Glottal aperture and buccal airflow leaks critically affect forced oscillometry measurements

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Glottal aperture and buccal airflow leaks critically affect forced oscillometry

measurements

Andras Bikov MD, PhD1,2, Neil B. Pride MD, PhD1, Michael D. Goldman MD, PhD1,

Hull JH MD, PhD1, Ildiko Horvath MD, PhD2, Peter J. Barnes DM, DSc, Master

FCCP1, Omar S. Usmani MBBS PhD FHEA FRCP1*, Paolo Paredi MD, PhD1*

1Airway Disease Section, National Heart and Lung Institute, Imperial College London

& Royal Brompton Hospital, London, United Kingdom

2Department of Pulmonology, Semmelweis University, Budapest, Hungary

*joint contributors and senior authors

Conflicts of Interest: Dr. Usmani reports grants and honoraria in the last three

years from Aerocrine, Astra Zeneca, Boehringer Ingelheim, Chiesi, Edmond

Pharma, Glaxosmithkline, Napp, Mundipharma, Sandoz, Prosonix, Takeda,

Zentiva, outside of the submitted work. All others declare no conflicts of

interest.

Corresponding author:

Dr. Paolo Paredi, Airway Disease Section, National Heart and Lung Institute,

Imperial College, Dovehouse Street, London SW3 6LY, UK; [email protected]

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ABSTRACT

Background: Forced oscillation technique (FOT) measures respiratory resistance

and reactance; however, the upper airways may affect the results. In this study we

quantified the impact of glottal aperture and buccal air leaks.

Methods: In the glottal aperture study (a) ten healthy subjects (34±2 years)

performed a total lung capacity (TLC) manoeuvre followed by 10 second breath-hold

with and without total glottal closure (b) additionally, the effects of humming

(incomplete glottal narrowing) on FOT measurements were studied in six healthy

subjects. Glottal narrowing was confirmed by direct rhino-laryngoscopy. In the air

leak study, holes of increasing diameter (3.5 mm, 6.0 mm, and 8.5 mm) were made

on the breathing filters. Eleven healthy (33±2 years) and five COPD (69±3 years)

subjects performed baseline FOT measurements (IOS, Wurzburg, Germany) and

with the three modified filters.

Results: Narrow glottal apertures and humming generated R5 “peaks”, increased R5

(1.49±0.37 vs. 0.34±0.01 kPa/L/s, p<0.001) and decreased X5 values (-2.10±0.51

vs. -0.09±0.01 kPa/L/s, p<0.001). The frequency dependency of resistance was

increased.

Holes in the breathing filters produced “indentations” on the breathing trace. Even

the smaller holes reduced R5 in healthy subjects (0.33±0.02 to 0.24 ±0.02 kPa/L/s,

p<0.01) and COPD patients (0.50±0.04 to 0.41±0.04 kPa/L/s, p<0.05) whereas X5

became less negative (from -0.09±0.01 to -0.05±0.01 in healthy, p<0.01, and from -

0.22±0.06 to -0.11±0.03 kPa/L/s in COPD subjects, p<0.05).

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Conclusions: Visual inspection of the data is required to exclude glottal narrowing

and buccal air leaks identified as R5 peaks and volume indentations respectively, as

these significantly affect FOT measurements.

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INTRODUCTION

Spirometry measures airflow obstruction but it provides no information on the

underlying pathophysiological mechanisms. In contrast, airflow resistance (Raw)

measured by body plethysmography 1 provides a more physiological assessment of

airflow obstruction. However, it is limited by cumbersome equipment, and requires

an experienced operator.

Forced oscillation technique (FOT), also an half-a-century old technique 2, is a

more user- and patient-friendly method. FOT analyses the pressure/flow responses

of the airways to small forced oscillations delivered at the mouth, and has noticeable

advantages over spirometry and plethysmography as it is effort independent,

requires only tidal breathing and therefore can be carried out in children3, during

sleep 4 and general anaesthesia 5. Furthermore, FOT requires a shorter operator

training. FOT also measures respiratory reactance (Xrs), which, in patients with

COPD6 is a surrogate marker of expiratory flow limitation 6,7. For these reasons, there

has been recent interest in FOT in different lung diseases 8,9. Indeed, some FOT parameters

are useful measurements of small airways dysfunction 10.

The European Respiratory Society, recognising the value of FOT 11 and published

the standardization of this technique. Unfortunately, even though tongue position,

cheek movement and swallowing were acknowledged 12, the impact of upper airways

including glottis aperture and buccal air leaks were not fully discussed.

Glottal aperture is a major determinant of airway resistance and because of its

variability 13;14 , particularly in patients with airway obstruction 15,16, it may

significantly affect respiratory impedance 17. Therefore a sensitive FOT marker for

this phenomenon is required.

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Buccal air leaks arise from the lips not being tightly sealed around the mouthpiece

or from loose parts of the equipment, preventing airflow generated by the FOT

loudspeaker from reaching the lungs affecting FOT parameters. In this study we

developed a practical method to identify and quantify the impact of the glottal

aperture and buccal air leaks on FOT measurements.

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METHODS

Subjects

Healthy volunteers had no history of chronic respiratory disease and normal

spirometry. Patients with COPD were diagnosed according to the Global Initiative for

Chronic Obstructive Lung Disease (GOLD) strategy 18 and had a mean post-

bronchodilator FEV1 of 67.0 ± 4.0 % of predicted. All COPD patients used inhaled

corticosteroids with a combination of a long-acting beta-agonist, and were instructed

not to take their respiratory medications for at least 12 h prior to measurements.

None of the participating subjects had suffered from a respiratory tract infection in

the four weeks preceding the study and all were current non-smokers. The studies

were approved by the National Research Ethics Committee (reference 08/H0709)

and subjects gave their written informed consent before enrolment.

Glottal aperture study

The effects of the glottal aperture on FOT parameters were investigated using two

experimental approaches. In the first approach we studied the effect of total glottal

occlusion in ten healthy volunteers (34 ± 2 years, 6 men). Subjects performed a

standardised breathing cycle divided into three phases: tidal breathing for 20

seconds, followed by inhalation to total lung capacity (TLC) and then breath-hold for

10 seconds to induce glottal closure, followed by normal breathing for 10 seconds.

The same cycle was repeated after instructing the subjects to relax, thereby

preventing glottal closure 19. Direct visualisation using rhino-laryngoscopy (ENF-VQ,

Tokyo, Japan) was applied to ascertain the positioning of the glottal aperture in four

of the subjects.

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In the second approach we assessed the effects of incomplete glottal occlusion

In six healthy subjects (34 ± 2 years, 4 male) who were instructed to inhale to end

inspired volume (0.5 - 1 L) and then to hum for 10 seconds, thus producing

incomplete glottal narrowing. The effects of humming on FOT measurements were

compared to those measurements undertaken during tidal breathing. The glottal

aperture was visualised directly as described above in two subjects during humming.

Buccal air leak study

In this study we simulated an air leak from the lips of the volunteers, where the lips

did not have a tight seal around the mouthpiece. Eleven healthy subjects (33 ± 2

years, 7 men) and five COPD patients (69 ±3 years, 1 man) participated and

subjects performed FOT measurements in the following sequence; a) first, as

normal, breathing through the commonly employed MicriGrad disposable barrier

breathing filters and then b) the measurements were repeated three times using the

same type of filters but with artificial holes of increasing diameter (3.5, 6.0 and 8.5

mm) drilled in the upper aspect of the filter at one cm from its edge.

Forced oscillometry measurements

FOT measurements were performed using an Impulse Oscillometry System device

(IOS, Jaeger, Wurzburg, Germany) in accordance with the European Respiratory

Society guidelines 11,7. The pneumotachometer was calibrated daily using a three-

litre syringe, and pressure calibration was checked weekly with a reference

resistance (0.2 kPa/l/s). In all measurements, a ‘free-flow’ mouthpiece was utilised

with a built-in tongue depressor to stabilise the position of the tongue. Subjects firmly

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supported their cheeks and the floor of their mouth (with their hands/chin rest), while

seated with their neck in a comfortable neutral posture. Subjects wore a noseclip.

FOT pressure impulses (with a peak-to-peak amplitude of 0.40 - 0.50 kPa)

were applied to the airways five times per second for 60 seconds utilising a minute

ventilation of <10 L/min. Mean values of Rrs and Xrs were calculated between

frequencies of 5 and 35Hz. Peak-to-peak impulse pressures 20 were estimated by

analysing the pressure curves on the IOS primary tracings.

Data analysis

Primary data from the IOS tracings showing airway pressure, volume and flow were

assessed using IOS software (version 4.67). In the baseline analysis, artefacts such

as coughing and swallowing were excluded by limiting the analysis to periods free of

spikes in magnitudes of R5 and X5 as previously reported 21. In baseline

measurements, airflow leaks were excluded by high-gain display of volume in time,

analysing only tidal breaths free of large impulse transients (Figure 1). We tabulated

mean whole-breath values of resistance and reactance at 5Hz (R5, X5, respectively),

resistance at 15Hz (R15), resonant frequency (Fres) and low-frequency reactance

area (AX; which is the integrated Xrs from 5Hz to Fres). To avoid confusion in the

description of Xrs values becoming more negative, we describe the absolute

magnitude of Xr. In the individual inspiratory and expiratory within breath analysis of

the data, we report the mean values of inspiratory and expiratory R5 (R5i, R5e,

respectively) and X5 (X5i, X5e, respectively) as assessed using the IOS software.

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Statistical analysis

Data were analysed using Graph Pad Prism 5.03 (GraphPad Software Inc., La Jolla,

CA, USA). The results of healthy and COPD subjects were compared using

student’s t-test. Two-way ANOVA applied with the Bonferroni post hoc test was

utilised to compare the effects of air leaks and glottal changes on R5 as well as X5 in

healthy vs. COPD groups. Repeated measures of analysis of variance (ANOVA)

were used to assess changes in air leak markers, peak impulse pressures, glottal

aperture markers, R5, X5, R5i, R5e, X5i, X5e as well as R5i-R5e and X5i-X5e

values. Linear regression analysis was used to evaluate the relationships between

air leak markers and FOT parameters. Data are presented as mean ± standard error

of the mean (SEM).

RESULTS

Glottal aperture study

Glottal aperture was visualised directly using a rhino-laryngoscope in four healthy

subjects (Figure 2). Total glottal closure at TLC was associated with

characteristically tall R5 spikes (Figure 2A). These R5 fluctuations were not detected

when breath hold at TLC was repeated with a relaxed open glottis (Figure 2B).

Compared to total glottal closure, smaller increases in R5 peaks were observed

during humming, which recreated incomplete glottal closure (Figure 2 C).

Effect of glottal aperture on FOT parameters

Breath hold with the glottis closed at TLC greatly increased R5 (p<0.001) and X5

became more negative (p<0.001)(Table 1). Furthermore, a significant increase was

observed in peak-to-peak impulse pressures during the TLC manoeuvre (p<0.001).

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Similar to the breath hold manoeuvre, humming also significantly increased R5

(1.27±0.19 kPa/L/s,p<0.05) and the absolute value of X5 (-1.75±0.25 kPa/L/s, p<0.05)

became more negative.

In contrast, when subjects relaxed their glottis during the TLC manoeuvre, R5

decreased (p<0.001) and X5 became more negative (p<0.001) compared to values

during tidal breathing. Furthermore, impulse pressures also decreased significantly

(p<0.001). Notably, breath hold with closed glottis significantly increased frequency

dependency of resistance and reactance (Figure 3).

Buccal air leak study

At baseline, in the absence of air leaks, COPD patients had higher whole breath R5

(0.50±0.04 kPa/L/s) and more negative X5 values (-0.22±0.06 kPa/L/s ) compared to

healthy subjects (0.33±0.02 kPa/L/s and-0.09±0.01 kPa/L/s for R5 and X5

respectively p<0.01) (Table 2).

Within breath analysis showed that both the inspiratory (R5i) and expiratory

(R5e) components of R5 were higher in COPD (0.39±0.03 kPa/L/s and 0.58±0.06

kPa/L/s respectively) compared to healthy subjects (0.31±0.02 kPa/L/s and

0.34±0.02 kPa/L/s respectively p<0.010).

Similarly, in COPD patients, both the inspiratory (X5i) (-0.15±0.02 kPa/L/s)

and expiratory (X5e) (-0.31±0.12 kPa/L/s) components of X5 were larger (absolute

value) compared to healthy subjects (-0.11±0.01 kPa/L/s and -0.08±0.01 kPa/L/s for

X5i and X5e respectively, p<0.05). X5i-X5e was larger in COPD patients (0.16±0.09

kPa/L/s) compared to healthy subjects (-0.03±0.01 kPa/L/s, p=0.01).

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Identification of an air leak marker

In the presence of air leaks we identified volume “transients”, defined as rapid

volume changes (∆V, Figure 1, Panel B ), which were synchronous with the pressure

pulses. ∆V were more clearly visible by enlarging (high-gain display) the IOS

volume/time tracings and resembled step wise “indentations” that were particularly

pronounced on the expiratory limb of the breathing volume. Larger holes resulted in

bigger air leaks and produced corresponding larger ∆V on the volume curves

suggesting ∆V as a possible marker of this phenomenon. . In the absence of an air

leak the volume tracing appears to be smooth with only minor indentations that may

be better described as a “tremor”. In the presence of an air leak these “indentations”

become very noticeable. ∆V was affected by air leaks to a similar extent in healthy

subjects and COPD patients (p>0.05).

Effect of air leak on FOT parameters

With increasingly bigger holes in the filters, the magnitude of peak-to-peak impulse

pressures decreased similarly in both subject groups (p<0.001, Table 2). Notably,

both whole breath R5 (p<0.001) and X5 (p<0.001, Figure 4) values were decreased

(larger magnitude for X5) even with the smallest air leak (3.5 mm). These changes

were more significant in COPD patients compared to healthy subjects (p<0.01,

Figure 4). However, both the R5 and X5 baseline differences between these two

groups of subjects were progressively attenuated with larger air leaks. ∆V correlated

with changes in R5 and X5 in both healthy subjects and COPD patients. Air leaks

also significantly decreased within-breath R5i, R5e and increased R5i-R5e values in

both subject groups (p<0.01).

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The magnitude of X5i and X5e decreased (less negative) both in healthy

subjects and COPD patients (p<0.01), however X5i-X5e decreased only in the

COPD group (p=0.07) and not in healthy subjects (p=0.26, Table 1).

DISCUSSION

In this study, we have identified for the first time in vivo in man, using direct

visualization of the glottal anatomy, IOS markers that accurately detect and quantify

the effects of changes in the glottal aperture. In addition, we have determined the

importance of buccal airflow leaks on FOT measurements. We have shown that

minor changes of the glottal aperture and small buccal airflow leaks can significantly

affect FOT.

European Respiratory Society guidelines standardised FOT11, however, the

critical influence of changes in the glottal aperture or the phenomenon of buccal

airflow leaks were not fully addressed 22. Flow signal analysis was suggested as a

possible method to identify artefacts, however, there are no studies investigating the

usefulness of this aspecific and only qualitative marker. Improving these limitations

may increase the utility of FOT, in the measurement of airway resistance, expiratory

flow limitation 6 and small airway function 23 also considering that most FOT

analysers available on the market do not automatically reject measurements affected

by artefacts

During the normal respiratory cycle, the vocal cords physiologically partially

abduct with inhalation and partially adduct with end-exhalation providing positive

end-expiratory pressure (PEEP). Therefore, air flows are largely affected by glottis

aperture, which can in turn affect IOS measurements. Notably, involuntary glottal

closure is more common in patients with airway disease and importantly contributes

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to the syndrome of laryngeal dysfunction in clinical practice 15. Indeed, subjects with

severe airway obstruction tend to unintentionally adduct their vocal cords, even

during restful tidal breathing. This results in a reduced/narrowed glottal aperture and

increased PEEP, a mechanism that, like pursed lips breathing results in keeping the

airway open 15 16.

The effect of glottal aperture on FOT parameters has previously been

investigated only in limited number of studies 24,25;26 which were either only

undertaken in animals, did not visualise glottal aperture, or simulated an unnatural

adduction of the vocal cords. Klein and colleagues 24 observed increased respiratory

resistance and reactance, in a swine animal model by altering the posture of the

head of the animals causing a decrease in the cross-section of the pharyngeal and

laryngeal region 25;26. We have confirmed these experimental findings for the first

time in vivo in man using direct visualization of the vocal cords.

Consistent with our results in adults, a study in children with asthma or

chronic cough, confirmed that a 1 to 2 second closure of the glottis caused a

significant increase of total respiratory resistance 17.

Rigau and colleagues used a mechanical experimental model to prove that

changes in R5 (∆R5) could be used to detect glottal closure 27 in vocal cord

dysfunction (VCD), a condition characterised by airway obstruction due the

paradoxical adduction of the vocal cords. We have confirmed this experimental

finding, for the first time in vivo in man. As ∆R5 is a marker of variation in glottal

aperture, FOT may be of aid in the diagnosis of VCD. This may be of particular

interest in the differential diagnosis of VCD and asthma.

Our study has not only confirmed that glottal aperture significantly affects

respiratory resistance and reactance, but importantly, it has identified ∆R5 as a

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marker of glottal closure in man. The analysis of resistance tracing identified ∆R5

spikes when the glottis was closed following an inhalation to TLC and breath hold 19.

However, such changes were not present when the same breathing manoeuvre was

repeated with a relaxed glottis 28. Crucially, not only was the experiment carried out

in vivo, but for the first time, the position of the vocal cords was confirmed

endoscopically. Rhynolaryngoscopy allows complete and reproducible visualization

of the glottal aperture enhancing the reliability of our results and conclusions.

Interestingly, ∆R5 spikes were also detected during more physiological incomplete

glottal closure during humming, indicating that ∆R5 may identify a partial reduction of

the glottal area. As these R5 spikes re sudden and rapidly reversible they are

unlikely to be affected by the baseline airway obstruction.

Rrs decreased during the TLC manoeuvre with relaxed glottis, this may have been

related to increased lung volumes 29 or opening of the glottis 30.

Notably, we observed that glottis aperture not only affected IOS parameters, but it

also interfered significantly with the frequency dependency of resistance. This FOT

parameter, defined as the progressive decreases of resistances from lower to higher

frequencies, has been advocated as a marker of small airways dysfunction 11;31.

Further studies are now required to verify the influence of upper airway physiology

on the frequency dependency of resistance in patients with airway obstruction.

Some subjects find it difficult to seal their lips around the mouthpiece tightly

because of anatomic reasons or poor oropharyngeal muscle strength. This may lead

loss of FOT pressure and impaired test results 32;33. We simulated these airflow leaks

by producing holes of increasing diameter in the breathing filters attached to our FOT

machine. Notably, the presence of holes in the breathing filters resulted in

indentations particularly on the expiratory limb of the breathing volume tracings

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(volume transients, ∆V, Figure 1) which were synchronous with the pressure pulses

generated by the FOT machine. Larger filter holes resulted in bigger airflow leaks

and corresponding larger ∆V compared to smaller filter holes suggesting ∆V as a

possible airflow leak marker. This was further confirmed by the strong correlation

between ∆V and R5 in both healthy subjects and patients with COPD. Remarkably,

even the smallest diameter holes (3.5 mm) significantly decreased airway resistance

and affected reactance values (Figure 4) indicating that a quality control of the

tracing should always be carried out. Interestingly, airflow leaks significantly impaired

FOT parameters even in healthy subjects and larger airflow leaks eliminated

differences in R5 and X5 between COPD patients and normal subject reducing the

sensitivity and usefulness of this technique. Within breath FOT analysis was also

significantly affected, this may have significant clinical implications as it will reduce

the ability of this technique to identify expiratory flow limitation. Therefore, we

suggest that all FOT tracings should be inspected for the presence of volume

transients. When these are detected, subjects should be encouraged to wrap their

lips tighter around the mouthpiece.

We used a IOS device in this study, which applies stronger peak-to-peak

impulse pressures compared to pseudorandom noise instruments 20. Progressively

greater air leaks decreased the size of impulse pressures. These results were in

concordance with the reduction of respiratory resistance. Similarly, glottal closure

increased, while glottal abduction decreased impulse pressure sizes in parallel with

alterations in respiratory resistance.

In summary, glottal aperture and even small air leaks significantly affect FOT

parameters. To correct these errors, we have identified ∆R5 and ∆V as markers of

glottal occlusion and air leaks respectively. We suggest that the tracings with primary

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data of every measurement should be carefully checked before accepting the

results. Further studies are required to investigate the use of FOT in the diagnosis of

vocal cord dysfunction.

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ACKNOWLDGEMENTS

Andras Bikov was supported by a European Respiratory Society Long-Term

Fellowship. Dr Omar S Usmani is a recipient of an NIHR (National Institute of Health

Research, UK) Career Development Fellowship. The study was supported by the

NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and

Harefield NHS Foundation Trust and Imperial College London.

Author contributions:

Dr Paredi had full access to all of the data in the study and takes responsibility for the

integrity of the data and the accuracy of the data analysis.

Dr Paredi: contributed to the study design; data analysis; and writing, editing, and final

approval of the manuscript.

Professor Goldman: had the original idea and designed the study with Dr Paredi and

Professor Pride.

Professor Pride: Designed the study, provided continued support and feedback during its

execution and edited its final version

Professor Barnes: contributed to the study concept and design and writing, editing, and final


Dr Usmani: contributed to the study design and supervision, data analysis, and writing and

final approval of the manuscript

Dr Hull: performed the rhino-laryngoscopy, participated in the writing and final approval of

the manuscript

Professor Horvath: contributed to the study concept and design and writing, editing, and final


Dr Bikov: carried out most of the measurements, performed the first data analysis and wrote

the first draft of the manuscript.

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NOTE

This study is entirely based on projects that, Professor Michael Goldman was sadly

unable to finish before his passing in 2010. His ideas have been instrumental to the

study design and interpretation of the data. We hope that our conclusions and this

manuscript will do justice to his passion for science and to his legacy.

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Table 1. Changes of forced oscillometry parameters during various breathing Phases

(N=10)

Closed glottis

Tidal breathing TLC Tidal breathing P

R5 (kPa/L/s) 0.34±0.01 1.49±0.37 0.33±0.02 p<0.001

X5 (kPa/L/s) -0.09±0.01 -2.10±0.51 -0.09±0.02 p<0.001

Impulse pressure (kPa) 0.47±0.01 0.54±0.01 0.47±0.01 p<0.001

Relaxed glottis

Tidal breathing TLC Tidal breathing P

R5 (kPa/L/s) 0.33±0.02 0.20±0.02 0.31±0.02 p<0.001

X5 (kPa/L/s) -0.09±0.01 -0.18±0.01 -0.08±0.01 p<0.001

Impulse pressure (kPa) 0.47±0.01 0.43±0.01 0.44±0.01 p<0.001

R5-resistance at 5 Hz, X5-reactance at 5 Hz. Data are presented as mean±SEM.

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Table 2. Changes of forced oscillometry parameters using different breathing filters

holes.

Healthy subjects (N=11)

Baseline 3.5 mm hole 6.0 mm hole 8.5 mm hole P

R5 (kPa/L/s) 0.33±0.02 0.24±0.02** 0.19±0.01 0.15±0.01 <0.001

X5 (kPa/L/s) -0.09±0.01 -0.05±0.01** -0.02±0.00 -0.01±0.00 <0.001

R5i (kPa/L/s) 0.31±0.02 0.23±0.02** 0.19±0.01 0.14±0.01 <0.001

R5e (kPa/L/s) 0.34±0.02 0.26±0.02** 0.20±0.01 0.15±0.01 <0.001

X5i (kPa/L/s) -0.11±0.01 -0.05±0.01** -0.03±0.00 -0.01±0.00 <0.001

X5e (kPa/L/s) -0.08±0.01 -0.04±0.01** -0.02±0.00 -0.01±0.00 <0.001

R5i-R5e (kPa/L/s) -0.04±0.01 -0.02±0.01 -0.01±0.00 -0.01±0.00 0.01

X5i-X5e (kPa/L/s) -0.03±0.01 -0.01±0.01 -0.01±0.00 0.00±0.00 0.26

∆V (mL) 2.2±0.2 5.3±0.5** 8.8±0.9 14.4±0.9 <0.001

Impulse pressure (kPa) 0.45±0.02 0.42±0.01** 0.39±0.01 0.35±0.01 <0.001

COPD subjects (N=5)

Baseline 3.5 mm hole 6.0 mm hole 8.5 mm hole P

R5 (kPa/L/s) 0.50±0.04 0.41±0.04* 0.29±0.02 0.18±0.01 <0.001

X5 (kPa/L/s) -0.22±0.06 -0.11±0.03* -0.04±0.02 -0.01±0.01 <0.001

R5i (kPa/L/s) 0.39±0.03 0.34±0.03* 0.26±0.02 0.17±0.01 <0.001

R5e (kPa/L/s) 0.58±0.06 0.47±0.05* 0.31±0.03 0.19±0.00 <0.001

X5i (kPa/L/s) -0.15±0.02 -0.10±0.01** -0.04±0.01 -0.02±0.00 <0.001

X5e (kPa/L/s) -0.31±0.12 -0.13±0.04 -0.04±0.02 -0.01±0.00 0.006

R5i-R5e (kPa/L/s) -0.19±0.05 -0.13±0.05 -0.05±0.03 -0.02±0.00 0.002

X5i-X5e (kPa/L/s) 0.16±0.09 0.03±0.03 0.00±0.01 -0.01±0.00 0.07

∆V (mL) 2.4±0.7 5.0±1.6 7.7±1.6 14.8±1.9 <0.001

Impulse pressure (kPa) 0.48±0.02 0.46±0.02* 0.41±0.02 0.36±0.01 <0.001

R5-whole breath resistance at 5 Hz, X5-whole breath reactance at 5 Hz, R5i–inspiratory

resistance at 5 Hz, R5e–expiratory resistance at 5 Hz, X5i–inspiratory resistance at 5 Hz,

X5e–expiratory resistance at 5 Hz. ∆V–leakage volume on the expiratory phase of the

volume curve. Data are presented as mean±SEM. * indicates t-test p<0.05 and ** p<0.01

baseline vs. 3.5 mm, The P column is ANOVA results

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Figure legends

Figure 1. Volume/time tracings illustrating volume transients (∆V) only visible as

“indentations” synchronous with pressure pulses (P) particularly on the expiratory

limb during air leak (3.5 mm hole, panel B) but not at baseline (Panel A).

Figure 2. Tracings of respiratory volume (V) and airway resistance at 5 Hz (R5)

during a simultaneous visualization of the glottis during tidal breathing followed by

breath hold at total lung capacity (TLC) with total occlusion of the glottis (panel A),

relaxed glottis at TLC (Panel B) and during humming (Panel C). R5 is increased only

when the glottis area is reduced.

Figure 3. Effect of breath hold with a closed glottis compared to tidal breathing on

frequency dependence of Rrs and Xrs. The grey continuous lines indicate normal

resistance (upper panel) and reactance (lower panel) values

Figure 4. Effect of different holes sizes produced in the breathing filters to simulate

air leaks of increasing magnitude on respiratory resistance (R5) and reactance at 5

Hz (X5) in healthy subjects (•) and COPD patients (▲). (* = p<0.05). The grey

continuous lines indicate normal resistance (upper panel) and reactance (lower

panel) values

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22

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Panel B Panel A

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0 5 10 15 20 25 30 35 40

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0 Tidal breathing

Breathold at TLC

Frequency (Hz)

Xrs (kP

a/L/s)

Rrs (

kPa/L/s

)

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Basel ine

3. 5

m

m

6. 0

m

m

8. 5

m

m

- 0 . 3

- 0 . 2

- 0 . 1

- 0 . 0

0 . 1

0 . 2

0 . 3

0 . 4

0 . 5

0 . 6H e a l t h y

C O P D

* *

*

* *X5

(

kP

a/

L/

s)

R5

(

kP

a/

L/

s)

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Documents

Glottal aperture and buccal airflow leaks critically affect forced oscillometry measurements