A comparison between two diagnostic tools to identify dynamic hyperinflation in COPD-patients :
1. Metronome-Paced hyperventilation with inspiratory capacity manoeuvres.
2. CPET with inspiratory capacity manoeuvres.

Chronic obstructive pulmonary disease (COPD) is a progressive, treatable
disease characterized by not fully reversible airflow limitation. The main
feature is airway inflammation, induced by noxious particles like smoke or
burning fumes. The airway inflammation leads to structural changes in the
airway walls and loss of elasticity of the lung parenchyma.
The changes have important consequences for the expiratory airflow. During
exercise, limitation of expiratory airflow may induce dynamic hyperinflation,
an increase in end-expiratoy lung volume that is associated with exercise
limitation in COPD.
Measurements of dynamic hyperinflation are commonly taken during
cardiopulmonary exercise testing (CPET). CPET, however, is complex and
laborious and only performed in a clinical setting. The development of dynamic
hyperinflation, especially in patients with mild and moderate COPD, therefore
may go unnoticed until considerable exercise limitations occur. With an
accurate simple screening tool to detect dynamic hyperinflation in patients
with COPD early interventions, such as optimal bronchodilation or exercise
training, can be offered to allow patients to continue their activities and
prevent deconditioning. Such a simple surrogate to exercise testing might be
metronome-paced hyperventilation (MPH). Gelb e.a. (2004) showed that dynamic
hyperinflation induced by breathing for 20s at twice the resting breathing rate
was similar to dynamic hyperinflation after maximal exercise testing in 16
patients with moderate-to-severe COPD. In subsequent studies, MPH was used to
investigate lung volume responses to bronchodilator use (Gelb 2007, 2009) and
the behaviour of dynamic hyperinflation during 2-year follow-up (Hannink,
2010).
More recently Lahaije et al (2013) found a good overall accuracy (sens 85%,
spec 85%) to identify subjects with COPD susceptible to develop dynamic
hyperinflation during CPET (the gold standard).
In our observational study at the MCL (Leeuwarden), we would like to
investigate, whether we could find the same diagnostic accuracy for dynamic
hyperinflation of MPH, thereby confirming the value of MPH as a diagnostic tool
in clinical practice and improving our diagnostic process in COPD with less
effort of the patients.

The purpose of this study is to compare the Metronome-Paced
Hyperventilationtest (MPH) with cardiopulmonary exercise testing (CPET) in
patients with COPD for detecting dynamic hyperinflation, thereby establishing
the diagnostic accuracy for dynamic hyperinflation in COPD patients of the MPH.
With the CPET with inspiratory capacity manoeuvres as the gold standard for
establishing dynamic hyperinflation, we would like to determine diagnostic
equivalence of MPH in our laboratory and our COPD population.

hypothesis: Dynamic hyperinflation(DH) in patients with COPD in CPET is not
different from DH in MPH. DH will be assessed by inspiratory capacity
manoeuvres and represented by delta-IC (*IC).

Patients with COPD sent for a cardiopulmonary exercise test for any reason by
the pulmonologist will be asked to voluntary participate in this study.
participants will perform MPH and subsequently CPET (cardiopulmonary exercise
testing), both with IC manoeuvres. Based on CPET, subjects will be classified
as hyperinflators or non-hyperinflators. In this observational study the
diagnostic accuracy of MPH for dynamic hyperinflation will be investigated.
Because CPET can be very exhausting, MPH, that is much easier te perform, will
precede CPET in the same visit to the pulmonary function laboratory.

Metronome-paced hyperventilation test (MPH)
Subjects are seated, breathing through a mouthpiece connected to the
spirometer. After a quiet and stable breathing pattern is obtained, baseline IC
(ICrestMPH) will be determined by taking the mean of three acceptable
manoeuvres. Then, a metronome is set at twice the resting breathing rate and
subjects will be asked to breathe at this pace for 20 s, immediately followed
by a maximal inspiratory manoeuvre (ICMPH). To test reliability of ICMPH, the
procedure will be repeated after subjects have returned to their resting
breathing level. In line wit the criteria for baseline IC manoeuvres, mean
ICMPH will be calculated from three acceptable manoeuvres, within 10% of each
other. MPH-induced dynamic hyperinflation (* ICMPH) will be calculated as the
difference between mean ICMPH and ICrestMPH).

Cardiopulmonary exercise test (CPET)
All subjects will perform a symptom-limited incremental exercise test using an
electrically braked cycle ergometer (Lode B.V., Lode Excalibur Sport,
Groningen, The Netherlands). Subjects wear a leak-age-free face mask with a
turbine flow transducer and a gas sampling tube (ZAN, zan100, Accuramed,
Belgium).
Measurements are performed according to the American Thoracic Society/European
Respiratory Society guidelines for CPET (2003). Reference equations for the
calculation of predicted values are those produced by Wasserman.
Dynamic hyperinflation will be estimated by measuring changes in IC. While the
subjects sit upright and relaxed on the bike, baseline IC (ICrestCPET) will be
determined by measuring three maximal inspiratory manoeuvres from a position of
passive end-tidal expiration. At peak exercise, IC will be measured (ICCPET)
and dynamic hyperinflation (*ICCPET) is calculated as the difference between
ICCPET en ICrestCPET.

Pulmonary function tests
All measurements will be performed according to the American Thoracic
Society/European Respiratory Society guidelines for lung function measurements
(Miller e.a., 2005, Wanger e.a., 2005). Reference equations for the calculation
of predicted values are those produced by the European Community for Steel and
Coal (Quanjer,1993) and predicted values for inspiratory capacity (IC) are
calculated as predicted total lung capacity (TLC) minus predicted functional
residual capacity (FRC).

Statistics
This is an observational study. CPET will be used as the gold standard
procedure for assessment of dynamic hyperinflation.

For the analysis we postulate diagnostic equivalence between both tests if the
difference of delta-IC of both tests is not larger than 10%. one-sided paired
t-test and the 95% confidence interval of the difference of delta-IC of both
tests will be determined.
Bland-Altman plot will be used for agreement between both tests, illustrating
the difference in amount of delta-IC measured by both methods in the full range
of results.
ROC-analysis (receiver operator curve) will be performed for diagnostic
accuracy of MPH.
Sensitivity and specificity will be calculated using a cross table.

sample size calculation: Number of participants: 110.
A sample size of 110 pairs with a correlation of 0.200 (conservative
estimation) the two tests achieves 80% power to detect equivalence when the
margin of equivalence is from -0.250 to 0.250 and the actual mean difference is
0.000.
The significance level (alpha) is 0.050 using two one-sided Paired T-Tests.
These results are based on 5000 Monte Carlo samples from the null distribution:
Normal(M0 S) - Normal(M1 S) and the alternative distribution: Normal(M0 S) -
Normal(M0 S).
As stated for this analysis we postulate diagnostic equivalence between both
tests if the difference of delta-IC of both tests is not larger than 10%. From
the paper of Lahaije et al, the delta-IC in the COPD population of 2.6 liter
(SD 0.7 liter) is used in this calculation.

Because of the conservative estimation of the used correlation coefficient of
0.20 an interim analysis will be performed after 60 patients to verify the
assumptions of the sample size calculation.

Statistics will be analyzed by an independent epidemiologist. SPSS (SPSS
Chicago, IL, USA) will be used.

not applicable