title: Different response to doubling and fourfold dose increases in methacholine provocation tests in healthy subjects.
abstract: BACKGROUND
  In a modified methacholine provocation test that was used to study changes in airway responsiveness to occupational irritants or sensitizers in healthy subjects, two protocols were used: a long protocol (doubling methacholine concentrations between dose steps) or a short protocol (fourfold increases in concentration). This modified methacholine provocation allows measurements of the provocative dose causing 20% decrease in FEV(1) (PD(20)) in a high proportion of a normal population.
  
  
  METHODS
  The distribution of PD(20) was investigated in healthy nonatopic men without history of allergy or asthma symptoms using the long protocol (n = 101) or the short protocol (n = 309). In addition, 30 healthy subjects underwent methacholine provocation tests using both protocols.
  
  
  RESULTS
  PD(20) was defined in 79% of subjects with the long protocol and in 48% of subjects with the short protocol. The provocative concentration of methacholine causing a 20% decline in FEV(1) (PC(20)) and PD(20) were significantly lower using the long protocol: long-protocol PC(20) (median [25th to 75th percentile]), 19.9 mg/mL (3.9 to > 32 mg/mL) compared with short-protocol PC(20), > 32 mg/mL (8.7 to >32 mg/mL; p < 0.0001); long-protocol PD(20), 4.2 mg (1.6 to 20 mg) compared with short-protocol PD(20), > 13.7 (2.6 to > 13.7 mg; p = 0. 006). The differences in PD(20) using short and long protocols were confirmed in a randomized trial of 30 healthy subjects tested with both protocols.
  
  
  CONCLUSIONS
  Using doubling concentrations, PC(20) and PD(20) could be defined in a higher proportion of healthy subjects than a protocol using fourfold dose increases. Furthermore, the doubling protocol results in a PD(20) estimate that is less than half the value obtained when using a protocol with fourfold concentrations between dose steps. The difference remains, whether the methacholine effect is regarded as cumulative or noncumulative. The explanation for the difference between the protocols is unclear.
authors.affiliation: Programme for Respiratory Health and Climate, National Institute for Working Life, Stockholm, Sweden. Britt-Marie.Sundblad@niwl.se
authors.forename: B M
authors.initials: BM
authors.lastname: Sundblad
authors.forename: P
authors.initials: P
authors.lastname: Malmberg
authors.forename: K
authors.initials: K
authors.lastname: Larsson
mesh_terms: D000328:Adult; D000368:Aged; D000485:Allergens / Q000009:adverse effects; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D001985:Bronchial Provocation Tests / Q000379:methods*; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D016009:Chi-Square Distribution; D004305:Dose-Response Relationship, Drug; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007509:Irritants / Q000009:adverse effects; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage; D008875:Middle Aged; D016273:Occupational Exposure; D013147:Spirometry; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D000485:Allergens; D016085:Bronchoconstrictor Agents; D007509:Irritants; D016210:Methacholine Chloride