Benzalkonium Chloride in Albuterol Solutions: Time for a Change?

Benzalkonium chloride (BAC), a quaternary ammonium compound, is a common antimicrobial agent used in many everyday household products. It kills on contact most bacteria, fungi, and some viruses, with a relatively long duration of action. It has surfactant qualities and can penetrate bilipid membrane layers, allowing for deeper penetration of medicines delivered dermally. In high concentrations (>7.5%), BAC can be caustic and, if ingested, can cause severe gastrointestinal injury, respiratory depression, and neurologic toxicity.¹  Even at lower concentrations, BAC can be a skin, eye, and oral mucosa irritant. However, when used as a preservative in medicinals, BAC is so dilute that such effects are usually not an issue.

Children’s airways have a limited repertoire of physiologic mechanisms (eg, edema, inflammation, and bronchoconstriction) to deal with exogenous chemicals, resulting in coughing, wheezing, and difficulty breathing. Introducing any chemical into a child’s airways should entail careful scrutiny, weighing both risks and benefits. For many years, BAC has been employed as a preservative in some inhalant albuterol solutions used in the management of wheezing in asthma despite previous reports of its ability to precipitate bronchospasm.^2–5  In this month’s issue of Pediatrics, Pertzborn et al⁶  further investigate the risk of BAC in albuterol solutions intended for use in the management of children suffering from severe asthma exacerbations. These researchers conducted a retrospective cohort study of 477 children with severe asthma requiring a period of administration of albuterol by continuous nebulization. A natural experiment at their hospital allowed them to study clinical outcomes during a 1.5-year period when preservative-free, sterile, unit-dose (UD) vials of albuterol were exclusively used in pharmacy preparations versus a 1.5-year period when multidose 20-mL bottles of BAC-containing albuterol were exclusively used. Controlling for other factors so as to ensure that both groups were similar in asthma severity and demographics, the authors found that when BAC was present in the solution, the length of time during the hospitalization during which continuous albuterol nebulization was required was prolonged. The control group was more likely to discontinue continuous nebulization therapy and additional respiratory support earlier than the BAC group, suggesting that BAC paradoxically exacerbated their respiratory distress, prolonging the need for such therapy. Any retrospective cohort study has design limitations; the authors’ results should be viewed cautiously. For example, the overall length of stay in the hospital was not different between the 2 groups.

The amount of BAC in the currently available multidose albuterol nebulization solution from Hi-Tech Pharmacal is 0.01% (0.1 mg/mL).⁷  When further prepared for continuous inhalation in 0.9% sodium chloride (NaCl), the concentration may be diluted significantly. For example, common standard dilutions ranging from 16 mg (3.2 mL) of albuterol 0.5% in 240 mL of 0.9% NaCl to 160 mg (32 mL) of albuterol 0.5% in 240 mL of 0.9% NaCl result in 0.0013 mg/mL (0.00013%) and 0.013 mg/mL (0.0013%) of BAC. Continuous albuterol is generally dosed at 0.5 mg/kg per hour to a maximum of 20 mg per hour. At maximum dosing, this would result in 96 mL of 0.5% albuterol and 9.6 mg of BAC in 24 hours, or 0.4 mg per hour (400 μg per hour). The authors note that the threshold for bronchospasm was 300 μg (0.3 mg) of BAC, which was derived from a report that delivered BAC as 3 inhalations each over 1 to 2 seconds.⁸ 

Of note, it is important to highlight the outbreak of Burkholderia cepacia in patients that was attributed to multidose bottles of albuterol 0.5% in 1995, 1998, and again in 2006.^9–11  Hamill et al⁹  reported on the degradation of BAC after multidose bottles were opened (decreasing to 85 μg/mL by day 5) and the suboptimal bacteriostatic properties at the pH level induced by the addition of sulfuric acid. Although it is unknown which brand was used in these cases, several manufacturers ceased production of the 20-mL multidose bottles, leaving only the Hi-Tech product on the market. When approved in 1998, the Hi-Tech formulation contained BAC.¹²  Cross-contamination remains a risk, particularly in institutions that are unable to provide UD preservative-free nebulization vials. Additionally, the work required to produce a concentration of 160 mg of albuterol in 240 mL of 0.9% NaCl would require opening 64 individual UD plastic vials (0.5% [0.5 mL] or 0.083% [3 mL]). With a standard administration rate of 30 mL per hour, this could require 192 plastic ampules per day for a single patient. This is not only a repetitive-motion injury risk, it also is a time-intensive process that can result in delays, which is exactly the reason for the hospital’s switch to multidose bottles that was cited in the article.

While acknowledging the need for additional prospective studies to confirm their results, the authors are advocating for preservative-free albuterol solutions as the safer treatment for patients with asthma. Although removing or (more likely) replacing BAC is a laudable goal, it must be balanced with safety and the practicalities of delivering care.

BAC

benzalkonium chloride

NaCl

sodium chloride

UD

unit dose