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
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.