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Communications to the Editor |

Extrapolation of Methacholine PC20 FREE TO VIEW

Beth E. Davis, BSc; Donald W. Cockcroft, MD, FCCP
Author and Funding Information

Royal University Hospital Saskatoon, SK, Canada

Correspondence to: Donald W. Cockcroft, MD, FCCP, Division of Respiratory Medicine, Royal University Hospital, Saskatoon, SK, Canada S7N 0W8; e-mail: cockcroft@sask.usask.ca



Chest. 2002;122(4):1499-1500. doi:10.1378/chest.122.4.1499
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Published online

To the Editor:

We have demonstrated1that the provocative concentration of a substance (methacholine) causing a 20% fall in FEV1 (PC20) could be extrapolated with reasonable accuracy from a 15 to 19% fall in FEV1 using a single-point formula. In that study, all individuals had a methacholine PC20, as measured by the tidal breathing method,2 of ≤ 16 mg/mL. It may be possible to apply this approach to subjects with 10 to 15% fall in FEV1; however, the smaller the fall in FEV1 (< 20%), the greater the error, and this procedure cannot be recommended. There are also individuals who will inhale concentrations of > 16 mg/mL and develop a plateau response.3 In our laboratory, this only occurs when airway hyperresponsiveness (AHR) is in the normal range. We have observed that PC20 extrapolation cannot be applied accurately when subjects are approaching or are actually achieving a plateau response.

To investigate this, we retrospectively analyzed 271 methacholine challenges that were conducted in a hospital pulmonary function laboratory and a clinical research laboratory. We examined the percentage fall in the FEV1 following the inhalation of the last and the second-to-last concentrations of methacholine. Subjects were categorized into the following four groups, based on American Thoracic Society guidelines,4 by the severity of AHR to methacholine: moderate to marked (PC20, ≤ 1.0 mg/mL); mild (PC20, 1 to 4 mg/mL); borderline (PC20, 4 to 16 mg/mL); and normal (PC20, > 16 mg/mL).

The results are shown in Figure 1 . The mean percentage fall in FEV1 following the second-to-last inhalation of methacholine was about 12% independent of AHR severity. If the last concentration inhaled was ≤ 16 mg/mL, we found that the percentage fall in FEV1 was similar across the AHR severity scheme (about 25%). At concentrations of > 16 mg/mL, the average fall in FEV1 was approximately 15%.

The responses reflect the fact that a theoretical mathematical model of a doubling dose generating a doubling response and a single-point extrapolation formula for individuals with a methacholine PC20 of ≤ 16 mg/mL can be employed with confidence, as has been documented previously.1 Those individuals who inhaled concentrations of > 16 mg/mL and who are thus classified as having normal AHR did not exhibit a doubling-dose/doubling-response characteristic. A much lower ratio (ie, 1.3 vs 2.1) in the fall in FEV1 between the second-to-last and the last inhalation occurred when the concentration of methacholine was > 16 mg/mL. As has been documented, a plateau is achieved in these individuals, and the dose-response curve will begin to flatten and become flat regardless of the increases in the concentration of methacholine administered. This phenomenon would lead to an overestimation of the PC20 when extrapolating from a response of < 20%. Therefore, it is necessary in individuals with a PC20 of > 16 mg/mL to generate an actual interpolated PC20 or to establish the presence of a plateau. An extrapolation would not be accurate and would likely overestimate the response. In conclusion, PC20 should not be extrapolated when concentrations of > 16 mg/mL are administered.

Dr. Cockcroft is Ferguson Professor and is supported by the Saskatchewan Lung Association.

Figure Jump LinkFigure 1. Mean percentage decrease in FEV1 (± SEM) following the last concentration (closed bars) and second to last concentration (open bars) of inhaled methacholine by group according to AHR severity.Grahic Jump Location
Jokic, R, Davis, EE, Cockcroft, DW (1998) Methacholine PC20extrapolation.Chest114,1796-1797
 
Cockcroft, DW, Killian, DN, Mellon, JJA, et al Bronchial reactivity to inhaled histamine: a method and clinical survey.Clin Allergy1977;7,235-243. [PubMed] [CrossRef]
 
Woolcock, AJ, Salome, CM, Yan, K The shape of the dose-response curve to histamine in asthmatic and normal subjects.Am Rev Respir Dis1984;130,71-75. [PubMed]
 
Crapo, RO, Casaburi, R, Coates, AL, et al Guidelines for methacholine and exercise challenge testing-1999: this official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999.Am J Respir Crit Care Med2000;161,309-329. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Mean percentage decrease in FEV1 (± SEM) following the last concentration (closed bars) and second to last concentration (open bars) of inhaled methacholine by group according to AHR severity.Grahic Jump Location

Tables

References

Jokic, R, Davis, EE, Cockcroft, DW (1998) Methacholine PC20extrapolation.Chest114,1796-1797
 
Cockcroft, DW, Killian, DN, Mellon, JJA, et al Bronchial reactivity to inhaled histamine: a method and clinical survey.Clin Allergy1977;7,235-243. [PubMed] [CrossRef]
 
Woolcock, AJ, Salome, CM, Yan, K The shape of the dose-response curve to histamine in asthmatic and normal subjects.Am Rev Respir Dis1984;130,71-75. [PubMed]
 
Crapo, RO, Casaburi, R, Coates, AL, et al Guidelines for methacholine and exercise challenge testing-1999: this official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999.Am J Respir Crit Care Med2000;161,309-329. [PubMed]
 
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