Continuous Albuterol With Benzalkonium in Children Hospitalized With Severe Asthma

The albuterol dropper bottle used to prepare solutions for continuous nebulization contains the chemical preservative benzalkonium chloride (BAC). BAC, by itself, has been shown to cause bronchospasm. BAC is contained in the 0.5% multidose 20-mL dropper bottle of albuterol. All other albuterol products for nebulization are single-dose sterile, preservative-free vials of concentrate or varying dilutions with saline. The authors hypothesize that BAC would decrease the therapeutic efficacy of albuterol in patients with acute asthma exacerbations.

Patients treated at the University of Florida Health Shands Children’s Hospital <18 years of age receiving continuous nebulized albuterol with and without BAC over a 3-year period. A total of 477 patients were included in the analysis (236 exposed to BAC and 241 controls). Intubation was an exclusion criterion.

This was a retrospective cohort study. The primary end point was the duration of continuous albuterol nebulization. The two groups were compared with Kaplan–Meier estimate of survival curves, a log-rank test of difference, and adjusted for baseline characteristics using multivariable Cox regression. A P value of <.05 was considered significant.

The duration of continuous nebulization was significantly longer in the BAC group than in the control group (median of 9 vs 6 hours; 15.7% required continuous nebulization compared with 5.8% of controls at 24 hours). The control group was 79% more likely to stop continuous nebulization at any particular point in time (hazard ratio: 1.79; 95% confidence interval: 1.45 to 2.22; P < .001) and 43% more likely to stop additional respiratory support (hazard ratio 1.43; 95% confidence interval: 1.16 to 1.75; P < .001). (Respiratory support was defined as conventional nasal cannula, high-flow nasal cannula, or non-invasive positive pressure ventilation.) The total dose of albuterol administered by continuous nebulization was significantly greater in the BAC group (mean [SD]:185 mg [371]) than in the control group (86 mg [102]; P < .001). There were no statistically significant differences in the other clinical end points, such as length of hospital stay and total hospital charges.

BAC is a functional albuterol antagonist associated with a longer duration of continuous albuterol nebulization treatment and additional respiratory support, suggesting that preservative-free albuterol formulations are safer for use in continuous nebulization.

These findings suggest that using preservative-free albuterol formulations is a safer approach for continuous albuterol nebulization treatment of children hospitalized with severe asthma exacerbations. A prospective, double-blinded, placebo-controlled, randomized study to confirm these findings would be scientifically helpful but may not be ethically feasible.