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Clinical Investigations: INHALATION |

Different Response to Doubling and Fourfold Dose Increases in Methacholine Provocation Tests in Healthy Subjects*

Britt-Marie Sundblad, BSc; Per Malmberg, MD, PhD; Kjell Larsson, MD, PhD, FCCP
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*From the Programme for Respiratory Health and Climate, National Institute for Working Life, Stockholm, Sweden.

Correspondence to: Britt-Marie Sundblad, BSc, Program for Respiratory Health and Climate, National Institute for Working Life, S-112 79 Stockholm, Sweden; e-mail: Britt-Marie.Sundblad@niwl.se



Chest. 2000;118(5):1371-1377. doi:10.1378/chest.118.5.1371
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Rationale: 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 FEV1 (PD20) in a high proportion of a normal population.

Methods: The distribution of PD20 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: PD20 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 FEV1 (PC20) and PD20 were significantly lower using the long protocol: long-protocol PC20 (median [25th to 75th percentile]), 19.9 mg/mL (3.9 to > 32 mg/mL) compared with short-protocol PC20, > 32 mg/mL (8.7 to >32 mg/mL; p < 0.0001); long-protocol PD20, 4.2 mg (1.6 to 20 mg) compared with short-protocol PD20, > 13.7 (2.6 to > 13.7 mg; p = 0.006). The differences in PD20 using short and long protocols were confirmed in a randomized trial of 30 healthy subjects tested with both protocols.

Conclusion: Using doubling concentrations, PC20 and PD20 could be defined in a higher proportion of healthy subjects than a protocol using fourfold dose increases. Furthermore, the doubling protocol results in a PD20 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.

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