Bronchoconstrictor additives in bronchodilator solutions

J Allergy Clin Immunol. 1999 Aug;104(2 Pt 2):S53-60. doi: 10.1016/s0091-6749(99)70274-5.


Nebulized bronchodilator solutions are available in the United States as both nonsterile and sterile-filled products. Sulfites, benzalkonium chloride (BAC), or chlorobutanol are added to nonsterile products to prevent bacterial growth, but there have been reports of contaminated solutions containing preservatives. Ethylenediamine tetraacetic acid (EDTA) is added to some products to prevent discoloration of the solution. With the exception of chlorobutanol, all of these additives are capable of inducing bronchospasm in a concentration-dependent manner. However, it is rarely apparent to the patient or health care provider that the additive diminishes the bronchodilator effects. Older products (eg, isoproterenol and isoetharine) contain enough sulfites to produce bronchospasm in most patients with asthma, even in those without a prior history of sulfite sensitivity. Bronchoconstriction from inhaled BAC is cumulative, prolonged, and correlates directly with basal airway responsiveness. The multidose dropper bottle of albuterol contains 50 microg BAC/dose, which is below the threshold for bronchoconstriction whereas the screwcap unit-dose vial contains 300 microg/dose, which is above the threshold for many patients. If the screwcap product is used in the emergency department, a patient could receive as much as 1800 microg of BAC in the first hour. Three sterile-filled unit dose albuterol products contain no additives, whereas a fourth, (manufactured by Dey Laboratories) contains 300 microg of EDTA, which is also below the threshold dose for bronchoconstriction. Only additive-free sterile solutions should be used for hourly or continuous nebulization of albuterol. The multidose dropper bottle or the Dey product can be used when the interval between doses is longer, whereas the screwcap product should not be used for acute therapy. Ipratropium is available only as a sterile, additive-free unit-dose vial, as is levalbuterol.

Publication types

  • Review

MeSH terms

  • Administration, Inhalation
  • Animals
  • Benzalkonium Compounds / adverse effects
  • Bronchoconstriction
  • Bronchoconstrictor Agents / administration & dosage
  • Bronchoconstrictor Agents / adverse effects*
  • Bronchodilator Agents / administration & dosage*
  • Bronchodilator Agents / therapeutic use
  • Chlorobutanol / adverse effects
  • Drug Contamination
  • Edetic Acid / adverse effects
  • Humans
  • Nebulizers and Vaporizers
  • Preservatives, Pharmaceutical / adverse effects*
  • Sulfites / adverse effects
  • United States


  • Benzalkonium Compounds
  • Bronchoconstrictor Agents
  • Bronchodilator Agents
  • Preservatives, Pharmaceutical
  • Sulfites
  • Edetic Acid
  • Chlorobutanol