Concluding remarks: can we explain the association of beta-agonists with asthma mortality? A hypothesis.

Beta-agonists have clearly demonstrated benefits for the treatment of both acute and chronic asthma. Therefore, it is perhaps surprising that many of the articles in this issue have focused on concerns about their safety. Much of this concern can be traced back to the "beta-agonist controversy"--the association of high-dose isoprenaline and fenoterol inhalers with asthma mortality in the 1960s and 1970s. Although a causal link was never proven, lingering doubts about the safety of beta-agonists remain. It is unclear whether a similar adverse effect is responsible for recently reported association of long-acting beta-agonists with asthma deaths. No mechanism for the beta-agonist controversy was established, but the evidence presented in this collection of articles points to a number of contributing factors. I suggest that a combination of these effects provides a plausible mechanism for the association of frequent beta-agonist use with asthma mortality. Rebound bronchoconstriction and bronchial hyperresponsiveness occur on withdrawal of regular beta-agonist treatment. Regular use of fenoterol is associated with a reduction in morning peak flow suggesting that the overnight interval between doses is sufficient to allow rebound bronchoconstriction. This has not been observed with terbutaline or salbutamol, although rebound phenomena do occur when these drugs are withdrawn for slightly longer periods. Regular use of beta-agonists also leads to tolerance to their bronchoprotective and bronchodilator effects. Tolerance becomes more apparent with worsening bronchoconstriction. In severe asthma, this could result in a poor response to emergency treatment. The combination of rebound deterioration of asthma and a poor response to beta-agonist treatment resulting from tolerance could explain the increased mortality associated with fenoterol and isoprenaline. Both effects are probably caused by downregulation of beta-receptors which occurs with all beta-agonists. Long-acing beta-agonists cause a similar degree of tolerance to short-acting beta-agonists, but avoid the problem of overnight withdrawal. Long-acting beta-agonists have also been shown to improve asthma control when taken in combination with inhaled corticosteroids. The clinical significance of tolerance in this context remains to be determined.