Preservatives in nebulizer solutions: Risks without benefit

Edetate disodium (EDTA) and benzalkonium chloride (BAG) are often present as preservative or stabilizing agents in nebulizer solutions used to treat asthma and chronic obstructive pulmonary disease. Benzalkonium chloride is a potent bronchoconstrictor when inhaled in concentrations similar to those in which it is present in these solutions. Inclusion of BAC (together with EDTA) in the ipratropium bromide (Atrovent) nebulizer solution resulted in paradoxic bronchoconstriction in some asthmatic patients and an overall reduction in bronchodilator efficacy. The presence of BAC in albuterol nebulizer solutions does not affect the short-term bronchodilator response to a single dose, although case reports suggest that its repeated use in patients with severe asthma may result in paradoxic bronchoconstriction. When inhaled by asthmatic subjects, EDTA also causes dose-dependent bronchoconstriction, although it is less potent than BAG. The use of preservative-free bronchodilator nebulizer solutions does not result in clinically significant bacterial contamination if they are dispensed in sterile unit-dose vials, in volumes and concentrations that do not require modification by the user. Despite this evidence, in the United States a number of solutions, including some preparations of albuterol, contain either BAC or EDTA. Current regulations do not require that the concentration of preservatives be documented on the product; however, considerably different doses of BAC are delivered with different products. For example, a standard 2.5-mg dose of albuterol nebulizer solution contains 50 mu g of BAC when administered from the multidose dropper bottle and 300 mu g from the unit-dose screw-cap product. Furthermore,it is legal for pharmacists to substitute or compound solutions containing high concentrations of BAC when the physician has prescribed a preservative-free product. We recommend that the United States follow the practice of most Western countries and withdraw bronchodilator nebulizer solutions that contain preservatives such as BAG. We further recommend that the solutions should be prepared under sterile conditions, formulated preservative free, and made available in unit-dose vials.