what is the clinical value of lung volumes?rc.rcjournal.com/content/respcare/57/1/26.full.pdf ·...

What Is the Clinical Value of Lung Volumes?

Gregg L Ruppel MEd RRT RPFT FAARC

IntroductionIs a Low TLC (ie, Restriction) a Useful Measurement?Do Lung Volumes Tell Us Anything Meaningful About Obstruction?Does It Make Any Difference How You Measure Lung Volumes?Summary

Lung volumes are considered part of a complete pulmonary function test, but their value forenhancing clinical decision making is unknown. Unlike spirometry and diffusing capacity of thelung for carbon monoxide (DLCO), which do contribute to confirming or excluding a diagnosis, thereare few clear indications when lung volumes are discriminatory. Confirming restriction whenvital capacity (VC) or FVC is reduced is perhaps the most important. A restrictive pattern can havemany etiologies, and clinicians often use VC or FVC as a primary index of lung volume. This makesphysiologic sense because, in healthy subjects, and in patients with true restriction, VC comprisesmost of the total lung capacity (TLC). Mixed obstruction-restriction and the nonspecific pattern (ie,reduced FVC and FEV1, normal FEV1/FVC and TLC) require measuring TLC to confirm theunderlying physiology. In obesity, VC and TLC may remain within normal limits, but functionalresidual capacity (FRC) can exponentially decrease. Increased lung volumes, particularly residualvolume (RV), are commonly observed in airway obstruction. TLC may be normal, but is frequentlyincreased in the late stages of COPD. Hyperinflation and air-trapping are terms commonly used toreflect these changes, but are not well standardized. The variability of lung volumes related todegree of obstruction suggests that measuring gas-trapping may be needed to monitor therapy.Changes in inspiratory capacity, RV, or FRC may be important gauges of response to broncho-dilators or other hyperinflation-reducing therapies. How lung volumes are measured may be im-portant, especially in patients who have moderate or severe airway obstruction. Body plethysmog-raphy is often considered more accurate than gas dilution methods in the presence of obstruction.However, the differences between techniques are not completely understood. Newer approachessuch as computed tomography, although not suitable for routine testing, may help to delineate thetrue underlying physiology. Key words: pulmonary function; lung volumes. [Respir Care 2012;57(1):2635. 2012 Daedalus Enterprises]

Introduction

The use of computer controlled pulmonary functionequipment allows laboratories to perform an array of tests

to investigate lung function in a repeatable and standard-ized manner. In addition to spirometry, measurements ofdiffusing capacity of the lung for carbon monoxide (DLCO)

Mr Ruppel is affiliated with the Department of Pulmonary, Critical Care,Sleep Medicine, and with the Pulmonary Function Laboratory, SaintLouis University Hospital, Saint Louis, Missouri.

Mr Ruppel presented a version of this paper at the 48th RESPIRATORYCARE Journal Conference, Pulmonary Function Testing, held March 2527, 2011, in Tampa, Florida.

Mr Ruppel has disclosed relationships with Medical Graphics, GileadSciences, Biomedical Systems, and GlaxoSmithKline.

Correspondence: Gregg L Ruppel MEd RRT RPFT FAARC, PulmonaryFunction Laboratory, Saint Louis University Hospital, 3635 Vista Ave-nue, St Louis MO 63104. E-mail: [email protected].

DOI: 10.4187/respcare.01374

26 RESPIRATORY CARE JANUARY 2012 VOL 57 NO 1

and lung volumes have become de rigueur components ofa complete pulmonary function test (PFT). Lung vol-umes in this context include measurements of total lungcapacity (TLC) and its components, functional residualcapacity (FRC) and residual volume (RV). None of thesevolumes can be measured directly by spirometry; eachdepends on measurement of the gas trapped in the lungafter a maximal exhalationthe RV. Spirometry providesthe vital capacity (VC) or FVC and its components, in-spiratory capacity (IC) and expiratory reserve volume(ERV), but must be combined with other methods (pleth-ysmography, gas dilution, or imaging) to estimate thetrapped volume. While spirometry and DLCO each have alengthy list of indications related to specific disease enti-ties, the clinical indications for measurement of lung vol-umes are less well defined.

All the component tests of a complete PFT are measuresof lung physiology. These tests are used to answer a spe-cific clinical question (eg, why is the patient short ofbreath?), and the results of each should be considered aseither supporting or negating the pre-test probability of asuspected diagnosis.1 Like cardiopulmonary exercise test-ing, lung volume measurements do not usually reveal aspecific diagnosis when used to evaluate dyspnea at rest orduring exertion.2 As is the case with exercise tests, lungvolume measurements describe underlying physiologic pat-terns that should help to refine the differential diagnosis.In much of the literature, the concept of restriction is as-sessed solely using the VC or FVC,3 particularly when theetiology relates to chest wall abnormalities. This makesphysiologic sense because the VC accounts for approxi-mately 75% of the TLC in healthy young adults, with the

proportion decreasing to around 60% in old age (Fig. 1).FVC is easily measured, and a low value is suggestive ofa reduction in TLC as well.4 This relationship betweenFVC (VC) and TLC can be expressed as:

TLC FVC RV

and considering that:

1 (RV/TLC) (FVC/TLC)

TLC can be estimated:

TLC FVC/[1 (RV/TLC)]

This has practical applications in that a predicted TLCcan be estimated from predicted FVC (VC), but is depen-dent on how well the predicted FVC fits the patient (age,height, ethnicity, etc), as well as the assumption that RV/TLC ratio is solely a function of age.5

In many clinical situations, measurement of VC or FVCis all that may be required to assess a patients lung func-tion.6 This is particularly true when the subjects diagnosishas been established and pulmonary function testing isbeing used to track the progression of the disease or re-sponse to therapy. It is important to note that measurementof VC or FVC must be performed acceptably. Poorly per-formed spirometry, whether a forced or slow maneuver,will usually underestimate the true lung volume.7 Unlikemany diagnostic procedures, spirometry and lung volumemeasurements require effort and cooperation on the partof the subject, along with attention to acceptability and

Fig. 1. Ratio of residual volume (RV) to total lung capacity (TLC), plotted as a function of age for authors of white predicted sets in whichthe ratio was reported. In each study, age is the main coefficient, describing the relationship between RV and TLC (see text).

WHAT IS THE CLINICAL VALUE OF LUNG VOLUMES?

RESPIRATORY CARE JANUARY 2012 VOL 57 NO 1 27

repeatability judged by the testing personnel. In additionto the quality of the data obtained, reference values needto be carefully selected.1 Although validated referencesets are available for some groups (National Health andNutrition Examination Survey III for whites, African-Americans, and Mexican-Americans), there are other pop-ulations for whom healthy normal values are not widelyavailable. VC and FVC are often expressed as percents ofthe predicted value. Percents of predicted introduce ageand height bias. Using a fixed percentage, such as 80% ofpredicted, as the lower limit of normal (LLN) is inappro-priate for judging if the FVC (or any other lung volume) isabnormally low.8

If the VC maneuver is properly performed and the re-sult is below a statistically valid LLN, additional lungvolume measurements may be indicated. A low FVC canbe caused by either obstruction or restriction. In the formercase, airway obstruction has already been diagnosed bypre- and post-bronchodilator spirometry. Measurement oflung volumes (ie, TLC) in the presence of obstruction willusually show a normal or increased volume. For patientswith end-stage emphysema who are candidates for lung-volume reduction, or in the case of bullous emphysema,assessment of RV/TLC may be useful for planning ther-apy.9 Lung volumes measured plethysmographically maybe compared to those made using dilutional techniques toestimate the volume of trapped gas (see last section of thisreview). Less commonly, airway obstruction and a restric-tive process may co-exist so that TLC is reduced below theLLN in spite of the obstructive process.10 Some patientswho present with symptoms of asthma may have a normalFEV1/FVC ratio but a decreased FVC or TLC, suggestingtrue restriction.11,12

If the FVC or VC is reduced and there is no evidence ofobstruction, lung volumes may be indicated to determine

whether the RV is also decreased (see next section). Thecauses of a restrictive pattern (reduced VC, RV and TLC)can be divided into three categories:

Intrinsic (eg, interstitial lung disease, pneumonitis)

Extrinsic (eg, kyphoscoliosis, cardiomegaly)

Neuromuscular (eg, myasthenia, ALS)

A differential diagnosis based on the patients historyand physical findings, along with a chest x-ray, may besufficient to establish the cause of the reduced VC. Mea-surements of RV or TLC help to quantify the extent of thedefect, but typically do not provide additional clinical in-formation useful for therapeutic intervention. In cases wherethe therapy seeks to reverse pulmonary impairment, suchas corrective surgery for kyphoscoliosis, lung volumes maybe useful to document the improvement. There are a fewclinical situations in which lung volumes are characteris-tically reduced and TLC may be more useful than VC orFVC alone (Table 1).

Is a Low TLC (ie, Restriction) aUseful Measurement?

Aaron and colleagues4 demonstrated what might be con-sidered intuitive regarding the relationship between FVC,RV, and TLC. They evaluated 470 patients who had re-striction (TLC 5% CI) to assess whether a low FVCcould be used to predict that restriction. When the FVCwas within the normal range, the probability of a restric-tive pattern was very low (2.4%). If the FVC was reduced,the probability of a reduced RV (and hence a low TLC)was in the range of 5060%. In effect, a validly performedFVC excludes restriction if it is normal, but requires anadditional evaluation if it is low. They also found that a

Table 1. Clinical Conditions in Which Measurement of Lung Volumes May Be Indicated

Clinical Condition Lung Volume Clinical Importance First Author

Asthma TLC Restrictive impairment occurred in 8% of asthmatics,without increase in FRC or RV

Miller12

Interstitial lung disease TLC Loss of TLC may be greater than loss of VC ininterstitial lung disease patients

Boros13

Radiation and chemotherapy TLC Chemo radiation exacerbates post-treatment decreasein TLC and DLCO

Gopal14

Combined obstruction and restriction TLC Severity of obstruction may be overestimated in patientswith combined obstruction/restriction. Combinedpattern occurs infrequently; clinicians overestimate itsprevalence

Balfe10

Gardner15

Diaz-Guzman16

Obesity FRC, TLC Reduced thoracic expansion and chest wall fat accountfor restriction in some obese subjects

Watson17

Babb18

TLC total lung capacityFRC functional residual capacityRV residual volumeDLCO diffusing capacity of the lung for carbon monoxide



low FVC accompanied by evidence of obstruction (that isa low FEV1/FVC ratio) reduced the likelihood of restric-tion even further (Fig. 2).

The same group modeled and validated an algorithm toassist in decision making regarding when to perform lungvolumes to diagnose restriction.19 Their model suggestedthat an FVC 85% of predicted and an FEV1/FVC 55%identified patients in whom lung volumes were needed toexclude restriction. This approach had a sensitivity of 96%and a negative predictive value of 98%. Vandervoordeet al20 found similar results in a large cohort of patientsusing the FEV6 as a surrogate for FVC, and FEV1/FEV6 asa surrogate for the standard ratio. A normal FVC or FEV6almost always excludes a restrictive pattern. Unless thereis evidence from the patients history or physical exami-nation suggesting restriction, measurement of TLC is notneeded if the FVC is within normal limits. Restriction isalso unlikely in the presence of moderate to severe ob-struction.

Hyatt et al21 characterized a commonly observed patternin which FVC and FEV1 are reduced, FEV1/FVC is nor-mal or increased, and TLC is within normal limits; thiscombination has been termed the nonspecific pattern. Ina sample of 100 patients with this pattern, two thirds hadevidence of airways disease, while the remainder showedsigns of thoracic restriction (eg, obesity, etc). The studyinvestigators postulate a volume de-recruitment mecha-nism to explain the relationship between FVC, RV, andTLC in the subjects with airway involvement. In a fol-low-up study, Iyer et al22 looked at a larger cohortof patients with the nonspecific pattern who were tested onmore than one occasion. They observed that the non-spe-cific pattern persisted in 64% of the subjects, with equal

numbers converting to either an obstructive or a restrictivepattern (15% and 16%, respectively). The overall preva-lence of this nonspecific pattern is unknown but may be ashigh as 1015%. Accurate measurement of TLC (alongwith FVC and VC) is required to make the diagnosis, butdistinction between true restriction and the nonspecificpattern may be ascertained by clinical diagnosis as well.23

A reduced TLC can occur in patients with concomitantairway obstruction (ie, mixed obstruction and restriction).The prevalence of mixed obstruction-restriction is unknownbut assumed to be an infrequent occurrence. Dykstra andcolleagues24 evaluated 4,774 patients with airway obstruc-tion and found that only 9.5% of those with a reduced FVCalso had a TLC below the LLN. In this study, patients whohad mixed obstruction-restriction had a higher FEV1/FVCratio and less severe obstruction. Balfe and co-workers10

looked at the possibility of overestimation of the degree ofobstruction when there is co-existing restriction. FEV1 %predicted is used almost universally to categorize the se-verity of obstruction. But because restrictive lung diseasecan reduce FEV1 along with FVC and TLC, the severity ofobstruction may be less than in subjects who do not havea restrictive component. Balfe et al found this to be thecase in a small cohort of patients and recommended grad-ing severity of obstruction on the basis of their FEV1/FVC.Recently, Gardner et al15 identified 199 patients from alarge database who had combined obstruction and restric-tion. These investigators adjusted the FEV1 % predictedby dividing it by the TLC % predicted and found that threequarters of the patients moved into a less severe categoryof obstruction (using American Thoracic Society/EuropeanRespiratory Society [ATS/ERS] grading for COPD). Sim-ilar shifts were observed using asthma severity guidelines.They also noted that adjusted FEV1 % predicted valuescorrelated better with the observed RV/TLC ratios in thesepatients. Measurement of TLC is needed to identify mixedobstructive-restrictive patterns and may be useful for moreaccurately assessing the obstructive component.

Some older studies of lung volumes suggested that obe-sity resulted in a restrictive pattern.25 A recent investiga-tion by Jones et al26 looked at lung volumes in 373 pa-tients, across a range of body mass index (BMI) values. Inthis population increasing BMI was associated with a lin-ear decline in both VC and TLC, but with few individualpatients falling below the LLN for either parameter, evenin those with morbid obesity. However, the study found anexponential decrease in FRC and ERV, with the steepestdecline in those patients in 2535 kg/m2 BMI range (Fig. 3).Because airway resistance increases as FRC decreases, theauthors speculate that increased shortness of breath mayoccur as BMI migrates from overweight into mild obesity.Leone and colleagues27 investigated the relationship be-tween abdominal obesity and impaired lung function in avery large population residing in Paris. They found that the

Fig. 2. Probability of restrictive lung disease plotted against FVC(percent of predicted) for a large population of subjects referredfor pulmonary function tests. As FVC falls the likelihood of restric-tion increases, but only to about 50%, and it differs depending onthe degree of obstruction present. (From Reference 4, with per-mission.)



larger the waist size, the lower the FVC, even in subjectswhose overall weight was normal. This degree of abdom-inal obesity has become commonplace in the United Statesand is associated with increased risk of death from car-diovascular disease or cancer.28 Some clinicians regardthese spirometric findings as evidence of restriction, with-out measurement of TLC or FRC. As was observed in thestudy by Jones and Nzekwu,26 VC can be significantlyreduced but still within normal limits. Spirometry alonemay not be able to answer the question, Is the patientsshortness of breath due to obesity?

Do Lung Volumes Tell Us Anything MeaningfulAbout Obstruction?

The terms air-trapping and hyperinflation are fre-quently used in the interpretation of PFTs, although thereare no widely accepted definitions for either. These de-scriptors are usually taken to mean that there are altera-tions in the normal configuration of lung volume compart-

ments. The RV is increased, both in its absolute volumeand in relation to the VC, the TLC, or both.29 Two pre-sentations of increased RV are commonly observed: one inwhich RV increases at the expense of the VC, with TLCremaining within normal limits, or a second scenario inwhich RV increases but with a preserved VC, resulting inan increased TLC.30 It is unclear how best to describethese changes, but ratios such as the RV/TLC expressed asa percentage have been widely adopted. Many laboratoriesuse a percent of predicted with fixed cutoffs (ie, 80120%)to assess increases or decreases in lung volumes. Quanjer,in unpublished data (Phillip H Quanjer, on behalf of thePulmonaria Group, personal communication, 2011), com-puted the upper limit of normal (ULN) for RV, usinganthropometric data (age, height, sex) from the NationalHealth and Nutrition Examination Survey III populationand the lung volume equations promulgated by the Euro-pean Community for Coal and Steel.31 The value for theupper 5th percentile for each subject was expressed as apercentage of the predicted value. As shown in Figure 4(for white subjects) the upper limit of normal for RV is inthe range of 140150% of predicted in young subjects,and decreases to 125135% in elderly subjects. These datasuggest that RV is quite variable in healthy subjects, andthat the widely used fixed criterion of 120% may result inan overestimation of gas trapping.

Dykstra and colleagues24 evaluated TLC, RV, and theRV/TLC ratio in a large group of patients with airwayobstruction to see whether lung volumes could discrimi-nate between asthma and COPD. They found that RV andRV/TLC were more sensitive than TLC to the degree ofairway obstruction. As airway obstruction (gauged by theFEV1 % predicted) falls from mild to moderate (50%),RV increases while TLC tends to remain the same. Ingeneral, lung volumes are not able to distinguish whetherthe increases are caused by COPD versus asthma, partic-ularly when the diseases have progressed to moderate orsevere airway obstruction. However, as shown in Figure 5,there is a great deal of variability in RV/TLC, particularlyaround the LLN for FEV1. Although RV or RV/TLC maynot help make a diagnosis as to whether the patient hasasthma or COPD, it may be important to know how muchhyperinflation is present if reducing it is a therapeuticgoal.32,33

There has been substantial interest in the IC as an indexof hyperinflation.34,35 FRC typically increases as airwayobstruction worsens; this frequently results in a reductionin IC, while TLC does not change significantly. For thisreason, IC, which can be measured by spirometry, may bea useful way to assess lung volumes without actually mea-suring FRC or RV. Casanova et al36 used the ratio ofIC/TLC as one such indicator and related it to survival ina population of patients with COPD. They observed sig-nificantly increased respiratory and overall mortality when

Fig. 3. Lung volume changes in obesity. Functional residual ca-pacity (FRC) and expiratory reserve volume (ERV) % predictedplotted versus body mass index (BMI) in 373 patients. Changesin each parameter are exponential (solid curved line), with thegreatest change in the transition between overweight ( 25 kg/m2)and obese ( 30 kg/m2). (From Reference 26, with permission.)



the IC/TLC fell to less than 25%. In addition to serving asan index for survival, IC has also emerged as a useful toolfor assessing changes in gas trapping for various therapies.For example, Van Noord and co-workers37 measured ICover a 24 hour epoch to evaluate reduction in air trappingfollowing treatment with different combinations of bron-chodilators. This study recorded acute improvement in IC,which exceeded that of the FEV1, as well as a larger av-erage increment in IC over the 24-hour period (215 vs198 mL). Multiple reports from ODonnell and col-leagues34,38 have demonstrated that air-trapping, whethermeasured by FRC or estimated from IC, is closely relatedto the sensation of dyspnea and to exercise limitation inpatients who have COPD. A recent study from this grouplooked at bronchodilator response as gauged by spiro-

metric (FVC, FEV1, IC) and lung volume (FRC, RV, TLC)parameters.39 Notably, they found an increased RV in mild,moderate, and severe obstruction. They also observed thatthe largest change in percent of predicted following bron-chodilator and the frequency of a positive response wasgreatest for RV (Fig. 6). Barisione and co-workers40 re-ported a decrease in hyperinflation in a small group ofsubjects experiencing the bronchiolitis obliterans syndromeafter hematopoietic stem cell transplantation. They ob-served an increase in partial flow volume curves that cor-responded with a decrease in FRC, even though FEV1 andFVC did not change. The data from these studies suggestthat air-trapping and hyperinflation, and the variables thatquantify them, may be important for treating those whohave obstruction. IC is a convenient tool for making thesetypes of assessments, but RV may present the best way toevaluate therapies aimed at reducing air-trapping.41

Does It Make Any Difference How You MeasureLung Volumes?

In 2005 a joint committee of the ATS/ERS publishedthe first comprehensive guidelines for performance of lungvolumes.6 Included in these were recommendations forperformance of plethysmographic and gas dilution lungvolumes. No one methodology was promoted over theothers, but the advantages and disadvantages of each werelaid out, along with best practices, as judged by thecommittee. Body plethysmography was recognized as atechnique that overcomes problems of maldistribution ofgas within the lung, but at the same time could overesti-mate lung volumes unless the subject was coached to pantat frequencies 1 Hz.42 The guidelines also recognizedthat dilutional techniques (ie, He dilution or N2 washout)could underestimate lung volume in patients who haveairway obstruction. Because each of these techniques mea-sures FRC, linked slow VC maneuvers were recommended

Fig. 4. Residual volume (RV) upper limit of normal plotted as a percentage of the predicted value. Height and age of white subjects enrolledin the National Health and Nutrition Examination Survey III study were used to calculate the predicted RV and its upper limit of normal, usingthe European Community for Coal and Steel equations. All values fall above 120% of predicted, a value frequently used as the upper limitof normal when assessing air-trapping. (Unpublished data from Phillip H Quanjer, used with permission.)

Fig. 5. Residual volume (RV) to total lung capacity (TLC) ratioversus FEV1 % predicted. RV/TLC, expressed as a percent, isplotted against the % predicted FEV1 for 4,774 patients withasthma or COPD, with solid lines representing the best fit for each.The shaded area or gray zone represents the large degree of vari-ability for subjects near the lower limit of normal for the FEV1.(From Reference 24, with permission.)



for the calculation of RV and TLC. The guidelines notethat imaging techniques (computed tomography [CT],chest roentgenogram, etc) compare favorably with pleth-ysmography and gas dilution. However, imaging technol-ogies require the patient to breath-hold at or near TLC,may expose the patient to excessive radiation, and tend tobe prohibitively expensive for routine measurements.

Plethysmographic overestimation of thoracic gas vol-ume (VTG) in patients with moderate or severe obstructionwas pointed out almost 30 years ago by Rodenstein andStanescu43 and Shore et al.44 This was demonstrated bymeasuring esophageal pressure during plethysmographicmaneuvers and comparing it to the conventional mouthpressure signal. In healthy subjects these 2 signals arequite similar, both reflecting changes in alveolar pressure.In obstructed patients, mouth pressure may not equal al-veolar pressure for any of several reasons, and true alve-olar pressure changes are usually underestimated. Theremay also be a significant phase shift between mouth andbox pressures. As a result, the slope of the line that definesthe relationship between mouth pressure and box pressureis spuriously reduced and VTG is overestimated. Fortu-nately, these phenomena are frequency dependent; the

magnitude of the error increases as panting frequenciesrise above 1 Hz. To minimize overestimation of VTG inobstructed patients, coach them to pant slowly at, 0.5 to1.0 Hz.

A recent study by ODonnell and colleagues45 resur-rected the discussion regarding overestimation of lung vol-umes by the plethysmographic method. These investiga-tors looked at 132 patients in 3 centers and compared lungvolumes measured by body plethysmography, He dilution,and CT. Standardized methodology was used for each lungvolume technique. Significant differences were observedbetween plethysmography and either CT or He dilution,but not between CT and He dilution. In subjects withobstruction the mean differences between body plethys-mograph and the other 2 techniques were approximately1 L (Table 2). The largest differences ( 1 L) were usuallyin patients with very severe obstruction (FEV1 30%predicted). These results suggest that perhaps plethys-mography, even if performed properly, may overestimatelung volumes in severely obstructed patients. It is note-worthy that this paper generated a substantial volume ofresponses.46,47 Most of these pointed out basic differencesin the methodologies (eg, CT performed supine, breath-holding at TLC, etc). Milite et al48 examined differencesbetween single- and multiple-breath dilutional techniquesand body plethysmograph in 55 patients with emphysema.In their comparison of He dilution and plethysmographiclung volumes they observed a mean difference of approx-imately 500 mL, which appeared to be unrelated to theseverity of obstruction (P for interaction .25). This studyalso confirmed what has been demonstrated repeatedly,that lung volumes measured by single-breath dilution aresignificantly lower than either multiple-breath dilution orplethysmographic volumes49,50 (Fig. 7). When lung vol-umes are used to make therapeutic/clinical decisions, themethod by which those volumes are derived may need tobe considered.32,51

CT scanning provides an option to body plethysmogra-phy or gas dilution for measuring lung volumes.52 How-ever, it is more expensive than any of the conventionalmethods. It also requires the subject to breath-hold at or

Fig. 6. A: Changes in percent of predicted following bronchodilatorfor spirometric and lung volumes variables. B: Frequency of apositive bronchodilator response (10% or greater change frombaseline) in patients with COPD. RV showed the largest changeand had the greatest frequency of positive responses. GOLD Global Initiative for Chronic Obstructive Lung Disease. IC in-spiratory capacity. FRC functional residual capacity. RV re-sidual volume. TLC total lung capacity. (From Reference 39,with permission.)

Table 2. Comparison of Mean Differences in Lung Volumes inPatients With Airway Obstruction*

Volume ComparisonMean

Difference (L)P

Plethysmography versus helium dilution 0.93 .001Plethysmography versus CT 1.07 .001Helium dilution versus CT 0.15 .82

* Post hoc comparison (Scheffe).CT computed tomography(Adapted from Reference 45.)



near TLC, which may be difficult for many patients.53

Although spirometry can be used to verify that the patientinspired to near TLC, this is not done routinely. A recentreview of low dose ionizing radiation from proceduresdone after myocardial infarction suggests that there is anincreased risk of cancer as result of these procedures.54 CTof the chest typically gives a lower dose than myocardialperfusion imaging (7 vs 15.6 milli-Sieverts), but is similarto that of a cardiac catheterization or CT of the abdomen.55

If a patient needs a chest CT for diagnostic purposes,calculation of lung volume may be a useful adjunct.

Summary

Lung volumes do not provide much additional informa-tion for clinical decision making in most patients. An es-timate of TLC may be required to resolve whether pro-portionately reduced FVC and FEV1 are caused byobstruction or restriction. TLC is indicated only if it assistsin confirming or rejecting a diagnosis, or if it is needed forplanning a course of therapy. Clinicians should ask thequestion, What will I do with the result of the lung vol-ume measurement?

Because the FVC (or VC) comprises most of the TLCin healthy subjects and in those with pure restrictive dis-orders, a valid measurement of FVC provides valuableinformation about the lung volumes in general. Many pa-tients present with a nonspecific ventilatory pattern in whichFVC and FEV1 are reduced, but FEV1/FVC is normal orsupra-normal. The other feature of the nonspecific patternis a normal TLC. In order to confirm this pattern, an es-timate of TLC is needed. Current evidence suggests that

the nonspecific pattern may be associated with airway ob-struction or obesity, but a majority of these patients do notconvert to a conventional obstructive or restrictive pattern.Mixed obstructive-restrictive patterns are not common butmay occur in about 10% of patients referred for PFTs.Measurement of TLC (% predicted) can be used to adjustthe FEV1 % predicted to better categorize the degree ofobstruction in patients who have mixed disease. Obesity isfrequently assumed to cause restriction, but it appears thatthe most significant reductions occur, not in TLC or VC,but in FRC and ERV. These reductions tend to be expo-nential, with the most significant changes in those who arejust overweight or mildly obese.

The usefulness of lung volumes is largely dependent onwhether or not we need to know how large the RV is. RVappears to be quite variable in healthy subjects, and theupper limit of normal is probably significantly greater than120% of predicted. It is clear that RV, TLC, and the RV/TLC ratio all increase as airway obstruction worsens, butnone of these measures does very well at distinguishingbetween asthma, COPD, or other causes of obstruction.But the variability of RV when the FEV1 is near its LLNmay be reason enough to measure it if the result can assistin making therapeutic decisions. IC also reveals a lot aboutair-trapping because it reflects the end-expiratory level (ie,the FRC). Measuring IC requires only a spirometer; hence,it has demonstrated usefulness for quantifying increases inair-trapping during exercise as well as for decreases re-sulting from bronchodilator therapy. The prognosis forpatients with airway obstruction, however, requires thatthe IC be related to the TLC (ie, IC/TLC ratio). Lastly,there is some evidence that changes in RV may be better

Fig. 7. Comparison of total lung capacity (TLC) measured by single-breath (SB) gas dilution, rebreathing (RB) gas dilution, and plethys-mography (pleth) as the reference in normal subjects and patients with emphysema. Bars represent quartiles of FEV1 % predicted as anindex of obstruction: quartile 1 lowest quartile for FEV1 %. P values represent the interaction between FEV1 % (as a continuous measure)and the respective lung volume. P values .05 indicate that lung volume agreement varies with the degree of obstruction (FEV1 %). TLCSBsignificantly underestimates lung volume when compared to either RB or pleth. TLCRB does not show significant interaction with FEV1 %in the patients with emphysema, suggesting that the rebreathing technique is minimally affected by airway obstruction. (From Reference 48,with permission.)



than changes in FVC, FEV1, IC, or TLC to account for anindividual patients response to bronchodilator, particu-larly in advanced obstruction.

There are currently multiple methods for measuring lungvolumes, including body plethysmography, single- andmultiple-breath gas dilution, and imaging techniques suchas CT scanning. The most recent ATS/ERS guidelineswisely refrained from advocating any one method over theothers. Plethysmography, although sometimes consideredthe gold standard, can overestimate lung volumes in ob-struction. Multiple-breath dilution techniques, long con-sidered sub-optimal in patients with obstruction, may bet-ter represent the true lung volume than previouslythought. Single-breath dilution techniques do progressivelyunderestimate lung volumes as airway obstruction wors-ens. But this underestimation itself can be used as an indexof ventilatory inhomogeneity within the lung. AlthoughCT scanning offers an accurate alternative to the conven-tional methods, it is generally more expensive than tradi-tional lung volume measurements. Technical problems suchas prolonged breath-holding, and exposure to significantlevels of ionizing radiation further limit its usefulness.

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Discussion

Culver: With regard to the variabil-ity of the RV, the RV may vary a lotamong normal individuals, but, as yousaid in the conclusion, the RV mea-surement itself is certainly variable.Some of that is just mathematical; wemeasure an FRC, we add and subtractother increments, all those errors getadded and then the sum gets dividedby a denominator thats 1.5 to 2 litersand it becomes a large percent error.With 3 different 150-milliliter errorswhen you make those measurements,it can end up with 25% variability justin the mathematics, superimposed on

whatever human variability there is.We often see that when there is anerror in the plethysmographic mea-surement and you end up with TLCthats 80% and an FRC thats 70%and the RV is 20% and you say,Howcould that happen? Just because thatsame absolute error has been appliedto each subdivision and it looks big-gest when its applied to the smallestone.

Ruppel: I agree with that, and I thinkthe current guideline that recommendsaveraging IC and using that along witha mean measurement of FRC is prob-ably a good approach. It can be prob-

lematic, depending on who makes themeasurements and who decides howto average the values. It is an issuethat we deal with on a day-to-day ba-sis.

Culver: In big studies RV has beenshown to be quite a subtle and sensi-tive indicator of early airway obstruc-tion, but in any individual patient itsvery dicey. To use 20% is just onemore misapplication of that silly rule.

Busse: Ron Sorkness evaluated1 thedata from the SARP [Severe AsthmaResearch Program] network throughthe NIH [National Institutes of Health].



He has determined RV in patients withasthma. In patients with more severedisease there is an increase in RV andair trapping. Whether it reflects air-way parenchyma and coupling or notis not clear, but it might tell you some-thing about the disease and the lungfunctions associated with severeasthma. Air trapping is associated withincreased risk for exacerbations.

1. Sorkness RL, Bleecker ER, Busse WW,Calhoun WJ, Castro M, Chung KF, et al;Heart, Lung, and Blood Institute SevereAsthma Research Program. Lung functionin adults with severe but stable asthma: airtrapping and incomplete reversal of obstruc-tion with bronchodilation. J Appl Physiol2008;104(2):394-403.

MacIntyre: A comment and then aquestion. The comment is that one ofthe things I find useful about lung vol-ume measurements is in helping in-terpret the diffusing capacity. Specif-ically, what Im interested in is howclosely the single-breath measurementof lung volume (ie, alveolar volume)is to what we think is the real lungvolume.

As you pointed out quite nicely, inobstructive lung disease those 2 thingsare often quite disparate, and when Isee that on a diffusing capacity test,where alveolar volume is like 50% ofthe known TLC, I put up a big redflag and say, Im not sure you caninterpret that DLCO, because the gasesobviously didnt mix very well. Ifthe methane or the xenon or whateveryou happen to be using as your tracergas didnt mix, I guarantee you theCO didnt mix either. I dont knowany way to fix that other than to saydiffusing capacity is probably very dif-ficult if not impossible to interpret.

A question I have that comes up allthe time is the pattern of a patient whohas a flat out normal VC but a 70%TLC. A lot of people try and tell methat means restriction, and I have a lotof trouble thinking about that physio-logically because it would mean thatthe restrictive process is attacking theRV and leaving the VC alone. I, for

one, cant think of a disease processthat preferentially goes only after RV.Maybe Im missing something, but Idappreciate somebodys commentsthere.

Hnatiuk: During my fellowshiptraining, one of the staff informed methat early interstitial lung disease couldpresent with a decrease in the residualvolume before other lung volumeswere affected. Now, Ive never goneback and looked for data that myself

MacIntyre: Wait, before I let youoff the hook here, Ive looked for this,and the reading Ive done suggests thatearly interstitial lung disease makesthe lung stiff. As the lung gets stiff,you tend to lose VC first and the RVmay trail behind it. So maybe afterthis conference we can finally findsome literature to help us answer thisquestion.

Culver: I can comment on that, butI dont have a lot of data. Because RVbeyond a 35 or 40 is mostly a functionof airway closure, if you do have in-creased recoil, then you have delayedairway closure and you can get to alower RV, and so its rational that aninterstitial process could be associatedwith that.

MacIntyre: Did you just describe alarger RV? Im sorry; did I misunder-stand?

Culver: No, theres more recoil, sothe airways are less inclined to close.They go to a lower volume before theyclose and cause RV to be low. Thatpattern has been described, more par-ticularly in sarcoidosis for some rea-son, which seems a little curious, be-cause that often has an airwaycomponent as well, but I recall therewas a small series years ago thatshowed that pattern in sarcoid patients.

Ruppel: The reference that I showedfrom Piotr Boros1 in which they lookedat ILD [interstitial lung disease] con-

cluded that the TLC was reduced morethan the vital capacity in ILD patients,which suggests that the RV may bechanging.

1. Boros PW, Franczuk M, Wesolowski S.Value of spirometry in detecting volumerestriction in interstitial lung disease pa-tients. Respiration 2004;71(4):374-379.

Enright: A common problem is thatthe reference equations (predicted val-ues) and the lower limits for FVC andfor the TLC are taken from 2 entirelydifferent studies. The lower limits maynot have been appropriately analyzedin one or both of those studies. Thatcould cause the difference. Referencevalues for spirometry and lung vol-umes should come from the same pop-ulation-based study.

Coates: What is going on in a lot ofpediatric labs may be very differentfrom adult labs, but despite the stan-dards suggesting the frequency ofpanting should be at 1 Hz, I frequentlyfind them panting at 2, 3, or 4 Hz. Nomatter how many times we tell thetechnicians, they and the patient bothfind it easier to pant at a much higherrate. That is going to introduce errorsinto the measurements, and those er-rors may well be the explanation as towhy there is this discrepancy betweendilutional techniques and plethysmo-graphic techniques. It is possible thatthe plethysmographic techniques justwere not done the right way.

Ruppel: The ODonnell paper that Idiscussed1 didnt go into great detail,but they suggested each of their tech-niques (helium dilution, CT scanning,and plethysmography) followed thecurrent guidelines.

1. ODonnell CR, Bankier AA, StielbellehnerL, Reilly JJ. Comparison of plethysmo-graphic and helium dilution lung volumes:which is best in COPD? Chest 2010;137(5):1108-1115.

Coates: We try to insist in our labthat we follow the current guidelines,



but as soon as I walk out the door, Ioften can hear rapid panting.

Miller: Paul once again raised a crit-ical issue. If you look at your own labreports and at the predicted FVC ver-sus the predicted VC, youll see mark-edly different predicted values. Thislack of concordance between referencevalues raises the question of what doesthe TLC really mean. One thing wevetried to do is take the RV/TLC or VC/TLC ratio from your lung volume pre-dicteds and apply it to the FVC fromyour spirometric predicteds and gen-erate a new RV and TLC from that.Statistically, the spirometry predictedsare much better, theyre based on manymore individuals who are better de-fined as normal, so I think thats auseful approach.

Id like to bring up this question oflosing out to the radiologists again,and I think thats really going to hap-pen for reporting lung volume and di-agnosing emphysema, because whenyou look at your patients, especiallyin the teaching centers, theyre all get-ting CTs. It is available to the radiol-ogist to report many things, emphy-sema score, percentage of lung volumewith emphysema, TLC, and so on.They dont do it because nobodys in-terested, but very few of your patientswhom youre considering as havingsevere emphysema or ILD escape get-ting a CT scan.

The last question Id like to ask issomething I get asked by my fellowsall the time and I dont know how toanswer. When you have something re-ducing your ERV, and of course obe-sity does this very readily, and thereisnt necessarily a proportional changein FRC. So if obesity or some othercondition like patient testing variabil-ity is giving you a low ERV and youremeasuring a more or less normal FRC,then youre going to have to have ahigh RV. And what does that high RVmean in the presence of a low ERV?Does anybody have any suggestionsthere? I see youre nodding, Paul.

Enright: What is the definition ofhyperinflation? A high RV, a high RV/TLC, a high FRC, a high FRC/TLC,or a high trapped air volume? Whichof those is best correlated with theairway obstruction in asthma orCOPD, and which of those is the mostresponsive to interventions? Our ATS/ERS committee never addressed thosedefinitions, and it leads to continuedconfusion in the literature.

Kaminsky: The issue of the discrep-ancy youve talked about, Ive alwaysbeen puzzled by that as well. Why inobese patients do we see the relativelyhigh RV to TLC? Are they really gastrapping and so it has to do with earlyairway closure? Or one thing Ive al-ways wondered is whether its moreof a mechanical effect, that is, sinceits an effort-dependent maneuver,these patients just cant squeeze downto lung emptying as they would oth-erwise be able to do if they werentobese. But I dont know the answer tothat.

Pichurko: As a pulmonary fellow Iwas introduced to RV as a volumethat is either dynamically determined,that is, representing roughly the pointof predominant airway closure andresidual gas trapping, or statically-determined, as in disorders that re-duce chest wall compliance and limitthe ride down the respiratory sys-tems static pressure-volume curve.Obesity, absent concurrent airwaydisease, is a common prototype ofthe statically determined elevated RVthat is well above the airway closingvolume. Neuromuscular weakness isanother.

Hnatiuk: In our lab, when you get alow FVC, a normal TLC, and a nor-mal RV/TLC ratio. the question be-comes, What is going on? This leadsus to look at the maximum inspiratorypressure and maximum expiratorypressure. If they are normal, then weattribute the low FVC to submaximalpatient effort during the FVC maneu-

ver. But I think Gregg had a refer-ence addressing this group of patientsin his talk, who were followed lon-gitudinally and I believe a substan-tial portion of them developed dis-ease?

Ruppel: Yes, the Mayo Clinicgroup.1 Their patients had the nonspe-cific pattern, which is a little differentthan what we were just talking about,but yes, some of them did go on todevelop restrictive disorders whenthey were tested sequentially. Thelarge majority (64%) tended to remainin the nonspecific pattern grouping,but some did go into a restrictive pat-tern and some went into an obstruc-tive pattern. That was similar to whatHyatt observed in the original group.2

Obesity and subclinical obstructionseemed to be the characteristics ofthose patients who had that pattern.

1. Iyer VN, Schroeder DR, Parker KO, HyattRE, Scanlon PD. The nonspecific pulmo-nary function test: longitudinal follow-upand outcomes. Chest 2011;139(4):878-886.

2. Hyatt RE, Cowl CT, Bjoraker JA, ScanlonPD. Conditions associated with an abnor-mal nonspecific pattern of pulmonary func-tion tests. Chest 2009;135(2):419-424.

Hnatiuk: So is it worth it to say inthe report, repeat the spirometry in ayear and see where these people endup?

Ruppel: I think that might be thecase. If you observe the nonspecificpattern, the question would be, is thispatient on the path to developing re-striction? Again, you have to do thelung volume measurement.

Salzman: To follow up on the issueof this nonspecific pattern and thewhole interaction of obesity withasthma or mild obstructive lung dis-ease, I think part of the problem isthat we tend to interpret with thresh-olds, and its a black-and-white ap-proach: youre either normal or ab-normal. The reality is that a lot of these



things are a continuum, and we dontknow how to deal with that in an in-dividual patient.

I thought it was very interesting thatyou pointed out that with obesity, FVCand other lung volumes tend to mi-grate within the normal range, suchthat you end up with measurementsthat are still normal, but youre nearthe lower limit of normal. I think thesame thing happens with mild obstruc-tive lung disease, the FEV1 and the

FEV1/FVC ratio are in that area justnorth of lower limit of normal, a littlenorth of say 80% for FEV1 or 0.70 forFEV1/FVC. So when you combineobesity and asthma, two very com-mon conditions, you end up with whatthe Mayo Clinic is calling the nonspe-cific pattern.

I think the better term that has lostout is pseudo-restriction. Its what yousee a lot. I think obesity tends to causea slightly low-normal FVC, and if

were talking about somebody whohas mixed asthma and obesity, theFVC migrates downward from theobesity, the FEV1 migrates downwardfrom the obstructive lung disease,and you end up with a normal FEV1/FVC ratio that you cant frankly callobstruction and you dont quite knowhow to deal with it, it looks like bor-derline restriction. I think its avery common pattern that you see inPFT labs.

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