Bronchodilators for wheeze in young children presenting to primary care: a randomised, placebo-controlled, multicentre, parallel group trial.

10% of infants are prescribed short-acting bronchodilators for wheezing per
year, yet evidence to support this treatment in children younger than two years
old is scarce.

What is the (cost-)effectiveness of salbutamol inhalations (4x200*g for 7 days)
versus placebo in children aged 6-24 months presenting to their primary care
physician with wheezing?

A primary care based, randomized, placebo-controlled, multicentre, parallel
group trial in 40 general practices and community paediatrics in Belgium and
the Netherlands.

Salbutamol inhalation 4x200ug for 7 days or inhalation of placebo.

Considering the trial includes young children with an acute illness, we have
attempted to keep the burden on participants and their families to an absolute
minimum while collecting essential information to assess efficacy of the active
treatment. Participants will remain in the trial for 4 weeks, treatment with
active treatment or placebo will last 7 days. This includes the inclusion visit
with the primary care physician at day 0, a telephone call by a study nurse on
day 3 and 7, a study nurse or medical student home visit on day 5, and
telephone calls by the study nurse at 2 and 4 weeks. Study nurses (and medical
students) will be flexible to be able to call parents at the preferred time of
the day, and the home visit can be made at a time that suits parents (e.g.
during the evening). Parents of participating children will be asked to record
their child*s symptoms in a diary during the first 2 weeks, preferably using a
diary-app. After 4 weeks, healthcare utilisation will be extracted from the
child*s medical records. Data collection methods and associated burden to
participants have been extensively discussed with the parents that were
interviewed, and the proposed trial was judged as both feasible and acceptable
by the majority of parents. Similar methods have been successfully applied in
our previous trials.

Children allocated to salbutamol are exposed to side effects inherent to
salbutamol (rare events include cardiovascular problems and paradoxal
bronchospasm; in practice side effects of salbutamol that are reported most
often are tachycardia and tremor) Since salbutamol is currently included in the
national guidelines as a therapeutic option, these children may or may not have
been prescribed salbutamol in usual care and are therefore not necessarily
treated differently in the trial (the Dutch National Guideline states: consider
a trial of salbutamol treatment and evaluate after 1-2 weeks). Children
allocated to the placebo group children may experience a prolonged disease
course and might need subsequent treatment with salbutamol if salbutamol indeed
is effective (which is currently unknown). We however (1) do not include
patients with comorbidities or patients that are severely ill who definitely
require inhalation therapy, antibiotics or referral, and (2) we do not
anticipate large differences in treatment failures between the two trial arms
since the few studies performed previously in primary care found small or no
effects. Based on these considerations, we clinically regard the proposed study
as a low risk study. Yet, since the study is performed in young children and
medication is involved, we will consider the study a medium risk study to be on
the safe side.

Group relatedness: The current trial needs to be performed in the group of
young children 6-24 month old since, since acute wheeze in this age group is
essentially different (and much more prevalent) compared to older patients. The
anatomy and pathophysiology in younger children differs from older children.