**2.2. EFL in restrictive respiratory disorders**

**2.1. EFL in chronic obstructive pulmonary disease (COPD) and asthma**

128 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

almost always in the supine posture (Baydur et al., 2004; Boczkowski et al., 1997).

ing intrathoracic EFL (see below).

Fifty years ago, Hyatt (1961) suggested that patients with severe COPD may exhibit expira‐ tory flow limitation (EFL) at rest. This phenomenon could be demonstrated by the finding that they breathed tidally along or above their maximal expiratory flow-volume curves. This pattern of tidal breathing leads to hyperinflation, increased work of breathing, impaired res‐ piratory muscle function, hemodynamic compromise (Gottfried, 1991), and dyspnea (El‐ tayara et al., 1996; O'Donell et al., 1987). A high prevalence of tidal EFL is found in patients with COPD (Baydur et al., 2004; Gottfried et al., 1991; Hyatt et al., 1961) (Figure 5). As many as one-third of patients were flow-limited in seated and supine postures in the report of Baydur et al. (2004). A smaller percentage of patients with asthma in remission exhibit EFL,

The NEP technique can be used to advantage in young children unable to perform forced expiratory volume maneuvers (Braggion et al., 1998; Goetghebeur et al., 2002; Jiřičkova et al., 2009; Jones et al., 2000; Tauber, et al., 2003). Goetghebeur et al [10] described EFL in chil‐ dren aged older than 12 years with cystic fibrosis. These patients exhibited markedly de‐ creased inspiratory capacity (IC) and forced expiratory volume at 1 sec (FEV1). The NEP technique has also been used to evaluate EFL in infants (Braggion et al., 1998; Jiřičkova et al., 2009; Jones et al., 2000). Jiřičkova et al. (2009), applying the NEP technique in newborns and pre-school children, found nearly half of their patients to be intrathoracically flow-limited. The same number of children, however, exhibited transient upper airway collapse (UAC). The authors did not specify, if in some children, the UAC may have obscured any underly‐

An advantage of using the NEP technique in the evaluation of intrathoracic EFL is the avoidance of variability in the forced expiratory vital capacity maneuver related to the pat‐ tern of inspiratory maneuver preceding forceful expiration. Fast inspiration followed imme‐ diately by forced expiration results in greater forced vital capacities (FVC) and peak expiratory flows (PEF) by generating higher elastic recoil; in contrast, performing a breath‐ hold between inspiration and expiration diminishes elastic recoil and results in lower FVC and PEF. This finding, observed in both in healthy volunteers (D'Angelo et al., 1993; Tzele‐ pis et al., 1997; Wanger et al., 1996) and patients (Braggion et al., 1996; D'Angelo et al., 1994; D'Angelo et al., 1996; Wanger et al., 1996), has been ascribed to the viscoelastic properties of the lung (D'Angelo et al., 1991) and to greater activation of expiratory muscles (Tzelepis et al., 1997) occurring with fast maneuvers. The NEP method also avoids underestimation of lung volumes during rapid expiratory maneuvers due to gas compression (Ingram & Schil‐ ler, 1966; Koulouris et al., 1995).The technique also avoids incorrect alignment of the tidal and maximal expiratory flow–volume curves. Such alignment is usually made considering the total lung capacity (TLC) as a fixed reference point, and this assumption may not always

The NEP technique has also been used to detect EFL during exercise (Koulouris et al., 1997). In normal young subjects, there is no evidence of EFL during submaximal exercise. By con‐ trast, most patients with COPD exhibit NEP-generated EFL during light exercise. These findings are in agreement with exercise studies employing conventional forced expiratory

be valid (Kosmas et al., 2004; Koulouris, 1997; Murciano et al., 2000).

In individuals with restrictive disorders (particularly those with infiltrative disorders, such as idiopathic pulmonary fibrosis) maximal expiratory flows are well preserved despite a marked decrease in lung volume (Bergofsky, 1995). Consequently, breathing occurs at low lung volumes (near residual volume) where maximal expiratory flows are relatively small. Furthermore, some patients with interstitial lung diseases exhibit a decrease in dynamic compliance with breathing frequency (Bergofsky, 1995; Fulmer et al., 1977). In some of these patients, including non-smokers, flow rates are reduced with respect to transpulmonary pressure (Fulmer et al., 1977; Gaultier et al., 1980; Murphy et al., 38). Baydur et al. (1997, 2004) did not find any patients with restrictive disorders who exhibited intrathotracic EFL in either body position. The absence of EFL can be attributed to the increase in elastic recoil associated with these disorders. Others, however, have described the presence of EFL in pa‐ tients with cardiac failure (Duguet et al., 2000), acute respiratory distress syndrome (Kout‐ soukou et al., 2000), and pleural effusions (Spyratos et al., 2007).

## **2.3. EFL in sleep apnea; differences in FL pattern from COPD and asthma as assessed by the NEP method**

The NEP technique has also been used to assess upper airway collapsibility in patients with OSA, in which EFL has been described as a transient or sustained decrease in expiratory flow (frequently below the control tidal expiratory flow) during application of NEP (Baydur et al., 2004; Liistro et al., 1999; Van Meerhaeghe et al., 2004; Verin et al., 2002) (Figure 7).

Factors that contribute to OSA include increase in upper airway compliance (Isono et al., 1997), less negative critical (or closing) pressure of the passive upper airways as compared to snorers and normal subjects (related to structural soft tissue and bony changes) (Liistro et al., 1990), and smaller upper airway lumens during wakefulness and sleep, and greater pharyngeal airway length in OSA patients (Brown et al., 1985). Dyspnea in obese individu‐ als is related to increased work of breathing related to decrease in FRC with resultant in‐ crease in intrathoracic EFL and intrinsic positive end-expiratory pressure, increased respiratory drive, and intermittent narrowing or collapse of the upper airway upon assum‐ ing the supine position (C.-K. Lin & C.-C. Lin, 2012).

**1.** EFL was expressed as percentage of the expired tidal volume over which the NEP-in‐ duced flow did not increase above the immediately preceding tidal expiratory flow (EFL%) (Baydur et al., 1997, 2004; Eltayara et al., 1996; Koulouris et al., 1995) for each

Expiratory Flow Limitation in Intra and Extrathoracic Respiratory Disorders…

http://dx.doi.org/10.5772/53270

131

**2.** The magnitude of the decrease in expiratory flow during NEP below the preceding con‐ trol expiratory curve was expressed as the percentage of the area under the control curve (AUC%, Figure 3), modified from the method of Tamisier et al. (2005). This value was expressed as the median of the same10 acceptable NEP breaths in each posture.

**3.** To further improve the discrimination between COPD and OSA, the ratio AUC% EFL% was computed as changes in EFL% and AUC% were not always of the same magnitude or direction. Thus, an increase AUC% EFL% would reflect a greater degree of upper air‐ way EFL rather than intrathoracic EFL, while a decrease with preservation of EFL% would be more consistent with intrathoracic EFL. This quantity was expressed as an ar‐ bitrary unit, as the median of the same 10 acceptable NEP breaths in each posture. This study was the first to quantitatively compare EFL in patients with COPD, non-OSA

**1.** COPD patients exhibited the highest EFL% in seated posture, consistent with intra‐ thoracic flow limitation. Percent EFL increased in all cohorts but COPD upon assuming

**2.** While seated, when compared to other cohorts, OSA patients exhibited a greater ten‐ dency to upper airway collapsibility as evidenced by higher AUC% and AUC/% EFL% values, although median values exhibited variability of individual values that prevent‐ ed differences between cohorts to be statistically significant. In supine posture, COPD

**3.** The AUC% method was able to only differentiate COPD patients from those with mild-

**4.** The AUC% method demonstrated higher AUC% in patients with OSA than in obese subjects, but was unable to clearly differentiate between the two groups because of

An increase in the AUC% and AUC/% EFL% reflects a greater degree of extrathoracic air‐ flow limitation (as occurs in obese and OSA subjects) while an increase in EFL% in the ab‐ sence of an increase in AUC% indicates the presence of intrathoracic flow limitation (as in COPD). Thus, subjects with greater increases in AUC/% EFL% than in EFL% upon assuming supine posture exhibit an increase in upper airway resistance rather than intrathoracic air‐ flow limitation. At the same time, in patients with COPD, EFL% increases in supine posi‐ tion, a finding more likely to occur as FEV1 decreases (Baydur et al., 1997, 2004; Eltayara et al., 1996; Koulouris et al., 1995).Variability in measurements using the NEP technique has been similarly reported by others (Hadcroft & Calverley, 2001; Walker et al., 2007) and is

obesity and OSA in seated and supine postures. Its main findings were:

patients exhibited the greatest AUC% but not AUC/% EFL.%

moderate OSA in the seated position.

likely due to a number of factors, discussed below.

the supine position.

overlapping values.

subject in both postures as the median of 10 acceptable NEP breaths (Figure 3).

Flow limitation can be assessed by computing the exhaled volume at specified time intervals during the application of NEP and expressed as percentage of the previous exhaled volume. Expiratory volumes at 0.2 and 0.5 sec after the application of NEP are significantly higher in awake healthy subjects than in awake patients with OSA (Insalaco et al., 2005; Romano et al., 2011). Expiratory volumes decline as disease severity increases., in these 2 studies, the ex‐ haled volume at 0.2 sec exhibited a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) to detect the presence of OSA of 81%, 93%, 98% and 53%, respectively (Insalaco et al., 2005; Romano et al., 2011). Sensitivity and negative predic‐ tive value both approached and reached 100% for moderate to severe [apnea-hypopnea in‐ dex (AHI) 15-30], and severe (AHI >30) OSA, respectively. The authors concluded that FL measurements at 0.2 sec may be a useful screening test for suspected OSA (Insalaco et al., 2005; Romano et al., 2011).

Using a similar computational technique, Ferretti et al (2006) found that in awake OSA patients the exhaled volume during the first 0.5 sec after the onset of NEP averaged 20% and 31% less than snorers and control subjects, respectively, in supine posture (differen‐ ces statistically significant). Under these conditions, an optimal cut-off value of 393 mL at NEP 0.5 sec exhibited a sensitivity, specificity, PPV and NPV of 76%, 74%, 84% and 64%, respectively. These differences were found to be less significant in the seated posi‐ tion. These authors concluded that while the NEP technique is potentially useful in eval‐ uating upper airway collapsibility in OSA and its mechanisms while awake, it was not precise enough to differentiate simple snorers from those with OSA. Thus it cannot be recommended as a tool robust enough to screen obese patients or snorers for undergoing polysomnography (Ferretti et al., 2006).

#### *2.3.1. Recent research by these authors*

In patients with both COPD and OSA, EFL due to the intrathoracic component may be ob‐ scured by the presence of upper airway collapse or narrowing which frequently leads to a reduction in expiratory flow below that of the preceding control breath during application of NEP. Furthermore, distinguishing EFL in OSA from that of COPD can be problematic be‐ cause patients may exhibit overlapping or combined EFL patterns combining features of both conditions. Baydur et al. (2012) compared the ability of the NEP technique to distin‐ guish individuals with COPD from those with OSA and non-OSA obesity. EFL was quanti‐ tated using the following methods (Fig. 2):

**1.** EFL was expressed as percentage of the expired tidal volume over which the NEP-in‐ duced flow did not increase above the immediately preceding tidal expiratory flow (EFL%) (Baydur et al., 1997, 2004; Eltayara et al., 1996; Koulouris et al., 1995) for each subject in both postures as the median of 10 acceptable NEP breaths (Figure 3).

Factors that contribute to OSA include increase in upper airway compliance (Isono et al., 1997), less negative critical (or closing) pressure of the passive upper airways as compared to snorers and normal subjects (related to structural soft tissue and bony changes) (Liistro et al., 1990), and smaller upper airway lumens during wakefulness and sleep, and greater pharyngeal airway length in OSA patients (Brown et al., 1985). Dyspnea in obese individu‐ als is related to increased work of breathing related to decrease in FRC with resultant in‐ crease in intrathoracic EFL and intrinsic positive end-expiratory pressure, increased respiratory drive, and intermittent narrowing or collapse of the upper airway upon assum‐

Flow limitation can be assessed by computing the exhaled volume at specified time intervals during the application of NEP and expressed as percentage of the previous exhaled volume. Expiratory volumes at 0.2 and 0.5 sec after the application of NEP are significantly higher in awake healthy subjects than in awake patients with OSA (Insalaco et al., 2005; Romano et al., 2011). Expiratory volumes decline as disease severity increases., in these 2 studies, the ex‐ haled volume at 0.2 sec exhibited a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) to detect the presence of OSA of 81%, 93%, 98% and 53%, respectively (Insalaco et al., 2005; Romano et al., 2011). Sensitivity and negative predic‐ tive value both approached and reached 100% for moderate to severe [apnea-hypopnea in‐ dex (AHI) 15-30], and severe (AHI >30) OSA, respectively. The authors concluded that FL measurements at 0.2 sec may be a useful screening test for suspected OSA (Insalaco et al.,

Using a similar computational technique, Ferretti et al (2006) found that in awake OSA patients the exhaled volume during the first 0.5 sec after the onset of NEP averaged 20% and 31% less than snorers and control subjects, respectively, in supine posture (differen‐ ces statistically significant). Under these conditions, an optimal cut-off value of 393 mL at NEP 0.5 sec exhibited a sensitivity, specificity, PPV and NPV of 76%, 74%, 84% and 64%, respectively. These differences were found to be less significant in the seated posi‐ tion. These authors concluded that while the NEP technique is potentially useful in eval‐ uating upper airway collapsibility in OSA and its mechanisms while awake, it was not precise enough to differentiate simple snorers from those with OSA. Thus it cannot be recommended as a tool robust enough to screen obese patients or snorers for undergoing

In patients with both COPD and OSA, EFL due to the intrathoracic component may be ob‐ scured by the presence of upper airway collapse or narrowing which frequently leads to a reduction in expiratory flow below that of the preceding control breath during application of NEP. Furthermore, distinguishing EFL in OSA from that of COPD can be problematic be‐ cause patients may exhibit overlapping or combined EFL patterns combining features of both conditions. Baydur et al. (2012) compared the ability of the NEP technique to distin‐ guish individuals with COPD from those with OSA and non-OSA obesity. EFL was quanti‐

ing the supine position (C.-K. Lin & C.-C. Lin, 2012).

130 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

2005; Romano et al., 2011).

polysomnography (Ferretti et al., 2006).

tated using the following methods (Fig. 2):

*2.3.1. Recent research by these authors*


This study was the first to quantitatively compare EFL in patients with COPD, non-OSA obesity and OSA in seated and supine postures. Its main findings were:


An increase in the AUC% and AUC/% EFL% reflects a greater degree of extrathoracic air‐ flow limitation (as occurs in obese and OSA subjects) while an increase in EFL% in the ab‐ sence of an increase in AUC% indicates the presence of intrathoracic flow limitation (as in COPD). Thus, subjects with greater increases in AUC/% EFL% than in EFL% upon assuming supine posture exhibit an increase in upper airway resistance rather than intrathoracic air‐ flow limitation. At the same time, in patients with COPD, EFL% increases in supine posi‐ tion, a finding more likely to occur as FEV1 decreases (Baydur et al., 1997, 2004; Eltayara et al., 1996; Koulouris et al., 1995).Variability in measurements using the NEP technique has been similarly reported by others (Hadcroft & Calverley, 2001; Walker et al., 2007) and is likely due to a number of factors, discussed below.

Percent AUC tended to be greater in OSA patients while seated indicating the presence of mechanisms maintaining upper airway patency while supine. By contrast, in COPD patients AUC% was greatest in supine posture, almost twice the value when seated. Thus, mecha‐ nisms preserving patency in supine COPD patients seem not to be as effective as in supine obese or OSA individuals. Reductions in lung volume (as occur in supine posture) result in decreases in caudal traction on the upper airway and concomitant increases in upper airway collapsibility (Owens et al., 2010; Squire et al., Thut et al., 1993; Van de Graaf, 1991). In addi‐ tion, supine positioning promotes laryngeal edema and upper airway narrowing (Jafari & Mohsenin, 2011; Shepard et al., 1996). In COPD, mobilization of secretions when supine may have contributed to this finding. Yet, the finding of an overall increase in EFL% in supine position without concomitant increases in AUC% (or AUC/% EFL%) in most other cohorts indicated a greater degree of intrathoracic tidal EFL [as defined by Koulouris et al (1995)] than extrathoracic FL. This is likely related to decrease in lung volume when supine.)

could be classified as frank sleep apnea (Caterall et al., 1983; Aoki et al., 2005). Care was tak‐ en in this study, however, to exclude subjects with symptoms of sleep apnea. None of the

Expiratory Flow Limitation in Intra and Extrathoracic Respiratory Disorders…

http://dx.doi.org/10.5772/53270

133

In conclusion, the EFL% and AUC% methods are useful in determining the magnitude of intrathoracic or extrathoracic FL in patients with COPD and OSA, but fail to distinguish co‐ horts on the basis of EFL quantification using the area under the curve method because of interindividual variabilities. In this respect, our findings were similar to those of Ferretti, et al. (2006). Pattern recognition of NEP tracings remains the best way to differentiate intra‐

While the NEP method may be regarded as the new standard for the detection of tidal flow limitation (Koulouris, & Hardavella, 2011), further research should include its validation in conditions other than COPD that exhibit intrathoracic EFL. Comparison with other techni‐ ques such as the esophageal balloon, forced oscillation and abdominal compression (proba‐ bly the easiest and least uncomfortable) methods should provide additional information in this regard. In the assessment of extrathoracic airway FL, the NEP technique offers a means to evaluate upper airway dynamics in patents with OSA, but is not able to differentiate snor‐

The authors thank Dr. Joseph Milic-Emili for valuable input to the manuscript; Mr. Louis Wilkinson for his valuable technical assistance; Dr. Danielle Kushner and Mr. Shadman Chowdhury for assistance in tabulating data. Dr. Cheryl Vigen and Dr. Zhanghua Chen pro‐ vided critical statistical and data analysis. The authors also thank the technical staff of the Pulmonary Function Laboratory at Los Angeles County + University of Southern California Medical Center for performing the lung function and polysomnograhic testing, and all the

obese COPD patients gave a history of symptoms of sleep apnea.

**3. Conclusion**

thoracic from extrathoracic EFL.

ers from those with OSA.

**Acknowledgements**

patients and volunteers who participated in the study.

AUC: Area under preceding control curve subtended by the NEP curve

**Abbreviation/Nomenclature list**

AHI: Apnea-hypopnea index

EFL: Expiratory flow limitation

BMI: Body mass index

The differing findings amongst cohorts can be explained thus: During early expiration, there is post-inspiratory inspiratory activity (PIIA) which may negate the effect of NEP. At the be‐ ginning of expiration, PIIA may oppose NEP (resistance posed by pliometric contraction [= lengthening] of the inspiratory muscles) (Shee et al., 1985). This implies that NEP should not be applied too early in expiration (when PIIA is high). In our subjects, NEP was applied im‐ mediately after the onset of expiratory flow so that PIIA is likely to have influenced variabil‐ ity of EFL within cohorts.

Our method for computing AUC% was similar to that of Tamisier et al. (2005) who de‐ vised a quantitative index corresponding to the ratio of the area under the expiratory flow-volume curves between NEP and control tidal volume. They did not, however, study subjects with mild OSA (BMI 5-15), and their control subjects were younger than ours. They also applied NEP near end-expiratory volume which stimulates activation of the genioglossus (Tantucci et al., 1998). This can change the area under the terminal por‐ tion of the NEP curve, affecting the quantitative index used to assess the upper airway collapsibility. Our results suggest that obese and OSA patients are more likely to experi‐ ence upper airway narrowing while seated than COPD patients, indicating reduced PIIA and genioglossus activity in that posture.

There were some methodological limitations in this investigation. This study and those of others (Baydur et al., 2004, 2012; Insalaco et al., 2005; Liistro et al., 1999; Rouatbi et al., 2009; Van Meerhaeghe et al., 2004; Verin et al., 2002) assumed that upper airway collapsibility can be identified solely when expiratory flow during NEP decreases below the control curve. As such, detecting upper airway collapsibility only by computing the span of the preceding control tidal volume over which the NEP curve drops below the control breath may be mis‐ leading. It is possible that in this study some patients with upper airway narrowing may not have been identified if they exhibited only a reduction in the increase of expiratory flow (but still greater than the preceding control flow) during NEP.

Another limitation in this study was that sleep studies were not obtained in COPD patients and controls. Sleep-related disordered breathing (SDB) and nocturnal desaturations have been reported in COPD patients, giving rise to an "overlap syndrome" although not all SDB could be classified as frank sleep apnea (Caterall et al., 1983; Aoki et al., 2005). Care was tak‐ en in this study, however, to exclude subjects with symptoms of sleep apnea. None of the obese COPD patients gave a history of symptoms of sleep apnea.
