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(Chest. 2005;128:2159-2165.)
© 2005 American College of Chest Physicians

A New Method of Negative Expiratory Pressure Test Analysis Detecting Upper Airway Flow Limitation To Reveal Obstructive Sleep Apnea*

Giuseppe Insalaco, MD; Salvatore Romano, MSc; Oreste Marrone, MD; Adriana Salvaggio, MD and Giovanni Bonsignore, MD, FCCP

* From the Italian National Research Council, Institute of Biomedicine and Molecular Immunology "A. Monroy," Section of Respiratory Pathophysiology, Palermo, Italy.

Correspondence to: Giuseppe Insalaco, MD, Italian National Research Council, Institute of Biomedicine and Molecular Immunology "A. Monroy," Section of Respiratory Pathophysiology, Via Ugo La Malfa, 153–90146 Palermo, Italy; e-mail: insalaco{at}ibim.cnr.it


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Expiratory flow limitation (EFL) by negative expiratory pressure (NEP) testing, quantified as the expiratory flow-limited part of the flow-volume curve, may be influenced by airway obstruction of intrathoracic and extrathoracic origins. NEP application during tidal expiration immediately determines a rise in expiratory flow () followed by a short-lasting drop ({Delta}), reflecting upper airway collapsibility.

Purpose: This study investigated if a new NEP test analysis on the transient expiratory {Delta} after NEP application for detection of upper airway limitation is able to identify obstructive sleep apnea (OSA) subjects and its severity.

Methods: Thirty-seven male subjects (mean ± SD age, 46 ± 11years; mean body mass index [BMI], 34 ± 7 kg/m2) with suspected OSA and with normal spirometric values underwent nocturnal polysomnography and diurnal NEP testing at – 5 cm H2O and – 10 cm H2O in sitting and supine positions.

Results: {Delta} (percentage of the peak [%peak]) was better correlated to apnea-hypopnea index (AHI) than the EFL measured as , during NEP application, equal or inferior to the corresponding during control (EFL), and expressed as percentage of control tidal volume (%VT). AHI values were always high (> 44 events/h) in subjects with BMI > 35 kg/m2, while they were very scattered (range, 0.5 to 103.5 events/h) in subjects with BMI < 35 kg/m2. In these subjects, AHI still correlated to {Delta} (%peak) in both sitting and supine positions at both NEP pressures.

Conclusions: OSA severity is better related to {Delta} (%peak) than EFL (%VT) in subjects referred to sleep centers. {Delta} (%peak) can be a marker of OSA, and it is particularly useful in nonseverely obese subjects.

Key Words: expiratory flow limitation • extrathoracic airway obstruction • negative expiratory pressure • obesity • obstructive sleep apnea • upper airway collapse


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The obstructive sleep apnea (OSA) syndrome has important social implications related to accidents,1 cardiovascular risk,23 neuropsychological impairment,4 reduction in quality of life,5 and increased health-care utilization,67 so that its underrecognition may have important consequences. However, the diagnostic procedures are expensive, and predictive criteria are still unsatisfactory. Parameters of obesity are important predictors,8 but not all OSA patients are obese and not all obese subjects have OSA. Identification of new markers of OSA would be useful. As increased upper airway collapsibility is one of the main determinants of OSA,910 the response to negative expiratory pressure (NEP) application11 could be a predictor of this disorder.

The NEP test is performed by applying a negative pressure at the mouth during expiration.12 It is easy to perform and requires minimal subject cooperation. It is based on the principle that, in the absence of expiratory flow limitation (EFL), the increase in pressure gradient between the alveoli and the airway opening caused by NEP should result in increased expiratory flow. NEP was initially introduced as a test to evaluate intrathoracic EFL in patients with obstructive lung disease. These subjects are considered flow limited when NEP application does not elicit an increase in flow () during the terminal portion of the tidal expiration compared to the previous flow-volume loop.1213 More recently, NEP has also been applied to study upper airway properties in subjects with obesity and/or OSA.111415161718 It has been suggested that in the absence of intrathoracic airway obstruction, the response to NEP application may reflect upper airway collapsibility.11161718

So far, EFL in obese and OSA subjects has been quantified by the percentage of tidal expiration over which NEP does not induce any appreciable increase in with respect to the control expired tidal volume.111617 However, this method does not always discern if EFL is of extrathoracic or intrathoracic origins.111617 Alternative assessments of the effects of NEP application to detect upper airway obstruction could be useful. NEP application elicits a spike due mainly to a dynamic airway compression downstream from the compliant oral and neck structures, and to a small extent to common mode rejection ratio of the differential pressure transducer used to measure ,1319 followed by a drop ({Delta}) of variable degree among subjects. The sudden {Delta} is caused by an increase in resistance of the oropharyngeal structures,1819 reflecting upper airway collapsibility (extrathoracic EFL). The purpose of this study was to investigate if the transient expiratory {Delta} after NEP application is correlated to the presence and severity of OSA better than the EFL measurements previously used.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Thirty-seven male subjects referred to our sleep laboratory for suspected OSA syndrome after evaluation of spirometry to exclude subjects with bronchial obstruction were recruited for the study. Mean ± SD age was 46 ± 11 years, and mean body mass index (BMI) was 34 ± 7 kg/m2. None of the subjects had acute or known chronic cardiopulmonary or neuromuscular diseases. Each patient gave informed consent, and the study protocol was approved by the local scientific committee. All subjects underwent spirometry, nocturnal monitoring by a portable cardiorespiratory system, and NEP testing during tidal expiration.

Pulmonary function tests were performed during the day with the patient in a sitting position with a plethysmograph (Med Graphics Élite; Med Graphics Corporation; St. Paul, MN) according to the guidelines of the European Respiratory Society.20 Nocturnal monitoring was performed by a computerized system (Poly-MESAM; MAP; Martinsried, Germany). All recordings lasted > 6 h. was detected by nasal cannulas connected to a pressure transducer (Pneumoflow; MAP). Apneas and hypopneas were visually scored. Apneas were defined as lack of flow for at least 10 s. Hypopneas were defined as discernible reductions in or thoracoabdominal movements ≥ 10 s followed by an arterial oxygen saturation fall > 3%.21 Apnea-hypopnea index (AHI) was calculated as number of apneas plus hypopneas per hour of estimated total sleep time.

NEP was generated by a circular Venturi device (AeroMech Devices; Almonte, ON, Canada) attached to a tank of compressed air via an electrically operated solenoid valve. The solenoid valve had an opening time of 50 ms; it was automatically activated in early expiration and kept open for 2 s by software control (DirecWin version 2.18a; Raytech Instruments; Vancouver, BC, Canada). A pneumotachograph (model 3830; Hans Rudolph; Kansas City, MO) was connected to the mouthpiece. and mouth pressure were also measured (DirecNEP model 200A; Raytech Instruments). The changes in after application of NEP, inherent in our measuring set-up, were assessed by occluding the mouthpiece with a stopper and applying NEPs of – 5 cm H2O and – 10 cm H2O. As shown in Figure 1 , after application of NEP, there was an initial spike in that lasted approximately 20 ms and was followed by progressively decreasing oscillations that became very small after another 80 ms when became constant. Similar results were obtained with NEP of – 10 cm H2O, except that the magnitude of the spike increased. With NEP of – 5 cm H2O, the initial spike in corresponded to approximately 0.3 L/s, while with NEP of – 10 cm H2O it amounted to approximately 0.4 L/s. In both instances, however, the initial spikes were much smaller that those observed in our experimental subjects.



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  		Figure 1.. Comparison of flow signal behavior in a subject (upper trace) and in the experimental set-up with mouthpiece occluded by a stopper (lower trace) when applying NEP of – 5 cm H2O. Both signals have NEP application coincident.

 
In all subjects, NEP tests at – 5 cm H2O and – 10 cm H2O in sitting and supine positions were performed in a random order during quiet breathing with a nose clip. NEP was readministered after breathing pattern stabilization. For this purpose, at least four regular breaths were allowed between two consecutive NEP applications. During the test, care was taken to keep the neck in a neutral position and the subjects awake. The and mouth pressure signals were filtered through a low-pass filter and sampled at 200 Hz. Both digital signals were displayed in real-time on the computer screen and stored on computer for subsequent analysis. Data analysis was performed using software developed in our laboratory written in MATLAB 6.5 (The MathWorks; Natick, MA).

Data Analysis
A new method was assessed in this study to evaluate upper airway obstruction, ie, extrathoracic EFL was measured as {Delta} expressed as percentage of the peak (%peak) immediately after NEP application (Fig 2 ). The minimum was identified in the first 200 ms of NEP application to avoid reflex and voluntary reactions to NEP stimulus.22 We also assessed EFL induced by NEP as , in the flow-volume loop, during NEP application equal or inferior to the corresponding in any part of the control flow-volume loop (EFL), expressed as percentage of control tidal volume (%VT) [Fig 2] as previously performed.17 Values of EFL (%VT) and {Delta} (%peak) were the average of four measurements.



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  		Figure 2.. Measurement of flow limitation on superimposed flow-volume curve during quiet breathing and during NEP by flow limitation evaluated as {Delta} (%peak); and EFL measured as , in the flow-volume loop, during NEP application, equal or inferior to the corresponding flow during control (EFL) expressed as %VT.

 
Data are reported as mean ± SD and range. The values of {Delta} (%peak) and EFL (%VT) were linearly correlated to AHI. Statistical analysis was performed by commercial software (StatView; Abacus Concepts; Berkeley, CA). A p < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
All subjects had normal forced expiratory flow volume loops (FVC and FEV1 of 101 ± 12% of predicted and 100 ± 12% of predicted, respectively). Nocturnal monitoring showed an AHI of 51 ± 32 events/h in the whole population studied. Most subjects were obese (BMI range, 27 to 59 kg/m2), and 10 of them had BMI > 35 kg/m2. Table 1 shows anthropometric and respiratory characteristics of subjects with BMI < 35 kg/m2 and with BMI > 35 kg/m2.


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  		Table 1.. Anthropometric and Respiratory Data of Subjects According to BMI*

 
NEP application during tidal expiration produced an immediate peak followed by a sudden drop of variable degrees in all subjects. Examples of different shapes of flow-volume loops during NEP application of – 10 cm H2O in the supine position are shown in Figure 3 .



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  		Figure 3.. Examples of NEP tracing (– 10 cm H2O in the supine position). Observe how a 100% {Delta} (%peak) [top, left] is associated with a prolonged airway occlusion (top, right) and a low value of EFL expressed as %VT. Bottom, left, and bottom, right: a subject with OSA and a subject with a different {Delta}, respectively.

 
Figure 4 shows the scatter plots between AHI and EFL (%VT) during NEP applications of – 5 cm H2O and –10 cm H2O with subjects in the sitting and in the supine positions. Many subjects exhibited EFL (%VT) equal to 0, particularly in the sitting position (23 subjects and 12 subjects in the sitting position at – 5 cm H2O and – 10 cm H2O; 9 subjects and 6 subjects in the supine position at – 5 cm H2O and – 10 cm H2O, respectively). In both positions, AHI was not correlated with EFL (%VT) obtained at a NEP of – 5 cm H2O, while they were correlated to values measured at NEP of – 10 cm H2O.



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  		Figure 4.. Relationship between AHI and EFL, expressed as EFL %VT, with NEPs of – 5 cm H2O and – 10 cm H2O in the sitting and supine positions. Solid circles indicate subjects with BMI < 35 kg/m2; open circles indicate subjects with BMI > 35 kg/m2. NS = not significant.

 
The same analysis performed with {Delta} (%peak) showed stronger correlations with AHI at both pressures and in both positions (Fig 5 ). The best relationship between {Delta} (%peak) and AHI was obtained in the setting position at NEP of – 10 cm H2O.



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  		Figure 5.. Relationship between AHI and {Delta} expressed as %peak with NEPs of – 5 cm H2O and – 10 cm H2O in the sitting and supine positions. Solid circles indicate subjects with BMI < 35 kg/m2; open circles indicate subjects with BMI > 35 kg/m2.

 
In agreement with the well-known relationship between obesity and OSA, a significant correlation between AHI and BMI was found (R2 = 0.27; p < 0.001); however, a lower degree of dispersion was found in subjects with BMI > 35 kg/m2 (Fig 6 ). The patients with BMI < 35 kg/m2 did not show a significant correlation between AHI and BMI, while the group with BMI > 35 kg/m2 had a very close correlation (R2 = 0.77; p = 0.0008). AHI values were always high (> 44 events/h) in the more obese subjects, while they were very scattered (range, 0.5 to 103.5 events/h) in the subjects with BMI < 35 kg/m2.



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  		Figure 6.. Relationship between BMI and AHI. The dashed vertical line separates subjects with BMIs > 35 kg/m2 and < 35 kg/m2.

 
In the subjects with BMI < 35 kg/m2, the correlation between AHI and EFL (%VT) was present only at – 10 cm H2O in the sitting position (R2 = 0.16; p = 0.0396). Conversely, the correlation between AHI and {Delta} (%peak) was significant in all the tested conditions: at NEP of – 5 cm H2O in the sitting (R2 = 0.19; p = 0.0249) and supine (R2 = 0.17; p = 0.0315) positions; at NEP of – 10 cm H2O in the sitting (R2 = 0.22; p = 0.0136) and supine (R2 = 0.32; p = 0.0022) positions. Therefore, the supine position at NEP of – 10 cm H2O showed the best relationship between {Delta} (%peak) and AHI also in the group with BMI < 35 kg/m2 taken alone.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The main finding of the present study is that, to assess upper airway flow limitation in a population attending a sleep center for suspected OSA, the NEP test is more usefully evaluated by {Delta} (%peak) than by EFL (%VT). In fact, {Delta} (%peak) was better correlated to AHI than EFL (%VT). In addition, {Delta} (%peak) was always correlated with AHI in the group with BMI < 35 kg/m2, while EFL (%VT) showed some correlations with AHI, mostly when severely obese patients were included. Thus, {Delta} (%peak) is superior to evaluate risk for OSA than EFL (%VT).

It has been recognized that EFL (%VT) cannot always distinguish between extrathoracic and intrathoracic flow limitation,111617 and hence cannot be clearly interpreted in OSA subjects with obstructive pulmonary disease or with other causes of intrathoracic flow limitation. Conversely, the {Delta} (%peak) may also be applied to subjects with both airway obstruction and increased upper airway collapsibility since it mainly reflects upper airway behavior. In this study, other important limitations of the EFL (%VT) test to detect upper airway collapsibility have been found. Despite EFL (%VT) measured after NEP of – 10 cm H2O being significantly correlated to AHI, low EFL (%VT) values were associated with a wide range of AHI. As shown in Figure 3, EFL (%VT) may be low even when complete upper airway occlusion occurs, as clearly demonstrated by the flow-time curve; in other cases, a partial airway obstruction is not detected at all by EFL (%VT) since the NEP curve never falls to the reference flow-volume loop.

It has been suggested that the sharp transient decrease in shortly after NEP application is not related to lower airway obstruction, and it may reflect a temporary increase in upper airway resistance,121518 independent of any voluntary or reflex upper airway muscle activation. In fact, NEP is applied at the beginning of tidal expiration, and the {Delta} is detected in the first 200 ms, before any voluntary or reflex muscular activation could actively influence upper airway patency: Tantucci et al22 have shown that during application of NEP, a reflex response of the genioglossus muscle, a major upper airway dilator muscle, is elicited much more commonly at the end rather than at the onset of expiration. Once the transient {Delta} has been reversed, likely by the reflex activation of upper airway muscles, the subsequent behavior may be representative of lower airway properties.

Epidemiologic studies232425 have shown that 40 to 98% of morbidly obese male subjects are affected by OSA. The data of this study, on a small sample of severely obese subjects referred to our sleep center, show that BMI alone is a good marker of OSA. By contrast, in moderately obese or normal-weight subjects, only {Delta} (%peak) measured after NEP application was always correlated to AHI. Therefore, the NEP test could prove particularly useful as a marker of OSA in nonseverely obese subjects.

In conclusion, the finding of a high {Delta} (%peak) value after NEP application during tidal expiration in patients with suspected OSA may reinforce the suspicion of OSA, while traditional analysis by EFL (%VT) gives much more approximate indications. {Delta} (%peak) in the supine position at NEP of – 10 cm H2O is the best indicator of OSA severity and may be of help particularly in nonseverely obese subjects. The NEP test is easy to apply and could be adopted as a screening test for the evaluation of suspected OSA patients if future analysis on larger samples of subjects shows high sensitivity and specificity of the {Delta} (%peak) for OSA.


   Acknowledgements
 
The authors wish to thank Dr. Pietro Abate for his help and Mr. Giovanni Sciortino for technical support.


   Footnotes
 
Abbreviations: AHI = apnea hypopnea index; BMI = body mass index; EFL = expiratory flow limitation; NEP = negative expiratory pressure; OSA = obstructive sleep apnea; = flow; {Delta} = flow drop; %peak = percentage of peak flow; %VT = percentage of control tidal volume

This study was supported by the Italian National Research Council.

Received for publication February 17, 2005. Accepted for publication March 21, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Sassoni, A, Findley, LJ, Kryger, M, et al (2004) Reducing motor-vehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. Sleep 27,453-458[ISI][Medline]
  2. Nieto, FJ, Young, TB, Lind, BK, et al Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study: Sleep Heart Health Study. JAMA 2000;12:283,1829-1836
  3. Peker, Y, Hedner, J, Kraiczi, H, et al Respiratory disturbance index: an independent predictor of mortality in coronary artery disease. Am J Respir Crit Care Med 2000;162,81-86[Abstract/Free Full Text]
  4. Kim, HC, Young, T, Matthews, CG, et al Sleep-disordered breathing and neuropsychological deficits: a population-based study. Am J Respir Crit Care Med 1997;156,1813-1819[Abstract/Free Full Text]
  5. Flemons, WW, Tsai, W Quality of life consequences of sleep-disordered breathing. J Allergy Clin Immunol 1997;99,S750-S756[CrossRef][ISI][Medline]
  6. Smith, R, Ronald, J, Delaive, K, et al What are obstructive sleep apnea patients being treated for prior to this diagnosis? Chest 2002;121,164-172[Abstract/Free Full Text]
  7. Otake, K, Delaive, K, Walld, R, et al Cardiovascular medication use in patients with undiagnosed obstructive sleep apnoea. Thorax 2002;57,417-422[Abstract/Free Full Text]
  8. Flemons, WW, McNicholas, WT Clinical prediction of the sleep apnea syndrome. Sleep Med Rev 1997;1,19-32[CrossRef][Medline]
  9. Gold, AR, Schwartz, AR The pharyngeal critical pressure: the whys and hows of using continuous positive pressure diagnostically. Chest 1996;110,1077-1088[Free Full Text]
  10. Fogel, RB, Malhotra, A, White, DP Sleep: II. Pathophysiology of obstructive sleep apnoea/hypopnoea syndrome. Thorax 2004;59,159-163[Abstract/Free Full Text]
  11. Van Meerhaeghe, A, Delpire, P, Stenuit, P, et al Operating characteristics of the negative expiratory pressure technique in predicting obstructive sleep apnoea syndrome in snoring patients. Thorax 2004;59,883-888[Abstract/Free Full Text]
  12. Valta, P, Corbeil, C, Lavoie, A, et al Detection of expiratory flow limitation during mechanical ventilation. Am J Respir Crit Care Med 1994;150,1311-1317[Abstract]
  13. Koulouris, NG, Valta, P, Lavoie, A, et al A simple method to detect expiratory flow limitation during spontaneous breathing. Eur Respir J 1995;8,306-313[Abstract]
  14. Pankow, W, Podszus, T, Gutheil, T, et al Expiratory flow limitation and intrinsic positive end-expiratory pressure in obesity. J Appl Physiol 1998;85,1236-1243[Abstract/Free Full Text]
  15. Ferretti, A, Giampiccolo, P, Cavalli, A, et al Expiratory flow limitation and orthopnea in massively obese subjects. Chest 2001;119,1401-1408[Abstract/Free Full Text]
  16. Liistro, G, Veriter, C, Dury, M, et al Expiratory flow-limitation in awake sleep-disordered breathing subjects. Eur Respir J 1999;14,185-190[Abstract]
  17. Verin, E, Tardif, C, Portier, F, et al Evidence for expiratory flow limitation of extrathoracic origin in patients with obstructive sleep apnoea. Thorax 2002;57,423-428[Abstract/Free Full Text]
  18. Baydur, A, Wilkinson, L, Mehdin, R, et al Extrathoracic expiratory flow limitation in obesity and obstructive and restrictive disorders. Chest 2004;125,98-105[Abstract/Free Full Text]
  19. Koulouris, NG, Dimopoulou, I, Valta, P, et al Detection of expiratory flow limitation during exercise in COPD patients. J Appl Physiol 1997;82,723-731[Abstract/Free Full Text]
  20. Quanjer, PH, Tammeling, GJ, Cotes, JE, et al Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official statement of the European Respiratory Society. Eur Respir J 1993;6,5-40[Medline]
  21. American Academy of Sleep Medicine Task Force Report.. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999;22,667-689[ISI][Medline]
  22. Tantucci, C, Mehiri, S, Duguet, A, et al Application of negative expiratory pressure during expiration and activity of genioglossus in humans. J Appl Physiol 1998;84,1076-1082[Abstract/Free Full Text]
  23. Vgontzas, AN, Tan, TL, Bixler, EO, et al Sleep apnea and sleep disruption in obese patients. Arch Intern Med 1994;154,1705-1711[Abstract]
  24. Resta, O, Foschino-Barbaro, MP, Legari, G, et al Sleep-related breathing disorders, loud snoring and excessive daytime sleepiness in obese subjects. Int J Obes Relat Metab Disord 2001;25,669-675[CrossRef][ISI][Medline]
  25. Valencia-Flores, M, Orea, A, Castano, VA, et al Prevalence of sleep apnea and electrocardiographic disturbances in morbidly obese patients. Obes Res 2000;8,262-269[ISI][Medline]




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