GAINESVILLE, FLA—How well your asthma patients respond to nebulized bronchodilators may depend on the additives used in the nebulizer solutions. A new study has found that benzalkonium chloride (BAC) induces clinically significant bronchospasm, but that EDTA does not have the same effect.[1]

The study supports earlier research showing that BAC has adverse effects on pulmonary function in asthma patients.[2]

“There are nebulized products that contain BAC and those that don’t. Given the fact that there is some potential for products that contain BAC to cause bronchoconstriction, it doesn’t make sense to use those products,” Michael J. Asmus, PharmD, told RESPIRATORY REVIEWS. EDTA appears to be safe, however.

Questions about the safety of EDTA arose after a small British study found that the additive induced bronchospasm in six subjects; however, the amount of EDTA required to achieve that effect was much greater than the amount delivered by a disposable nebulizer.[3] But patients with severe acute asthma often undergo multiple inhalations, and thus it has been unclear whether the total amount of EDTA administered is sufficient to cause problems.

To investigate this issue, Dr. Asmus and colleagues conducted a double-blind crossover study to determine the effects of EDTA inhalation on forced expiratory volume in one second (FEV1). Since previous studies had provided evidence that BAC induced bronchospasm, the researchers used BAC as a positive control.

Study subjects included 18 nonsmoking patients with stable asthma and a baseline FEV1 of 65% or greater of predicted. All were responsive to methacholine challenge. The patients were randomly assigned to receive up to four inhaled doses of nebulized EDTA (600 µg), BAC (600 µg), or normal saline (3 mL) on separate days; all patients eventually underwent all three treatments. FEV1 was measured 15 minutes after each inhalation; treatments were repeated every 20 minutes until FEV1 decreased by 20% or greater, or until a maximum of four doses had been administered.

EDTA did not induce bronchospasm in any of the subjects, even after repeated dosings, as would occur in the emergency department treatment of severe acute asthma. “EDTA is as safe as placebo, according to our study,” said Dr. Asmus, an Assistant Professor in the College of Pharmacy at the University of Florida. The mean maximum decrease in FEV1 was 1.8% after EDTA inhalation and 3.6% after placebo use. None of the patients had a decrease in FEV1 of greater than 10% after EDTA inhalation.

In contrast, 10 of 18 subjects experienced at least a 20% dose- and/or time-dependent decrease in FEV1 after BAC inhalation. The mean maximum percent decrease in FEV1 was 16.6% for all subjects. Three subjects experienced a 20% or greater decrease in FEV1 after inhaling only one dose of BAC. Two other subjects experienced unacceptable bronchoconstriction after inhaling two doses of BAC; one of these subjects had a 47% drop in FEV1. Five additional subjects experienced a 20% or greater drop in FEV1 after inhaling a third dose of BAC.

Dr. Asmus said, “The next step will be to determine whether giving multiple doses of nebulized albuterol in combination with BAC will blunt the effect of albuterol.”

—Deborah L. O’Connor