The current ATS/ERS guidelines require that an individual have a post-bronchodilator increase in FEV1 or FVC of at least 12% and 200 ml in order for it to be considered a significant response. Numerous studies have shown however, that many patients that don’t meet these criteria, particularly those with COPD, do have a clinically significant improvement with bronchodilators.

The September 2014 issue of Chest had a point-counterpoint set of editorials on this standard and on assessing the response to bronchodilator in general. Both sides had a number of interesting things to say but to a large extent one side was talking apples (physiology) and the other side oranges (statistics). I actually think that both sides feel there are significant problems with the ATS/ERS standards, they just differ in what they think is wrong and in the best way to fix it.

One statistical argument was that the ATS/ERS guideline is a one-size-fits-all solution that is designed more to detect asthmatic-type responses than the more subtle changes that can occur in individuals with COPD that although small, are clinically relevant. I am inclined to agree with this but as much as I and others think that the current ATS/ERS standard likely needs revision the difficulty with this is that spirometry is a “noisy” measurement with a lot of variability.

Spirometry variability and the limits to its accuracy comes from issues to familiar to all of us:

• the patient’s ability to understand and perform spirometry
• the technician’s ability to encourage and guide a patient through a spirometer maneuver
• the spirometer’s ability to measure exhaled flow and volume accurately

“Noise” is one of the reasons why it can be difficult to determine statistically and clinically significant changes. It’s also why the threshold for significant post-bronchodilator change is set as high as it is and may also be the reason why it shouldn’t be lowered.

Even though there may be reasons why the ATS/ERS guidelines for post-bronchodilator improvements in FEV1 and FVC shouldn’t be revised at the very least they need to become more inclusive and consider more factors. There is too much emphasis placed on the changes in FEV1 and FVC as the sole indication for a response to bronchodilator particularly since there are other ways in which a response can be measured.

Inspiratory flow:

During a forced expiration airways tend to narrow because of the increase in transpulmonary pressure. This narrowing may reduce or otherwise mask post-bronchodilator improvements in airway caliber. For this reason improvements in inspiratory flows may be a better indicator of bronchodilation.

Patients with COPD have been shown to have significant increases in Peak Inspiratory Flow (PIF), Forced Inspired Volume in one second (FIV1) and their Forced Inspiratory Vital Capacity (FIVC) following a bronchodilator. These increases are usually as large and frequently larger than FEV1, FVC and FEFmax (both as an absolute and as a relative change). Of note, inspiratory flows were often shown to increase even when FEV1 did not change significantly.

Compared to the number of studies on expiratory flows there are a miniscule number of studies on inspiratory flow. Analysis of results is not helped by the lack of standards either for the inspiratory maneuver or for what constitutes a significant change in the inspiratory flow rates. Nevertheless, improvements in inspiratory flow rates are linked to a decrease in symptoms of dyspnea. It would seem that a comprehensive evaluation of the spirometric response to bronchodilator, particularly in individuals with COPD, should include an inspiratory maneuver and inspection of the PIF and FIVC results.

TLC, FRC, RV and IC:

A number of investigators have shown that individuals with COPD that do not have a significant FEV1 response to bronchodilator can show significant decreases in FRC and RV. Measuring changes in FRC and RV is a time consuming process that requires specialized equipment, however. For this reason Inspiratory Capacity (IC) measurements are frequently used as a surrogate for FRC measurements. There is a lot of evidence that a increase in IC improves both dyspnea and exercise capacity even when there isn’t a significant change in FEV1.

It would seem that IC should be routinely be measured when assessing an individuals response to bronchodilator and an increase in IC of 200 ml and/or 10% of predicted has been proposed as marker for significant change following a bronchodilator. IC however, cannot be measured as part of a forced vital capacity and needs to be measured during a slow vital capacity maneuver instead. Performing both forced and slow vital capacity maneuvers increases the complexity and time for a spirometry session and this may act as a disincentive to performing both maneuvers. The fact that there is no additional reimbursement for performing both maneuvers is a further disincentive.

RAW, sGAW:

RAW and sGAW have been shown to improve post-bronchodilator in almost all subjects. As expected individuals with asthma tend to show the greatest improvement but individuals with COPD and with normal lungs improve as well. Because sGAW measurements have a high level of variance this means that a changes in RAW or sGAW need to be considered carefully, particularly since it is not necessarily clear what consititutes a clinically significant change.

RAW and sGAW measurements require a plethysmograph and repeatable measurements requires a fair degree of technical proficiency and patient cooperation. For these reasons it’s not clear that RAW and sGAW really have any particular advantage over spirometric measurements in routine clinical practice. A number of investigators have shown however, that the deep inhalation that precedes a forced vital capacity maneuver can cause bronchoconstriction and therefore decrease the apparent response to bronchodilator. It would seem that the best use of RAW and sGAW for assessing bronchodilator response would be in research and clinical trial when for one reason or another a forced vital capacity maneuver is contraindicated.

Oscillometry:

Forced Oscillation and Impulse oscillometry have been used to assess the response to bronchodilators. Investigators have reported that the greatest changes post-bronchodilator occur in resistance and reactance at specific frequencies, notably R5, R20, X5 and the resonant frequency (RF).

It’s less clear what the changes in oscillometric parameters means in terms of clinical significance particularly since oscillometry is sensitive primarily to the central and peripheral airways. A high level of variance has also been noted in oscillometry measurements of normal subjects. In addition some investigators have noted that oscillometry resistance measurements are less sensitive than spirometric measurements in both a statistical and a clinical sense. The primary advantage of oscillometry is that is only requires passive breathing by a patient which makes it ideal for use with children and this reason alone makes it a useful technique.

 

The most effective ways to assess the response to bronchodilator has been debated for decades and that is not likely to change any time soon. Changes in FEV1 and FVC have been the central point in these debates but the changes in lung physiology that occur after a bronchodilator are complex. For this reason changes in PIF, FIV1, FIVC, IC, RAW, sGAW and oscillometry can and have been used to detect improvements in airflow that are not reflected solely in the FEV1 and FVC. The current ATS/ERS standards are largely based on statistics and on the ability to defect changes. Clinically significant changes are not necessarily the same as statistically significant changes however, and the standards likely need to be revised and updated.

If I was asked (however unlikely that may be) my recommendation would be to revise the standards for spirometry to include separate forced inspiratory, forced expiratory and slow vital capacity maneuvers, particularly for a first assessment or when pre- and post-bronchodilator measurements are being made. This would permit routine measurement of PIF, FIVC, FIV1, SVC and IC as well as the regular expiratory parameters. This would provide a broader base of measurements when assessing an individual’s response to bronchodilator and would also help make sure the highest vital capacity is used to calculate the FEV1/VC ratio and that inspiratory obstruction is routinely evaluated.

Until the ATS/ERS standards are updated each lab must decide for itself which additional tests, if any, should be performed as part of a response to bronchodilator assessment, but for COPD patients in particular it is likely necessary for us to look beyond just FEV1 and FVC.

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