what does airway resistance tell us about lung...

What Does Airway Resistance Tell Us About Lung Function?

David A Kaminsky MD

IntroductionPhysiologyMeasurement of Airway Resistance by Body Plethysmography

Clinical Utility of sRaw and sGaw

Measurement of Airway Resistance by the Forced Oscillation TechniqueMeasurement of Airway Resistance by the Interrupter TechniqueComparing sRaw, FOT, and Rint

Summary

Spirometry is considered the primary method to detect the air flow limitation associated withobstructive lung disease. However, air flow limitation is the end-result of many factors that con-tribute to obstructive lung disease. One of these factors is increased airway resistance. Airwayresistance is traditionally measured by relating air flow and driving pressure using body plethys-mography, thus deriving airway resistance (Raw), specific airway resistance (sRaw), and specificairway conductance (sGaw). Other methods to measure airway resistance include the forced oscil-lation technique (FOT), which allows calculation of respiratory system resistance (RRS) and reac-tance (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, makingthem particularly suited to patients who cannot perform spirometry, such as young children,patients with neuromuscular disorders, or patients on mechanical ventilation. Since spirometry alsorequires a deep inhalation, which can alter airway resistance, these alternative methods mayprovide more sensitive measures of airway resistance. Furthermore, the FOT provides uniqueinformation about lung mechanics that is not available from analysis using spirometry, bodyplethysmography, or the interrupter technique. However, it is unclear whether any of these mea-sures of airway resistance contribute clinically important information to the traditional measuresderived from spirometry (FEV1, FVC, and FEV1/FVC). The purpose of this paper is to review thephysiology and methodology of these measures of airway resistance, and then focus on their clinicalutility 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 andCritical Care Medicine, University of Vermont College of Medicine,Burlington, Vermont.

Dr Kaminsky presented a version of this paper at the 48th RESPIRATORY

CARE Journal Conference, “Pulmonary Function Testing,” heldMarch 25–27, 2011, in Tampa, Florida.

Dr Kaminsky has disclosed relationships with Medical Graphics and Merck.

Correspondence: David A Kaminsky MD, Pulmonary Disease and Crit-ical Care Medicine, University of Vermont College of Medicine, GivenD-213, 89 Beaumont Avenue, Burlington VT 05405. E-mail: [email protected].

DOI: 10.4187/respcare.01411

RESPIRATORY CARE • JANUARY 2012 VOL 57 NO 1 85

Introduction

Spirometry is considered the gold standard method tomeasure air flow limitation. However, since air flow lim-itation occurs in part due to increased airway resistance, itmakes sense that measuring airway resistance directly mayprovide additional information. Traditionally, airway re-sistance has been measured by relating air flow and driv-ing pressure through the use of body plethysmography,thus deriving airway resistance (Raw), specific airway re-sistance (sRaw), and specific airway conductance (sGaw).1-4

Other methods to measure airway resistance, which re-quire less cumbersome equipment and less patient tech-nique and cooperation, are the forced oscillation technique(FOT),5-7 which allows calculation of respiratory systemresistance (RRS) and reactance (XRS), and the interruptertechnique, which allows calculation of interrupter resis-tance (Rint).8-11 All of these methods may be used clini-cally, but a major question is whether they add anything tothe traditional measures derived from spirometry (FEV1,FVC, and FEV1/FVC). The purpose of this paper is toreview the physiology and methodology of each of thesemeasures of airway resistance, and then focus on theirclinical utility in relation to each other and to spirometry.

Physiology

Resistance to air flow in the lung is determined by mea-suring the pressure difference across the airways and di-viding this difference by the flow. When flow is laminarthrough a rigid tube, the pressure difference is related tothe characteristics of the tube and the gas through thePoiseuille equation (Fig. 1A):

�P � 8l�V/�r4 (1)

where l � the length of the tube, � � gas viscosity,V � flow, and r � the radius of the tube. Since resistanceis �P/V, this equation highlights key points about resis-tance under laminar flow conditions: resistance is relatedinversely to flow and directly to the length of the tube,varies inversely with the 4th power of the radius of thetube, and varies with the viscosity of the gas. When flowis turbulent, the Poiseuille equation is modified

�P � 8l�V2/�r4 (2)

where � � gas density (see Fig. 1B). This equation nowillustrates that under turbulent conditions, resistance varieswith gas density, not viscosity, and is no longer linearlyrelated to flow.12

In the human lung, laminar and turbulent flow bothcontribute to air flow, thus resulting in a mathematically

complex relationship between airway geometry, flow, andgas composition. In addition, the airways are flexible, notcollapsible, so flow limitation occurs based on wave speedtheory and the development of choke points.13 Finally, theairways are connected in both series and parallel, so thattotal airway resistances must be added in a reciprocal fash-ion:

1/Rtotal � 1/R1 � 1/R2 � … � 1/Rn (3)

Modeling total airway resistance reveals that, based ontotal cross sectional areas at each airway generation, air-way resistance initially falls from the trachea to genera-tion 4, then rises again in generations 5–8, before fallingoff dramatically in subsequent generations12 (Fig. 2). Atbreathing frequencies, small airways (� 2 mm in diame-ter) account for only 10% of total airway resistance,14-16

with the remainder arising from the viscoelastic propertiesof the lung parenchymal tissue (40%) and flow resistancein the larger airways (50%).17

Measurement of Airway Resistanceby Body Plethysmography

If one considers the lung as a simple, linear model madeup of a rigid tube attached to a flexible parenchymal com-partment, then the pressure required to move air into and

Fig. 1. A: Illustration of laminar flow through a rigid tube, where thepressure difference is related to the characteristics of the tube andthe gas through the Poiseuille equation: �P � 8l�V/�r4. B: Illus-tration of turbulent flow through a rigid tube, where the Poiseuilleequation is modified to �P � 8l�V2/�r4. (From Reference 12, withpermission.)

WHAT DOES AIRWAY RESISTANCE TELL US ABOUT LUNG FUNCTION?

86 RESPIRATORY CARE • JANUARY 2012 VOL 57 NO 1

out of the model can be expressed as the equation ofmotion for the system:

P � EV � RV � IV (4)

where P � pressure, V � volume, V � flow, V � accel-eration, and the constants E, R, and I, representing elas-tance, resistance, and inertance, respectively, determinethe mechanical properties of the system. One could theo-retically measure resistance if volume fluctuations are keptvery low (EV term approaches zero). The IV term wouldalready be negligible at breathing frequencies up to �8 Hz.Thus, P � RV, which we commonly recognize as the gaspressure-flow relationship analogous to Ohm’s law. In1956, Dubois and colleagues published their description ofa method to measure airway resistance using body pleth-ysmography, which essentially applied this simplified equa-tion of motion under conditions of low breathing volume.18

The rapid shallow panting maneuver involved in the air-way resistance measurement would also optimize the sig-nal-to-noise ratio and increase the accuracy of measure-ment by: minimizing thermal shifts and gas exchange;reducing glottic obstruction of the airway; minimizing flowturbulence and gas compression; and maintaining a rela-tively stable lung volume.1,18 To calculate resistance oneneeded to know flow and alveolar pressure; the formercould be measured directly, but the latter could not. WhatDubois realized was that under conditions of no-flow,mouth pressure would approximate alveolar pressure, andso he related flow to no-flow conditions to derive the

relationship of pressure to flow, and hence resistance19

(Fig. 3).An important technical factor that must be considered in

measuring airway resistance by body plethysmography isdeciding where to draw the slope of V versus box pressure,since different slopes can be drawn from the same flow-pressure loop when the loop has a complex configura-tion.1,20 For loops used in conjunction with thoracic gasvolume (TGV) to derive Raw, the slope is conventionallytaken at the transition between the end of inspiration andthe beginning of expiration between �0.5 and �0.5 L/sflow. Other slopes that can be drawn when calculatingsRaw (see below) include connecting the points of maxi-mal flow (sRaw-total), connecting the points of maximalvolume shift (sRaw-MaxVol), or connecting the mid-volumesat �0.5 L/s and �0.5 L/s (sRaw-Mid). In the case of bothRaw and sRaw, there may be circumstances where resis-tance is differentiated between inspiration and expiration.For example, Ingenito and colleagues demonstrated thatpatients undergoing lung-volume-reduction surgery for em-physema who had less elevated inspiratory resistance werethe ones more likely to demonstrate an increase in FEV1

following surgery21 (Fig. 4). They speculated that this wasbecause these patients were more likely to have more se-vere emphysema, which would lead to dynamic airwaycollapse from loss of parenchymal tethering. Reducinglung volume via surgery in such patients is thought toimprove elastic recoil.

Fig. 2. Relationship of total airway resistance to airway generation.Computational modeling reveals that, based on total cross sec-tional areas at each airway generation, airway resistance initiallyfalls from the trachea to generation 4, then rises again in genera-tions 5–8, before falling off dramatically in subsequent genera-tions. (From Reference 12, with permission.)

Fig. 3. Relationship of mouth pressure (Pmo) and box pressure(Pbox) by body plethysmography under closed-loop panting con-ditions (left) and open-loop panting conditions (right). Under con-ditions of no-flow (left), mouth pressure would approximate alve-olar pressure, so the relationship of alveolar pressure to change inlung volume (as determined by change in box pressure) is mea-sured. When the shutter is opened (right), the relationship betweenflow and lung volume (change in box pressure) is measured. Air-way resistance (Raw) is calculated as the change in alveolar pres-sure (Palv) divided by flow, which is derived by multiplying theslope of the closed shutter maneuver and the inverse slope of theopen shutter maneuver, with the lung volume terms cancelling out.(From Reference 3, with permission.)



Airway resistance as measured by body plethysmogra-phy is usually expressed as Raw. Since Raw varies withlung volume, and lung volume may vary under differentexperimental conditions or different times of measurement,Raw is usually corrected for lung volume by expressing itas sRaw or sGaw. When measured in conjunction with TGV(from a closed shutter maneuver), the reciprocal of Raw,Gaw, is divided by the TGV at which the measurement wasmade to derive sGaw, which now expresses Raw indepen-dent of lung volume (Fig. 5). Thus, sGaw is a stable mea-sure that can be used in serial studies of Raw. The in-creased sensitivity of sGaw for airway resistance comparedto FEV1 is especially useful in pharmacologic studies thatinvolve normal healthy subjects.4 However, sGaw is lessreproducible, making repeated measurements important todetermine an accurate mean value, and there are limitedstudies establishing normal values.4 It should be noted thatin patients with airways disease such as asthma, the as-sumption of mouth pressure equal to alveolar pressure atzero flow may not hold true, and in fact TGV may beoverestimated.22 This, in turn, would alter the calculationand accuracy of sGaw.

In children, the closed shutter maneuver may be diffi-cult to achieve, so TGV cannot be measured. Instead, flowis related to the small shifts in lung volume that occurduring tidal breathing to derive sRaw.1,2,20,23,24 Mathemat-ically, the relationship between pressure and flow duringpanting and its relationship to TGV (ie, Raw) is equivalentto dividing sRaw by TGV, so Raw � sRaw/TGV, orsRaw � Raw � TGV.2,20 This latter expression reveals thatsRaw reflects not only Raw but also lung volume, and is nota resistance per se, but rather a form of work (pressure �

volume).2,20 Thus, sRaw reflects the work related to changesin lung volume while overcoming a fixed resistance, whileRaw reflects the pressure related to air flow. Because sRaw

encompasses lung volume, and Raw and lung volume varyinversely, sRaw is relatively stable with respect to changesin lung volume (ie, as lung volume decreases, Raw in-creases, so the product sRaw remains the same, and viceversa). In this way, sRaw is similar to sGaw because it takesinto account lung volume. However, sGaw reflects onlyRaw, whereas sRaw reflects both Raw and lung volume.This may be illustrated by considering an obstructed pa-tient with hyperinflation versus an obstructed patient with-out hyperinflation.2 In the former, Raw is elevated andsRaw is increased (increased work to move air through ahigher lung volume), but the increased TGV associatedwith hyperinflation corrects conductance back to normal(normal sGaw). In the latter, Raw is increased and sRaw isincreased (increased work to move air through an increasedresistance), but sGaw is reduced (elevated Raw is not re-duced by altered lung volume).

Clinical Utility of sRaw and sGaw

Due to geometric considerations, whereby the total crosssectional area of the airways decreases dramatically as onemoves from the periphery to the central regions of thelung, any measure of overall airway resistance, like sGaw,will be very sensitive to central airway pathology but lesssensitive to peripheral changes. Thus, sGaw may pick upchanges in large central airways that may be missed byspirometry. Indeed, sGaw has been shown to be sensitive toupper airway involvement in vocal cord dysfunction25 andvocal cord paralysis.26 However, this is not necessarilytrue in all cases, as one study has shown that sGaw was

Fig. 5. Relationship between airway resistance (Raw) and lung vol-ume, the reciprocal of Raw (conductance of the airways [Gaw]) andlung volume, and Gaw/TGV (thoracic gas volume) (specific airwayconductance [sGaw]) and lung volume. Notice that only sGaw isindependent of lung volume. RV � residual volume. FRC � func-tional residual capacity. TLC � total lung capacity. (From Refer-ence 3, with permission.)Fig. 4. Relationship between change in FEV1 following surgery

versus inspiratory lung resistance at baseline in patients undergo-ing lung-volume-reduction surgery. The lower the resistance, themore the FEV1 improved after surgery. (From Reference 21, withpermission.)



more sensitive than FEV1 in bronchiolitis obliterans syn-drome, a disease confined to the lung periphery. This mayrelate to the loss of sensitivity of FEV1 due to the deepinhalation involved (see below).27

Theoretically sGaw should be sensitive to changes inresistance anywhere along the airway, whereas FEV1 willbe sensitive to only those changes occurring upstream fromthe choke point.28 Thus, depending on the location of air-way narrowing or dilation in response to a bronchocon-strictor or bronchodilator, the FEV1 may change withoutsignificant change in sGaw, or vice versa.28 In the case ofairway narrowing, hyperinflation might result. Smith andcolleagues found that spirometry alone failed to find bron-chodilator reversibility in 15% of patients with suspectedreversible airway obstruction and clinical responses to bron-chodilator, but that these patients could be identified bychanges in sGaw or TGV or isovolume maximal flow29

(Fig. 6). These results suggest that the patients involvedwere responding to bronchodilator by changes in lung vol-ume-related parameters but not changes in spirometry.Since these patients had clinical improvement, such vol-ume-related changes are clinically relevant.

Another factor to consider in differentiating sGaw fromFEV1 is the deep breath necessarily associated with per-forming spirometry, but not part of the sGaw measure.Healthy subjects and those with mild asthma tend to bron-chodilate after a deep inhalation, so mild bronchoconstric-tion could be masked by the bronchodilating effects ofmeasuring FEV1, but should still be evident by sGaw.30

This would make sGaw a more sensitive test to detectair-flow limitation, especially in mildly obstructed patients.Many studies have investigated the relative response inFEV1 versus sGaw during bronchial challenge tests. In 1983,

Dehaut and colleagues demonstrated that the PC40 (provo-cational concentration that produces a 40% decrease) insGaw was more sensitive than the PC20 FEV1 at detectingbronchoconstriction to inhaled histamine, but the PC20 wasa more reproducible measure (coefficient of varia-tion � 2.6% vs 10%).31 Goldstein and colleagues haveshown that adding non-FEV1 parameters, such as sGaw, toFEV1 during a methacholine challenge test increases thesensitivity of the test, although most of the increase wasdue to addition of FVC and the forced expiratory flowduring the middle half of the FVC maneuver (FEF25–75).32

Recently, Khalid and colleagues questioned the 40%cutoff for positivity of the PC sGaw during methacholinechallenge.33 Based simply on comparing the PC20 FEV1

with the change in sGaw at that level in patients withsuspected asthma, they found that the mean change insGaw was 56%. Further analysis by receiver-operator char-acteristic curves suggested that the optimal cutoff was achange of 52%. While this is only slightly higher than thecurrently accepted 40% change, it does suggest that aslightly higher cutoff may be more appropriate by enhanc-ing the predicative value of the test. The cost of a test withsuch high sensitivity is typically loss of specificity. In-deed, many years ago Fish and colleagues demonstratedthat sGaw was less specific at distinguishing normal fromasthmatic subjects than FEV1.34 The authors proposed thatthe airways hyper-responsiveness that characterizes asthmamight be less a reflection of intrinsic increased respon-siveness of the airways than an impaired ability to bron-chodilate their constricted airways.35

Another study demonstrated that when the methacho-line challenge test was negative, small changes in FEV1,but not in sGaw, were predictive of future development ofasthma, suggesting again that the FEV1 is a more specificmeasure for asthma.36 When Parker and colleagues com-pared patients who responded to methacholine with changesin sGaw, but not in FEV1, to those who responded by FEV1

only, they found that such patients had smaller lung vol-umes, higher FEV, and higher FEF25–75/FVC, indicativeof relatively larger airway to lung size, a mismatch re-ferred to as lung dysanapsis.37 Patients with lung dysanap-sis with smaller airway to lung size (lower FEF25–75) havebeen found to be more hyper-responsive than those with-out in the Normative Aging Study.38 Thus, comparing re-sponses in FEV1 and sGaw may lend insight into the basicphysical relationship between airway size and lung size.

As mentioned above, sRaw is commonly used in chil-dren but is rarely used in adults.39 Details regarding tech-niques of measurement, quality control, and interpretationare available in recent, excellent reviews.20,23,24,40 sRaw hasbeen measured in children as young as 2 years old, and hasbeen used in assessment of bronchodilators and responseto methacholine, histamine, and cold air.24 Other studieshave included measuring the effects of short- and long-

Fig. 6. The phenomenon of an isovolume shift is illustrated byplotting flow-volume loops before and after bronchodilator on anabsolute volume scale. At isovolume (vertical line), flow is increasedin the post-bronchodilator, compared to the pre-bronchodilator,loop, despite no change in FEV1 or FVC.



acting bronchodilators, inhaled corticosteroids, and leuko-triene receptor antagonists in asthmatic children.20 Serialmeasurements have been made in children with cystic fi-brosis and demonstrated more consistent abnormalities thaneither FOT or Rint.41 Since sRaw is primarily used in chil-dren, normative data are mainly limited to pediat-rics.20,23,24,40 As most of the children involved in thesestudies would likely not have been able to perform reliablespirometry, using sRaw as a measure of airways disease isa valuable tool in pediatric lung disease.

Measurement of Airway Resistanceby the Forced Oscillation Technique

Another non-spirometric method to measure airway re-sistance is the FOT. First described by Dubois in 1956,42

the FOT involves applying a forced perturbation of flow atthe mouth and measuring the resulting pressure.5-7 Thisoccurs while the subject continues to breathe quietly. Theapplied flow is typically either pseudorandom in nature,meaning composed of many, typically mutually prime,frequencies, or truly random, as generated by a mechanicalimpulse. In both cases, the ratio of pressure measured toflow applied is analyzed across the frequency domain byfast Fourier transformation to arrive at a complex numberknown as the impedance of the respiratory system (ZRS).Impedance encompasses all the forces that hinder air flowinto and out of the lung, and thus include the resistance,elastance, and inertance of the system. The component ofZRS in-phase with flow is the real component, respiratorysystem resistance (RRS), and this reflects the energy dis-sipated due to resistive losses. The components of ZRS

out-of-phase with flow make up the imaginary component,respiratory system reactance (XRS). The reactance, in turn,is made up of out-of-phase lagging flow, which is elas-tance, and out-of-phase leading flow, which is inertance;both of these components reflect energy storage. Whenplotted against frequency, ZRS demonstrates a relativelyfrequency-independent resistance in healthy subjects, ex-cept at the very lowest frequencies (� 1 Hz), where neg-ative frequency dependence occurs. This is thought to re-flect tissue viscoelastic properties in healthy subjects, whilethere is increased frequency dependence of resistance dueto mechanical inhomogeneities in subjects with obstruc-tive diseases like asthma or COPD.43 Reactance is fre-quency-dependent in all subjects, but enhanced in thosewith obstructive lung disease, where reactance values aremore negative. Where the XRS curve crosses zero, theelastance and inertance values are equal and opposite, andthe frequency at which this occurs is the resonant fre-quency. With increasing degrees of obstruction, the XRS

curve is shifted to the right, the resonant frequency isincreased, and the area under the XRS curve (AX) is in-creased.5 Impedance data at breathing frequencies reveal a

substantial contribution of tissue viscoelastance to totalrespiratory resistance. In general, lower frequency data(� 5 Hz) reflect the more peripheral regions of the lung,while higher frequency data (� 8 Hz) are most represen-tative of the larger, central airways.43

Unlike Raw measured by body plethysmography, theresistance measured by the FOT represents total respira-tory system resistance, and thus contains contributions fromboth the lung and chest wall. At 6 Hz, RRS by the FOT isvery comparable to Raw, but slightly higher due to contri-butions from the chest wall.44,45 At higher frequencies,RRS by the FOT tends to underestimate Raw, especially athigher Raw values, likely due to shunting of flow into theupper airways (ie, cheeks, floor of mouth).44,45 Since theFOT is performed during tidal breathing, no deep breathsare involved that might interfere with measurement. Be-cause of this, RRS by the FOT is highly sensitive to changesin bronchial tone, but is less specific for asthma or otherunique disease states.

The FOT has become popular because of its ease ofadministration. It requires minimal subject cooperation andis thus suitable for use in children and any patient whocannot cooperate or manage spirometry (eg, ventilated pa-tients, paralyzed patients). There is only one commerciallyavailable FOT system in the United States, called the im-pulse oscillometry system. This device uses an impulse offlow made up of random frequencies and amplitudes tocompute RRS and XRS. Compared to the traditional FOTusing pseudorandom noise, resistance measured by theimpulse oscillometry system tends to overestimate RRS bythe FOT at lower frequencies, and Raw at all frequencies,likely due to non-linearities involved in measurement.45

The RRS by the impulse oscillometry system and the FOTagree well at higher frequencies (25 Hz).45

The FOT has been used in many applications, includingdifferentiating healthy from obstructed patients in COPDand asthma; detecting bronchoconstriction, which occursat lower doses of methacholine for impulse oscillometrysystem resistance than for FEV1

46; and measuring the se-verity of obstruction in asthma and COPD47,48 (Fig. 7).Methacholine-induced dyspnea is significantly associatedwith changes in RRS and XRS at 5 Hz (R5 and X5, respec-tively), but not changes in FEV1, suggesting that theseFOT measures are more sensitive to symptoms.49 How-ever, Houghton and colleagues have shown that the mostsensitive method varies between healthy and asthmaticsubjects, and with the degree of severity in asthma.50 Astatistical analysis found that some FOT parameters, in-cluding R5, are more sensitive than FEV1 in detectingbronchodilation in asthmatic subjects.51

Since the FOT requires no patient cooperation or tech-nique, it can be applied widely in many clinical settings.Indeed, the FOT is well suited to studies in children, theelderly, and any patients who cannot perform spirometry,



such as those with neuromuscular disease or on mechan-ical ventilation.6 For example, only impulse oscillometrybronchodilator responses, and not responses measured byFEV1, were able to distinguish 4-year-old children at riskfor persistent asthma participating in the Childhood AsthmaPrevention Study.52 A similar finding was seen in a cohortof children form Belgium.53 It also has unique applicationin studies of sleep and patients on mechanical ventilation,where the oscillatory signal can be applied on top of tidalbreathing.6 In all these situations, measuring FOT resis-tance will lend insight into the presence and severity ofobstructive disease.

More studies are also focusing on the XRS component ofZRS, which may yield different information related to theelastic properties of the lung. In some cases increased XRS

may be related to reduced lung volume due to airwayclosure. Indeed, Walker and colleagues showed that in

moderate to severe COPD, the fall in FEV1 with metha-choline was more closely related to a fall in XRS than a risein RRS, and this occurred in association with a decrease ininspiratory capacity, suggesting that airway closure wasthe main response to methacholine.54 Asthmatics had asmaller change in lung volume and a larger change in RRS,suggesting more of an airway response in asthmatics. Inother cases the increase in XRS is thought to represent anartifact of central airway shunting, which occurs underconditions of extreme peripheral airway resistance, lead-ing to shunting of forced flow into the more central air-ways.55 Reactance has been noted to differentiate mildair-flow obstruction before changes in RRS occur56 andmay detect flow limitation in patients with COPD.57 Alsoin COPD, Kolsum and colleagues have shown that R5, X5,and resonant frequency were significantly associated withFEV1, sGaw, total lung capacity, RV, and inspiratory ca-

Fig. 7. Impedance data from patients with asthma (left) and COPD (right) according to severity of underlying disease. Notice the consistentrelationship between diseases of the changes in respiratory system resistance (RRS) and respiratory system reactance (XRS) with increasingseverity. 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.)



pacity, with the strongest associations between X5 andresonant frequency and FEV1, and X5 and resonant fre-quency and sGaw.58 A recent study in pediatric asthma hasshown that only reactance area (AX) continues to improveafter the initial 12 weeks of therapy with inhaled flutica-sone during a 48-week total study.59 The authors speculatethat this might reflect ongoing improvement in small air-way function in these patients. Two studies from Japannote that XRS relates more closely with quality of lifemeasures than FEV1 in both patients with asthma60 andCOPD.61

One of the benefits of the FOT is that one can separatelymeasure inspiratory from expiratory parameters. Using thistechnique, Paredi and colleagues have shown that whilewhole breath impulse oscillometry could not differentiatepatients with asthma and COPD, patients with COPD hadhigher mean expiratory X5 than those with asthma, whichthey thought might be due to enhanced dynamic airwaynarrowing on expiration in these patients.62 Another studyhas shown that in comparing FOT in patients with asthmaand COPD, only patients with COPD show a significantdifference in XRS between inspiration and expiration63

(Fig. 8). The authors speculate that the same process ofdynamic airway narrowing on expiration due to loss ofrecoil in COPD may explain this phenomenon. Interest-ingly, this theory mirrors the concept suggested by In-genito and colleagues, mentioned above, that describes therelationship between outcomes from LVRS and inspira-tory resistance.21 High inspiratory resistance may not onlyreflect differences in underlying physiology, but may re-

late to the pathogenesis of airway inflammation64 and acutelung injury.65

The methodology and analysis of FOT data are com-plex. The European Respiratory Society has publishedguidelines on methodology in 2003,6 but there have beenno updates since then. In general, the repeatability of thetechnique is similar to Raw from body plethysmographyand interrupter resistance (see below). The correlation withspirometry is highly variable, in part because of the deepbreath involved in spirometry, and in part due to the dif-fering mechanics assessed by the two techniques.5 TheFOT is subject to strong influence by upper airway shunt-ing, and this must be carefully controlled. Interestingly,the FOT does not yield distinctive data in patients withrestrictive lung disease.6 Many regression equations arenow available, but they each come from different popula-tions and use different devices and techniques, so theirapplicability is limited.6

The FOT is used commonly in research, from clinicalstudies to basic studies of lung mechanics. For example,Kaczka and colleagues have described the association ofmore severe asthma with increasing frequency dependenceof elastance, thought to be due to more severe peripheralairway resistance causing shunting of flow back into cen-tral airways.55 In a different study, Kaminsky and col-leagues have uniquely demonstrated hyper-responsivenessof the lung periphery in participants with asthma using theFOT.66 Because interpretation of ZRS depends on lungmodels, the technique yields information in relation tosuch models, and therefore is also limited by the propertiesof the model in use.67

Measurement of Airway Resistanceby the Interrupter Technique

A third method to noninvasively measure airway resis-tance, used primarily in children, is the interrupter tech-nique.8,9,11,68,69 The concept here is similar to that used inbody plethysmography, in that the alveolar pressure isestimated by mouth pressure during transient occlusion offlow. In this case, flow is occluded intermittently duringspontaneous breathing, and the mouth pressure recordedimmediately after the occlusion is related to the air flowmeasured immediately before the occlusion to calculateresistance. The display of data is unique and is importantfor monitoring for quality. During expiration, initially thereis a sharp increase in pressure, reflecting central airwayresistance, followed by rapid, damped oscillations of pres-sure, and finally a slowly rising steady pressure thought tobe due to tissue viscoelasticity9,11,69 (Fig. 9).

The pressure used for calculation of Rint is ideally im-mediately after occlusion, but in reality is back extrapo-lated to 15 ms after occlusion based on the slope of pres-sure between 30 and 70 ms after occlusion. Like the FOT,

Fig. 8. Comparison of change in respiratory system resistance at5 Hz (RRS5) and respiratory system reactance at 5 Hz (XRS5) be-tween inspiration and expiration in healthy control subjects, andsubjects with asthma and COPD. Notice that only the patients withCOPD had significant differences in XRS5 between inspiration andexpiration, differentiating them from both control subjects and sub-jects with asthma. (From Reference 63, with permission.)



numerous technical factors are important, such as reducingupper airway shunt by firm support of the cheeks and floorof mouth, timing of valve closure, taking the mean ormedian of repeated values, and use of a face mask or amouthpiece.8,68-70 Also, similar to the body plethysmogra-phy technique, the assumption of equilibration betweenmouth and alveolar pressure at zero flow may not hold truein patients with substantial airway heterogeneities. Be-cause it is noninvasive and performed during normal breath-ing, the technique is especially suitable for use in youngchildren, and has been demonstrated feasible in children asyoung as 2 years old. The intra-subject coefficient of vari-ation is similar to that of FOT (5–15%). There is a smallgroup of reference equations that derive from pediatricstudies.69

Clinically, Rint has been used in discriminating betweendifferent phenotypes of wheezy children and betweenhealthy children and children with asthma.69 In the lattergroup, a correlation coefficient of 0.73 was found for base-line values of spirometry and Rint.71 Rint has been used inconjunction with other measures to evaluate bronchodila-tor response in asthmatic children. As to discriminatingcapacity, Raw, R5, Rint, and X5 were found to be useful,with positive predictive values of 84%, 74%, 82%, and76%, respectively.72 The interrupter technique has alsobeen used to evaluate the response to cold air inhalation,

inhaled fluticasone,73 and oral montelukast therapy.74 Oneissue with the interrupter technique is determining the bestcutoff for bronchoconstrictor response. In adults, Sund-blad and colleagues have shown that a 20% change inFEV1 following methacholine corresponds to different lev-els of change of Gaw (reciprocal of Rint) determined by theinterrupter technique, depending on the underlying degreeof bronchial responsiveness, in this case, to a 39% changein Gaw in all subjects, but a 66% change in less responsivesubjects 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 re-sponsiveness.

Comparing sRaw, FOT, and Rint

There are limited studies directly comparing the aboveindices, and by their nature, appear mainly in children.Even though all 3 measures are based on differing me-chanical principles, in general all show consistent changesin relation to disease state or response to bronchodilator orbronchoconstrictor. These measures tend to be more sen-sitive to detection of bronchodilation and bronchoconstric-tion than FEV1, with one study demonstrating that Raw

was more sensitive than FOT and Rint in detecting bron-choconstriction in normal subjects.44 Technical factors arecritical in deriving robust measurements, with special at-tention given to reducing thermal artifact in sRaw mea-sures, and upper airway shunting in FOT and Rint. In chil-dren, all 3 measures have shown higher values in childrenwith asthma, but there is no clear agreement on cutoffs forabnormal values. This is especially important because evenhealthy children demonstrate reduced resistance in responseto bronchodilators when using these highly sensitive mea-sures. All 3 measures are commonly abnormal in youngchildren with asthma, but none appear to associate withclinical outcomes assessed 3 years later.76 sGaw, FOT, andRint allow differentiation of inspiratory and expiratory re-sistance, and the dynamic looping of resistance and flow,as seen by the sRaw and FOT methods, may yield impor-tant information about laryngeal narrowing, a commonoccurrence during testing. The FOT uniquely also pro-vides information about frequency dependence and reac-tance, which yield additional insight into peripheral airwaymechanics and inhomogeneities.5,7,43 A summary of thespecific measurement properties of FEV1 in comparison tosRaw, sGaw, FOT-R, and Rint is shown in Table 1.

Summary

Spirometry remains the gold standard pulmonary func-tion test for determining the presence and severity of air-flow limitation. However, spirometry has some key limi-tations: it is effort dependent and requires patient

Fig. 9. Pressure versus time during an interrupter maneuver duringexpiration. At time 0 the airway is transiently occluded, resulting inan abrupt spike in pressure, reflecting the initial pressure changeacross the respiratory system. The pressure then oscillates brieflybefore slowly climbing as pressure rises from viscoelastic prop-erties and gas redistribution in the lung. By convention, a commonmethod to calculate interrupter resistance (Rint) is to take the pres-sure at �15 ms determined by back extrapolation from t�30 andt�70 ms, and divide this pressure by the flow immediately beforethe occlusion. (From Reference 69, with permission.)



cooperation and skill; it involves a deep breath, which canalter underlying airway resistance; and it provides limitedinsight into lung mechanics. For patients who cannot per-form spirometry, measuring airway resistance with sRaw,FOT, or Rint remain important options. Measuring sRaw bybody plethysmography involves bulky equipment that doesnot allow portable measurement, and it provides an indexthat reflects both Raw and lung volume. In adults, sGaw istypically used, and provides a sensitive measure of airwaycaliber. However, due to high sensitivity, it has poor spec-ificity for asthma or other unique disease states. The FOTis easy to perform, but the equipment is sophisticated andthe method is very sensitive to upper airway shunting.Nevertheless, the FOT provides unique information re-lated to lung mechanics, information that is not availableby any other noninvasive technique. Measuring Rint alsoinvolves important technical issues and upper airway shunt,but is well tolerated by very young children. There are nodata comparing the clinical utility of these various mea-sures head to head with each other and with spirometry. Aswith all clinical tests, interfacing the physiological datawith the clinical picture is critical to properly using theinformation in the care of the patient.

REFERENCES

1. Blonshine S, Goldman M. Optimizing performance of respiratoryairflow resistance measurements. Chest 2008;134(6):1304-1309.

2. Criee C, Sorichter S, Smith H, Kardos P, Merget R, Heise D, BerdelD, et al. Body plethysmography—its principles and clinical use.Respir Med 2011;105(7):959-971.

3. Kaminsky D, Irvin C. Lung function in asthma. In: Barnes P, GrunsteinM, Leff A, Woolcock A, editors. Asthma. New York: Lippincott-Raven; 1997:1289.

4. Tattersfield A, Keeping I. Assessing change in airway calibre - mea-surement of airway resistance. Brit J Clin Pharm 1979;8(4):307-319.

5. Goldman M. Clinical application of forced oscillation. Pulm PharmTher 2001;14(5):341-350.

6. Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager K,Marchal F; ERS Task Force on Respiratory Impedance Measure-ments. The forced oscillation technique in clinical practice: method-ology, recommendations and future developments. Eur Respir J 2003;22(6):1026-1041.

7. Pride NB. Forced oscillation techniques for measuring mechanicalproperties of the respiratory system. Thorax 1992;47(4):317-320.

8. Beydon N. Interrupter resistance: what’s feasible? Paediatr RespirRev 2006;7(Suppl):S5-S7.

9. Child F. The measurement of airways resistance using the interruptertechnique (Rint). Paediatr Respir Rev 2005;6(4):273-277.

10. Merkus P, Mijnsbergen J, Hop W, de Jongste J. Interrupter resistancein preschool children. Measurement characteristics and referencevalues. Am J Respir Crit Care Med 2001;163(6):1350-1355.

11. Sly P, Lombardi E. Measurement of lung function in preschool chil-dren using the interrupter technique. Thorax 2003;58(9):742-744.

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. AnnRev Physiol 2010;72:437-462.

13. Hayes D, Kraman S. The physiologic basis of spirometry. RespirCare 2009;54(12):1717-1726.

14. Macklem PT, Mead J. Resistance of central and peripheral airwaysmeasured by a retrograde catheter. J Appl Physiol 1967;22:395-401.

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

Spirometry(FEV1)

Plethysmography(sRaw, sGaw)

RintFOT(RRS)

Patient cooperation/effort ��

Involves deep inhalation �� – – –Adjusts for lung volume – � – –Intra-subject variability (coefficient

of variation)5,6,31,44,69,77,783–5% 8–13% 5–15% 5–15%

Sensitivity to airway locationCentral � ��

Peripheral ��

Cutoff for bronchodilator/bronchoconstrictor6,20,24,69,78,79

12/20% 25/40% 35%/3SDw 40/50%

Insight into mechanics � � � ��

Global, nonspecific Raw, TGV Lung � chest wall Lung � chest wallStandardized methodology ��

Reference equations2,6,10,69,78 �� (pediatric) ��

� to �� Yes, with increasing strength or prevalence of feature– � NosRaw � specific airway resistancesGaw � specific airway conductanceRint � interrupter resistanceFOT � forced oscillation techniqueRRS � respiratory system resistanceSDw � within-subject standard deviationTGV� thoracic gas volume



15. Mead J. The lung’s “quiet zone”. N Engl J Med 1970;282(23):1318-1319.

16. Woolcock AJ, Vincent NJ, Macklem PT. Frequency dependence ofcompliance as a test for obstruction in the small airways. J Clin Inv1969;48(6):1097-1106.

17. Kaczka DW, Ingenito E, Suki B, Lutchen KR. Partitioning airwayand lung tissue resistances in humans: effects of bronchoconstriction.J Appl Physiol 1997;82(5):1531-1541.

18. Dubois A, Botelho S, Bedell G, Marshall R, Comroe J. A newmethod for measuring airway resistance in man using a body ple-thysmograph; values in normal subjects and in patients with respi-ratory disease. J Clin Invest 1956;35:327-335.

19. Dubois A. Airway resistance. Am J Respir Crit Care Med 2000;162(2 Pt 1):345-346.

20. Bisgaaard H, Nielsen K. Plethysmographic measurements of specificairway resistance in young children. Chest 2005;128:355-362.

21. Ingenito E, Evans R, Loring S, Kaczka D, Rodenhouse J, Body S,Sugarbaker D, et al. Relation between preoperative inspiratory lungresistance and the outcome of lung volume reduction surgery foremphysema. N Engl J Med 1998;338(17):1181-1185.

22. Shore S, Milic-Emili J, Martin J. Reassessment of body plethysmo-graphic technique for the measurement of thoracic gas volume inasthmatics. Am Rev Respir Dis 1982;126(3):515-520.

23. Klug B, Bisgaaard H. Measurement of the specific airway resistanceby plethysmography in young children accompanied by an adult. EurRespir J 1997;10(7):1599-1605.

24. Nielsen K. Plethysmographic specific airway resistance. PaediatrRespir Rev 2006;7(Suppl):S17-S19.

25. Vlahakis N, Patel A, Maragos N, Beck K. Diagnosis of vocal corddysfunction. The utility of spirometry and plethysmography. Chest2002;122(6):2246-2249.

26. Zapletal A, Kurland G, Boas S, Noyes B, Greally P, Faro A, Armit-age J, et al. Airway function tests and vocal cord paralysis in lungtransplant recipients. Pediatr Pulmonol 1997;23(2):87-94.

27. Bassiri A, Girgis R, Doyle R, Theodore J. Detection of small airwaydysfunction using specific airway conductance. Chest 1997;111(6):1533-1535.

28. Macklem P. The interpretation of lung function tests. In: HargreaveF, Woolcock A, editors. Airway responsiveness: measurement andinterpretation. Quebec: Astra; 1983:69-72.

29. Smith H, Irvin C, Cherniack R. The utility of spirometry in thediagnosis of reversible airways obstruction. Chest 1992;101(6):1577-1581.

30. Orehek J. Influence of lung volume history on measurement of air-way responsiveness. In: Hargreave F, Woolcock A, editors. Airwayresponsiveness: measurement and interpretation. Quebec: Astra;1983:73-75.

31. Dehaut P, Rachiele A, Martin RR, Malo JL. Histamine dose-re-sponse curves in asthma: reproducibility and sensitivity of differentindices to assess response. Thorax 1983;38(7):516-522.

32. Goldstein M, Pacana S, Dvorin D, Dunsky E. Retrospective analysesof methacholine inhalation challenges. Chest 1994;105(4):1082-1088.

33. Khalid I, Morris ZQ, DiGiovine B. Specific conductance criteria fora positive methacholine challenge test: are the American Thoracic So-ciety guidelines rather generous? Respir Care 2009;54(9):1168-1174.

34. Fish J, Peterman V, Cugell D. Effect of deep inspiration on airwayconductance in subjects with allergic rhinitis and allergic asthma. JAllergy Clin Immunol 1977;60(1):41-46.

35. Fish J, Ankin M, Kelly J, Peterman V. Regulation of bronchomotortone by lung inflation in asthmatic and non-asthmatic subjects. J AppPhysiol 1981;50(5):1079-1086.

36. Khalid I, Obeid I, DiGiovine B, Khalid U, Morris Z. Predictive valueof sGaw, FEF25-75, and FEV1 for development of asthma after anegative methacholine challenge test J Asthma 2009;46(3):284-290.

37. Parker A, McCool F. Pulmonary function characteristics in patientswith different patterns of methacholine airway hyperresponsiveness.Chest 2002;121(6):1818-1823.

38. Litonjua A, Sparrow D, Weiss S. The FEF25-75/FVC ratio is associ-ated with methacholine airway responsiveness. The normative agingstudy. Am J Respir Crit Care Med 1999;159(5 Pt 1):1574-1579.

39. Fasano V, Raiteri L, Bucchioni E, Guerra S, Cantarella G, MassariM, et al. Increased frequency dependence of specific airway resis-tance in patients with laryngial hemiplegia. Eur Respir J 2001;18(6):1003-1008.

40. Stocks J, Godfrey S, Beardsmore C, Bar-Yishay E, Castile R; ATS/ERS Task Force on Standards for Infant Respiratory Function Test-ing. Plethysmographic measurements of lung volume and airwayresistance. Eur Respir J 2001;17(2):302-312.

41. Nielsen K, Pressler T, Klug B, Koch C, Bisgaaard H. Serial lungfunction and responsiveness in cystic fibrosis during early childhood.Am J Respir Crit Care Med 2004;169(11):1209-1216.

42. Dubois A, Brody A, Lewis D, Burgess B. Oscillation mechanics oflungs and chest in man. J Appl Physiol 1956;8(6):587-594.

43. Bates JH, Suki B. Assessment of peripheral lung mechanics. RespirPhysiol Neurobiol 2008;163(1-3):54-63.

44. Phagoo S, Watson R, Silverman M, Pride N. Comparison of fourmethods of assessing airflow resistance before and after inducedairway narrowing in normal subjects. J App Physiol 1995;79(2):518-525.

45. Hellinckx J, Cauberghs M, De Boeck K, Demedts M. Evaluation ofimpulse oscillation system: comparison with forced oscillation tech-nique and body plethysmography. Eur Respir J 2001;18(3):564-570.

46. Vink G, Arets H, van der Laag J, van der Ent C. Impulse oscillom-etry: a measure for airway obstruction. Pediatr Pulmonol 2003;35(3):214-219.

47. Cavalcanti J, Lopes A, Jansen J, Melo P. Detection of changes inrespiratory mechanics due to increasing degrees of airway obstruc-tion in asthma by the forced oscillation technique. Respir Med 2006;100:2207-2219.

48. Di Mango A, Lopes A, Jansen J, Melo P. Changes in respiratorymechanics with increasing degrees of airway obstruction in COPD:detection by forced oscillation technique. Respir Med 2006;100(3):399-410.

49. Mansur A, Manney S, Ayres J. Methacholine-induced asthma symp-toms correlate with impulse oscillometry but not spirometry. RespirMed 2008;102(1):42-49.

50. Houghton C, Woodcock A, Singh D. A comparison of lung functionmethods for assessing dose-response effects of salbutamol. Brit J ClinPharm 2004;58(2):134-141.

51. Yaegashi M, Yalamanchili V, Kaza V, Weedon J, Heurich A, Ak-erman M. The utility of the forced oscillation technique in assessingbronchodilator responsiveness in patients with asthma. Respir Med2007;101(5):995-1000.

52. Marotta A, M K, Price M, Larsen G, Liu A. Impulse oscillometryprovides an effective measure of lung dysfunction in 4 year-oldchildren at risk for persistent asthma. J Allergy Clin Immunol 2003;112(2):317-322.

53. Oostveen E, Dom S, Desager K, Hagendorens M, De Backer W,Weyler J. Lung function and bronchodilator response in 4 year oldchildren with different wheezing phenotypes. Eur Respir J 2010;35(4):865-872.

54. Walker P, Hadcroft J, Costello R, Calverley P. Lung function changesfollowing methacholine inhalation in COPD. Respir Med 2009;103(4):535-541.

55. Kaczka DW, Ingenito EP, Israel E, Lutchen KR. Airway and lungtissue mechanics in asthma: effects of albuterol. Am J Respir CritCare Med 1999;159(1):169-178.



56. Clement J, Landser F, Van de Woestijne K. Total resistance andreactance in patients with respiratory complaints with and withoutairways obstruction. Chest 1983;83(2):215-220.

57. Dellaca R, Santus P, Aliverti A, Stevenson N, Centanni S, MacklemP, et al. Detection of expiratory flow limitation in COPD using theforced oscillation technique. Eur Respir J 2004;23(2):232-240.

58. Kolsum U, Borrill Z, Roy K, Starkey C, Vestbo J, Houghton C,Singh D. Impulse oscillometry in COPD: identification of measure-ments related to airway obstruction, airway conductance and lungvolumes. Respir Med 2009;103(1):136-143.

59. Larsen G, Morgan W, Heldt G, Mauger D, Boehmer S, Chinchill V,et al. Impulse oscillometry versus spirometry in a long-term study ofcontroller therapy for pediatric asthma. J Allergy Clin Immunol 2009;123(4):861-867.

60. Takeda T, Oga T, Niimi A, Matsumoto H, Ito I, Yamaguchi M, et al.Relationship between small airway function and health status, dys-pnea and disease control in asthma. Respiration 2010;80(2):120-126.

61. Haruna A, Oga T, Muro S, Ohara T, Sato S, Marumo S, et al.Relationship between peripheral airway function and patient-reportedoutcomes in COPD: a cross-sectional study. BMC Pulm Med 2010;10:10.

62. Paredi P, Goldman M, Alamen A, Ausin P, Usmani O, Pride N,Barnes P. Comparison of inspiratory and expiratory resistance andreactance in patients with asthma and chronic obstructive pulmonarydisease. Thorax 2010;65(3):263-267.

63. Kanda S, Fujimoto K, Komatsu Y, Yasuo M, Hanaoka M, Kubo K.Evaluation of respiratory impedance in asthma and COPD by animpulse oscillation system. Intern Med 2010;49(1):23-30.

64. Vassilakopoulos T, Roussos C, Zakynthinos S. The immune responseto resistive breathing. Eur Respir J 2004;24(6):1033-1043.

65. Toumpanakis D, Kastis G, Zacharatos P, Sigala I, Michailidou T,Kouvela M, et al. Inspiratory resistive breathing induces acute lunginjury. Am J Respir Crit Care Med 2010;182(9):1129-1136.

66. Kaminsky DA, Irvin CG, Lundblad L, Moriya HT, Lang S, Allen J,et al. Oscillation mechanics of the human lung periphery in asthma.J Appl Physiol 2004;97(5):1849-1858.

67. Bates JHT. Assessment of respiratory mechanics. In: Marini A,Slutsky AS, editors. Physiological basis of ventilatory support. NewYork: Marcel Dekker; 1998:231-259.

68. Bridge P, Lee H, Silverman M. A portable device based on theinterrupter technique to measure bronchodilator response in school-children. Eur Respir J 1996;9(7):1368-1373.

69. Kooi E, Schokker S, van der Moken T, Duiverman E. Airway re-sistance measurements in pre-school children with asthmatic symp-toms: the interrupter technique. Respir Med 2006;100(6):955-964.

70. Bridge P, McKenzie S. Airway resistance measured by the interrputertechnique: expiration or inspiration, mean or median? Eur Respir J2001;17(3):495-498.

71. Black J, Baxter-Jones A, Gordon J, Findlay A, Helms P. Assessmentof airway function in young children with asthma: comparison ofspirometry, interrupter technique, and tidal flow by inductance pleth-ysmography. Pediatr Pulmonol 2004;37(6):548-553.

72. Nielsen K, Bisgaard H. Discriminative capacity of bronchodilatorresponse measured with three different lung function techniques inasthmatic and healthy children aged 2 to 5 years. Am J Respir CritCare Med 2001;164(4):554-559.

73. Pao C, McKenzie S. Randomized controlled trial of fluticasone inpreschool children with intermittent wheeze. Am J Respir Crit CareMed 2002;166(7):945-949.

74. Straub D, Minocchieri S, Moeller A, Hamacher J, Wildhaber J. Theeffect of montelukast on exhaled nitric oxide and lung function inasthmatic children 2-5 years old. Chest 2005;127(2):509-514.

75. Sundblad B-M, Malmberg P, Larsson K. Comparison of airway con-ductance and FEV1 as measures of airway responsiveness to meth-acholine. Discrimination of small differences in bronchial respon-siveness with Gaw and FEV1. Clin Physiol 2001;21(6):673-681.

76. Klug B, Bisgaaard H. Lung function and short-term outcome inyoung asthmatic children. Eur Respir J 1999;14(5):1185-1189.

77. Chan E, Bridge P, Dundas I, Pao C, Healy M, McKenzie S. Repeat-ability of airway resistance measurements made using the interruptertechnique. Thorax 2003;58(4):344-347.

78. Pellegrino R, Viegi G, Brusasco V, Crapo R, Burgos F, Casaburi R,et al. Interpretative strategies for lung function tests. Eur Respir J2005;26(5):948-968.

79. Marchal F, Schweitzer C, Thuy L. Forces oscillations, interruptertechnique and body plethysmography in the preschool child. PaediatrRespir Rev 2005;6(4):278-284.

Discussion

Pichurko: I thank Dr Kaminsky forhis comments, and his interests cer-tainly overlap with my own. I wish torecognize my mentor Dr Roland In-gram, who guided me through an in-vestigation and its publication1 on vol-ume history as a determinant ofexpiratory flow in asthma. I believethis is an important issue in the per-formance of spirometry during bron-choprovocation. Two and a half de-cades of directing 6 pulmonaryfunction laboratories has taught methat unrecognized volume history ef-fects are an important and typicallyunrecognized source of error in bron-choprovocation studies.

Dr Kaminsky was kind enough todisplay a methacholine provocationdose-response slide representing onepatient’s experience. This is admit-tedly an extreme one, but it highlightsa point. This was my patient who askedto be tested at another hospital whereshe was employed. She returned af-terward describing a scenario that isrepresented on the posted slide. Es-sentially, afterinhaling a relatively lowconcentration of methacholine, shefelt tight and reported this to the tech-nician. The tech responded as appar-entlyinstructed, “I’m sorry but I’mobligated to keep giving you drug,because you have not yet declinedthe required amount.” So, despite herreported and worsening chest tight-

ness and distress, the only end pointrecognized by the testing lab was a20% drop in FEV1. Thus, the testsubject was given 2 additional doses,ultimately declining in FEV1 63%from baseline. She tuned cyanoticand was emergently transported tothe emergency department, whereshe just barely escaped intubation.

While there is understandably a lotof discussion about excessive sensi-tivities and false positive methacho-line responses, I am equally concernedabout false negatives. These occur dueto the bronchodilating effects of deepinhalation to total lung capacity thataccompanies all spirometric testing.This serves to mitigate or even reversethe constrictor response in mild and



some moderate asthmatic subjects,which are precisely the people we sendfor methacholine bronchoprovocation.I would make the case that this maybe more consequential than false pos-itives, as it produces apparently neg-ative results in asthmatic individuals,allowing these individuals at risk forbronchospastic events to be reassuredby the test results and to go undiag-nosed and untreated. Thus, theirasthma goes unnoticed.

If I had 3 wishes to be granted, thethird wish would be that every lab per-forming methacholine provocationwould be equipped to perform spirom-etry and also Raw. I do think that 40%is a little bit low. We observe 50%increase in Raw as threshold. Certainly,every pulmonary function lab medicaldirector should have a discussion withtheir technicians and inform them of theconfounding dilating effects of deep in-halation that limit the accuracy of spi-rometry and may expose the test subjectto risk.

1. Pichurko BM, Ingram RH Jr. Effects ofairway tone and volume history on maxi-mal expiratory flow in asthma. J ApplPhysiol 1987;62(3):1133-1140.

Ruppel: I’d like to follow up on that.We also do Raw and conductance inconjunction with bronchial challenge,and we don’t have the technologiststop when they observe a 50% de-crease in conductance. We use con-ventional criteria and look for thechange in FEV1. Would you considerthat a reasonable thing to do, or arewe unduly putting the patients at risk?

Pichurko: There’s a third signal thatwe use. We call it sustained chest tight-ness. This refers to the patient’s reportof progressive chest tightness lastingat least 2 minutes, sometimes com-bined with auscultation by the thera-pist to determine that air flow is re-duced. Of the 3 lines of evidence (PC20

FEV1, PC50 Raw, and sustained chesttightness), we use 2 to conclude thestudy. That assures that at least one

threshold airway measurement is ex-ceeded, but that we don’t ignore clin-ical evidence of sustained and progres-sive patient distress. This has improvedtest accuracy, but also recognizes thesubject’s safety.

Kaminsky: We do the same thing.If we get to 8 mg and they’re cough-ing or have tightness, even though theyhaven’t reached FEV1 criteria, butthey’ve reach conductance criteria bythat point, I stop the test.

Busse: To go back to your first slide,I don’t think what you presented wasatypical. I’m not a pulmonary physi-ologist, but many times I’ll have peo-ple coming in who complain of short-ness of breath and use medicationswithout relief. I’ll begin the measure-ment of Raw, and they are abnormaleven though lung functions tend to bereally quite normal.

We began our discussion this morn-ing talking about phenotypes, andasthma is a very broad definition andit may not encompass all things thathave altered physiology. And we don’thave good data, necessarily, on peo-ple who have just increases in Raw.We don’t test them under various con-ditions, nor do we necessarily test themafter we’ve given them medicationslike inhaled corticosteroids. This iscertainly not the usual approach to pa-tients who come in with symptomscompatible with asthma. In patientswho have symptoms of asthma butlargely normal lung function, vocalcord dysfunction is a high probability.These individuals have an inspiratoryloop cutoff. Addressing these patientsrequires going through an appropriatedifferential diagnosis and matching thelung function abnormalities to the clin-ical picture.

Kaminsky: I would agree with you,but in this case the symptoms werevery responsive to the inhaler, and Idon’t know if that was a placebo ef-fect or real. But we did document phys-iology that at least helps us under-

stand and be convinced that themedicine is doing some good. I willsay there’s a decent literature from the1970s and 1980s looking at this dif-ferent response to bronchodilator andbronchoconstrictor in the central air-ways versus peripheral airways. No-body knows quite what to make ofthat, and it’s a hot topic now becausewe’re all interested in giving thesesmall particle HFA [hydrofluoroal-kane] solution steroids that penetratedeeper, but we don’t know the ulti-mate clinical effect. I think there issomething phenotypically differentbetween asthmatics in particular whohave disease location in different partsof their lung. Like you say, we justdon’t understand a lot about it yet.

Busse: Right, we don’t know whatpart of the tree they’re on: the begin-ning part of the tree or somewhereelse. It’s amazing how long thesethings have been around and how lit-tle sophistication we have in knowingwhat to do with the data.

Coates: When I finished my train-ing, I thought I knew what cystic fi-brosis was, and I thought I knew whatasthma was. And now I’m looking atretirement, with cystic fibrosis beingdefined with a range between sterilityin males with no lung disease and nogastrointestinal disease and the full-blown syndrome with severe bronchi-ectasis and malnutrition. We still knowit’s all related to the same protein, butvariations in expression and type ofthe defect change the presentation dra-matically. I think asthma has becomeway more complicated. The lung hasvery few tricks up its sleeve, and re-versible bronchospasm is one of thosetricks. Hence, reversible bronchos-pasm may have manifestations that wemay later come to understand as sev-eral different disease processes.Hence, I’m not surprised that we keepseeing very different types of expres-sions of asthma while we actually maybe looking at different diseases thatwe just haven’t sorted out yet.



Kaminsky: I agree, and that’s whysome are calling asthma a syndromeas opposed to a disease: because itencompasses facets of different typesof symptoms, airway dysfunction, in-flammation, and so on.

Rundell:* You mentioned you mea-sure Raw as well as FEV1 during meth-acholine challenges. Do you do thatall the time?

Kaminsky: Yes.

Rundell: Do you do other chal-lenges? Exercise challenge or eucap-nic voluntary hyperventilation?

Kaminsky: We do exercise chal-lenge with the treadmill, and we onlydo spirometry during that challenge.It’s physically located in a differentroom than the body box, and the roomsare always going concurrently, so itmakes it hard to do.

Rundell: Now, have you found thatyou see the changes in the Raw beforeyou see changes in the FEV1?

Kaminsky: In terms of the metha-choline testing?

Rundell: Yeah.

Kaminsky: It’s highly variable. Ican’t say I’ve seen a specific patternthat’s consistent.

Hess:† If I can take the discussioninto the ICU just for a few minutes,which I guess is fair because I heardyou say you just came off service inthe unit.

Kaminsky: And I mentioned a me-chanical ventilator in here, too!

Hess: Not uncommonly, when we in-tubate a patient with obstructive lungdisease, we’ll use volume control ven-tilation, set the flow to 60 L/min, 1 L/s,measure the peak pressure, the pla-teau pressure, determine the Raw, and,anecdotally, we think that informationis useful and sometimes we follow itserially over time. Is that a worthwhilething to do? Do you do that in yourpractice? We can’t take the body boxinto the ICU.

Kaminsky: The answer is yes, Ithink it is worthwhile, and we do thatin our practice. We don’t follow Raw

per se, but I look at the differencebetween peak and plateau pressure asa surrogate for respiratory system re-sistance. In obstructed patients this isalso a valuable way to teach our fel-lows and residents. When we’re giv-ing bronchodilator therapy, one waywe know the patient is getting betteris their peak pressures are comingdown, the difference in peak and pla-teau pressure is narrowing, and pre-sumably the patient is moving betterair. But as we’ve been saying the wholeconference, it’s not just one factor:that’s one of many we’re looking at.Yes, I use that as part of the monitor-ing of these patients.

Hnatiuk: When you said you use 2of the 3 measures to stop the bron-choprovocation test, do you deem thatpositive then?

Kaminsky: Yes. I don’t use 2 of our3 specifically, like Bo [Pichurko], butfor us the clinical impression still over-rides everything. If the patient iscoughing or tight, no matter what thevalues are, the technologist will try toget a body box measurement and spi-rometry at that point in time. Then, ifeither criteria are met, FEV1 or con-ductance, we will stop. If the patientis asymptomatic, we’ll go up to 16 mg,and we still continue to look for bothresponses.

One of my jobs as pulmonary-func-tion-testing director is to be available

if they have any questions, and it’snot uncommon for me to run up to thelab and take a look at someone in themidst of their challenge to try and helpthe techs determine if it’s safe to goon or not. We try to put the clinicalresponse to methacholine togetherwith both aspects of physiology.

Enright: Do you then take the re-sponse to albuterol (the ability toquickly reverse the bronchospasm)into account when interpreting the re-sults?

Kaminsky: I take it into consider-ation, but it’s not the primary thingwe look at. As I’ve said before, I’venever seen a patient not reverse. Some-times we have to give another 2 puffs.Typically we give 2, but sometimes ittakes 4. Once we used ipratropiumthinking cholinergic/anticholinergic,and that got the patient out of theirmethacholine tightness. We like to seethe FEV1 come back within 10% ofbaseline before we discharge the pa-tient.

Salzman: I’m not sure I was hearingthe 2 of you correctly about this.You’re saying that you stopped thetest for safety reasons, even if youhaven’t dropped the FEV1, if you havesymptoms, such as wheezing andcoughing. Are you saying you call thetest positive with just subjective endpoints?

Kaminsky: No, I won’t call the testpositive with just subjective endpoints. We like to see one of those 2objective criteria being met in addi-tion to symptoms, but I’ll make a com-ment in my report that the patient diddevelop wheezing and tightness andthey did not meet the “official” ATS/ERS criteria for positive response.Then, and I’m not fudging on this, I’llsay this needs to be put into the clin-ical context. If that was my patient,it’s still someone I might put on a6-week trial of inhaled corticosteroidsand see how they do.

* Kenneth W Rundell PhD, Pharmaxis, Exton,Pennsylvania.† Dean R Hess PhD RRT FAARC, RespiratoryCare Services, Massachusetts General Hospital,Boston, Massachusetts, and Editor in Chief,RESPIRATORY CARE.



Pichurko: Similarly, I would requireexceeding the diagnostic threshold forat least one of those objective mea-sures before concluding the provoca-tion study. The additional support ofpatient symptomatology serves to val-idate the objective measure.

Coates: Didn’t we talk this morningabout the idea that the methacholinechallenge test was a good test to ruleout asthma? So, within what you justsaid, how do we fit that?

Kaminsky: To me, a negative test issomeone who goes up to 16 and fliesthrough it, and there are no changesphysiologically, and they have no dis-comfort. I don’t think they have asthmaif they respond that way.

Busse: Well, one could argue theother way. Allan, I think we’ve de-fined the positive response to metha-choline for what we consider to be theclassical, clinical asthma, haven’t we?You wonder if we’ve been overly con-strictive on what we’re calling a pos-itive test as far as the disease is con-cerned. Like you said, when I beganwork 35 years, ago I really felt like Iknew a lot about asthma, and as time

has gone on, my understanding of theambiguities has increased. I think weneed to open things up a little bit andlook at these various characterizationsand responses to tests to give us someideas about abnormalities in functionsand what they really mean.

Coates: No disagreement about that,because I am coughing and wheezingeven though my PC20 is greater than10.

Kaminsky: We have these arbitrarycutoffs. This [showing an additionalslide of a series of flow-volume loopsduring a methacholine challenge thatillustrates progressive truncation of in-spiratory flow] is a patient who re-sponded to methacholine with vocalcord dysfunction. The FEV1 didn’tchange a bit. The conductance didchange, as you would imagine, be-cause Raw elevated due to closure ofthe cords. This is a nice example ofsomeone who almost had no symp-toms: she kind of got a little coughand a little discomfort. I think we haveto take all the information together inmaking our clinical judgments. But ifeverything goes smoothly, at least atthat point in time, I would consider it

a negative challenge and I think it hasa high specificity in that case.

Rundell: One last question. You’redoing full FVC maneuvers then, dur-ing your methacholine challenge?With Raw?

Kaminsky: Yes, and we do the 5deep breaths method.

Rundell: Do you train these patientsbefore you test them, for 6 weeks orso? It seems that this would be veryfatiguing for the patient and quite timeconsuming. With the Aridol bronchialchallenge test, we used only FEV1

maneuvers after the baseline spirom-etry FVC maneuver, and with the meth-acholine test we (and others) prefer theFEV1 maneuver because of patient fa-tigue.1

1. Pearlman D. A phase III multicenter studyto demonstrate the sensitivity and specific-ity of Aridol (mannitol) challenge to pre-dict bronchial hyper-responsiveness asmanifested by a positive exercise challengein subjects presenting with signs and symp-toms suggestive of asthma but without adefinitive diagnosis. http://clinicaltrials.gov/ct2/show/NCT00252291. AccessedSeptember 26, 2011.



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