to normal feeding, and Both study syrups were identically clear, colorless, and time to normal sleeping. Normal feeding and normal sleeping citrus flavored. Equal volumes of medication, dispensed in were defined as each infant’s pre-illness pattern. Duration of opaque brown bottles, were prepared in advance with standard cough was defined as the time from study enrollment to the Fig 1. Patient allocation.
time when the infant coughed “rarely” or “infrequently” versus (Fig 1). Of the 231 potentially eligible infants, 60 parents de- “often” or “always.” The revisit and the hospital admission clined participation in the study, and another 42 infants were rates were compared between groups. We monitored all pa- not approached for study at the attending ED physician’s re- tients for adverse events and systematically documented quest. Age and sex distribution, baseline respiratory rate, and episodes of tremor and vomiting but not tachycardia, because nasopharyngeal aspirate results of these excluded 102 infants it could not be reliably measured by parents at home. Changes were similar to those of the study group. Of the remaining 129 in the infants’ condition and potential adverse events were infants, 64 were allocated to receive albuterol, and 65 received monitored by using a 24-hour on-call service for parents.
Infants in each treatment group were similar in baseline Sample Size and Statistical Methods
characteristics and illness severity at ED presentation (Table).
The primary analysis was performed according to inten- The mean age in months (SD) was 5.4 (3.1) for albuterol and tion-to-treat guidelines for enrolled patients, regardless of 5.1 (2.6) for placebo. Nasopharyngeal aspirate (NPA) results withdrawals or protocol deviations. The Student t test was were available from 61 infants; RSV was the pathogen found used to compare the mean time to ROI (in days) between most frequently (albuterol, 26/32, 81%; placebo, 23/29; 79%).
groups. To detect a mean difference of 2 days in ROI, with an Parainfluenza, influenza, and adenovirus strains were found in α = .05 and power = 80%, 126 infants were required (63 in the remainder of positive NPA results.
each group). This calculation was based on a mean duration of The mean (SD) time to ROI in days was similar: al- illness of 8 days (range, 7–10 days), with an estimated stan- buterol, 8.9 (4.0), and placebo, 8.4 (3.7) (t test P = .5); because dard deviation of 4 days. Kaplan-Meier survival log-rank tests of the skewed distribution, the median (95% CI) time in days were conducted to analyze the difference in time to ROI be- was considered a more appropriate presentation of results: al- tween groups. Similar techniques were applied to all second- buterol, 9.0 (8–13), and placebo, 8.0 (7–9) (log-rank test P = ary outcomes. Cox proportional hazards regression was used .30) (Fig 2, A). There were no significant group differences in to evaluate potential confounders.18 Group differences in the the secondary outcomes: duration of poor feeding, cough, baseline characteristics were evaluated descriptively, and clini- coryza, and noisy breathing (Fig 2, B-E). Similarly, there were cally relevant group differences were examined for potential no significant differences in the median time in days (95% CI) confounding. Interobserver reliability for the RDAI was test- normal infant sleeping (albuterol, 3 [2–4], vs placebo, 3 [3–4]; ed by using the weighted κ coefficient; a value of κ ≥0.8 was log-rank test P = 0.15) or normal parental sleeping (albuterol, 3 [2–4], vs placebo, 3 [3–6]; log-rank test P = 0.07).
There were two withdrawals in each treatment group.
In the albuterol group, one infant was reassessed on day 2 of During the study period, 1039 infants with acute viral follow-up, and the study medication was stopped at the dis- bronchiolitis were evaluated in the ED and were discharged cretion of a nonstudy physician. This child was prescribed oral directly home. Of these, 808 were not eligible for study albuterol syrup for 1 week, and follow-up telephone assess- Randomized, Double-Blind, Placebo-Controlled Trial of Oral Albuterolin Infants with Mild-to-Moderate Acute Viral Bronchiolitis Table. Baseline characteristics
Characteristics
Albuterol (n = 64)
Placebo (n = 65)
Median days ill before ED presentation, n (quartiles) *Percent hemoglobin oxygen saturation.
HR, Heart rate; RR, respiratory rate.
ments were discontinued at the parent’s request. A second fore 1 week, two because of recurrent vomiting, one because of child in the albuterol group was withdrawn when the parents shakiness and tremor, and two for unspecified reasons. While reported on day 2 that the infant had previously received oral treatment assignment was still blinded, three infants in the al- albuterol. In the placebo group, one patient was reassessed on buterol group were started on albuterol by metered dose in- day 3 by a nonstudy physician and the study medication dis- haler within the study period. In the placebo group, one infant continued. This infant was started on inhaled albuterol and discontinued the study medication on day 3 for unspecified fluticasone, and the family declined follow-up telephone as- reasons. A second infant in the placebo group was started on sessments. The second child withdrawn from the placebo inhaled albuterol during the study period.
group received one dose of the study medication in the ED; Secondary analyses excluding infants withdrawn, in- the family decided immediately after that they did not want to fants admitted to the hospital, and infants with major proto- col deviations, had results similar to the intent-to-treat results.
There were four infants assigned to albuterol who even- No significant group differences were found in any compari- tually required admission to the hospital for respiratory dis- son of baseline characteristics or outcome.
tress, two on day 2 and two on day 3 of follow-up. There were The median number (quartile range) of health care re- five infants in the placebo group who required hospital admis- visits within 14 days of study enrollment was similar between sion, two on day 2 and one infant each on days 3, 4, and 8.
groups: albuterol, 1.0 (0–1), and placebo, 0 (0–2). Fifteen pri- Study medications were discontinued at the time of admis- mary caregivers in each treatment group reported missing work sion, but follow-up measures were collected in all nine infants.
for >1 day during the study period (range, (albuterol) 1–9 days, All study protocol deviations were also recorded. A (placebo) 1–8 days). Trembling and vomiting were potential major protocol deviation was defined as one in which the infant adverse effects that were systematically considered. The medi- did not receive the complete prescribed 7 days of therapy with an number of days (quartile range) in which trembling was ob- the study medication. There were eight major deviations in served was 0 (0–2) for albuterol and 0 (0) for placebo. The the albuterol group and two in the placebo group. In the al- median number of days (quartile range) in which the infant buterol group, five infants stopped the study medication be- vomited was 1.0 (0–3) for albuterol and 1.0 (0–2) for placebo.
Blinding was tested on study day 14 with a question re- garding suspected treatment allocation. Both the primarycaregiver and the research nurse responded similarly: “don’tknow,” 60%; correct guess, 25%; and incorrect guess, 15%.
As in the single-dose studies,8,9 we found that extend- ed-use oral albuterol was not effective. There were no practi-cal benefits in terms of the time to ROI or any of the specificsymptoms. This study was designed to mimic the customaryclinical use of albuterol in this patient group. Meaningful out-comes for parents and clinicians were chosen. The consistencyof the results in the primary and secondary outcomes empha-sizes the lack of difference between the course of illness in thetwo treatment groups.
These results add to the growing body of evidence that suggests that bronchodilators, whether administered orally orby nebulization, are not effective therapies for infants withacute viral bronchiolitis. Two recent meta-analyses20,21 haveshown that the benefits of nebulized bronchodilators in thispatient group are limited. Some have suggested that bron-chodilators may be of benefit only in the very early stages ofillness, before epithelial necrosis predominates. Clinically itremains difficult to identify affected infants at this stage be-cause the first symptoms of bronchiolitis are common to manyviral infections. In otherwise healthy infants, we currently donot have the tools to predict, at the prodromal stage, whichinfants will develop bronchiolitis, nor the severity of illness.
Families seek healthcare when their affected infants developthe symptoms of respiratory distress; by then, the pathologicalpulmonary changes have already begun.
In this study, there was adequate power to show the in- tended 2-day difference in the time to illness resolution, amagnitude of difference defined a priori as having clinical rel-evance. The time to ROI was measured by using the time ofstudy enrollment as a zero point. In fact, infants in both treat-ment groups were ill for a median of 4 days before ED presen-tation, as reported by parents. This prodromal duration isconsistent with the natural history of bronchiolitis with typi-cal onset of coryza, cough, and low-grade fever for several daysbefore more severe respiratory distress develops.
For practical purposes, adherence with allocated therapy was measured by parental report. The numbers of singlemissed doses and late doses were similar between groups.
Overall reported adherence with the study medication washigh, regardless of allocation group. Interestingly, there weremore major protocol deviations in the albuterol group than inthe placebo group, and although five infants discontinued thetreatment, another three were actually started on off-study al-buterol by another physician. Of the five who discontinued Fig 2. Survival curve results (see separate print-out of graph). A,
treatment, three did so because of negative side effects of al- time to ROI; B, time to normal feeding; C, time to resolution of
cough; D, time to resolution of coryza; E, time to quiet breathing.
P values indicate significance by log-rank test.
Given budgetary constraints, a study nurse was available to recruit infants between 8:00 AM and 12:00 AM and between6:00 PM and 11:00 PM during the study period. These times ED were evaluated then. Nonetheless, 339 infants who were were chosen because pilot data indicated that the majority of potentially eligible were seen outside study hours. These in- infants with mild-to-moderate bronchiolitis presenting to the fants were similar in distribution by age and sex to infants in Randomized, Double-Blind, Placebo-Controlled Trial of Oral Albuterolin Infants with Mild-to-Moderate Acute Viral Bronchiolitis the study group and did not appear to be systematically differ- Hanson IC, Shearer WT. Bronchiolitis. In: Oski FA, DeAngelis CD, ent from infants evaluated during study hours. The 102 in- Feigin RD, et al, editors. Principles and practice of pediatrics. 2nd ed.
fants who were excluded because of lack of informed consent Philadelphia (PA): JB Lippincott Co; 1994. p. 1457-9.
6.
Barone MA, editor. The Harriet Lane handbook. 14th ed. St Louis were also similar to those in the study group. The majority of the 42 ED physician refusals for patient participation were Nahata MC, Schad PA. Pattern of drug usage in bronchiolitis. J Clin linked to four physicians who thought that randomization and blinded therapy were not appropriate in this patient group Gadomski AM, Aref GH, El Din OB, El Sawy IH, Khallaf N, Black based on their personal experiences. In accordance with the RE. Oral versus nebulized albuterol in the management of bronchiolitis inEgypt. J Pediatr 1994;124:131-8.
guidelines provided by our ethics review board, physicians’ Gadomski AM, Lichenstein R, Horton L, King J, Keane V, Permutt T.
wishes for nonparticipation in the trial were respected.
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considered in infants with bronchiolitis. Nebulized epineph- the response to epinephrine. Pediatrics 1987;79:939-45.
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16. Cruz MN, Stewart G, Rosenberg N. Use of dexamethasone in the
We thank Michael B. Smith, Natalie Ross, and Patricia Vandercruys outpatient management of acute laryngotracheitis.
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22. Patel H, Platt RW, Pekeles GS, Ducharme FM. A randomized, con-
Schweich P. Lower respiratory tract infections. In: Schwartz MW, trolled trial of the effectiveness of nebulized therapy with epinephrine com- Charney EB, Canny TA, et al, editors. Pediatric primary care. 2nd ed. Chica- pared with albuterol and saline in infants hospitalized for acute viral go (IL): Year Book Medical Publishers, Inc; 1990. p. 502-4.
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