What Does Airway Resistance Tell Us About Lung Function?

David A Kaminsky MD

Introduction Physiology Measurement of Airway Resistance by Body Plethysmography

Clinical Utility of sRaw and sGaw Measurement of Airway Resistance by the Forced Oscillation Technique Measurement of Airway Resistance by the Interrupter Technique

Comparing sRaw, FOT, and Rint Summary

Spirometry is considered the primary method to detect the air flow limitation associated with obstructive lung disease. However, air flow limitation is the end-result of many factors that contribute to obstructive lung disease. One of these factors is increased airway resistance. Airway resistance is traditionally measured by relating air flow and driving pressure using body plethys-

mography, thus deriving airway resistance (Raw), specific airway resistance (sRaw), and specific airway conductance (sGaw). Other methods to measure airway resistance include the forced oscillation technique (FOT), which allows calculation of respiratory system resistance (RRS) and reactance (XRS), and the interrupter technique, which allows calculation of interrupter resistance (Rint). An advantage of these other methods is that they may be easier to perform than spirometry, making them particularly suited to patients who cannot perform spirometry, such as young children, patients with neuromuscular disorders, or patients on mechanical ventilation. Since spirometry also requires a deep inhalation, which can alter airway resistance, these alternative methods may provide more sensitive measures of airway resistance. Furthermore, the FOT provides unique information about lung mechanics that is not available from analysis using spirometry, body plethysmography, or the interrupter technique. However, it is unclear whether any of these measures of airway resistance contribute clinically important information to the traditional measures

derived from spirometry (FEV1, FVC, and FEV1/FVC). The purpose of this paper is to review the physiology and methodology of these measures of airway resistance, and then focus on their clinical utility in relation to each other and to spirometry. Key words: airway resistance; forced oscillation; interrupter technique; body plethysmography; spirometry. [Respir Care 2012;57(1):85–96. © 2012 Daeda- lus Enterprises]

Dr Kaminsky is affiliated with the Department of Pulmonary Disease and Dr Kaminsky has disclosed relationships with Medical Graphics and Merck. Critical Care Medicine, University of Vermont College of Medicine, Burlington, Vermont. Correspondence: David A Kaminsky MD, Pulmonary Disease and Crit- ical Care Medicine, University of Vermont College of Medicine, Given D-213, 89 Beaumont Avenue, Burlington VT 05405. E-mail: david. Dr Kaminsky presented a version of this paper at the 48th RESPIRATORY [email protected]. CARE Journal Conference, “Pulmonary Function Testing,” held March 25–27, 2011, in Tampa, Florida. DOI: 10.4187/respcare.01411

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Introduction

Spirometry is considered the gold standard method to measure air flow limitation. However, since air flow limitation occurs in part due to increased airway resistance, it makes sense that measuring airway resistance directly may provide additional information. Traditionally, airway resistance has been measured by relating air flow and driving pressure through the use of body plethysmography, thus deriving airway resistance (Raw), specific airway re- 1-4 sistance (sRaw), and specific airway conductance (sGaw). Other methods to measure airway resistance, which require less cumbersome equipment and less patient technique and cooperation, are the forced oscillation technique (FOT),5-7 which allows calculation of respiratory system resistance (RRS) and reactance (XRS), and the interrupter technique, which allows calculation of interrupter resis- 8-11 tance (Rint). All of these methods may be used clinically, but a major question is whether they add anything to Fig. 1. A: Illustration of laminar flow through a rigid tube, where the the traditional measures derived from spirometry (FEV1, pressure difference is related to the characteristics of the tube and ⌬ ϭ ␮ ˙ ␲ 4 FVC, and FEV1/FVC). The purpose of this paper is to the gas through the Poiseuille equation: P 8l V/ r . B: Illus- review the physiology and methodology of each of these tration of turbulent flow through a rigid tube, where the Poiseuille ⌬ ϭ ␳ ˙ 2 ␲ 4 measures of airway resistance, and then focus on their equation is modified to P 8l V / r . (From Reference 12, with permission.) clinical utility in relation to each other and to spirometry.

Physiology complex relationship between airway geometry, flow, and gas composition. In addition, the airways are flexible, not Resistance to air flow in the lung is determined by mea- collapsible, so flow limitation occurs based on wave speed suring the pressure difference across the airways and di- theory and the development of choke points.13 Finally, the viding this difference by the flow. When flow is laminar airways are connected in both series and parallel, so that through a rigid tube, the pressure difference is related to total airway resistances must be added in a reciprocal fash- the characteristics of the tube and the gas through the ion: Poiseuille equation (Fig. 1A): ϭ ϩ ϩ ϩ ⌬P ϭ 8l␮V˙ /␲r4 (1) 1/Rtotal 1/R1 1/R2 … 1/Rn (3) where l ϭ the length of the tube, ␮ ϭ gas viscosity, Modeling total airway resistance reveals that, based on V˙ ϭ flow, and r ϭ the radius of the tube. Since resistance total cross sectional areas at each airway generation, air- is ⌬P/V˙ , this equation highlights key points about resis- way resistance initially falls from the trachea to genera- tance under laminar flow conditions: resistance is related tion 4, then rises again in generations 5–8, before falling inversely to flow and directly to the length of the tube, off dramatically in subsequent generations12 (Fig. 2). At varies inversely with the 4th power of the radius of the breathing frequencies, small airways (Ͻ 2 mm in diame- tube, and varies with the viscosity of the gas. When flow ter) account for only 10% of total airway resistance,14-16 is turbulent, the Poiseuille equation is modified with the remainder arising from the viscoelastic properties of the lung parenchymal tissue (40%) and flow resistance in the larger airways (50%).17 ⌬P ϭ 8l␳V˙ 2/␲r4 (2) where ␳ ϭ gas density (see Fig. 1B). This equation now Measurement of Airway Resistance illustrates that under turbulent conditions, resistance varies by Body Plethysmography with gas density, not viscosity, and is no longer linearly related to flow.12 If one considers the lung as a simple, linear model made In the human lung, laminar and turbulent flow both up of a rigid tube attached to a flexible parenchymal com- contribute to air flow, thus resulting in a mathematically partment, then the pressure required to move air into and

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Fig. 3. Relationship of mouth pressure (Pmo) and box pressure (Pbox) by body plethysmography under closed-loop panting conditions (left) and open-loop panting conditions (right). Under con- Fig. 2. Relationship of total airway resistance to airway generation. ditions of no-flow (left), mouth pressure would approximate alve- Computational modeling reveals that, based on total cross sec- olar pressure, so the relationship of alveolar pressure to change in tional areas at each airway generation, airway resistance initially lung volume (as determined by change in box pressure) is mea- falls from the trachea to generation 4, then rises again in genera- sured. When the shutter is opened (right), the relationship between tions 5–8, before falling off dramatically in subsequent genera- flow and lung volume (change in box pressure) is measured. Air- tions. (From Reference 12, with permission.) way resistance (Raw) is calculated as the change in alveolar pressure (Palv) divided by flow, which is derived by multiplying the slope of the closed shutter maneuver and the inverse slope of the open shutter maneuver, with the lung volume terms cancelling out. out of the model can be expressed as the equation of (From Reference 3, with permission.) motion for the system: relationship of pressure to flow, and hence resistance19 P ϭ EV ϩ RV˙ ϩ IV¨ (4) (Fig. 3). An important technical factor that must be considered in where P ϭ pressure, V ϭ volume, V˙ ϭ flow, V¨ ϭ accel- measuring airway resistance by body plethysmography is eration, and the constants E, R, and I, representing elas- deciding where to draw the slope of V˙ versus box pressure, tance, resistance, and inertance, respectively, determine since different slopes can be drawn from the same flow- the mechanical properties of the system. One could theo- pressure loop when the loop has a complex configura- retically measure resistance if volume fluctuations are kept tion.1,20 For loops used in conjunction with thoracic gas ¨ very low (EV term approaches zero). The IV term would volume (TGV) to derive Raw, the slope is conventionally already be negligible at breathing frequencies up to ϳ8 Hz. taken at the transition between the end of inspiration and Thus, P ϭ RV˙ , which we commonly recognize as the gas the beginning of expiration between ϩ0.5 and Ϫ0.5 L/s pressure-flow relationship analogous to Ohm’s law. In flow. Other slopes that can be drawn when calculating

1956, Dubois and colleagues published their description of sRaw (see below) include connecting the points of maxi- a method to measure airway resistance using body pleth- mal flow (sRaw-total), connecting the points of maximal ysmography, which essentially applied this simplified equa- volume shift (sRaw-MaxVol), or connecting the mid-volumes 18 ϩ Ϫ tion of motion under conditions of low breathing volume. at 0.5 L/s and 0.5 L/s (sRaw-Mid). In the case of both The rapid shallow panting maneuver involved in the air- Raw and sRaw, there may be circumstances where resis- way resistance measurement would also optimize the sig- tance is differentiated between inspiration and expiration. nal-to-noise ratio and increase the accuracy of measure- For example, Ingenito and colleagues demonstrated that ment by: minimizing thermal shifts and gas exchange; patients undergoing lung-volume-reduction surgery for em- reducing glottic obstruction of the airway; minimizing flow physema who had less elevated inspiratory resistance were turbulence and gas compression; and maintaining a rela- the ones more likely to demonstrate an increase in FEV1 tively stable lung volume.1,18 To calculate resistance one following surgery21 (Fig. 4). They speculated that this was needed to know flow and alveolar pressure; the former because these patients were more likely to have more se- could be measured directly, but the latter could not. What vere emphysema, which would lead to dynamic airway Dubois realized was that under conditions of no-flow, collapse from loss of parenchymal tethering. Reducing mouth pressure would approximate alveolar pressure, and lung volume via surgery in such patients is thought to so he related flow to no-flow conditions to derive the improve elastic recoil.

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Fig. 5. Relationship between airway resistance (Raw) and lung volume, the reciprocal of Raw (conductance of the airways [Gaw]) and lung volume, and Gaw/TGV (thoracic gas volume) (specific airway conductance [sGaw]) and lung volume. Notice that only sGaw is independent of lung volume. RV ϭ residual volume. FRC ϭ func- tional residual capacity. TLC ϭ total lung capacity. (From Refer- Fig. 4. Relationship between change in FEV1 following surgery ence 3, with permission.) versus inspiratory lung resistance at baseline in patients undergoing lung-volume-reduction surgery. The lower the resistance, the more the FEV1 improved after surgery. (From Reference 21, with 2,20 permission.) volume). Thus, sRaw reflects the work related to changes in lung volume while overcoming a fixed resistance, while Airway resistance as measured by body plethysmogra- Raw reflects the pressure related to air flow. Because sRaw encompasses lung volume, and R and lung volume vary phy is usually expressed as Raw. Since Raw varies with aw lung volume, and lung volume may vary under different inversely, sRaw is relatively stable with respect to changes experimental conditions or different times of measurement, in lung volume (ie, as lung volume decreases, Raw increases, so the product sR remains the same, and vice Raw is usually corrected for lung volume by expressing it aw versa). In this way, sR is similar to sG because it takes as sRaw or sGaw. When measured in conjunction with TGV aw aw into account lung volume. However, sG reflects only (from a closed shutter maneuver), the reciprocal of Raw, aw R , whereas sR reflects both R and lung volume. Gaw, is divided by the TGV at which the measurement was aw aw aw This may be illustrated by considering an obstructed pa- made to derive sGaw, which now expresses Raw indepen- tient with hyperinflation versus an obstructed patient with- dent of lung volume (Fig. 5). Thus, sGaw is a stable mea- out hyperinflation.2 In the former, R is elevated and sure that can be used in serial studies of Raw. The in- aw sR is increased (increased work to move air through a creased sensitivity of sGaw for airway resistance compared aw higher lung volume), but the increased TGV associated to FEV1 is especially useful in pharmacologic studies that 4 with hyperinflation corrects conductance back to normal involve normal healthy subjects. However, sGaw is less reproducible, making repeated measurements important to (normal sGaw). In the latter, Raw is increased and sRaw is determine an accurate mean value, and there are limited increased (increased work to move air through an increased studies establishing normal values.4 It should be noted that resistance), but sGaw is reduced (elevated Raw is not re- in patients with airways disease such as asthma, the as- duced by altered lung volume). sumption of mouth pressure equal to alveolar pressure at zero flow may not hold true, and in fact TGV may be Clinical Utility of sRaw and sGaw overestimated.22 This, in turn, would alter the calculation and accuracy of sGaw. Due to geometric considerations, whereby the total cross In children, the closed shutter maneuver may be diffi- sectional area of the airways decreases dramatically as one cult to achieve, so TGV cannot be measured. Instead, flow moves from the periphery to the central regions of the is related to the small shifts in lung volume that occur lung, any measure of overall airway resistance, like sGaw, 1,2,20,23,24 during tidal breathing to derive sRaw. Mathemat- will be very sensitive to central airway pathology but less ically, the relationship between pressure and flow during sensitive to peripheral changes. Thus, sGaw may pick up panting and its relationship to TGV (ie, Raw) is equivalent changes in large central airways that may be missed by ϭ to dividing sRaw by TGV, so Raw sRaw/TGV, or spirometry. Indeed, sGaw has been shown to be sensitive to ϭ ϫ 2,20 25 sRaw Raw TGV. This latter expression reveals that upper airway involvement in vocal cord dysfunction and 26 sRaw reflects not only Raw but also lung volume, and is not vocal cord paralysis. However, this is not necessarily ϫ a resistance per se, but rather a form of work (pressure true in all cases, as one study has shown that sGaw was

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Dehaut and colleagues demonstrated that the PC40 (provo- cational concentration that produces a 40% decrease) in

sGaw was more sensitive than the PC20 FEV1 at detecting bronchoconstriction to inhaled histamine, but the PC20 was a more reproducible measure (coefficient of variation ϭ 2.6% vs 10%).31 Goldstein and colleagues have

shown that adding non-FEV1 parameters, such as sGaw,to FEV1 during a methacholine challenge test increases the sensitivity of the test, although most of the increase was due to addition of FVC and the forced expiratory flow 32 during the middle half of the FVC maneuver (FEF25–75). Recently, Khalid and colleagues questioned the 40%

cutoff for positivity of the PC sGaw during methacholine 33 challenge. Based simply on comparing the PC20 FEV1 with the change in sGaw at that level in patients with Fig. 6. The phenomenon of an isovolume shift is illustrated by suspected asthma, they found that the mean change in plotting flow-volume loops before and after bronchodilator on an absolute volume scale. At isovolume (vertical line), flow is increased sGaw was 56%. Further analysis by receiver-operator char- in the post-bronchodilator, compared to the pre-bronchodilator, acteristic curves suggested that the optimal cutoff was a loop, despite no change in FEV1 or FVC. change of 52%. While this is only slightly higher than the currently accepted 40% change, it does suggest that a slightly higher cutoff may be more appropriate by enhanc- more sensitive than FEV1 in bronchiolitis obliterans syn- ing the predicative value of the test. The cost of a test with drome, a disease confined to the lung periphery. This may such high sensitivity is typically loss of specificity. In- relate to the loss of sensitivity of FEV1 due to the deep deed, many years ago Fish and colleagues demonstrated 27 inhalation involved (see below). that sGaw was less specific at distinguishing normal from 34 Theoretically sGaw should be sensitive to changes in asthmatic subjects than FEV1. The authors proposed that resistance anywhere along the airway, whereas FEV1 will the airways hyper-responsiveness that characterizes asthma be sensitive to only those changes occurring upstream from might be less a reflection of intrinsic increased respon- the choke point.28 Thus, depending on the location of air- siveness of the airways than an impaired ability to bron- way narrowing or dilation in response to a bronchocon- chodilate their constricted airways.35 strictor or bronchodilator, the FEV1 may change without Another study demonstrated that when the methacho- 28 significant change in sGaw, or vice versa. In the case of line challenge test was negative, small changes in FEV1, airway narrowing, hyperinflation might result. Smith and but not in sGaw, were predictive of future development of colleagues found that spirometry alone failed to find bron- asthma, suggesting again that the FEV1 is a more specific chodilator reversibility in 15% of patients with suspected measure for asthma.36 When Parker and colleagues com- reversible airway obstruction and clinical responses to bron- pared patients who responded to methacholine with changes chodilator, but that these patients could be identified by in sGaw, but not in FEV1, to those who responded by FEV1 29 changes in sGaw or TGV or isovolume maximal flow only, they found that such patients had smaller lung vol- (Fig. 6). These results suggest that the patients involved umes, higher FEV, and higher FEF25–75/FVC, indicative were responding to bronchodilator by changes in lung vol- of relatively larger airway to lung size, a mismatch re- ume-related parameters but not changes in spirometry. ferred to as lung dysanapsis.37 Patients with lung dysanap-

Since these patients had clinical improvement, such vol- sis with smaller airway to lung size (lower FEF25–75) have ume-related changes are clinically relevant. been found to be more hyper-responsive than those with- 38 Another factor to consider in differentiating sGaw from out in the Normative Aging Study. Thus, comparing re- FEV1 is the deep breath necessarily associated with per- sponses in FEV1 and sGaw may lend insight into the basic forming spirometry, but not part of the sGaw measure. physical relationship between airway size and lung size. Healthy subjects and those with mild asthma tend to bron- As mentioned above, sRaw is commonly used in chil- chodilate after a deep inhalation, so mild bronchoconstric- dren but is rarely used in adults.39 Details regarding tech- tion could be masked by the bronchodilating effects of niques of measurement, quality control, and interpretation 30 20,23,24,40 measuring FEV1, but should still be evident by sGaw. are available in recent, excellent reviews. sRaw has This would make sGaw a more sensitive test to detect been measured in children as young as 2 years old, and has air-flow limitation, especially in mildly obstructed patients. been used in assessment of bronchodilators and response Many studies have investigated the relative response in to methacholine, histamine, and cold air.24 Other studies

FEV1 versus sGaw during bronchial challenge tests. In 1983, have included measuring the effects of short- and long-

RESPIRATORY CARE • JANUARY 2012 VOL 57 NO 189 WHAT DOES AIRWAY RESISTANCE TELL US ABOUT LUNG FUNCTION? acting bronchodilators, inhaled corticosteroids, and leuko- substantial contribution of tissue viscoelastance to total triene receptor antagonists in asthmatic children.20 Serial respiratory resistance. In general, lower frequency data measurements have been made in children with cystic fi- (Ͻ 5 Hz) reflect the more peripheral regions of the lung, brosis and demonstrated more consistent abnormalities than while higher frequency data (Ͼ 8 Hz) are most represen- 41 43 either FOT or Rint. Since sRaw is primarily used in chil- tative of the larger, central airways. dren, normative data are mainly limited to pediat- Unlike Raw measured by body plethysmography, the rics.20,23,24,40 As most of the children involved in these resistance measured by the FOT represents total respira- studies would likely not have been able to perform reliable tory system resistance, and thus contains contributions from spirometry, using sRaw as a measure of airways disease is both the lung and chest wall. At 6 Hz, RRS by the FOT is a valuable tool in pediatric lung disease. very comparable to Raw, but slightly higher due to contributions from the chest wall.44,45 At higher frequencies,

Measurement of Airway Resistance RRS by the FOT tends to underestimate Raw, especially at by the Forced Oscillation Technique higher Raw values, likely due to shunting of flow into the upper airways (ie, cheeks, floor of mouth).44,45 Since the Another non-spirometric method to measure airway re- FOT is performed during tidal breathing, no deep breaths sistance is the FOT. First described by Dubois in 1956,42 are involved that might interfere with measurement. Be- the FOT involves applying a forced perturbation of flow at cause of this, RRS by the FOT is highly sensitive to changes the mouth and measuring the resulting pressure.5-7 This in bronchial tone, but is less specific for asthma or other occurs while the subject continues to breathe quietly. The unique disease states. applied flow is typically either pseudorandom in nature, The FOT has become popular because of its ease of meaning composed of many, typically mutually prime, administration. It requires minimal subject cooperation and frequencies, or truly random, as generated by a mechanical is thus suitable for use in children and any patient who impulse. In both cases, the ratio of pressure measured to cannot cooperate or manage spirometry (eg, ventilated pa- flow applied is analyzed across the frequency domain by tients, paralyzed patients). There is only one commercially fast Fourier transformation to arrive at a complex number available FOT system in the United States, called the im- known as the impedance of the respiratory system (ZRS). pulse oscillometry system. This device uses an impulse of Impedance encompasses all the forces that hinder air flow flow made up of random frequencies and amplitudes to into and out of the lung, and thus include the resistance, compute RRS and XRS. Compared to the traditional FOT elastance, and inertance of the system. The component of using pseudorandom noise, resistance measured by the

ZRS in-phase with flow is the real component, respiratory impulse oscillometry system tends to overestimate RRS by system resistance (RRS), and this reflects the energy dis- the FOT at lower frequencies, and Raw at all frequencies, 45 sipated due to resistive losses. The components of ZRS likely due to non-linearities involved in measurement. out-of-phase with flow make up the imaginary component, The RRS by the impulse oscillometry system and the FOT 45 respiratory system reactance (XRS). The reactance, in turn, agree well at higher frequencies (25 Hz). is made up of out-of-phase lagging flow, which is elas- The FOT has been used in many applications, including tance, and out-of-phase leading flow, which is inertance; differentiating healthy from obstructed patients in COPD both of these components reflect energy storage. When and asthma; detecting bronchoconstriction, which occurs plotted against frequency, ZRS demonstrates a relatively at lower doses of methacholine for impulse oscillometry 46 frequency-independent resistance in healthy subjects, ex- system resistance than for FEV1 ; and measuring the se- cept at the very lowest frequencies (Ͻ 1 Hz), where neg- verity of obstruction in asthma and COPD47,48 (Fig. 7). ative frequency dependence occurs. This is thought to re- Methacholine-induced dyspnea is significantly associated flect tissue viscoelastic properties in healthy subjects, while with changes in RRS and XRS at 5 Hz (R5 and X5, respec- there is increased frequency dependence of resistance due tively), but not changes in FEV1, suggesting that these to mechanical inhomogeneities in subjects with obstruc- FOT measures are more sensitive to symptoms.49 How- tive diseases like asthma or COPD.43 Reactance is fre- ever, Houghton and colleagues have shown that the most quency-dependent in all subjects, but enhanced in those sensitive method varies between healthy and asthmatic with obstructive lung disease, where reactance values are subjects, and with the degree of severity in asthma.50 A more negative. Where the XRS curve crosses zero, the statistical analysis found that some FOT parameters, in- elastance and inertance values are equal and opposite, and cluding R5, are more sensitive than FEV1 in detecting the frequency at which this occurs is the resonant fre- bronchodilation in asthmatic subjects.51 quency. With increasing degrees of obstruction, the XRS Since the FOT requires no patient cooperation or tech- curve is shifted to the right, the resonant frequency is nique, it can be applied widely in many clinical settings. increased, and the area under the XRS curve (AX) is in- Indeed, the FOT is well suited to studies in children, the creased.5 Impedance data at breathing frequencies reveal a elderly, and any patients who cannot perform spirometry,

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Fig. 7. Impedance data from patients with asthma (left) and COPD (right) according to severity of underlying disease. Notice the consistent relationship between diseases of the changes in respiratory system resistance (RRS) and respiratory system reactance (XRS) with increasing Ͻϳ severity. In both cases, as severity increases, RRS rises and becomes more frequency dependent, especially at lower frequencies ( 16 Hz), and XRS falls to more negative values, with an increase in the resonant frequency (point at which XRS crosses zero). (Left from Reference 47, with permission. Right from Reference 48, with permission.)

such as those with neuromuscular disease or on mechan- moderate to severe COPD, the fall in FEV1 with metha- 6 ical ventilation. For example, only impulse oscillometry choline was more closely related to a fall in XRS than a rise bronchodilator responses, and not responses measured by in RRS, and this occurred in association with a decrease in FEV1, were able to distinguish 4-year-old children at risk inspiratory capacity, suggesting that airway closure was for persistent asthma participating in the Childhood Asthma the main response to methacholine.54 Asthmatics had a 52 Prevention Study. A similar finding was seen in a cohort smaller change in lung volume and a larger change in RRS, of children form Belgium.53 It also has unique application suggesting more of an airway response in asthmatics. In in studies of sleep and patients on mechanical ventilation, other cases the increase in XRS is thought to represent an where the oscillatory signal can be applied on top of tidal artifact of central airway shunting, which occurs under breathing.6 In all these situations, measuring FOT resis- conditions of extreme peripheral airway resistance, lead- tance will lend insight into the presence and severity of ing to shunting of forced flow into the more central air- obstructive disease. ways.55 Reactance has been noted to differentiate mild 56 More studies are also focusing on the XRS component of air-flow obstruction before changes in RRS occur and 57 ZRS, which may yield different information related to the may detect flow limitation in patients with COPD. Also elastic properties of the lung. In some cases increased XRS in COPD, Kolsum and colleagues have shown that R5, X5, may be related to reduced lung volume due to airway and resonant frequency were significantly associated with closure. Indeed, Walker and colleagues showed that in FEV1,sGaw, total lung capacity, RV, and inspiratory ca-

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late to the pathogenesis of airway inflammation64 and acute lung injury.65 The methodology and analysis of FOT data are complex. The European Respiratory Society has published guidelines on methodology in 2003,6 but there have been no updates since then. In general, the repeatability of the

technique is similar to Raw from body plethysmography and interrupter resistance (see below). The correlation with spirometry is highly variable, in part because of the deep breath involved in spirometry, and in part due to the differing mechanics assessed by the two techniques.5 The FOT is subject to strong influence by upper airway shunting, and this must be carefully controlled. Interestingly, the FOT does not yield distinctive data in patients with restrictive lung disease.6 Many regression equations are Fig. 8. Comparison of change in respiratory system resistance at now available, but they each come from different popula-

5Hz(RRS5) and respiratory system reactance at 5 Hz (XRS5) be- tions and use different devices and techniques, so their tween inspiration and expiration in healthy control subjects, and applicability is limited.6 subjects with asthma and COPD. Notice that only the patients with The FOT is used commonly in research, from clinical COPD had significant differences in XRS5 between inspiration and expiration, differentiating them from both control subjects and sub- studies to basic studies of lung mechanics. For example, jects with asthma. (From Reference 63, with permission.) Kaczka and colleagues have described the association of more severe asthma with increasing frequency dependence of elastance, thought to be due to more severe peripheral pacity, with the strongest associations between X5 and airway resistance causing shunting of flow back into central airways.55 In a different study, Kaminsky and col- resonant frequency and FEV1, and X5 and resonant fre- 58 leagues have uniquely demonstrated hyper-responsiveness quency and sGaw. A recent study in pediatric asthma has shown that only reactance area (AX) continues to improve of the lung periphery in participants with asthma using the 66 after the initial 12 weeks of therapy with inhaled flutica- FOT. Because interpretation of ZRS depends on lung sone during a 48-week total study.59 The authors speculate models, the technique yields information in relation to that this might reflect ongoing improvement in small air- such models, and therefore is also limited by the properties 67 way function in these patients. Two studies from Japan of the model in use. note that X relates more closely with quality of life RS Measurement of Airway Resistance measures than FEV in both patients with asthma60 and 1 by the Interrupter Technique COPD.61 One of the benefits of the FOT is that one can separately A third method to noninvasively measure airway resis- measure inspiratory from expiratory parameters. Using this tance, used primarily in children, is the interrupter tech- technique, Paredi and colleagues have shown that while nique.8,9,11,68,69 The concept here is similar to that used in whole breath impulse oscillometry could not differentiate body plethysmography, in that the alveolar pressure is patients with asthma and COPD, patients with COPD had estimated by mouth pressure during transient occlusion of higher mean expiratory X5 than those with asthma, which flow. In this case, flow is occluded intermittently during they thought might be due to enhanced dynamic airway spontaneous breathing, and the mouth pressure recorded 62 narrowing on expiration in these patients. Another study immediately after the occlusion is related to the air flow has shown that in comparing FOT in patients with asthma measured immediately before the occlusion to calculate and COPD, only patients with COPD show a significant resistance. The display of data is unique and is important 63 difference in XRS between inspiration and expiration for monitoring for quality. During expiration, initially there (Fig. 8). The authors speculate that the same process of is a sharp increase in pressure, reflecting central airway dynamic airway narrowing on expiration due to loss of resistance, followed by rapid, damped oscillations of pres- recoil in COPD may explain this phenomenon. Interest- sure, and finally a slowly rising steady pressure thought to ingly, this theory mirrors the concept suggested by In- be due to tissue viscoelasticity9,11,69 (Fig. 9). genito and colleagues, mentioned above, that describes the The pressure used for calculation of Rint is ideally im- relationship between outcomes from LVRS and inspira- mediately after occlusion, but in reality is back extrapo- tory resistance.21 High inspiratory resistance may not only lated to 15 ms after occlusion based on the slope of pres- reflect differences in underlying physiology, but may re- sure between 30 and 70 ms after occlusion. Like the FOT,

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inhaled fluticasone,73 and oral montelukast therapy.74 One issue with the interrupter technique is determining the best cutoff for bronchoconstrictor response. In adults, Sund- blad and colleagues have shown that a 20% change in

FEV1 following methacholine corresponds to different lev- els of change of Gaw (reciprocal of Rint) determined by the interrupter technique, depending on the underlying degree of bronchial responsiveness, in this case, to a 39% change

in Gaw in all subjects, but a 66% change in less responsive subjects and a 27% change in more responsive subjects.75 Thus, the range of cutoff of a positive test varies widely, depending on the nature of the underlying bronchial responsiveness.

Comparing sRaw, FOT, and Rint

There are limited studies directly comparing the above indices, and by their nature, appear mainly in children. Fig. 9. Pressure versus time during an interrupter maneuver during expiration. At time 0 the airway is transiently occluded, resulting in Even though all 3 measures are based on differing mean abrupt spike in pressure, reflecting the initial pressure change chanical principles, in general all show consistent changes across the respiratory system. The pressure then oscillates briefly in relation to disease state or response to bronchodilator or before slowly climbing as pressure rises from viscoelastic prop- bronchoconstrictor. These measures tend to be more sen- erties and gas redistribution in the lung. By convention, a common sitive to detection of bronchodilation and bronchoconstric- method to calculate interrupter resistance (Rint) is to take the pressure at ϩ15 ms determined by back extrapolation from tϩ30 and tion than FEV1, with one study demonstrating that Raw tϩ70 ms, and divide this pressure by the flow immediately before was more sensitive than FOT and Rint in detecting bron- the occlusion. (From Reference 69, with permission.) choconstriction in normal subjects.44 Technical factors are critical in deriving robust measurements, with special at-

tention given to reducing thermal artifact in sRaw mea- numerous technical factors are important, such as reducing sures, and upper airway shunting in FOT and Rint. In chil- upper airway shunt by firm support of the cheeks and floor dren, all 3 measures have shown higher values in children of mouth, timing of valve closure, taking the mean or with asthma, but there is no clear agreement on cutoffs for median of repeated values, and use of a face mask or a abnormal values. This is especially important because even mouthpiece.8,68-70 Also, similar to the body plethysmogra- healthy children demonstrate reduced resistance in response phy technique, the assumption of equilibration between to bronchodilators when using these highly sensitive mea- mouth and alveolar pressure at zero flow may not hold true sures. All 3 measures are commonly abnormal in young in patients with substantial airway heterogeneities. Be- children with asthma, but none appear to associate with 76 cause it is noninvasive and performed during normal breath- clinical outcomes assessed 3 years later. sGaw, FOT, and ing, the technique is especially suitable for use in young Rint allow differentiation of inspiratory and expiratory re- children, and has been demonstrated feasible in children as sistance, and the dynamic looping of resistance and flow, young as 2 years old. The intra-subject coefficient of vari- as seen by the sRaw and FOT methods, may yield impor- ation is similar to that of FOT (5–15%). There is a small tant information about laryngeal narrowing, a common group of reference equations that derive from pediatric occurrence during testing. The FOT uniquely also pro- studies.69 vides information about frequency dependence and reac-

Clinically, Rint has been used in discriminating between tance, which yield additional insight into peripheral airway different phenotypes of wheezy children and between mechanics and inhomogeneities.5,7,43 A summary of the 69 healthy children and children with asthma. In the latter specific measurement properties of FEV1 in comparison to group, a correlation coefficient of 0.73 was found for base- sRaw,sGaw, FOT-R, and Rint is shown in Table 1. 71 line values of spirometry and Rint. Rint has been used in conjunction with other measures to evaluate bronchodila- Summary tor response in asthmatic children. As to discriminating capacity, Raw, R5, Rint, and X5 were found to be useful, Spirometry remains the gold standard pulmonary func- with positive predictive values of 84%, 74%, 82%, and tion test for determining the presence and severity of air- 76%, respectively.72 The interrupter technique has also flow limitation. However, spirometry has some key limi- been used to evaluate the response to cold air inhalation, tations: it is effort dependent and requires patient

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Table 1. Characteristics of Different Lung Function Tests Related to Airway Resistance

Spirometry Plethysmography FOT Rint (FEV1) (sRaw,sGaw) (RRS) Patient cooperation/effort ϩϩϩ ϩϩ ϩ ϩ Involves deep inhalation ϩϩϩ –– – Adjusts for lung volume – ϩ –– Intra-subject variability (coefficient 3–5% 8–13% 5–15% 5–15% of variation)5,6,31,44,69,77,78 Sensitivity to airway location Central ϩ ϩϩ ϩϩϩ ϩϩϩ Peripheral ϩϩ ϩ ϩ ϩϩϩ Cutoff for bronchodilator/ 12/20% 25/40% 35%/3SDw 40/50% bronchoconstrictor6,20,24,69,78,79 Insight into mechanics ϩ ϩ ϩ ϩϩϩ ϩ ϩ Global, nonspecific Raw, TGV Lung chest wall Lung chest wall Standardized methodology ϩϩϩ ϩϩ ϩ ϩϩ Reference equations2,6,10,69,78 ϩϩϩ ϩϩ ϩϩ (pediatric) ϩϩ

ϩ to ϩϩϩ ϭ Yes, with increasing strength or prevalence of feature – ϭ No sRaw ϭ specific airway resistance sGaw ϭ specific airway conductance Rint ϭ interrupter resistance FOT ϭ forced oscillation technique RRS ϭ respiratory system resistance SDw ϭ within-subject standard deviation TGVϭ thoracic gas volume

cooperation and skill; it involves a deep breath, which can 2. Crie´e C, Sorichter S, Smith H, Kardos P, Merget R, Heise D, Berdel alter underlying airway resistance; and it provides limited D, et al. Body plethysmography—its principles and clinical use. insight into lung mechanics. For patients who cannot per- Respir Med 2011;105(7):959-971. 3. Kaminsky D, Irvin C. Lung function in asthma. In: Barnes P, Grunstein form spirometry, measuring airway resistance with sRaw, M, Leff A, Woolcock A, editors. Asthma. New York: Lippincott- FOT, or Rint remain important options. Measuring sRaw by Raven; 1997:1289. body plethysmography involves bulky equipment that does 4. Tattersfield A, Keeping I. Assessing change in airway calibre - mea- not allow portable measurement, and it provides an index surement of airway resistance. Brit J Clin Pharm 1979;8(4):307-319. that reflects both R and lung volume. In adults, sG is 5. Goldman M. Clinical application of forced oscillation. Pulm Pharm aw aw Ther 2001;14(5):341-350. typically used, and provides a sensitive measure of airway 6. Oostveen E, MacLeod D, Lorino H, Farre´ R, Hantos Z, Desager K, caliber. However, due to high sensitivity, it has poor spec- Marchal F; ERS Task Force on Respiratory Impedance Measure- ificity for asthma or other unique disease states. The FOT ments. The forced oscillation technique in clinical practice: method- is easy to perform, but the equipment is sophisticated and ology, recommendations and future developments. Eur Respir J 2003; the method is very sensitive to upper airway shunting. 22(6):1026-1041. 7. Pride NB. Forced oscillation techniques for measuring mechanical Nevertheless, the FOT provides unique information re- properties of the respiratory system. Thorax 1992;47(4):317-320. lated to lung mechanics, information that is not available 8. Beydon N. Interrupter resistance: what’s feasible? Paediatr Respir by any other noninvasive technique. Measuring Rint also Rev 2006;7(Suppl):S5-S7. involves important technical issues and upper airway shunt, 9. Child F. The measurement of airways resistance using the interrupter but is well tolerated by very young children. There are no technique (Rint). Paediatr Respir Rev 2005;6(4):273-277. data comparing the clinical utility of these various mea- 10. Merkus P, Mijnsbergen J, Hop W, de Jongste J. Interrupter resistance in preschool children. Measurement characteristics and reference sures head to head with each other and with spirometry. As values. Am J Respir Crit Care Med 2001;163(6):1350-1355. with all clinical tests, interfacing the physiological data 11. Sly P, Lombardi E. Measurement of lung function in preschool chil- with the clinical picture is critical to properly using the dren using the interrupter technique. Thorax 2003;58(9):742-744. information in the care of the patient. 12. Bosse´ Y, Riesenfeld E, Pare´ P, Irvin C. It’s not all smooth muscle: non-smooth muscle elements in control of resistance to airflow. Ann Rev Physiol 2010;72:437-462. REFERENCES 13. Hayes D, Kraman S. The physiologic basis of spirometry. Respir Care 2009;54(12):1717-1726. 1. Blonshine S, Goldman M. Optimizing performance of respiratory 14. Macklem PT, Mead J. Resistance of central and peripheral airways airflow resistance measurements. Chest 2008;134(6):1304-1309. measured by a retrograde catheter. J Appl Physiol 1967;22:395-401.

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Discussion Dr Kaminsky was kind enough to ness and distress, the only end point display a methacholine provocation recognized by the testing lab was a

Pichurko: I thank Dr Kaminsky for dose-response slide representing one 20% drop in FEV1. Thus, the test his comments, and his interests cer- patient’s experience. This is admit- subject was given 2 additional doses, tainly overlap with my own. I wish to tedly an extreme one, but it highlights ultimately declining in FEV1 63% recognize my mentor Dr Roland In- a point. This was my patient who asked from baseline. She tuned cyanotic gram, who guided me through an in- to be tested at another hospital where and was emergently transported to vestigation and its publication1 on vol- she was employed. She returned af- the emergency department, where ume history as a determinant of terward describing a scenario that is she just barely escaped intubation. expiratory flow in asthma. I believe represented on the posted slide. Es- While there is understandably a lot this is an important issue in the per- sentially, afterinhaling a relatively low of discussion about excessive sensi- formance of spirometry during bron- concentration of methacholine, she tivities and false positive methacho- choprovocation. Two and a half de- felt tight and reported this to the tech- line responses, I am equally concerned cades of directing 6 pulmonary nician. The tech responded as appar- about false negatives. These occur due function laboratories has taught me entlyinstructed, “I’m sorry but I’m to the bronchodilating effects of deep that unrecognized volume history ef- obligated to keep giving you drug, inhalation to total lung capacity that fects are an important and typically because you have not yet declined accompanies all spirometric testing. unrecognized source of error in bron- the required amount.” So, despite her This serves to mitigate or even reverse choprovocation studies. reported and worsening chest tight- the constrictor response in mild and

96 RESPIRATORY CARE • JANUARY 2012 VOL 57 NO 1 WHAT DOES AIRWAY RESISTANCE TELL US ABOUT LUNG FUNCTION? some moderate asthmatic subjects, threshold airway measurement is ex- stand and be convinced that the which are precisely the people we send ceeded, but that we don’t ignore clin- medicine is doing some good. I will for methacholine bronchoprovocation. ical evidence of sustained and progres- say there’s a decent literature from the I would make the case that this may sive patient distress. This has improved 1970s and 1980s looking at this dif- be more consequential than false pos- test accuracy, but also recognizes the ferent response to bronchodilator and itives, as it produces apparently neg- subject’s safety. bronchoconstrictor in the central air- ative results in asthmatic individuals, ways versus peripheral airways. No- allowing these individuals at risk for Kaminsky: We do the same thing. body knows quite what to make of bronchospastic events to be reassured If we get to 8 mg and they’re cough- that, and it’s a hot topic now because by the test results and to go undiag- ing or have tightness, even though they we’re all interested in giving these nosed and untreated. Thus, their haven’t reached FEV1 criteria, but small particle HFA [hydrofluoroal- asthma goes unnoticed. they’ve reach conductance criteria by kane] solution steroids that penetrate If I had 3 wishes to be granted, the that point, I stop the test. deeper, but we don’t know the ulti- third wish would be that every lab per- mate clinical effect. I think there is forming methacholine provocation Busse: To go back to your first slide, something phenotypically different would be equipped to perform spirom- I don’t think what you presented was between asthmatics in particular who atypical. I’m not a pulmonary physi- have disease location in different parts etry and also Raw. I do think that 40% is a little bit low. We observe 50% ologist, but many times I’ll have peo- of their lung. Like you say, we just ple coming in who complain of short- don’t understand a lot about it yet. increase in Raw as threshold. Certainly, every pulmonary function lab medical ness of breath and use medications director should have a discussion with without relief. I’ll begin the measure- Busse: Right, we don’t know what their technicians and inform them of the ment of Raw, and they are abnormal part of the tree they’re on: the begin- confounding dilating effects of deep in- even though lung functions tend to be ning part of the tree or somewhere halation that limit the accuracy of spi- really quite normal. else. It’s amazing how long these rometry and may expose the test subject We began our discussion this morn- things have been around and how lit- to risk. ing talking about phenotypes, and tle sophistication we have in knowing asthma is a very broad definition and what to do with the data. 1. Pichurko BM, Ingram RH Jr. Effects of it may not encompass all things that airway tone and volume history on maxi- have altered physiology. And we don’t Coates: When I finished my train- mal expiratory flow in asthma. J Appl have good data, necessarily, on peo- ing, I thought I knew what cystic fi- Physiol 1987;62(3):1133-1140. ple who have just increases in Raw. brosis was, and I thought I knew what We don’t test them under various con- asthma was. And now I’m looking at Ruppel: I’d like to follow up on that. ditions, nor do we necessarily test them retirement, with cystic fibrosis being We also do Raw and conductance in after we’ve given them medications defined with a range between sterility conjunction with bronchial challenge, like inhaled corticosteroids. This is in males with no lung disease and no and we don’t have the technologist certainly not the usual approach to pa- gastrointestinal disease and the full- stop when they observe a 50% de- tients who come in with symptoms blown syndrome with severe bronchi- crease in conductance. We use con- compatible with asthma. In patients ectasis and malnutrition. We still know ventional criteria and look for the who have symptoms of asthma but it’s all related to the same protein, but change in FEV1. Would you consider largely normal lung function, vocal variations in expression and type of that a reasonable thing to do, or are cord dysfunction is a high probability. the defect change the presentation dra- we unduly putting the patients at risk? These individuals have an inspiratory matically. I think asthma has become loop cutoff. Addressing these patients way more complicated. The lung has Pichurko: There’s a third signal that requires going through an appropriate very few tricks up its sleeve, and re- we use. We call it sustained chest tight- differential diagnosis and matching the versible bronchospasm is one of those ness. This refers to the patient’s report lung function abnormalities to the clin- tricks. Hence, reversible bronchos- of progressive chest tightness lasting ical picture. pasm may have manifestations that we at least 2 minutes, sometimes com- may later come to understand as sev- bined with auscultation by the thera- Kaminsky: I would agree with you, eral different disease processes. pist to determine that air flow is re- but in this case the symptoms were Hence, I’m not surprised that we keep duced. Of the 3 lines of evidence (PC20 very responsive to the inhaler, and I seeing very different types of expres- FEV1,PC50 Raw, and sustained chest don’t know if that was a placebo ef- sions of asthma while we actually may tightness), we use 2 to conclude the fect or real. But we did document phys- be looking at different diseases that study. That assures that at least one iology that at least helps us under- we just haven’t sorted out yet.

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Kaminsky: I agree, and that’s why Hess: Not uncommonly, when we in- if they have any questions, and it’s some are calling asthma a syndrome tubate a patient with obstructive lung not uncommon for me to run up to the as opposed to a disease: because it disease, we’ll use volume control ven- lab and take a look at someone in the encompasses facets of different types tilation, set the flow to 60 L/min, 1 L/s, midst of their challenge to try and help of symptoms, airway dysfunction, in- measure the peak pressure, the pla- the techs determine if it’s safe to go flammation, and so on. teau pressure, determine the Raw, and, on or not. We try to put the clinical anecdotally, we think that information response to methacholine together Rundell:* You mentioned you mea- is useful and sometimes we follow it with both aspects of physiology. sure Raw as well as FEV1 during meth- serially over time. Is that a worthwhile acholine challenges. Do you do that thing to do? Do you do that in your Enright: Do you then take the re- all the time? practice? We can’t take the body box sponse to albuterol (the ability to into the ICU. quickly reverse the bronchospasm) Kaminsky: Yes. into account when interpreting the re- Kaminsky: The answer is yes, I sults? Rundell: Do you do other chal- think it is worthwhile, and we do that lenges? Exercise challenge or eucap- in our practice. We don’t follow Raw Kaminsky: I take it into consider- nic voluntary hyperventilation? per se, but I look at the difference ation, but it’s not the primary thing between peak and plateau pressure as we look at. As I’ve said before, I’ve Kaminsky: We do exercise chal- a surrogate for respiratory system re- never seen a patient not reverse. Some- lenge with the treadmill, and we only sistance. In obstructed patients this is times we have to give another 2 puffs. do spirometry during that challenge. also a valuable way to teach our fel- Typically we give 2, but sometimes it It’s physically located in a different lows and residents. When we’re giv- takes 4. Once we used ipratropium room than the body box, and the rooms ing bronchodilator therapy, one way thinking cholinergic/anticholinergic, are always going concurrently, so it we know the patient is getting better and that got the patient out of their makes it hard to do. is their peak pressures are coming methacholine tightness. We like to see

down, the difference in peak and pla- the FEV1 come back within 10% of Rundell: Now, have you found that teau pressure is narrowing, and pre- baseline before we discharge the pa- you see the changes in the Raw before sumably the patient is moving better tient. you see changes in the FEV1? air. But as we’ve been saying the whole conference, it’s not just one factor: Salzman: I’m not sure I was hearing Kaminsky: In terms of the metha- that’s one of many we’re looking at. the 2 of you correctly about this. choline testing? Yes, I use that as part of the monitor- You’re saying that you stopped the ing of these patients. test for safety reasons, even if you

Rundell: Yeah. haven’t dropped the FEV1, if you have Hnatiuk: When you said you use 2 symptoms, such as wheezing and Kaminsky: It’s highly variable. I of the 3 measures to stop the bron- coughing. Are you saying you call the can’t say I’ve seen a specific pattern choprovocation test, do you deem that test positive with just subjective end that’s consistent. positive then? points?

Hess:† If I can take the discussion Kaminsky: Yes. I don’t use 2 of our Kaminsky: No, I won’t call the test into the ICU just for a few minutes, 3 specifically, like Bo [Pichurko], but positive with just subjective end which I guess is fair because I heard for us the clinical impression still over- points. We like to see one of those 2 you say you just came off service in rides everything. If the patient is objective criteria being met in addi- the unit. coughing or tight, no matter what the tion to symptoms, but I’ll make a com- values are, the technologist will try to ment in my report that the patient did Kaminsky: And I mentioned a me- get a body box measurement and spi- develop wheezing and tightness and chanical ventilator in here, too! rometry at that point in time. Then, if they did not meet the “official” ATS/

either criteria are met, FEV1 or con- ERS criteria for positive response. ductance, we will stop. If the patient Then, and I’m not fudging on this, I’ll * Kenneth W Rundell PhD, Pharmaxis, Exton, is asymptomatic, we’ll go up to 16 mg, say this needs to be put into the clin- Pennsylvania. and we still continue to look for both ical context. If that was my patient, † Dean R Hess PhD RRT FAARC, Respiratory Care Services, Massachusetts General Hospital, responses. it’s still someone I might put on a Boston, Massachusetts, and Editor in Chief, One of my jobs as pulmonary-func- 6-week trial of inhaled corticosteroids RESPIRATORY CARE. tion-testing director is to be available and see how they do.

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Pichurko: Similarly, I would require has gone on, my understanding of the a negative challenge and I think it has exceeding the diagnostic threshold for ambiguities has increased. I think we a high specificity in that case. at least one of those objective mea- need to open things up a little bit and sures before concluding the provoca- look at these various characterizations Rundell: One last question. You’re tion study. The additional support of and responses to tests to give us some doing full FVC maneuvers then, dur- patient symptomatology serves to val- ideas about abnormalities in functions ing your methacholine challenge? idate the objective measure. and what they really mean. With Raw?

Coates: Didn’t we talk this morning Coates: No disagreement about that, Kaminsky: Yes, and we do the 5 about the idea that the methacholine because I am coughing and wheezing deep breaths method. challenge test was a good test to rule even though my PC20 is greater than out asthma? So, within what you just 10. Rundell: Do you train these patients said, how do we fit that? before you test them, for 6 weeks or Kaminsky: We have these arbitrary so? It seems that this would be very Kaminsky: To me, a negative test is cutoffs. This [showing an additional fatiguing for the patient and quite time someone who goes up to 16 and flies slide of a series of flow-volume loops consuming. With the Aridol bronchial through it, and there are no changes during a methacholine challenge that challenge test, we used only FEV1 physiologically, and they have no dis- illustrates progressive truncation of in- maneuvers after the baseline spirom- comfort. I don’t think they have asthma spiratory flow] is a patient who re- etry FVC maneuver, and with the meth- if they respond that way. sponded to methacholine with vocal acholine test we (and others) prefer the cord dysfunction. The FEV didn’t 1 FEV maneuver because of patient fa- Busse: Well, one could argue the change a bit. The conductance did 1 tigue.1 other way. Allan, I think we’ve de- change, as you would imagine, be- fined the positive response to metha- cause R elevated due to closure of aw 1. Pearlman D. A phase III multicenter study choline for what we consider to be the the cords. This is a nice example of to demonstrate the sensitivity and specific- classical, clinical asthma, haven’t we? someone who almost had no symp- ity of Aridol (mannitol) challenge to pre- You wonder if we’ve been overly con- toms: she kind of got a little cough dict bronchial hyper-responsiveness as strictive on what we’re calling a pos- and a little discomfort. I think we have manifested by a positive exercise challenge itive test as far as the disease is con- to take all the information together in in subjects presenting with signs and symptoms suggestive of asthma but without a cerned. Like you said, when I began making our clinical judgments. But if definitive diagnosis. http://clinicaltrials. work 35 years, ago I really felt like I everything goes smoothly, at least at gov/ct2/show/NCT00252291. Accessed knew a lot about asthma, and as time that point in time, I would consider it September 26, 2011.

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