Study Finds Poorer Asthma Outcomes with Preservative-Containing Nebulization Solution

Continuous nebulization with an albuterol product preserved with benzalkonium chloride instead of a preservative-free formulation delays the recovery time of children hospitalized for acute asthma exacerbation, according to a report in the April issue of Pediatrics.

The retrospective cohort study found that the median duration of continuous nebulization was 9 hours for 236 children treated with a benzalkonium chloride-containing albuterol solution and 6 hours for the 241 children in the control group, who were treated with a preservative-free albuterol solution.

Twenty-four hours after the initiation of continuous nebulization — the typical planned duration of the therapy — about 16% of the children treated with the preservative-containing product were still receiving the therapy. At that time, just 6% of those treated with a preservative-free formulation still required continuous nebulization.

Report coauthor Leslie Hendeles, professor emeritus of pharmacy and Pediatrics at the University of Florida, said he wasn’t surprised by these results.

“We were fully expecting this,” he said.

He added that it’s been known for years that benzalkonium chloride causes bronchospasm in patients with stable asthma.

FDA in 2017 posted labeling changes for 20-mL multidose albuterol sulfate products, which contain benzalkonium chloride, stating that the preservative “has been associated with bronchospasm in a dose-dependent manner.” The warnings were not added to the labeling of smaller-volume unit-dose formulations because they contain no preservatives.

The warning recommends a trial of a short-acting, benzalkonium chloride-free bronchodilator if continuous nebulization, or other procedures using “high doses” of the preservative-containing albuterol product, fails to resolve the patient’s bronchospasm.

Of note, the FDA-approved labeling for the only currently marketed 20-mL albuterol multidose solution does not include an indication or recommended dosage for continuous nebulization procedures.

The National Asthma Education and Prevention Program’s asthma management guideline has dosage recommendations for albuterol sulfate continuous nebulization, but the document does not address the issue of preservatives in the inhalation solution. The guideline was released in 2007 and is currently being revised.

Hendeles and his coauthors examined continuous nebulization outcomes in the 18 months before and after University of Florida Health Shands Children’s Hospital switched from a preservative-free albuterol sulfate inhalation solution to the benzalkonium chloride-containing product.

Each medication dose for the children in the control group had required the pharmacy staff to manipulate the contents of 16–32 0.5 mL unit-dose vials of preservative-free albuterol sulfate inhalation solution. After the 2015 switch to the 20-mL preservative-containing product, each dose required the manipulation of just one vial.

Hendeles and others have previously reported pediatric hospitals often use the 20-mL bottle for convenience.

Hendeles said he hopes the findings from the Pediatrics study will prompt hospitals to rethink the use of benzalkonium chloride-containing albuterol solution for continuous nebulization.

“To me, it makes no sense giving a bronchoconstrictor to somebody who’s having life-threatening bronchospasm,” Hendeles said.

According to the Pediatrics report, an instance of delay in initiating therapy prompted the hospital’s switch to the benzalkonium-containing albuterol formulation for continuous albuterol nebulization.

Hendeles said one way to avoid such delays is to prepare preservative-free albuterol stock solutions in advance so that unit-dose syringes can be quickly sent to the bedside when needed.

A better solution, he said, would be for manufacturers to produce a preservative-free version of the currently marketed 20-mL product.

He stated that one manufacturer has indicated that it will begin marketing such a product in May. At presstime, the company had not publicly announced the release of the preservative-free product or responded to an inquiry to confirm the product’s launch.

ASHP’s House of Delegates recently approved revisions to policy 1528, Excipients in Drug Products. The group recommended that ASHP “promote research that evaluates the safety of excipients to guide clinical practice” and “support the reporting and dissemination of this information via published literature, registries, and other mechanisms.”

[This news story will appear in an upcoming issue of AJHP.]