Please wait. Loading...
 
Αποστολή σε φίλο
 
Negative Expiratory Pressure: a new diagnostic tool in chest medicine
ABSTRACT. The term expiratory flow limitation is used to indicate that maximal expiratory flow is achieved during tidal breathing and is characteristic of intrathoracic airflow obstruction. Despite the severe consequences of expiratory flow-limitation, the prevalence and clinical significance of this phenomenon have not been adequately studied in COPD, asthma, and patients with other pulmonary and non-pulmonary disease. The latter is due to the fact that the previously used method to detect expiratory flow-limitation, (i.e., the one proposed by Hyatt based on comparison of maximal to tidal expiratory flow-volume curve), has several methodological and theoretical deficiencies. Therefore, its use is no longer recommended. In order to overcome these difficulties, a more precise technique, namely the negative expiratory pressure (NEP) method, has been introduced. It essentially consists in applying negative pressure (-3 to -5 cmH2O) at the mouth during tidal expiration. The NEP method is based on the principle that in the absence of pre-existing flow limitation, the increase in pressure gradient between the alveoli and the airway opening caused by NEP should result in increased expiratory flow. By contrast, in flow-limited subjects application of NEP should not change the expiratory flow. The NEP technique has been applied and validated in mechanically ventilated ICU patients by concomitant determination of isovolume flow-pressure relationships. With this method the volume and time history of the control and test tidal expiration are the same. Application of NEP is not associated with any unpleasant sensation, cough, or other side effects. This method does not require patient’s collaboration, performance of FVC manoeuvres or use of a body plethysmograph. It can be used apart from spontaneous breathing subjects in any body position, during exercise, and in ICU settings. This new tool may provide new insights in the physiology and patho-physiology of several diseases and the symptom of dyspnoea. Pneumon 2002, 15(3):254-262.

The term expiratory flow limitation (FL) is used to indicate that maximal expiratory flow is achieved during tidal breathing and is characteristic of intrathoracic airflow compression and obstruction. It should be noted that some experts use the term chronic airflow limitation as a synonym for COPD to indicate the reduction in maximum expiratory flow that occurs in this disease (and indeed in other pulmonary diseases); the latter term does not imply that expiratory flow limitation actually occurs during tidal breathing1-3.

The presence of expiratory FL during tidal breathing promotes dynamic pulmonary hyperinflation and intrinsic positive end-expiratory pressure (PEEPi), with concomitant increase of work of breathing, impairment of inspiratory muscle function, and adverse effects on haemodynamics. This together with flow-limiting dynamic airway compression during tidal breathing may contribute to dyspnoea4,5. Despite the severe consequences of FL, the prevalence and clinical significance of this phenomenon have not been adequately studied in COPD, asthma, and patients with other pulmonary and non-pulmonary disease.

The demonstration of expiratory flow limitation requires, by definition, the demonstration of an increase in transpulmonary pressure with no increase in expiratory flow. Therefore, direct assessment of expiratory FL requires determination of isovolume relationships between flow and trans-pulmonary pressure (V'-P), an approach that is the gold standard. However, this method is technically complex, time consuming and invasive, because it requires the passage of an oesophageal balloon6.

In practice, the conventional method used to detect expiratory flow-limitation during tidal breathing is the one proposed by Hyatt3, in 1961. It consists in correctly placing a flow-volume loop (V'-V) of a tidal breath within a maximum flow-volume curve. This analysis has been the kernel for understanding respiratory dynamics. Flow-limitation is not present when the patient breaths lower than the maximal expiratory flow-volume (MEFV) curve. According to this technique, normal subjects may not reach flow-limitation even at maximum exercise. In contrast, FL is present when a patient breathes tidally along or higher than the MEFV curves. It has long been suggested that patients with severe chronic obstructive pulmonary disease (COPD) may exhibit FL even at rest, as reflected by the fact that they breathe tidally along or above their maximal flow-volume curve1-6. However, the conventional method to detect flow-limitation based on comparison of maximal and tidal expiratory flow-volume curves has several methodological deficiencies. These include: a) thoracic gas compression artifacts. To minimize such errors, volume should be measured with a body plethysmograph, instead of using, as it is common practice, a pneumotachograph or a spirometer7. The corollary of this is that in practice flow-limitation may be assessed only in seated subjects at rest; b) incorrect alignment of tidal and maximal expiratory -V curves. Such alignment is usually made considering the total lung capacity (TLC) as a fixed reference point. This assumption may not always be valid8,9; c) effect of previous volume and time history. Since the previous volume and time history of a spontaneous tidal breath is necessarily different from that of an FVC manoeuvre, it is axiomatic that comparison of tidal with maximal -V curves is problematic. In fact, there is not a single maximal -V curve but rather a family of different curves, which depend on the time-course of the inspiration preceding the FVC manoeuvre10-12. Therefore, comparison of tidal and maximal -V curves is incorrect; d) respiratory mechanics and time constant inequalities are different during the tidal and maximal expiratory efforts also making comparisons of the two -V curves problematic13-15; e) exercise may result in bronchodilation or bronchoconstriction and other changes of lung mechanics, which may also affect correct comparisons of the two -V curves16; f) patient's cooperation. Another important limitation of the conventional method and performance of IC manoeuvres during exercise is that it requires patient's cooperation. This is not always feasible8,9.

From the above considerations it appears that detection of expiratory flow-limitation based on comparison of tidal with maximal -V curves is not valid even when a body-box is used. In fact, this has been clearly demonstrated in several studies17-20. As a result, the use of the conventional method is no longer recommended.

Recently, in order to overcome these technical and conceptual difficulties, a more reliable technique, namely the negative expiratory pressure or NEP method has been introduced17-20 (Figure 1). The NEP technique has been applied and validated in mechanically ventilated ICU patients by concomitant determination of isovolume flow- pressure relationships18 (Figure 2). This method does not require performance of FVC manoeuvres, collaboration on the part of the patient or use of a body plethysmograph, and can be used apart from spontaneous breathing subjects in any body position21, during exercise19 and ICU setting 18,22,23. With this method the volume and time history of the control and test expiration are the same.

Figure 2. Expiratory iso-volume flow-pressure relationships under control conditions and during test breaths with different methods to assess flow-limitation in two mechanically ventilated patients. NEP 10: negative expiratory pressure of –10 cmH2O; NEP 5: negative expiratory pressure of -5 cmH2O; ATM: expiration into atmosphere; )R1 and )R2: expiration with added expiratory resistance; Pst, rs: static pressure of respiratory system during lung deflation. Upper panel: A representative non flow-limited patient (NFL), as indicated with the increase in flow with NEP and ATM compared with control. Lower panel: A representative flow-limited (FL) patient, as indicated by unchanged expiratory flow and ATM compared with control (from ref 18).

Figure 1 depicts the experimental set-up used to assess expiratory FL. A flanged plastic mouthpiece is connected in series to a pneumotachograph and a T-tube. One side of the T-tube is open to the atmosphere, whilst the other side is equipped with a one-way pneumatic valve, which allows for the subject to be rapidly switched to negative pressure generated by a vacuum cleaner or a Ventouri device. The pneumatic valve consists of an inflatable balloon connected to a gas cylinder filled with helium and a manual pneumatic controller. The latter permits remote-control balloon deflation, which is accomplished quickly (30-60 ms) and quietly, allowing rapid exposure to negative pressure during expiration (NEP). Alternatively, a rapid solenoid valve can be used. The NEP (usually set at about -3 to -5 cmH2O) can be adjusted with a potentiometer on the vacuum cleaner or by controlling the Ventouri device. Airflow () is measured with the heated pneumotachograph and pressure at the airway opening (Pao) is simultaneously measured through a side port on the mouthpiece. Volume (V) is obtained by numerical integration of the flow signal17-20.

The NEP method is based on the principle that in the absence of pre-existing FL, the increase in pressure gradient between the alveoli and the airway opening caused by NEP should result in increased expiratory flow. By contrast, in flow-limited subjects application of NEP should not change the expiratory flow. Our analysis essentially consists in comparing the expiratory -V curve obtained during a control breath with that obtained during the subsequent expiration in which NEP is applied17,18.

Subjects in whom application of NEP does not elicit an increase of flow during part or all of the tidal expiration (Figure 3; right) are considered flow-limited (FL). By contrast, subjects in whom flow increases with NEP throughout the entire tidal volume range (Figure 3; left) are considered as non flow-limited (NFL). If expiratory FL is present when NEP is applied, there is a transient increase of flow (spike), which mainly reflects sudden reduction in volume of the compliant oral and neck structures. To a lesser extent a small artefact due to common-mode rejection ratio of the system of measuring flow may also contribute to the flow transients17-19. Such spikes are useful markers of FL. The degree of FL can be assessed using three different FL indices: a) as a continuous variable expressed as %VT in both seated and supine positions17 (Figure 3); b) as a discrete variable in the form of three categories classification i.e., NFL both seated and supine; FL supine but not seated; FL both seated and supine17; and c) as discrete variable in the form of the five-categories classification20 (5-point FL score), which is shown in Table.

Figure 3. Flow-volume loops of test breaths and preceding control breaths of two representative bronchiectatic patients with different degrees of flow-limitation: not flow-limited (NFL) (left), flow-limited (FL) over less than 50% VT (right). Arrows indicate points at which NEP was applied and removed (from ref 38).

Application of NEP is not associated with any unpleasant sensation, cough, or other side effects17-20. However, there is a potential limitation of the NEP technique, which concerns normal snorers and patients with obstructive sleep apnoea syndromes (OSAS)24,25. A typical example is clearly illustrated in Figure 4. On the left (A), it shows a flow-volume loop obtained with NEP and preceding control tidal breath in a sitting snorer at rest. Arrows indicate the onset and end of NEP application (-5 cmH2O). With NEP expiratory flow shows a transient drop below control flow, reflecting a temporary increase in upper airway resistance. After this transient decrease in flow, expiratory flow with NEP exceeded control flow, showing there is no intrathoracic FL. On the right (B), same as in left but flow with NEP remained below control throughout expiration, reflecting prolonged increase in upper airway resistance. In this case, NEP test is not valid for assessing intrathoracic FL. However, this phenomenon is usually uncommon even in snorers. Furthermore, valid measurements may be obtained with repeated NEP tests using lower levels of NEP e.g., -3 cmH2O).

Figure 4. Flow-volume loops of obtained with NEP and preceding control tidal breath in two sitting representative snorers (A & B) at rest (from ref 24). For explanation see text.

 

Figure 5. Flow-volume curves obtained in a patient with COPD (FEV1: 45% pred) at rest and at two different levels of exercise, expressed as a fraction of maximal power output (max). Zero volume represents the end-expiratory lung volume (EELV) at rest. In each instance the flow-volume loops of two consecutive breathing cycles are shown: that of a test breath during which negative pressure (NEP) of -5 cmH2O was applied during expiration and that of the preceding control breath. NEP was applied during early expiration (first arrow) and maintained throughout expiration (second arrow). With NEP flow increased at rest but not during exercise, indicating that expiratory flow-limitation was present at both levels of exercise but not at rest. Also shown by dotted line is the expiratory flow-volume curve obtained during an FVC manoeuvre. With the latter test he would be classified as flow-limited at rest and during exercise (from ref 19).

Since its proposal the NEP technique has been applied to detect FL in several studies under different conditions, i.e., different body postures21, rest and exercise19,26, and in spontaneously breathing and mechanically ventilated subjects18,22,23.

Expiratory FL was determined during resting breathing in sitting and supine positions in 117 stable COPD patients. Although, on average, the patients who were experiencing FL when both seated and supine had lower FEV1 %pred than those who were not experiencing FL, there was a marked scatter of the data. Indeed, 60% of the NFL group had an FEV1 <49% pred, and was classified as having severe to very-severe airway obstruction. Thus, FEV1 is not a good predictor of tidal expiratory FL in COPD patients20.

Intuitively, one would expect patients with the most severe airway obstruction, as assessed with routine lung function measurements, to be the most dyspneic. However, some patients with severe airway obstruction are minimally symptomatic, whereas others with little objective dysfunction appear to be very dyspneic. In fact many studies have shown that the correlation between chronic dyspnoea and FEV1 is weak. In contrast, FL measured with the NEP technique is a much better predictor of chronic dyspnoea than FEV1 in COPD patients20. Furthermore, it is also shown that there is a high prevalence of orthopnoea in these patients27.

Therefore, it appears that in stable COPD patients there is a high prevalence of FL even when taking into account the severity of airways obstruction in terms of FEV1. Indeed, 48% of COPD patients were FL as compared with 15% of asthmatics at comparable FEV1 values17,20,27-29. This discrepancy between asthma and COPD may reflect lower elastic recoil in the latter condition.

In contrast with COPD patients, most asthmatics do not exhibit FL during resting breathing seated and/or supine28-31. During acute bronchoconstriction in asthma, FL can be absent because in these circumstances end-expiratory lung volume (EELV) is rapidly increased by enhanced braking of the inspiratory muscles during expiration, gas trapping due to premature small airway closure, reduction in size of the glottic aperture and narrowing of the intrathoracic airways, which both increase expiratory flow resistance, and often causes concomitant tachypnoea. Therefore, the development of FL in asthmatics is prevented to a large extent by the ensuing acute, progressive dynamic hyperinflation until very severe degree of bronchoconstriction and/or marked reduction of inspiratory capacity is attained.

Beyond COPD and asthma, we have demonstrated that FL at rest is present in the majority of patients with bilateral bronchiectasis32, and furthermore that resting FL determines the exercise performance in these patients33.

We studied the feasibility of using the NEP technique during exercise and assessed the implications of FL on exercise performance19,26 in both normal subjects and COPD patients. Figure 5 shows flow-volume curves of a COPD patient both at rest and two levels of exercise. With NEP, flow increased at rest, but not during exercise, indicating that expiratory FL was present at both levels of exercise but not at rest. With the conventional test, i.e., comparing the tidal flow-volume to the maximal flow-volume curve, this patient would be classified as flow-limited at rest and during exercise. This method has the great advantage that it allows for all the effects discussed earlier including bronchoconstriction or bronchodilation occurring during exercise. In this context, using the NEP test, Murciano et al were able to show that although that patients after single lung transplantation were not flow limited at rest, most of them become flow-limited during exercise26. Using the NEP application at rest and different intensities of exercise, we have also documented that although FL is uncommon during resting breathing in asthmatic patients, this is not the case during exercise. We have studied 20 asymptomatic mild asthmatics and we found that although only one single patient was flow-limited at rest, 13 patients develop FL at different stages of steady-state exercise (1/3, 2/3 or 90% of maximal power output)34.

We have also shown that NEP can be used to detect FL in mechanically ventilated patients18,22,23. In fact, at first, the NEP method has been applied and validated during mechanical ventilation in different body postures. It was found that almost all COPD patients who require mechanical ventilation are flow-limited over the entire range of tidal expiration ant that the supine posture promotes flow-limitation. It should be noted, that FL is reversed in lateral decubitus, and on hands and knees positions in spontaneous breathing COPD patients21. Other studies have shown that most patients with acute respiratory failure of pulmonary origin present tidal expiratory FL whilst the ones with acute respiratory failure of extra-pulmonary origin did not23. The same authors found that most ARDS patients exhibit expiratory FL probably associated with small airways closure and a concomitant PEEPi22. Therefore, the assessment of expiratory FL in mechanically ventilated patients could provide useful information concerning respiratory mechanics.

In the past, there was no on line method available to assess whether the flows during the FVC manoeuvres were maximal or not. Recently, however, a simple method to assess FVC performance has been developed35,36. It is based on a variation of the NEP technique, i.e., application of short NEP pulses of -10 cmH2O during the FVC manoeuvre. If the expiratory flow increases during the application of the NEP pulse, the expiratory flow is sub-maximal. In contrast, if flow does not increase with the negative pressure, expiratory FL has been reached. Thus, with this method it is possible to determine whether the maximal flows are low as a result of insufficient respiratory effort (e.g., weak respiratory muscles, lack of coordination, malingering) or the presence of a lung disorder.

In summary, the NEP technique has been used clinically in studies with: a) COPD (during mechanical ventilation and exercise, correlation with dyspnoea, orthopnoea, and other lung function indexes, before and after bronchodilatation, various postures)17-21,27,28,37-39, b) asthma (stable asthma, during methacholine bronchocostriction, and during exercise)29-31,34, c) cystic fibrosis40 and bronchiectasis32,33, d) restrictive lung disease39, e) obesity41,42, f) mechanically ventilated with acute respiratory failure and ARDS18,22,23, g) left heart failure43, h) after single lung transplantation26.

In conclusion: a) application of the NEP technique provides a simple, rapid, non-invasive, and reliable test to detect tidal expiratory FL44,45; b) it does not require a body-box or any cooperation on the patient's part; c) it can be applied in any body position, during mechanical ventilation, and during exercise; d) it may provide new insights in the physiology and patho-physiology of several diseases and the symptom of dyspnoea.

References

  1.  Pride NB. Tests of forced expiration and inspiration. In: Hughes JMB & Pride NB (eds). Lung function tests: Physiological principles and clinical applications. London: WB Saunders 1999: p 3-25.

  2.  Leaver DG, Pride NB. Flow-volume curves and expiratory pressures during exercise in patients with chronic airways obstruction. Scan J Respir Dis 1971, 77(Suppl): 23-27.

  3.  Hyatt RE. The interrelationship of pressure, flow and volume during various respiratory maneuvers in normal and emphysematous patients. Am Rev Respir Dis 1961, 83: 676-683.

  4.  Pepe PE and Marini JJ. Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction: the auto-PEEP effect. Am Rev Respir Dis 1982, 126: 166-170.

  5.  O'Donnell DE, Sanii R, Anthonisen NR, Younes M. Effect of dynamic airway compression on breathing pattern and respiratory sensation in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1987, 135: 912-918.

  6.  Rodarte J. Invited editorial on "Detection of expiratory flow limitation during exercise in COPD patients". J Appl Physiol 1997, 82: 721-722.

  7.  Ingram RH Jr, and Schilder DP. Effect of gas compression on pulmonary pressure, flow, and volume relationship. J Appl Physiol 1966, 21: 1821-1826.

  8.  Stubbing DG, Pengelly LD, Morse JLC, and Jones NL.  Pulmonary mechanics during exercise in subjects with chronic airflow obstruction. J Appl Physiol 1980, 49: 511-515.

  9.  Younes M, Kivinen G. Respiratory mechanics and breathing pattern during and following maximal exercise. J Appl Physiol 1984, 57:1773-1782.

10.  D' Angelo E, Prandi E, Milic-Emili J. Dependence of maximal flow-volume curves on time-course of preceding inspiration. J Appl Physiol 1993, 75: 1155-9.

11.  D' Angelo E, Prandi E, Marrazzini L, Milic-Emili J. Dependence of maximal flow-volume curves on time course of preceding inspiration in patients with chronic obstructive lung disease. Am J Respir Crit Care Med 1994, 150: 1581-1586.

12.  Koulouris NG, Rapakoulias P, Rassidakis A, Dimitroulis J, Gaga M, Milic-Emili J, Jordanoglou J. Dependence of FVC manoeuvre on time course of preceding inspiration in patients with restrictive lung disease. Eur Respir J 1997, 10: 2366-2370.

13.  Melissinos CG, Webster P, Tien YK, Mead J. Time dependence of maximum flow as an index of nonuniform emptying. J Appl Physiol 1979, 47(5): 1043-1050.

14.  Fairshter RD. Airway hysteresis in normal subjects and individuals with chronic airflow obstruction. J Appl Physiol 1985, 58: 1505-1510.

15.  Wellman JJ, Brown R, Ingram RH Jr., Mead J, and McFadden ER. Effect of volume history on successive partial expiratory maneuvers. J Appl Physiol 1976, 41: 153-158.

16.  Beck KC, Offord KP, Scanlon PD. Bronchoconstriction occurring during exercise in asthmatic patients. Am J Respir Crit Care Med 1994, 149: 352-357.

17.  Koulouris NG, Valta P, Lavoie A, Corbeil C, Chassι M, Braidy J, and Milic-Emili J. A simple method to detect expiratory flow limitation during spontaneous breathing. Eur Respir J 1995, 8: 306-313.

18.  Valta P, Corbeil C, Lavoie A, Campodonico R, Koulouris N, Chassι M, Braidy J, and Milic-Emili J. Detection of expiratory flow limitation during mechanical ventilation. Am J Respir Crit Care Med 1994, 150: 1311-1317.

19.  Koulouris NG, Dimopoulou I, Valta P, Finkelstein R, Cosio MG, Milic-Emili J. Detection of expiratory flow limitation during exercise in COPD patients. J Appl Physiol 1997, 82: 723-731.

20.  Eltayara L, Becklake MR, Volta CA and Milic-Emili J. Relationship between chronic dyspnea and expiratory flow limitation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996, 154: 17260-1734.

21.  Dimitroulis J, Bisirtzoglou D, Retsou S, Latsi P, Vassilareas V, Koulouris NG, Jordanoglou J. Effect of posture on expiratory flow limitation in spontaneously breathing stable COPD patients. Am J Respir Crit Care Med 2001, 163(5): A410 (Abstract).

22.  Koutsoukou A, Armaganidis A, Stavrakaki-Kalergi C, Vassilakopoulos T, Lymberis A, Roussos Ch, Milic-Emili J. Expiratory flow limitation and intrinsic positive end-expiratory pressure at zero positive end-expiratory pressure in patients with adult respiratory distress syndrome. Am J Respir Crit Care Med 2000, 161: 1590-1596.

23.  Armaganidis A, Stavrakaki-Kalergi K, Koutsoukou A, Lymberis A, Milic-Emili J, Roussos Ch. Intrinsic positive end-expiratory pressure in mechanically ventilated patients with and without tidal expiratory flow limitation. Crit Care Med 2000, 28: 3837-3842.

24.  Tantucci C, Duguet A, Ferretti A, Mehiri S, Arnulf I, Zelter M, Similowski T, Derenne JP, Milic-Emili J. Effect of negative expiratory pressure on respiratory system flow resistance in awake snorers and nonsnorers. J Appl Physiol 1999, 87(3): 969-976.

25.  Liistro G, Veritier C, Dury M, Aubert G, Stanescu D. Expiratory flow limitation in awake sleep-disordered breathing subjects. Eur Respir J 1999, 14: 185-190.

26.  Murciano D, Ferretti A, Boczkowski J, Sleiman C, Fournier M, Milic-Emili J. Flow limitation and dynamic hyperinflation during exercise in COPD patients after single lung transplantation. Chest 2000, 118: 1248-1254.

27.  Eltayara L, Ghezzo H, Milic-Emili J. Orthopnea and tidal expiratory flow limitation in patients with stable COPD. Chest 2001, 119: 99-104.

28.  Tantucci C, Duguet A, Similowski T, Zelter M, Derenne JP, Milic-Emili J. Effect of salbutamol on dynamic hyperinflation in chronic obstructive pulmonary disease patients. Eur Respir J 1998, 12: 799-804.

29.  Boczkowski J, Murciano D, Pichot M-H, Ferretti A, Pariente R, Milic-Emili J. Expiratory flow limitation in stable asthmatic patients during resting breathing. Am J Respir Crit Care Med 1997, 156: 752-757.

30.  Tantucci C, Ellaffi M, Duguet A, Zelter M, Similowski T, Derenne J-P, Milic-Emili J. Dynamic hyperinflation and flow limitation during methacholine-induced bronchoconstriction in asthma. Eur Respir J 1999, 14: 295-301.

31.  Sulc J, Volta CA, Ploysongsang Y, Eltayara L, Olivenstein R, Milic-Emili J. Flow limitation and dyspnoea in healthy supine subjects during methacholine challenge. Eur Respir J 1999, 14: 1326-1331.

32.  Koulouris NG, Retsou S, Kosmas E, Dimakou K, Malagari A, Matzikopoulos G, Koutsoukou A, Milic-Emili J, Jordanoglou J. Tidal expiratory flow limitation, dyspnoea and exercise capacity in patients with bilateral bronchiectasis. Eur Respir J (submitted).

33.  Kosmas EN, Retsou S, Koulouris NG, Papadima K, Malagari A, Dimakou K, Milic-Emili J, Jordanoglou JB. Exercise capacity in patients with bilateral diffuse bronchiectasis. Eur Respir J 2001, 18(33): 83s

34.  Polychronaki A, Kosmas EN, Retsou S, Dimitroulis I, Gaga M, Orphanidou D, Milic-Emili J, Koulouris NG. Exercise-induced expiratory flow limitation and exercise capacity in patients with bronchial asthma (presented in the 12th ERS Annual Congress 2002).

35.  Volta CA, Ploysongsang Y, Eltayara L, Sulc J, Milic-Emili J. A simple method to monitor performance of forced vital capacity. J Appl Physiol 1996, 80: 693-8.

36.  Jones MH, Davies SD, Kisling JA, Howard JM, Castile R, Tepper RS. Flow limitation in infants assessed by negative expiratory pressure. Am J Respir Crit Care Med 2000, 161: 713-717.

37.  Diaz O, Villafranca C, Ghezzo H, Borzone G, Leiva A, Milic-Emili J, Lisboa C. Role of inspiratory capacity on exercise tolerance in COPD patients with and without tidal expiratory flow limitation at rest. Eur Respir J 2000, 16: 269-275

38.  Diaz O, Villafranca C, Ghezzo H, Borzone G, Leiva A, Milic-Emili J, Lisboa C. Breathing pattern and gas exchange at peak exercise in COPD patients with and without tidal expiratory flow limitation at rest. Eur Respir J 2001, 17: 1120-1127

39.  Baydur A, Milic-Emili J. Expiratory flow limitation during spontaneous breathing. Comparison of patients with restrictive and obstructive respiratory disorders. Chest 1997, 112: 1017-23.

40.  Braggion C, Polese G, Fenzi V, Carli MV, Pradal U, Milic-Emili J. Detection of tidal expiratory flow limitation in infants with cystic fibrosis. Pediatric Pulmonology 1998, 25(3): 213-215.

41.  Pankow W, Podszus T, Gutheil T, Penzel T, Peter JH, Von Wichert P. Expiratory flow limitation and intrinsic positive end-expiratory pressure in obesity. J Appl Physiol 1998, 85: 1236-1243.

42.  Ferretti A, Gaimpiccolo P, Cavalli A, Milic-Emili J, Tantucci C. Expiratory flow limitation and orthopnea in massively obese subjects. Chest 2001, 119: 1401-1408.

43.  Duguet A, Taantucci C, Lozinguez O, Isnard R, Thomas D, Zelter M, Derenne JP, Milic-Emili J, Similowski T. Expiratory flow limitation as a determinant of orthopnea in acute left heart failure. J Am Coll Cardiol 2000, 35: 690-700.

44.  Milic-Emili J, Koulouris NG, D'Angelo E. Spirometry and flow-volume loops. Eur Respir Mon 1999, 12: 20-32.

45.  Johnson BD, Beck KC, Zeballos RJ, Weisman IM. Advances in pulmonary laboratory testing. Chest 1999, 116: 1377-1387.

© 2011 PNEUMON Magazine, Hellenic Bronchologic Society.
Developed by LogicONE Logo LogicONE