Pharmacology of β-2 agonists

Salbutamol and terbutaline are similar β-2 adrenoceptor agonists that are believed to exert their maximal therapeutic effect through bronchodilation. Stimulation of β-2 receptors in airway smooth muscle induces the cyclic AMP (c-AMP) pathway. c-AMP is a molecule with various cellular functions. Increased activity of c-AMP-dependent protein kinase A inhibits myosin phosphorylation and lowers intracellular calcium concentration, which in turn relaxes smooth muscle and causes bronchodilation.4 Increased intracellular c-AMP may also inhibit mast cell inflammatory mediator release (figure 1; adapted from refs. 5 and 6). Severe airway obstruction may restrict delivery of inhaled salbutamol to the airway epithelium, thus providing a theoretical rationale for the use of intravenous preparations. Because adrenoreceptors are found in various organs and tissues, β-2 agonists can also cause various extrapulmonary adverse effects.

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Figure 1

An illustration of the mechanisms by which salbutamol and aminophylline may cause bronchodilation through increasing intracellular cyclic AMP levels.

Pharmacology of aminophylline

Aminophylline is a methylated xanthine derivative. It is a combination of theophylline (the active component) and ethylenediamine, which is a compound that increases the solubility of theophylline but has no known intrinsic pharmacological effects.

The mechanisms of action of aminophylline are not completely understood. Beneficial effects may result from both bronchodilation and reduced airway hypersensitivity, but the extent to which each mechanism confers benefit at therapeutic doses is unclear.16 ,17 Effective use of the drug also requires a consideration of its pharmacokinetics

RCTs of salbutamol (or terbutaline) and aminophylline

We identified RCTs that assessed the use of intravenous salbutamol, terbutaline or aminophylline in the paediatric population after searching the Cochrane register of controlled trials. The identified trials have been summarised in a series of tables (see online supplementary tables S1–3), and the main findings are outlined in the text below.

In three RCTs, intravenous salbutamol or terbutaline therapy have been compared with either placebo or nebulised treatment in a total of 130 children with acute asthma. Two of these^{W1 W2} were conducted in the emergency department (ED) and assessed the efficacy of a bolus of salbutamol, and one^W3 assessed the efficacy of a terbutaline infusion in a paediatric intensive care unit (PICU) setting.

Only one trial^W1 reported benefit with regards to the assessment of clinical severity. One trial showed no difference, and in one trial the outcome was not reported. No trials reported lung function outcomes. Neither of the trials conducted in ED reported the rates of admission to PICU. Length of hospital stay was improved in the group receiving intravenous salbutamol in one trial conducted in ED,^W2 but was not reported in the other.^W1 Two of these studies were included in a Cochrane review,28 which concluded that there was very little evidence to support the addition of intravenous salbutamol to nebulised therapy in children with acute asthma exacerbations.

Aminophylline has been compared with placebo or usual treatment (one study compared a control group who were managed with continuous nebulised albuterol, inhaled ipratropium and intravenous methylprednisolone with an aminophylline group given the above plus intravenous aminophylline) in children with acute asthma exacerbations in 12 RCTs involving 586 children.^W4–15 Three were conducted in ED, seven on hospital wards, one on PICU and in one study reported as a conference abstract the setting was unclear.

Three trials found that aminophylline improved clinical severity scores, but six did not. Three trials did not report this outcome. Two trials showed improved lung function scores, two did not and eight did not report this outcome. One trial showed that aminophylline reduced PICU admission rates, but none of the other studies reported any results for this outcome. No trials have found any benefit of aminophylline on length of hospital or PICU stay (seven found no difference, and five did not report this outcome). Also, 7 of these 12 trials have been included in a Cochrane review.29 The review concluded that intravenous aminophylline improved lung function within 6 h of treatment, but did not appear to reduce symptoms or length of hospital stay, and there was insufficient evidence to evaluate its impact on PICU rates.

Intravenous aminophylline and salbutamol (or terbutaline) have been compared, head-to-head, in four RCTs involving 202 children.^W16–19 Two were conducted in hospital wards, and one in PICU. In one RCT, reported as a conference abstract, the setting was unclear.

In the three trials that reported results for clinical severity scores, there was no difference between salbutamol and aminophylline. No studies reported lung function outcomes. In the one study reporting PICU admission rates, there was no difference between aminophylline and salbutamol. In two studies reporting length of hospital stay, there was no difference between groups, and in two studies this outcome was not reported. These paediatric studies have been included in a subgroup analysis in a Cochrane review.30 The review concluded that there was no consistent evidence to help decide between aminophylline and salbutamol as the first-line intravenous therapy of choice.

It is difficult to draw clear conclusions from RCTs about the relative safety profiles of the two treatments. There is wide variability in the assessment and reporting of adverse effects associated with the two treatments in clinical trials. It would appear that salbutamol does carry a risk of cardiovascular adverse effects. In one study,^W3 6/25 children treated with terbutaline had raised troponin-I levels and one was withdrawn because of arrhythmia. In one trial comparing salbutamol with aminophylline, the group receiving salbutamol demonstrated a significant trend towards tachycardia. Nausea and vomiting were the most commonly reported adverse effects associated with the use of intravenous aminophylline, as demonstrated in several trials and in a Cochrane review.29 In the trials involving intravenous aminophylline assessed for this review, there was only one reported case of a seizure.

Summary

Salbutamol and aminophylline cause bronchodilation in airways of children with exacerbations of asthma. Both agents probably work by inducing the c-AMP pathway, which reduces intracellular calcium concentrations, thereby relaxing airway smooth muscle. Aminophylline may have additional mechanisms of action, which are poorly understood. Both agents also have extrapulmonary adverse effects, which can be dangerous or distressing to children.

The evidence from RCTs for the intravenous administration of either drug to children during an asthma exacerbation is minimal and inconsistent. A bolus of intravenous salbutamol may reduce symptoms and hasten recovery.^W1 Aminophylline infusions may improve lung function, and in some studies have been shown to improve symptoms, but this finding is not replicated in all studies. It is unlikely that either agent reduces PICU admission rates or length of hospital stay, but these evaluations are hampered because many studies do not report these outcomes. Adverse effects were noted with the use of both treatments, but the available evidence does not enable comparison of the likelihood of adverse effects with either treatment.

Despite the minimal evidence of benefits from RCTs, intravenous therapy probably does have a role in managing certain children with either refractory or severe exacerbations of asthma, and those who have previously required PICU admission. Variation of practice at individual clinician and departmental level is likely to continue with regards which of these agents should be used first. Given that intravenous agents are likely to remain in widespread use, we suggest that the choice should take into account factors such as ease of prescription, preparation and administration (which have direct implications for risk management), availability of high-dependency beds and nursing preference. These factors are summarised in table 1.

Whichever therapy is used, we would advocate that children are assessed for objective markers of improvement of clinical status after the initial loading dose bolus to evaluate whether they really need to be treated with a subsequent infusion or not. We would also stress the importance of stringent, routine monitoring of the adverse effects that we have highlighted. Current uncertainty about these therapies, including guidelines on how drug levels and adverse effects should be monitored in children, must be addressed in future research studies.