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The negative expiratory pressure (NEP) method was used to detect expiratory flow limitation at rest and at different exercise levels in 4 normal subjects and 14 patients with chronic obstructive pulmonary disease (COPD). This method does not require performance of forced expirations, nor does it require use of body plethysmography. It consists in applying negative pressure (-5 cmH2O) at the mouth during early expiration and comparing the flow-volume curve of the ensuing expiration with that of the preceding control breath. Subjects in whom application of NEP does not elicit an increase in flow during part or all of the tidal expiration are considered flow limited. The four normal subjects were not flow limited up to 90% of maximal exercise power output (Wmax). Five COPD patients were flow limited at rest, 9 were flow limited at one-third Wmax, and 12 were flow limited at two-thirds Wmax. Whereas in all patients who were flow limited at rest the maximal O2 uptake was below the normal limits, this was not the case in most of the other patients. In conclusion, NEP provides a rapid and reliable method to detect expiratory flow limitation at rest and during exercise.

Airflow limitation has two well-defined components, increased resistance, which is found predominantly in the small airways, and loss of elastic recoil. Small airways contribute to the increased resistance to flow by the narrowing of the airway lumen. Morphometric studies have shown that smokers have increased epithelial abnormalities, cellular inflammatory infiltrates in the airway wall, increased muscle and fibrosis, when compared with nonsmokers. Along with these anatomical changes, an increased percentage of airways < 400 microns in diameter is found. In addition to the measured changes, other nonmeasurable, dynamic events occur in the airways of smokers, which further decrease lumen diameter. There is ample evidence to show that the airways of smokers react to nonspecific stimuli by constricting, which results in increased resistance and decreased forced expiratory volume in one second (FEV1). The pathological changes found in smokers, that could be responsible for active muscle constriction and airway narrowing include: 1) airway epithelial damage, resulting in increased permeability and impairment of other epithelial function; 2) chronic airway inflammation; 3) structural changes in the airway wall; and 4) loss of alveolar attachments. However, not all smokers develop the abovementioned airway abnormalities. We describe how smokers could develop either centrilobular emphysema (CLE), or panlobular emphysema (PLE). We have found that smokers with CLE have more abnormal and narrower small airways, and flow limitation is correlated with the small airway abnormalities and not with loss of recoil. In contrast, smokers with PLE have much less severe airway abnormalities, diffuse emphysema that can be detected microscopically at a stage when FEV1 might be only mildly abnormal, and early changes in elastic recoil as evidenced by the changes in the pressure-volume curve of the lung. Furthermore, in PLE, airflow limitation is correlated with loss of recoil but not with abnormalities in the small airways. We believe that the mechanisms involved in the pathogenesis of the two types of emphysema in smokers are different; an airborne mechanism for CLE, possibly related to airway hyperresponsiveness, and a bloodborne mechanism for PLE, which may be related to dysfunction of alpha 1-antiproteases. We conclude that the separation of smokers based on their emphysema type is essential if we are to understand the pathogenesis of chronic obstructive pulmonary disease (COPD) in these subjects.

Abnormal contours of the flow-volume loop, ie, flow oscillations and inspiratory flow plateaux, have been noted in disorders affecting upper-airway muscular function. In this study, we assessed the incidence and the value of these contours as a test of bulbar and upper-airway muscular involvement in neuromuscular disease. We therefore compared flow-volume loops and pulmonary function test results between ten patients with (group 1) and 20 patients without (group 2) clinically apparent bulbar muscle involvement in neuromuscular disease. An abnormal flow-volume loop occurred significantly more often in group 1 than in group 2 (9/10 or 90 percent vs 3/20 or 15 percent, respectively; p less than 0.001) and predicted bulbar and upper-airway muscle involvement with high sensitivity (90 percent), specificity (85 percent) and efficiency (87 percent). Based on commonly used spirometric criteria, upper-airway obstruction was not more common in group 1 than in group 2 (1/10 vs 2/20); however, all three patients with upper-airway obstruction suggested by these criteria had an abnormal flow-volume loop. Following this study, three patients incurred severe respiratory complications. All three patients had previously shown an abnormal flow-volume loop. We conclude that in patients with neuromuscular disease, involvement of the bulbar and upper-airway muscles is frequently associated with an abnormal contour of the flow-volume loop. Recognition of flow oscillations or flow plateaux on flow-volume loops in these patients seems important, since they may be potential markers of severe respiratory complications.

Flow oscillations on flow-volume loops (a "saw-tooth" pattern) have been reported as a manifestation of obstructive sleep apnea (OSA), but the specificity of this flow-volume loop pattern has not been determined. In a review of 2800 flow-volume loops performed in our pulmonary function laboratory, we identified flow oscillations in 40 patients, an incidence of 1.43%. Thirty-one of these 40 patients (77%) did not have OSA. In 16 of these 31 patients (52%), a structural disorder of the upper airway or neurologic disease involving the upper airway muscles was found. Flow oscillations were associated with physiological upper airway obstruction (UAO) in 14 of these 40 patients (35%), but were the only physiological evidence of upper airway dysfunction in the other 26 patients. Flow oscillations on flow-volume loops thus represent nonspecifically instability of the upper airway, caused by a variety of disorders, including OSA. Detection of this peculiar flow-volume loop configuration should lead to investigation of the upper airway and the surrounding musculature as it might be an early indicator of ongoing disorders eventually leading to UAO.

To identify the site and cause of airflow limitation in patients with parkinsonism, we tested pulmonary function in 27 patients with extrapyramidal disorders. In 24 patients, an abnormal flow-volume loop contour, showing either regular (18 patients) or irregular (6 patients) flow oscillations, was found. On direct fiberoptic visualization of the upper airway, these oscillations corresponded to either rhythmic (4 to 8 Hz) or irregular involuntary movements of glottic and supraglottic structures. Ten patients had physiologic evidence of upper-airway obstruction, which was symptomatic in four. We conclude that the upper-airway musculature is frequently involved in extrapyramidal disorders. This causes upper-airway dysfunction that can be severe enough to limit airflow.

In 3 patients with chronic respiratory symptoms, we identified rapid flow oscillations on flow-time and flow-volume recordings, corresponding to fluttering of lax but otherwise normal-appearing upper airway structures at cinefluoroscopy and fiberoptic endoscopy. This entity of upper airway dysfunction was responsible for, or at least contributed to, the respiratory symptoms as evidenced by dramatic relief of dyspnea following tracheostomy in one patient, and significant improvement of flow rates following helium breathing in the other 2 patients. We suggest that identification of flow oscillations on flow recordings, in particular flow-volume loops, should lead to investigation of the upper airway. When fluttering is the only abnormality observed, it should not be disregarded, but rather considered as possibly contributing to airflow limitation.