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(Chest. 2003;124:1762-1767.)
© 2003 American College of Chest Physicians

Diagnostic Value of Negative Expiratory Pressure for Airway Hyperreactivity*

Ping-Huai Wang, MD; Ping-Hung Kuo, MD; Chia-Lin Hsu, MD; Huey-Dong Wu, MD, FCCP; Yu-Shein Chang, BS; Sow-Hsong Kuo, MD, FCCP and Pan-Chyr Yang, MD, PhD, FCCP

* From the Departments of Internal Medicine (Drs. P-H Kuo, Hsu, Wu, S-H Kuo, and Yang, and Miss Chang), National Taiwan University Hospital, Taipei; and The Department of Internal Medicine (Dr. Wang), Far Eastern Memorial Hospital, Taipei County, Taiwan.

Correspondence to: Ping-Hung Kuo, MD, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Rd, Taipei, Taiwan; e-mail: kph{at}ntumc.org


   Abstract
TOP
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Study objectives: To examine the value of negative expiratory pressure (NEP) in the assessment of methacholine bronchoprovocation testing (BPT).

Design: Prospective, observational study.

Setting: Pulmonary function laboratory in a university hospital.

Participants: Fifty-nine patients with chronic cough referred from outpatient clinics for methacholine BPT.

Methods: Each subject inhaled successive doubling concentrations of methacholine (from 0.049 to 25 mg/mL) until the FEV1 decreased for > 20% or the maximum concentration of methacholine was inhaled. NEP was measured in the sitting position during tidal breathing before and after methacholine BPT. The FEV1 and forced oscillation airway resistance (Rrs) and interrupter airway resistance (Rint) were also obtained simultaneously. A positive BPT result was defined as a fall in FEV1 >= 20%.

Result: At baseline, only five patients had expiratory flow limitation as demonstrated by NEP (EFL-N). There were 39 patients with positive BPT results, and the other 20 patients had negative results. Among the BPT-positive patients, only 13 patients (33.3%) had EFL-N after methacholine challenge. The sensitivity indexes (absolute change/SD) of FEV1, NEP, Rrs, and Rint were 16.0 ± 9.6%, 1.1 ± 1.6%, 3.8 ± 4.5%, and 5.89 ± 4.4% (mean ± SD), respectively. The percentage changes in FEV1 in BPT-positive patients correlated with the percentage changes in Rrs (r = 0.419, p = 0.008) and only marginally with the percentage changes in Rint (r = 0.307, p = 0.058), but not with the changes in EFL-N (r = 0.048, p = 0.77).

Conclusion: These data suggest that NEP at sitting position is not sensitive in the assessment of methacholine bronchoprovocation as compared to FEV1 and airway resistance measurements.

Key Words: forced oscillation technique • interrupter airway resistance • methacholine bronchoprovocation • negative expiratory pressure • spirometry


   Introduction
TOP
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Airway hyperresponsiveness (AHR), airway inflammation, and remodeling are key pathophysiologic components of bronchial asthma. AHR, an abnormal increase in airflow limitation following exposure to a stimulus, is present in almost all patients with clinically current asthma.1 Reducing AHR in conjunction with optimizing symptoms and lung function leads to more effective control of asthma while alleviating chronic airways inflammation.2 This implies a role for the monitoring of AHR in the long-term management of asthma.

For the assessment of AHR, FEV1 is the most commonly used lung function parameter during bronchoprovocation testing (BPT). Repeated measurements of FEV1, however, are strongly dependent on the cooperation of the patient, which is particularly difficult to achieve in elderly patients and young children. Therefore, alternative approaches to assess airflow limitation during bronchoprovocation have been developed, including body plethysmography, forced oscillation technique, interrupter method, etc.

Recently, Valta and colleagues3 suggested that applying the negative expiratory pressure (NEP) technique during tidal expiration was a simple and reliable method for assessing expiratory flow limitation. The feasibility and minimal cooperative requirement has been proven in measurement of children.4 This method consists of applying a preset negative pressure at the mouth or artificial airway throughout the whole expiration. In normal condition, NEP elicits increased expiratory flow. If the expiratory flow rate cannot increase even under the traction power of NEP, it is implied expiratory flow limitation as demonstrated by NEP (EFL-N) and the presence of abnormal airway resistance. So NEP is possible to assess dynamic bronchoconstriction and flow limitation induced by methacholine challenge as an alternative method of spirometry.

To our knowledge, only two previous studies5 6 applied NEP in the assessment of AHR, but the benefits of this method remains unclear. In the present study, we compared the value of NEP in the assessment of AHR with traditional spirometry and the other two alternative methods.


   Patients and Methods
TOP
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Subjects
This study enrolled 59 patients who were referred to the pulmonary function laboratory for methacholine bronchoprovocation at the National Taiwan University Hospital from February to May 2002. Most of these patients were chronic coughers or presented with symptoms suggestive of asthma, and all underwent bronchochallenge for the confirmation of AHR. All patients were in stable conditions and able to perform tidal breathing as well as traditional spirometry. The exclusion criteria included a baseline FEV1 < 1.0 L or FEV1 percentage of the predicted value (FEV1%) < 50%. All subjects gave full informed consents.

Study Design
Baseline Pulmonary Function Testing: Before testing, all patients were instructed to abstain from the use of inhaled bronchodilators, antihistamines, and xanthine-containing drugs or foods for at least 24 h. The spirometry was performed using a computerized spirometer (Masterscreen-PFT; Jaeger; Hoechberg, Germany), which met the American Thoracic Society standards.7 Subjects were instructed to perform the FVC maneuver in the sitting position at least three times, and the highest recorded values of FEV1 and FVC were taken for analysis.

After baseline spirometry, the interrupter airway resistance (Rint) and NEP were measured using the Superspiro system (Micromedical; Rochester, UK). Airflow was automatically interrupted by the interrupter device of this system during tidal expiration at peak expiratory flow. The interrupter valve was closed and held in approximately 100 ms. Airway resistance calculated automatically by the minimized computer was the ratio of the difference between preocclusion mouth pressure and alveolar pressure to preinterruption flow, implying (alveolar pressure - preocclusion mouth pressure)/preinterruption flow. Alveolar pressure was acquired by linear back-extrapolation to the pressure at the time of closure of the interrupter, using the two mean pressures of 30 ms (25 to 35 ms) and 70 ms (65 to 75 ms). Measurement of Rint was repeated five times for each patient to ensure repeatability and accuracy. The NEP tests shared the same transducer and mouthpiece with the Rint measurement. NEP was applied at -2 cm H2O at the beginning of expiration and maintained throughout the entire expiration. The flow-volume curve of NEP test breath was compared with the preceding expiration curve, which served as control. The computer would calculate automatically the percentage of the flow-volume curves overlapping between test breath and control breath, as the percentage of EFL-N. All tests were performed in an identical comfortable seated posture with clipping the nose and slightly extending the neck. In measuring Rint, subjects had to support their cheeks by their hands to minimize the influence of upper airway resistance.

Methacholine Inhalation Challenge: Methacholine inhalation challenge was carried out using the Model Astograph, Jupiter 21 (Chest; Tokyo, Japan). Increasing doubling concentrations of methacholine (from 0.049 to 25 mg/mL) were inhaled every 1 min by the dosimeter. Forced oscillation airway resistance (Rrs) was monitored continuously throughout the procedure. Measurement of FEV1 was repeated if the Rrs showed a tendency to increase, and/or new wheezing detected by auscultation after inhalating a certain dose of methacholine. The test was continued until the FEV1 had dropped by > 20% from the baseline level or the maximum concentration of 25 mg/mL had been administered. A positive methacholine BPT result was defined as a fall in FEV1 induced by methacholine for >= 20%. Throughout the procedure, oxygen saturation was continuously monitored by pulse oximetry. The test was also stopped if oxygen saturation was < 90%. Measurements of Rint and NEP were repeated immediately after posttest spirometry was performed. Aerosolized terbutaline was administered to each subject to relieve bronchoconstriction.

Statistical Analysis
All data were expressed as mean ± SEM unless otherwise stated. Statistical analysis was performed by SPSS software (SPSS; Chicago, IL). The within-subject reproducibility of each parameter was calculated as a coefficient of variation (CV) by expressing the SD of repeated measurements as a percentage of the mean. The sensitivity index (SI) was defined as the absolute change in multiples of the baseline SD. The paired Student t test was used for the comparison of data before and after methacholine inhalation challenge. Differences between subgroups were assessed using the independent Student t test. The relationship of data were examined by linear regression. Significance was taken as p < 0.05.


   Results
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
A total of 59 patients completed methacholine bronchoprovocation and were classified into two groups based on the results. Positive methacholine BPT results were present in 39 patients, while the other 20 subjects had negative results. The demographic and baseline pulmonary function data are shown in Table 1 . The reproducibility of spirometry met the criteria of American Thoracic Society recommendations. The differences between the best two measurements of FEV1 and FVC were 1.9 ± 0.03% and 1.6 ± 0.9% (mean ± SD), respectively.


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  		Table 1.. Demographic and Baseline Pulmonary Function Data*

 
According to treatment response and follow-up course, 34 patients in the BPT-positive group and 1 patient in the BPT-negative group received a diagnosis of asthma. Twenty-nine of these asthmatics (85.3%) had normal results of pulmonary function testing before BPT. Only five asthmatics (14.7%) had obstructive ventilatory defects (FEV1% < 75%) at baseline, and all had positive methacholine BPT results. The baseline FEV1% and FEV1/FVC percentage in the BPT-positive group were significantly lower than those in the BPT-negative group (p = 0.03 and 0.001, respectively). Baseline NEP showed that EFL-N was present in five patients (four patients in the BPT-positive group, and one patient in the BPT-negative group), but the FEV1% was > 80% in four of these five patients (80%).

In comparison with the baseline, methacholine bronchoprovocation resulted in significant changes in FVC percentage of predicted value (FVC%), FEV1%, Rint, and Rrs (all p < 0.001) [Table 2 ]. The percentage changes in FVC ({Delta}FVC%), percentage changes in FEV1 ({Delta}FEV1%), percentage changes in Rint ({Delta}Rint%), percentage changes in Rrs ({Delta}Rrs%), and the absolute changes in EFL-N ({Delta}EFL-N) after methacholine bronchoprovocation are shown in Figure 1 . There were significant differences in {Delta}FVC%, {Delta}FEV1%, {Delta}EFL-N, and {Delta}Rrs% between the BPT-positive and BPT-negative groups (p < 0.001, p < 0.001, p = 0.002, and p = 0.023, respectively). {Delta}Rint% in the BPT-positive group was only marginally higher than the BPT-negative group (p = 0.093). These data suggest the potential of these four methods to assess airway responsiveness.


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  		Table 2.. Pulmonary Function Parameters After Methacholine Bronchoprovocation*

 


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  		Figure 1.. Changes in pulmonary function parameters after methacholine bronchoprovocation; p values represent comparisons between BPT-positive (BPT[+]) and BPT-negative (BPT[-]) groups. *p < 0.05, **p < 0.001, #p = 0.093.

 
The {Delta}FEV1% was correlated significantly with {Delta}FVC%, {Delta}Rint%, and {Delta}Rrs% in the total study population (p < 0.001, p = 0.009, and p < 0.001, respectively). In the BPT-positive group, {Delta}FEV1% was better correlated with {Delta}Rrs% (p = 0.008) than with {Delta}Rint% (p = 0.058) [Fig 2 ]. However, the {Delta}EFL-N correlated poorly with {Delta}FEV1% in the BPT-positive group (p = 0.772). In the BPT-negative group, {Delta}FEV1% had no relationship with {Delta}Rint%, {Delta}EFL-N, and {Delta}Rrs%.



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  		Figure 2.. Relationships between the {Delta}FEV1% and changes in the other four pulmonary function parameters in BPT-positive patients. The {Delta}FEV1% correlates with {Delta}FVC% (top left, A), {Delta}Rrs% (top right, B), and {Delta}Rint% (bottom left, C) in the BPT-positive group but not with {Delta}EFL-N (bottom right, D).

 
Thirteen patients (33.3%) in the BPT-positive group and 1 patient (5%) in the BPT-negative group demonstrated dynamic EFL-N changes after methacholine bronchoprovocation. There were no differences in the {Delta}FVC%, {Delta}FEV1, {Delta}Rrs%, and {Delta}Rint% between subjects with and without dynamic EFL-N (Table 3 ). In subjects with dynamic EFL-N, the {Delta}EFL-N correlated with {Delta}FVC% and {Delta}FEV1% (p = 0.006 and p = 0.005, respectively), but not with {Delta}Rint% and {Delta}Rrs% (p = 0.595 and p = 0.831, respectively). Neither of the changes in the parameters acquired by the other three methods correlated with {Delta}EFL-N in patients without dynamic changes in EFL-N induced by methacholine challenge.


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  		Table 3.. Changes in Pulmonary Function Parameters in Subjects With and Without Variable Flow Limitation After Methacholine Bronchoprovocation*

 
Based on repetitive measurements before methacholine bronchoprovocation, the CVs in FVC, FEV1, Rint, and Rrs (mean ± SEM) were 2.0 ± 0.01%, 2.3 ± 0.9%, 16.8 ± 8.0%, and 15.0 ± 7.0%, respectively (Fig 3 ). The CV of NEP could not be calculated because the baseline EFL-N in the majority of subjects was zero. An SI based on the ratio of prechallenge variability over the absolute change after bronchochallenge was also used to compare the sensitivity of these four methods in the assessment of AHR (Fig 4 ). A high SI indicates good repeatability (low SD) and/or the great difference to determine whether there is induced bronchoconstriction (high absolute change). The ordering of SI (mean ± SEM) from high to low was FEV1, FVC, Rint, Rrs, and NEP (16.0 ± 9.6%, 9.9 ± 4.7%, 5.9 ± 4.4%, 3.8 ± 4.5%, and 1.1 ± 1.6%, respectively). The SI of NEP was calculated only from the 14 subjects with dynamic changes in EFL-N after methacholine challenge. The within-subject variability of NEP was almost equal to its absolute change after methacholine bronchoprovocation.



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  		Figure 3.. The CV of spirometry, Rint, and Rrs at baseline. The CV of FEV1 was the lowest among these three parameters. The CV of NEP could not be calculated because baseline EFL-N was zero.

 


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  		Figure 4.. The SI of pulmonary function parameters (mean ± SD). The NEP was associated with the lowest SI, suggesting its poor sensitivity in detecting methacholine bronchoprovocation.

 

   Discussion
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our results in this study demonstrated that application of the NEP technique at sitting position is an insensitive method to detect dynamic bronchoconstriction during methacholine inhalation challenge. These data might provide new insights into the limitations of various tidal-breathing methods in the assessment of airflow obstruction.

Boczkowski et al8 first proposed the possibility of using NEP in the assessment of AHR after demonstrating the reversibility of expiratory flow limitation by inhaled salbutamol in asthmatics. Later, it was found that most stable asthmatics failed to develop detectable expiratory flow limitation after methacholine challenge despite showing a fall in FEV1 > 20%.6 In addition, changes in FEV1% and EFL-N were poorly correlated during bronchodilator testing.9 10 In this study, EFL-N was present in only 13 BPT-positive patients (33.3%); this proportion was comparable to that (20%) reported by Tantucci et al.6 We also observed that some of the BPT-positive patients demonstrated a posttest flow-volume curve more closely to the pretest flow-volume curve, implying a decreased strength of incremental expiratory flow by NEP after methacholine inhalation. In subjects with dynamic changes in EFL-N after methacholine challenge, there was still a correlation between {Delta}FEV1% and {Delta}EFL-N. This indicates that the threshold for detecting AHR was probably higher for NEP than for FEV1 measurements.

One possibility of the poor correlation between FEV1 and NEP measurements in the assessment of methacholine bronchoprovocation was the difference in the respiratory patterns. Before the development of NEP, expiratory flow limitation was measured by illustrating the difference between forced expiratory and tidal expiratory flow rates.11 12 The spirometry, however, has some limitations in the measurement of expiratory flow limitation. Apart from thoracic gas compression as a result of FEV1 maneuver, airway resistance and maximal expiratory flow are also dependent on lung volume. It has been shown that the conventional method for assessing flow limitation may lead to erroneous conclusion as compared to tidal volume measurements as NEP.8

Each lung volume has its maximal expiratory flow rate; therefore, changes in FEV1 may represent changes in airflow limitation or lung volume. The proposed mechanisms of dynamic hyperinflation during asthma attack or bronchoprovocation include bronchoconstriction, persistent inspiratory muscle activation, and expiratory glottic closure.13 14 This might change the lung volume and further influence FEV1 in asthmatics. One previous study6 demonstrated that dynamic hyperinflation occurred before the development of EFL-N in asthmatics undergoing methacholine BPT. Another study9 showed that the decreased dynamic hyperinflation after bronchodilator testing in patients with COPD might reduce the sensitivity of EFL-N measurement. Hyperinflation might lead to a decrement in inspiratory lung volume and subsequently a decrement in FEV1 before the appearance of EFL-N. This may partly explain that FEV1 has a better sensitivity than NEP and the lack of correlation between changes in FEV1 and EFL-N.

The results of NEP measurements can be affected by body positions. For some patients with COPD, EFL-N was present only in the supine position.15 Moreover, concomitant EFL-N in both sitting and supine positions was present only in patients with severe airway obstruction.15 In the supine position, the functional residual volume is reduced, leading to a concomitant expiratory flow reserve limitation.8 15 16 Therefore, the degree of EFL-N may be less pronounced in the sitting position, which might account for the low sensitivity of NEP observed in this study. The sensitivity of NEP may improve if it is performed in both supine and sitting positions and before the measurement of FEV1.

Our results were also compatible with previous studies showing a poor ability of NEP in the quantification of airflow limitation. Hadcroft and Calverley10 found that NEP results were poorly reproducible during bronchodilator testing. Johnson et al11 showed that NEP was not able to precisely quantify the degree of expiratory flow limitation. There was some noise in the early stage of expiration due to several factors, such as spike of negative pressure, braking action of the inspiratory muscle, and reflexive narrowing of upper airway.11 These factors may influence the sensitivity of NEP measurement, though the EFL-N usually occurs in the late expiration.

In the current study, EFL-N did not show any correlation with Rint and Rrs. In contrast to patient with COPD and with similar levels of FEV1, expiratory flow limitation was rarely present in patients with stable asthma.4 9 15 This discrepancy might be explained by the differences in lung elastic recoil and airway collapsibility. In this study, the driving pressure of NEP was higher than those in tidal breathing of interrupter and forced oscillation methods. It might cause variable effects on airway resistance according to individual airway collapsibility.

In this study, each subject underwent NEP measurements after spirometry. It was suggested that EFL-N was completely reversed after a deep inspiratory maneuver in healthy subjects undergoing methacholine challenge.5 Previous studies,17 18 however, showed that the deep inspiration had a bronchoprotective effect on health subjects but not on asthmatics, and the protective durations of deep inspiration varied from 45 s to 2 min. Therefore, the influence of deep inspiration on NEP measurement in our study would be minimal, especially for asthmatics.

One advantage of NEP over FEV1 is that NEP may be able to differentiate obstructive lung diseases from restrictive lung diseases.19 Baydur and Milic-Emili19 suggested that EFL-N was seldom present in restrictive lung diseases; thereafter, NEP might provide additional information to traditional spirometry. Our data also indicate that interrupter and forced oscillation techniques are alternative methods to assess methacholine BPT using tidal breathing. These methods may be especially helpful in children and elderly patients who cannot perform the FVC maneuvers.

In summary, application of NEP at sitting position was an insensitive method of detecting FEV1 changes during methacholine inhalation challenge. Further studies are required to assess the diagnostic value of NEP applied in both supine and sitting positions and in subjects unable to perform forced expiratory maneuvers.


   Footnotes
 
Abbreviations: AHR = airway hyperresponsiveness; BPT = bronchoprovocation testing; CV = coefficient of variation; EFL-N = expiratory flow limitation as demonstrated by negative expiratory pressure; {Delta}EFL-N = absolute change in expiratory flow limitation as demonstrated by negative expiratory pressure; FEV1% = FEV1 percentage of the predicted value; {Delta}FEV1% = percentage change in FEV1 after methacholine bronchoprovocation; FVC% = FVC percentage of predicted; {Delta}FVC% = percentage change in FVC after methacholine bronchoprovocation; NEP = negative expiratory pressure; Rint = interrupter airway resistance; {Delta}Rint% = percentage change in interrupter airway resistance after methacholine bronchoprovocation; Rrs = forced oscillation airway resistance; {Delta}Rrs% = percentage change in forced oscillation airway resistance after methacholine bronchoprovocation; SI = sensitivity index; VC = vital capacity

Financial support for this study was provided by The National Taiwan University Hospital and the National Science Committee (Taiwan).

Received for publication January 8, 2003. Accepted for publication May 2, 2003.


   References
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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P. M. A. Calverley and N. G. Koulouris
Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology
Eur. Respir. J., January 1, 2005; 25(1): 186 - 199.
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