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Extrathoracic Expiratory Flow Limitation in Obesity and Obstructive and Restrictive Disorders^*

Effects of Increasing Negative Expiratory Pressure

^* From the Divisions of Pulmonary and Critical Care Medicine (Drs. Baydur and Mehdian and Mr. Wilkinson), and General Medicine (Dr. Bains), Keck School of Medicine, University of Southern California, Los Angeles, CA; and the Meakins-Christie Laboratories (Dr. Milic-Emili), McGill University, Montreal, QC, Canada.

Correspondence to: Ahmet Baydur, MD, FCCP, 2025 Zonal Ave, GNH 11-900, Los Angeles, CA 90033; e-mail: baydur{at}hsc.usc.edu

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: The negative expiratory pressure (NEP) technique is used to detect intrathoracic expiratory flow limitation (EFL) in patients with respiratory disorders. Application of NEP may result in a sustained decrease of flow below control as a result of upper airway collapse, which may invalidate interpretation of the test. This response to NEP is common in patients with obstructive sleep apnea syndrome (OSAS). The prevalence of this phenomenon, however, has not been studied in healthy subjects and patients with obstructive and restrictive disorders without OSAS.

Purpose: The purpose of this study was as follows: (1) to assess the effects of increasing NEP levels on upper airway patency, and (2) to determine the factors that predispose to intrathoracic flow limitation or upper airway collapse during NEP application in different postures in healthy nonobese and obese subjects, and in patients with obstructive and restrictive respiratory disorders.

Subjects: Fifty-six patients with obstructive airway disease (21 patients with COPD, 16 patients with simple chronic bronchitis, and 19 patients with asthma) were compared with 47 patients with restrictive respiratory disorders, 20 nonobese and healthy subjects, and 9 obese subjects (body mass index > 30) without a history of snoring or OSAS.

Methods: NEP at levels of 5 cm H₂O, 10 cm H₂O, and 15 cm H₂O were applied at the mouth immediately after the onset of tidal expiration while seated and supine. Intrathoracic EFL was defined as no change in expiratory flow over any portion of the immediately preceding control breath. Upper airway collapse or narrowing was detected when flows decreased below those of the control breath.

Results: Ten patients (18%) with obstructive airway disease (7 patients with COPD) exhibited EFL at NEP of 5 cm H₂O (4 patients were supine only, and 6 patients were both supine and sitting). No patient with restrictive disorders or healthy obese and nonobese subjects presented EFL at NEP of 5 cm H₂O. In almost all subgroups, both seated and supine, subjects exhibited a transient decrease of flow below control immediately after the application of NEP in occasional breaths. As NEP increased, the number of subjects who exhibited this response in occasional breaths declined, while the number of subjects who displayed this pattern in all breaths increased. Conversely, there were very few subjects in each subgroup who exhibited a sustained decrease in flow below control in occasional breaths at NEP at 5 cm H₂O, and only one healthy obese subject who displayed this response in all breaths in supine position only.

Conclusions: In general, an increase in NEP resulted in only rare instances of sustained decrease in flow below control in all breaths. While transient decreases in flow exhibited immediately after the onset of NEP in all breaths are common and become more prevalent as NEP is increased beyond 5 cm H₂O, there are only rare instances of sustained decrease in flow below control throughout expiration at all levels of NEP tested, indicating an appropriate upper airway dilator response that maintains patency. Thus, in subjects without OSAS, assessment of intrathoracic EFL with NEP is valid in almost all instances.

Key Words: chronic obstructive airway disease • expiratory flow limitation • extrathoracic airway obstruction • negative expiratory pressure • obesity • posture • restrictive lung disease • upper airway collapse

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The detection of tidal intrathoracic expiratory flow limitation (EFL), defined as lack of difference between tidal and maximal expiratory flows under the prevailing conditions, is important to the pathophysiologic understanding of various clinical manifestations in conditions including COPD,^{1 2 3 4} cardiac failure,⁵ asthma,⁶ lung transplantation,^{7 8} cystic fibrosis,⁹ and obesity.^{10 11} The introduction of the negative expiratory pressure (NEP) technique has simplified the assessment of EFL by obviating the use of body plethysmography¹² and active cooperation from the subject.^{1 2} The technique simply consists of the application of a negative pressure at the airway opening during tidal expiration. The ensuing flow-volume curve is then compared with that of the previous control expiration.^{1 2} The application of negative pressure at the airway opening should increase the expiratory driving pressure (ie, the pressure gradient between alveoli and airway opening) and, accordingly, should enhance the expiratory flow if the patient is not flow limited. In contrast, in the presence of EFL, the application of negative pressure should not change the expiratory flow. However, studying the changes in expiratory flow in response to a negative pressure applied at the airway opening, as opposed to the response to positive alveolar pressure, has one potential drawback: it can elicit collapse of the extrathoracic airway with a concurrent drop in expiratory flow below the previous control expiration. If this phenomenon entails the whole expiration, the assessment of intrathoracic EFL with NEP is no longer valid because in this case the decrease in flow reflects upper airway obstruction. Such a phenomenon is common in patients with obstructive sleep apnea syndrome (OSAS).^{13 14} Though it has been anecdotally observed also in subjects without OSAS, its prevalence is not known. Accordingly, in the present investigation we have studied the effects of various levels of NEP on expiratory flow in a large population of subjects with normal lungs and in patients with restrictive and obstructive respiratory disorders but no documented OSAS, with the specific aim of assessing the prevalence of NEP tests in which there was a drop in flow below control throughout expiration in response to NEP.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
A total of 139 subjects were recruited for the study. These included 47 patients with stable restrictive respiratory disorders (pulmonary fibrosis/interstitial lung disease [n = 23], neuromuscular disease [n = 4], pneumonia [n = 4], metastatic cancer [n = 3], primary lung cancer [n = 2], pleural effusion [n = 4], abdominal ascites [n = 4], and kyphoscoliosis [n = 3]); 56 stable patients with chronic airways obstruction (COPD [n = 21], simple chronic bronchitis [mucus hypersecretion, n = 16], and asthma [n = 19]); 20 subjects free of cardiorespiratory illness with body mass index [BMI] < 30; and 9 subjects free of cardiothoracic disease with BMI > 30. None of these 132 subjects had historical evidence of sleep disturbance, nocturnal apnea, hypersomnolence, upper airway abnormality, or lung resection. Five subjects (two subjects with chronic airways obstruction, two subjects with restrictive disorders, and one control subject) were excluded from the study because of technical reasons (see "Procedure and Data Analysis"). Two additional subjects (both with chronic airways obstruction) were excluded because of inability to complete the study due to fatigue. Diagnoses were based on clinical history and criteria defined by the American Thoracic Society.¹⁵ The cut-off point of FEV₁/FVC for COPD was 70%. Predicted values for FEV₁, FVC, and FEV₁/FVC were obtained from Schoenberg et al¹⁶ and for lung volume subdivisions from Crapo et al.¹⁷ Predicted values of single-breath diffusion capacity of the lung for carbon monoxide (DLCO) were from Cotes.¹⁸ The anthropometric characteristics and pulmonary function data for each group are given in Table 1 . Spirometry, lung volumes by helium-dilution technique, and single-breath DLCO were obtained with a Collins GS /PLUS or DSII/Plus system (Warren Collins; Braintree, MA). Each patient gave written informed consent, and the study protocol was approved by the institutional review board. A BMI of 25 to 30 was classified as overweight, and BMI 30 was classified as obese according to criteria defined by the World Health Organization.¹⁹

Procedure and Data Analysis
Subjects were studied seated upright on a comfortable examining table at least 2 h after eating or drinking coffee. They breathed room air through the equipment assembly with a nose clip on. Each subject underwent an initial 5- to 10-min trial run in order to become accustomed to the apparatus and procedure. The pneumotachogram was continuously monitored on the screen of the computer. After regular breathing was achieved, as monitored on the computer, data acquisition began.

The NEP was applied at 5 cm H₂O, 10 cm H₂O, and 15 cm H₂O (adjusted by the variac) in random order for a series of three to eight test breaths. Each test breath was followed by a 20- to 30-s period of regular breathing. These serial maneuvers were then repeated in the supine position on the examining table. While performing the testing, patients were watched closely for leaks at the mouthpiece. In addition, by monitoring the volume records over time on the computer screen, a closed system was ensured by the fact that after the NEP tests the end-expiratory lung volume returned to the pre-NEP level.²¹ Only those tests in which the end-expiratory lung volume returned to the baseline value were included in this study. In all subjects, the coefficient of variations for tidal volume were 8% and 11%, respectively, in seated and supine postures. These findings are similar to those previously found in normal subjects and patients with COPD.^{22 23}

All but 1 of the 132 patients in whom successful tests were performed at NEP of 5 cm H₂O were included in the analysis for EFL in both seated and supine postures. One healthy obese individual could not be evaluated in supine posture because of sustained decrease in flow below control in all breaths, but her seated data were included in the analysis. Five other subjects (two subjects with chronic airways obstruction, two subjects with restrictive disorders, and one control subject) were excluded because of leaks around the mouthpiece or in the breathing circuit. Two additional subjects were excluded because of fatigue.

Assessment of Flow Limitation
The expiratory flow-volume loops generated in seated and supine positions were compared by superimposition with those obtained during the immediately preceding breath. The volume signal was corrected for any offset based on the observation during quiet breathing that inspired and expired volumes of the preceding breath were identical.²⁴ After the application of NEP, the expiratory flow either increased above the control flow throughout expiration (Fig 1 , top left, a), reflecting the absence of intrathoracic EFL; did not change during part of or the entire expiration (Fig 1 , top right, c), reflecting presence of intrathoracic EFL; or decreased transiently (Fig 1 , bottom left, b) or throughout expiration (Fig 1 , bottom right, d), reflecting the presence of transient or sustained upper airway collapse,²⁵ respectively.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Flow-volume loops during a control breath followed by a test breath during which an NEP of 5 cm H2O was applied at the onset of, and maintained throughout expiration, in (top left, a) a seated healthy subject without flow limitation, (bottom left, b) a seated obese subject (BMI of 38) with flow limitation but with a transient decrease in flow below control shortly after the application of NEP, (top right, c) a supine patient with severe COPD with intrathoracic EFL during most of expiration, and (bottom right, d) a supine control subject with a sustained decrease of flow () below control throughout expiration with NEP, indicating upper airway collapse. Arrows indicate application of NEP. See text for details.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

Patients With Restrictive Disease
These patients presented with a reduction in FVC, FEV₁, FRC, total lung capacity (TLC), IC, and DLCO with FEV₁/FVC within normal limits, characteristic of restrictive disorders. None of these patients exhibited EFL in either position (Table 2) . With NEP of 5 cm H₂O, Table 3 shows that 19 patients (40%) with restrictive respiratory disorders had a transient decrease in flow below control in occasional breaths while seated; in 6 of these patients (13%), this phenomenon occurred on all tests performed at NEP of 5 cm H₂O (Table 3) . At NEP > 5 cm H₂O, however, the numbers of patients with the latter response increased. A similar response was found in supine posture. Table 4 shows that with NEP of 5 cm H₂O, three patients (all with interstitial lung disease) exhibited occasional breaths with sustained decrease in flow throughout expiration. Four different patients exhibited a sustained decrease in flow below control at NEP of 5 cm H₂O only in the supine position; their diagnoses included interstitial lung disease (n = 1), ascites and obesity (BMI 38) [n = 1], kyphoscoliosis (n = 1), and L1 paraplegia (n = 1). Another patient with interstitial lung disease, who exhibited occasional breaths with sustained decrease in flow below control at NEP of 5 cm H₂O while seated, also presented with this response at NEP of 15 cm H₂O in the sitting position (Table 4) .

Patients With Obstructive Airway Disease
Lung function variables for patients with COPD, chronic bronchitis, and asthma are shown in Table 1 . Most of the patients with obstructive airway disorders who exhibited EFL were those with COPD (7 of 10 patients) and exhibited among the lowest FEV₁ values in this group (mean, 29% predicted; range, 15 to 49% predicted) and FEV₁/FVC (mean, 48% predicted; range, 33 to 64% predicted); three subjects with COPD were flow limited in both postures (Table 2) . Only three asthmatics exhibited EFL, and only in the supine posture. Table 3 shows that most patients exhibited a transient decrease in flow below control in occasional NEP tests and that their numbers declined as NEP increased, while the number of subjects who exhibited transient flow below control in all breaths increased in a reciprocal manner. This pattern was common in the asthmatics in both postures, but less prevalent in patients with simple chronic bronchitis and COPD. Figure 1 , top right, c shows the effects of NEP of 5 cm H₂O in a patient with COPD in a supine posture. Note that in this patient, flow limitation is present during most of expiration, as evidenced by a small increase in flow only during the initial part of expiration.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The main findings of the present study in a heterogeneous population of subjects without a history of OSAS and snoring is that with NEP of 5 cm H₂O, only one supine obese subject exhibited a sustained decrease in flow below control on all NEP tests performed, and that such a response was present on occasional tests in 11% of the total population while seated and 6% while supine. This implies that in virtually all subjects without a history of OSAS or snoring, NEP < 5 cm H₂O can be used to assess intrathoracic EFL. In a few subjects, however, several NEP tests may be required.

Intrathoracic EFL
In line with previous studies,^{1 2} a high prevalence of tidal EFL was found primarily in patients with COPD (Table 2) . Seven of the 21 patients (33%) were flow limited seated and/or supine. These patients also exhibited among the lowest FEV₁ and FEV₁/FVC values of all subjects, as described by others.^{1 2} Similarly, in line with Boczkowski et al,⁶ EFL was found in only 3 of the 19 asthmatic patients (16%) and was confined to the supine position. In line with Baydur and Milic-Emili,²¹ EFL was found in none of the patients with restrictive disorders. Also in line with previous results, all normal nonobese subjects were without EFL both seated and supine. Similarly, the healthy obese subjects were without EFL despite including one patient with a BMI of 60. In healthy morbidly obese subjects (BMI > 40), EFL is common in the supine position.¹¹ However, most of our obese patients had a BMI < 40, and EFL in such patients is not common.

Transient Decrease in Expiratory Flow Below Control With NEP
With NEP of 5 cm H₂O, a transient reduction in flow below control (Fig 1 , bottom left, b), reflecting upper airway collapse,^{1 2 25} was present in occasional NEP breaths in approximately half of the subjects in each group, both seated and supine (Table 3) . In 21% of subjects, however, this phenomenon occurred in all tests with NEP of 5 cm H₂O. As NEP increased, the latter response was exhibited by an increasing number of subjects.

EFL
We found few subjects in each group who exhibited sustained decrease in flow below control in occasional tests at NEP of 5 cm H₂O (Table 4) . Only one healthy obese patient (BMI of 38) presented this response in all tests at NEP of 5 cm H₂O, and this was observed in the supine position. This implies that a collapse of the upper airway throughout expiration is rare in the non-OSAS population; hence, in such subjects the assessment of intrathoracic EFL with NEP of 5 cm H₂O is valid. Our results also support the contention of Verin et al¹⁴ that sustained upper airway collapse with NEP is confined only to patients with OSAS, and hence the NEP test could be used as a simple method for screening for OSAS. These authors assumed that none of their patients had intrathoracic EFL from COPD, on the basis of normal FEV₁/FVC ratios and lung volumes, and deduced that all of their cases of flow limitation were due to extrathoracic origin.

In addition, we found that the number of subjects in all subgroups exhibiting sustained decrease in flow below control in occasional breaths declined as NEP increased. This finding was in contrast to that of Verin et al,¹⁴ who found that in supine patients with OSAS the response to NEP of 5 cm H₂O and NEP of 10 cm H₂O was not significantly different. They did not, however, use NEP as high as 15 cm H₂O. In contrast, we did not observe a reciprocal increase in the number of subjects exhibiting this response in all breaths (Table 4) , indicating that subjects with upper airway collapse in occasional breaths were able to compensate with a pharyngeal dilator response as NEP increased.²⁷ Finally, in the few cases where this response was observed, the subjects differed with increasing NEP.

In a recent study, Liistro et al¹³ observed that in many seated subjects with OSAS, flow rates during NEP application were equal to or less than the immediately preceding tidal expiration (for most of its duration) during quiet breathing. This phenomenon was attributed to upper airway collapse. In another study, Pankow et al¹⁰ had at least two obese subjects who exhibited sustained decrease in expiratory flow decreasing below the corresponding control flow during NEP (subjects 3 and 7 as shown in Fig 2 of Pankow et al¹⁰ ). Tantucci et al²⁸ similarly demonstrated a paradoxical decrease in airway flow, especially in the supine position, induced by NEP in awake healthy snorers. While these authors included subjects whose NEP flows decreased below control as also exhibiting intrathoracic EFL, in fact the presence or absence of true intrathoracic EFL may have been masked in these examples. In our study, a sustained decrease in flow below control in all breaths at NEP of 5 cm H₂O was not observed in any subject while seated, nor in nonobese healthy subjects and patients with simple chronic bronchitis in either posture. It was even uncommon in the healthy obese subjects; only one of them exhibited such a phenomenon in the supine posture. None of our nine obese subjects gave a history of snoring or other features of OSAS, which is in contrast to 46% of the massively obese subjects (mean BMI of 51) of Ferretti et al.¹¹ The rare finding of NEP breaths exhibiting a sustained decrease in flow below control facilitated the classification of our subjects as EFL or non-EFL, even in obese subjects. Valid assessment of EFL could still be obtained in all cases with repeated breath tests at NEP of 5 cm H₂O. Transient decreases in flow below control, however, were observed much more frequently, a phenomenon reported by other authors^{2 25} and indicative of upper airway collapse or narrowing occurring briefly after the onset of NEP.

In summary, EFL during tidal breathing occurred in one fifth of subjects with obstructive airway disease at NEP of 5 cm H₂O, whereas EFL was observed in none of the subjects with restrictive respiratory disorders. EFL was observed in obstructive patients with the lowest mean FEV₁ and FEV₁/FVC values (primarily in those with COPD). In most subjects, following an initial decrease in flow below control shortly after the onset of NEP, indicating transient upper airway collapse, there was an increase in expiratory flow. There was a decline in the numbers of subjects whose flow transiently decreased below control in occasional breaths as NEP increased from 5 to 15 cm H₂O; subjects in whom a transient decrease in flow below control was observed in all breaths increased in a reciprocal fashion, indicating that early upper airway collapse occurred more consistently as NEP increased, but still enabling a valid evaluation of the NEP test. Sustained decreases in flow below control in occasional breaths were seen in a few subjects (25% in control subjects, 22% in healthy obese subjects) whose numbers declined as NEP increased, suggesting an increase in the pharyngeal dilator response. Thus, NEPs > 5 cm H₂O rarely result in sustained upper airway collapse or narrowing in all NEP breaths, even in supine obese subjects without a history of snoring or sleep apnea syndrome. Consistent upper airway flow limitation throughout expiration with NEP is rare; therefore, in a non-OSAS population NEP of 5 cm H₂O can be used to assess intrathoracic EFL.

	Acknowledgements

 
The authors thank Hilkat Aral for assisting with data processing, and Lisa A. Doumak and Minerva Castillo for assisting in preparation of the manuscript.

	Footnotes

 
Abbreviations: BMI = body mass index; DLCO = diffusion capacity of the lung for carbon monoxide; EFL = expiratory flow limitation; FRC = functional residual capacity; IC = inspiratory capacity; NEP = negative expiratory pressure; TLC = total lung capacity

Received for publication January 22, 2003. Accepted for publication July 28, 2003.

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TOP Abstract Introduction Materials and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Baydur, A. Articles by Milic-Emili, J. Search for Related Content PubMed PubMed Citation Articles by Baydur, A. Articles by Milic-Emili, J.