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Bronchodilator response

A response to bronchodilator drugs is regarded as unambiguous if the change in FEV1 >12% of the predicted value. An isolated increase in (F)VC of >340 mL may be due either to better subject cooperation or a limited bronchodilator effect. In adults an increase in PEF larger than 60 L/s has been attributed to a bronchodilator response (ref. 1). A recent study suggests that, whilst PEF may be used to assess airways obstruction and exclude a response to bronchodilator drugs, it should not be used for assessing bronchodilator responsiveness in patients with chronic cough (ref. 2).

Often the change of FEV1, FVC or another index is expressed as a percentage of the initial value. This is wrong for various reasons, the most important being:

  1. The change is not proportional to initial level. In patients with a ‘poor’ initial value the change in FEV1 due to a bronchodilator drug even has the tendency to be somewhat larger than in the case of a favorable initial value. Indeed the response to a bronchodilator drug may diminish if treatment with e.g. corticosteroids has been effective (view experimental data in the animation).
  2. When measurements of FEV1 in adult patients with respiratory disease are repeated at short time intervals, spontaneous variability is up to 200 mL (ref. 3). In a patient whose initial FEV1 is 700 mL this comes to 29% change due to spontaneous variability. Yet, if the initial value were 2 liter, the 200 mL spontaneous variability would come to only 10%.

In healthy subjects the change in FEV1 or VC due to a bronchodilator drug is maximally 9-11% (ref. 3) . Bronchodilator responsiveness is therefore categorized as follows:

Bronchodilator effect Increase in FEV1
None < 9% of predicted value and < 200 mL
Moderate between 9% and 12% of predicted value and/or > 200 mL
Unambiguous > 12% of predicted value

Relationship between FEV1 and airways resistanceThe FEV1 is the best-studied index of lung function; hence the relationship of FEV1 and bronchodilator responsiveness with clinical condition or prognosis is well documented. One should keep in mind that a small increase in FEV1 due to a bronchodilator drug may be accompanied by a considerable fall in airway resistance during normal tidal breathing, and therefore in viscous work of breathing, which may be clinically relevant. Also, there may be symptomatic improvement without a significant increase in the FEV1 (ref. 4) .

It is not yet generally appreciated that FEV1 bronchodilator responsiveness differs significantly from that in FVC. The reason is as follows (see references 5). First, during a forced expiration intrahoracic gas is compressed, often by well over 10%. At that lower lung volume the elastic recoil pressure is reduced compared to that at the uncompressed lung volume. Due to the diminished tethering forces which extend the airways, airway diameter diminishes. The dual effect is that forced expiratory flow falls, and that the change in thoracic gas volume is larger than the volume measured at the mouth. The more severe the initial airways obstruction, the more pronounced this effect. Towards the end of the FVC manoeuvre large intrathoracic pressures cannot be sustained, so that the FVC is less affected by this compression effect; it is then determined by airway closure. In 2,371 healthy non-smokers and 29,157 clinical patients (age 4-95 years), in whom the severity of respiratory impairment was classified according to the ATS/ERS grading system, the median FEV1 response in subjects with mild obstruction was twice as large as in those without airways obstruction, was marginally larger in moderate airways obstruction, but then declined to the same level as that in subjects without airways obstruction. Conversely, the FVC response increased virtually linearly with the level of respiratory impairment. The net result was that the improvement in the FEV1/FVC ratio fell almost linearly to the level in patients with respiratory impairment. These findings signify that bronchodilation leads to opening up airways, thus diminishing airway closure, as testified by the important FVC response; the improvement the the FVC rsponse is proportional to the level of initial respiratory impairment. Conversely, in patients with airways obstruction there is little difference in the FEV1 response except in those with the severest respiratory impairment, where it falls to the same level as in subjects with airways obstruction. Because of the large age range and the age dependence of FEV1 or FVC expressed as percent of predicted, data were transformed to z-scores (see Quanjer et al., Chest 2017).

Ref. 1 - ECCS and ERS, now superseded by ERS Global Lung Function Initiative
In the revised 1993 version of the 1983 report ( Quanjer PhH (ed.) Standardized lung function testing. Bull Eur Physiopathol Respir 1983; 19 suppl. 5: 45-51) of the European Community for Coal and Steel (ECCS) predicted values of lung indices were unchanged. They are almost universally applied in Europe. The 1993 report was officially adopted by the European Respiratory Society (ERS).
The following chapter deals with spirometry, predicted values and bronchodilator responsiveness: Quanjer PhH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Eur Respir J 1993; 6 suppl. 16: 5-40. Erratum Eur Respir J 1995; 8: 1629. Please note, however, that they are now superseded by the predicted values from the ERS Task Force Global Lung Function Initiative; these reference values have been endorsed by the European Respiratory Society, American Thoracic Society, Australian and New Zealand Society of Respiratory Science, Asian Pacific Society for Respirology, the Thoracic Society of Australia and New Zealand, and the American College of Chest Physicians.
 
Ref. 2 - Do not use PEF to assess airway obstruction
Thiadens HA, de Bock GH, van Houwelingen JC, Dekker FW, de Waal MWM, Springer MP, Postma DS. Can peak expiratory flow measurements reliably identify the presence of airway obstruction and bronchodilator response as assessed by FEV1 in primary care patients presenting with a persistent cough? Thorax 1999; 54: 1055-1060.
 
Ref. 3 - Literature on bronchodilatation
1 Sourk RL, Nugent: Bronchodilator testing: confidence intervals derived from placebo inhalations. Am Rev Respir Dis 1983; 128: 153-157.
2 Tweeddale PM, Alexander F, McHardy GJR. Short term variability in FEV1 and bronchodilator responsiveness in patients with obstructive ventilatory defects. Thorax 1987; 42: 487-490.
3 Eliasson O, Degraff AC. The use of criteria for reversibility and obstruction to define patient groups for bronchodilator trials. Influence of clinical diagnosis, spirometric, and anthropometric variables. Am Rev Respir Dis 1985; 132: 858-864.
4 Meslier N, Racineux JL. Tests of reversibility of airflow obstruction. Eur Respir Rev 1991; 1: 34-40.
5 Quanjer PhH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Eur Respir J 1993; 6 suppl. 16: 5-40. Erratum Eur Respir J 1995; 8: 1629.
6 Brand PLP, Quanjer PhH, Postma DS, Kerstjens HAM, Koëter GH, Dekhuyzen PNR, Sluiter HJ, Dutch CNSLD Study Group. Interpretation of bronchodilator response in patients with obstructive airway disease. Thorax 1992; 47: 429-436.
7 Waalkens HJ, Merkus PJFM, van Essen-Zandvliet EEM, Brand PLP, Gerritsen J, Duiverman EJ, Kerrebijn KF, Knol K, Quanjer PhH. Dutch CNSLD Study Group. Assessment of bronchodilator response in children with asthma. Eur Respir J 1993; 6: 645-651.
8 Casan P, Roca J, Sanchis J: Spirometric response to a bronchodialtor. Reference values for healthy children and adolescents. Bull Europ Physiopath Resp 1983; 19: 567-569.
9 Pardos Martinez C, Fuertes Fernández-Espinar J, Nerín de la Puerta I, González Pérez-Yarza E: Cuándo se considera positivo el test de broncodilatación. Anales Españoles de Pediatria 2002; 57: 5-11.
10 Dales RE, Spitzer WO, Tousignat P, Schechter M, Suissa S: Clinical interpretation of airway response to a bronchodilator. Epidemiologic considerations. Am Rev Respir Dis 1988; 138: 317-320.
11 Dompeling E, van Schayck CP, Molema J, et al. A comparison of six different ways of expressing the bronchodilating response in asthma and COPD; reproducibility and dependence of prebronchodilator FEV1. Eur Respir J 1992; 5(8): 975-981.
12 Ries AL. Response to bronchodilators. In: Clausen JL, ed. Pulmonary function testing guidelines and controversies, New York: Academic Press, Inc. 1982;215-222.
13 Pellegrino R, Viegi G, Brusasco V, C et al. Interpretative strategies for lung function tests. Eur Respir J 2005;26(5) :948-968.
14 Johannessen A, Omenaas ER, Bakke PS, Gulsvik A. Implications of reversibility testing on prevalence and risk factors for chronic obstructive pulmonary disease: a community study. Thorax 2005; 60(10): 842-847.
15 Tan WC, Bourbeau J, Hernandez P, et al. Bronchodilator responsiveness and reported respiratory symptoms in an adult population. PLoS One 2013; 8 :e58932..
16 Tan WC, Vollmer WM, Lamprecht B, et al. Worldwide patterns of bronchodilator responsiveness: results from the Burden of Obstructive Lung Disease study. Thorax 2012; 67(8): 718–726.
17 Anthonisen NR, Wright EC. Bronchodilator response in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986; 133(5): 814-819.
18 Ward H, Cooper BG, Miller MR. Improved criterion for assessing lung function reversibility. Chest 2015; 148(4): 877-886.
19 Calverley P, Burge P, Spencer S, Anderson J, Jones P. Bronchodilator reversibility testing in chronic obstructive pulmonary disease. Thorax 2003; 58(8): 659-664.
20 Pérez-Padilla R, Wehrmeister FC, Montes de Oca M, et al. Instability in the COPD diagnosis upon repeat testing vary with the definition of COPD. PLoS One 2015; 10: e0121832.
21 O'Donnell DE, Forkert L, Webb KA. Evaluation of bronchodilator responses in patients with “irreversible” emphysema. Eur Respir J 2001; 18(6): 914-920.
22 Newton MF, O’Donnell DE, Forkert L. Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation. Chest 2002; 121(4): 1042-1050.
23 Schermer T, Heijdra Y, Zadel S, et al. Flow and volume responses after routine salbutamol reversibility testing in mild to very severe COPD. Respir Med 2007; 101(6): 1355-1362.
24 Walker PP, Calverley PM. The volumetric response to bronchodilators in stable chronic obstructive pulmonary disease. COPD 2008; 5(3): 147-152.
25 Ben Saad H, Préfaut C, Tabka Z, Zbidi A, Hayot M. The forgotten message from gold: FVC is a primary clinical outcome measure of bronchodilator reversibility in COPD. Pulm Pharmacol Ther 2008; 1(5): 767-773
26 Deesomchok A, Webb KA, Forkert L, et al. Lung hyperinflation and its reversibility in patients with airway obstruction of varying severity. COPD 2010; 7(6): 428-437.
27 Wang YT, Thompson LM, Ingenito EP, Ingram RH Jr. Effects of increasing doses of beta-agonists on airway and parenchymal hysteresis. J Appl Physiol 1990; 68(1): 363-368.
28 Pellegrino R, Rodarte JR, Brusasco V. Assessing the reversibility of airway obstruction. Chest 1998; 14(6): 607-612.
29 Cerveri I, Pellegrino R, Dore R, et al. Mechanisms for isolated volume response to a bronchodilator in patients with COPD. J Appl Physiol 2000; 88(6): 1989-1995.
30 Redelmeier DA, Guyatt GH, Goldstein RS. Assessing the minimal important difference in symptoms: a comparison of two techniques. J Clin Epidemiol 1996; 49(11): 1215-1219.
31 Redelmeier DA, Guyatt GH, Goldstein RS. Assessing the minimal important difference in symptoms: a comparison of two techniques. J Clin Epidemiol 1996; 49(11): 1215-1219.
32 Cazzola M, MacNee W, Martinez FJ, et al. American Thoracic Society/European Respiratory Society Task Force on outcomes of COPD. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J 2008; 31(2): 416-469.
33 O'Donnell DE, Laveneziana P. Lung hyperinflation in COPD: the impact of pharmacotherapy. Eur Respir Rev 2006; 15(100): 85–89.
32 Further list of references

Ref. 4 - Bronchodilator and symptomatic improvement
1 Eliasson O, Degraff AC. The use of criteria for reversibility and obstruction to define patient groups for bronchodilator trials. Am Rev Respir Dis 1985; 132: 858-864.
2 Guyatt GH, Townsend M, Nogradi S, Pugsley SO, Keller JL, Newhouse MT. Acute response to bronchodilator: an imperfect guide for bronchodilator therapy in chronic airflow limitation. Arch Intern Med 1988; 148: 1949-1952.
3 Redelmeier DA, Goldstein RS, Min ST, Hyland RT. Spirometry and dyspnea in patients with COPD. When small differences mean little. Chest 1996; 109: 1163-1168.
Ref. 5 - Forced expiratory efforts and intrathoracic gas compression
1 Sadoul P. Mesure de la capacité vitale et des débits maximaux. In: Denolin H, Sadoul P, Orie NGM eds. L'exploration fonctionnelle pulmonaire, 2me partie. Flammarion, Paris 1971.
2 Van de Woestijne KP, Afschrift M. Airway dynamics during forced expiration in patients with chronic obstructive lung disease. In: Orie NGM, Van der Lende R, eds. Bronchitis III. Royal Van Gorcum, Assen 1970; pp. 195-206.
3 lngram RH, Schilder DP. Effect of thoracic gas compression on the flow-volume curve of the forced vital capacity. Am Rev Respir Dis 1966;. 94: 56-63.
4 Krowka MJ, Enright PL, Rodarte JR, Hyatt RE. Effect of effort on measurement of forced expiratory volume in one second. Am Rev Respir Dis 1987; 136(4): 829–833.
5 Sharafkhaneh A, Babb TG, Officer TM, Hanania NA, Sharafkhaneh H, Boriek AM. The confounding effects of thoracic gas compression on measurement of acute bronchodilator response. Am J Respir Crit Care Med 2007; 175(4): 330-335.
6 Quanjer PH, Ruppel GL, Langhammer A, Krishna A, Mertens F, Johannessen A, Menezes AMB, Wehrmeister FC, Pérez-Padilla R, Swanney MP, Tan WC, Bourbeau J. Bronchodilator response in FVC is larger and more relevant than in FEV1 in severe airflow obstruction. Chest 2017. doi:10.1016/j.chest.2016.12.017. [Epub ahead of print]
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