• asthma
• children
• second line treatment

Most physicians would agree that first line treatment for an acute exacerbation of childhood asthma should be the administration of high dose inhaled bronchodilators¹ and corticosteroids administered either orally or intravenously,² but when a child with severe acute asthma is unresponsive to such treatment—what should come next? This is an important question that is faced by doctors every day in emergency departments, paediatric wards, and intensive care units the world over. Most commonly, physicians will reach next for intravenous salbutamol or intravenous aminophylline, although some will consider other treatments.

Salbutamol and aminophylline have been shown to be individually better than placebo in severe acute asthma.^3,4 Although a recent Cochrane systematic review appeared to cast doubt on this statement for salbutamol,⁵ many suspect that this is a flaw caused by the inclusion of several very weak early studies of salbutamol in the analysis. A large study of aminophylline⁶ and another Cochrane systematic review⁷ have confirmed its efficacy in improving a number of important outcomes including the need for, and duration of, mechanical ventilation in acute childhood asthma.

A study by Roberts et al⁸ in this edition of Thorax is the first to compare the two agents using a good trial design. The authors have attempted to study these second line treatments in a randomised controlled trial to compare an intravenous bolus of salbutamol with a loading dose of aminophylline followed by an intravenous infusion. They have inevitably come across two of the major obstacles faced by anyone studying acute asthma episodes in children: (1) how to study such very sick children and (2) what outcomes are both measurable and important in this context? Improvement in severity score and reduced length of hospital stay are clearly of interest but are not the main goals of treatment. Unfortunately, despite the inclusion of five hospitals in the study, their sample size is still relatively small with only 44 subjects. Although this was the required number from the calculations, it is too small to address important outcomes such as the need for intensive care admission or mechanical ventilation, and much too small to examine an impact on long term morbidity or mortality from severe asthma exacerbations. In their salbutamol group 11% of patients required intubation and ventilation, while only 4% in the aminophylline group required such intervention. It is a pity that the study is too small to draw any statistical inference from this difference.

The results of the study are useful but they could have been even more powerful if the investigators had chosen to use each of the agents in an optimal fashion. For the intravenous salbutamol arm, the study design would have been better if they had included either repeated bolus doses or an infusion of salbutamol. For the aminophylline arm, the loading dose given (5 mg/kg) was small and the levels achieved were probably inadequate to fully test the efficacy of the agent. Despite these limitations, the study was well conducted and the results have implications for everyday paediatric practice.

Efficacy is only one issue in choosing between treatments. For salbutamol and aminophylline cost differentials and administration practicalities are irrelevant, but differences in drug safety may be important. Aminophylline has a relatively narrow therapeutic margin, with nausea and vomiting being common even with drug levels in the therapeutic range. Severe toxicity has been reported when the drug is given in overdose.

There are a large number of children worldwide who suffer severe exacerbations of asthma each year; both salbutamol and aminophylline have been around for a long time and many studies have been conducted. It is therefore surprising that we still cannot unreservedly recommend which of these agents to choose first when faced with the scenario described above. On balance, it seems that aminophylline hasadvantages for efficacy but at the cost of additional adverse effects. There is also very limited evidence about the efficacy of using intravenous salbutamol and aminophylline together, although it is quite common practice for them to be used in this way.

To further complicate decision making in severe acute asthma, a number of other treatments present themselves as candidates for second line therapy. These include alternative β₂ agonists (such as adrenaline); inhalational anaesthetic agents (such as halothane); intravenous magnesium sulphate; inhaled helium-oxygen mixtures; or non-invasive mechanical respiratory support of various forms such as face mask continuous positive airway pressure (CPAP). Most of these treatments have only a theoretical basis for their use, or evidence from case reports or small studies comparing them with placebo or no treatment. There are no useful comparative studies, and it is going to become increasingly difficult to evaluate the place of the multitude of treatments available with any certainty. What is certain is that emergency treatment should not be delayed, and that any agents chosen must be used both optimally and safely.

The bad news for children with severe acute asthma is that the doctors caring for them will have to make decisions between complex treatment regimens with only limited scientific evidence to aid them. The good news, however, is that the risk of death or an adverse outcome from acute asthma is fortunately small once the child has reached a high quality health care facility.