STATIC IV: Efficacy of a loading dose of intravenous salbutamol in patients admitted to a PICU for severe acute asthma

In children, the standard therapy for severe acute asthma (SAA), unresponsive
to continuously inhaled bronchodilators and systemic corticosteroids, is
intravenous (IV) salbutamol. Although IV salbutamol is frequently used in
children in a wide range, pharmacodynamic data are scarce. To date, there is an
insufficient evidence base to guide initial and subsequent dosing
recommendation for its IV use in children. Especially the need for a loading
dose needs to be addressed. Therefore, pharmacodynamic and *kinetic data are
needed to guide initial dosing strategies of IV salbutamol in children.

To assess the efficacy of a loading dose of intravenous salbutamol in children
admitted to a PICU for severe acute wheeze or severe acute asthma. Efficacy is
measured by the reduction in asthma score (Qureshi) at 1 hour after
administration of the loading dose, compared to placebo.

To assess the following pharmacodynamics parameters of a loading dose of
intravenous salbutamol in children admitted to a PICU for severe acute wheeze
or severe acute asthma.
-Maximum rate and duration of infusion of IV salbutamol
-Total (cumulative) dose of IV salbutamol
-Length of stay on PICU
-Need for other medication (e.g. sodium bicarbonate, theophyllin, sevoflurane)
-Need for non-invasive/invasive mechanical ventilation (+ duration)
-Frequency of side effects (Tachycardia, Arrhythmia, Hypotension, Hypokalaemia,
Hyperglycaemia, Lactic acidosis)
-Distribution of ADBR2 receptor polymorphisms

Multi-centre, double blind randomised placebo controlled trial

Group 1 (intervention) will receive a loading dose of IV salbutamol, in
combination with standard care for SAA. Group 2 (control) will receive a
placebo *loading dose* in combination with standard care for SAA.

Patients will be treated according to the standard management protocol of SAA
in the PICU; in addition to standard care, the intervention group will receive
an IV loading dose of salbutamol of 15 mcg/kg in 10 minutes, in accordance with
current international guidelines. The effect on serum concentrations has been
estimated using a PK model recently developed in our hospital using NONMEM
analysis. The loading dose, added to the continuous infusion, reduces the time
in which therapeutic serum concentrations are reached in the patients. Both the
intervention and the control group are subject to side effects of IV
salbutamol, as detailed in the SPC. Blood samples for serum concentration of
salbutamol will be taken concomitantly with samples obtained for standard care;
either via indwelling arterial catheter (only if already in place for treatment
purposes), venipuncture or finger prick. Patients and/or guardians will be
asked to fill out a short questionnaire regarding patient- and family history
and disease specifics. No items of a sensitive nature are present. We will
collect urine during a 6-hour of 12-hour period (depending on availability) to
obtain data concerning metabolism and clearance of salbutamol. The study can
only be carried out in this population, as pharmacodynamic/-kinetic results
from adults cannot be extrapolated to children with SAA.