Pulmonary Function Testing

General description of procedure, equipment, technique

Pulmonary function testing refers to a battery of routinely performed lung function tests that include spirometry, lung volumes, and diffusing capacity.

Spirometry is one of the most commonly ordered tests of pulmonary function. The word “spirometry,” is derived from the Latin, spiro, meaning “to breathe,” and the Greek, metron, meaning “to measure.” Spirometry, which can be performed either in specialized pulmonary function laboratories or in physicians’ offices, measures airflow during forceful exhalation. Results are used primarily in distinguishing obstructive from restrictive lung diseases and in quantifying the degree of lung dysfunction.

Lung volume testing measures individual components of lung volumes, rather than airflow (Figure 1). One of three basic techniques–nitrogen helium dilution, or body plethysmography–may be used to measure lung volumes. Assessment begins with the measurement of functional residual capacity (FRC), which is the end-expiratory or resting lung volume. Once the FRC is known, expiratory reserve volume (ERV), vital capacity (VC), and inspiratory capacity (IC) are determined, and total lung capacity (TLC) and residual volume (RV) are calculated.

Figure 1.

Diffusing capacity (DLCO) provides information on the efficiency of gas transfer from alveolar air into the bloodstream. The transfer is affected by a multitude of factors, including alveolar membrane thickness, surface area for gas exchange, and red blood cell uptake of the tracer gas (carbon monoxide, CO) used in the test. Additional determinants include hemoglobin concentration, hemoglobin affinity for CO, and red blood cell flow through the lung. Consequently, DLCO should be viewed as parameter that is affected by many pathological processes.

The combination of spirometry, lung volumes, and DLCO may be useful in the diagnosis of lung disorders and in assessing their severity over time and their response to treatment. The routine battery of pulmonary function tests described here may be supplemented with more specialized tests of lung function when clinically indicated. (See “Specialized Tests of Pulmonary Function.”)

Indications and patient selection

Common indications for pulmonary function testing include:

• Evaluation of respiratory complaints, such as cough and dyspnea

• Assessment and monitoring of disease severity and progression

• Monitoring for drug toxicity and efficacy

• Pre-operative assessment

• Evaluation of the effects of occupational or hazardous exposures

• Participation in epidemiologic surveys

Because spirometry requires active patient participation, the patient must be cooperative and able to follow requests of the pulmonary technician. Because of stringent test performance criteria, many ill patients may not be able to complete the tests adequately. While lung volume testing is less dependent on maximal patient effort than is spirometry, the patient must be cooperative and be able to follow comparatively complex commands. In addition, assessment of lung volumes and DLCO necessitates that patients be off supplemental oxygen; hence, those with significant hypoxemia at rest may not be able to complete the testing. In addition, patients with very small lung volumes may not be able to perform DLCO testing because a fixed volume of the initial exhalation is discarded. With a small lung volume and a fixed-volume discard, insufficient lung volume may be left with which to make a reliable measurement.

Contraindications

There are few absolute contraindications to pulmonary function testing, but several conditions should raise the level of caution in conducting the tests that may adversely affect results. Pain, nausea, subjective discomfort, or altered mental status is likely to lead to unreliable results. American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines suggest that spirometry be terminated if sequential maneuvers demonstrate a 20 percent or greater decrease in either the forced expiratory volume in one second (FEV₁) or forced vital capacity (FVC).

Although there is a theoretical concern about transmission of infection to patients, including immunocompromised patients, maintenance of proper hygiene and proper handling of equipment minimize the risk.

Details of how the procedure is performed

Spirometry

Spirometry testing is performed with the patient seated or standing. The patient should wear comfortable, non-restrictive clothing and avoid vigorous exercise or ingestion of a large meal just prior to the test. Inhaled bronchodilators and other pulmonary-related medications are held or continued at the discretion of the clinician ordering the test. Age, height, weight, gender, and race/ethnicity should be recorded to allow for calculation of reference values.

The FVC maneuver has three phases: inhalation, the initial “blast” phase of exhalation, and completion of exhalation (Figure 2). The patient is instructed to inhale maximally and then to exhale immediately by “blasting” the breath out. The patient is coached to continue exhalation until airflow is no longer recorded and a minimum of six seconds has elapsed since initiation of the test. Application of a nose clip or manual occlusion of the nostrils is recommended.

Figure 2.

ATS/ERS guidelines have determined specific criteria for the start and end of the test. Since much of the test interpretation relies on the exhaled volume during the first second (FEV₁), a valid “time zero” is crucial for accurate measurement; patient hesitation or a slow start may lead to inaccuracy. The test’s end is determined as the point at which the patient can no longer exhale or when the patient stops exhalation because of discomfort. There should be no change in volume for at least one second, evident as a plateau in the volume-time curve, and exhalation should last at least six seconds for patients ten years old or older.

ATS/ERS have outlined criteria for test acceptability (Table 1), including a satisfactory start and end of the test. The subject must understand the instructions and perform with maximal effort, including maximal inhalation and smooth exhalation, without interruptions from cough or Valsalva maneuver (glottic closure). For an adequate test, the subject should perform at least three acceptable maneuvers. Although some circumstances warrant more maneuvers, eight consecutive attempts are a practical upper limit for most subjects. In addition to three acceptable maneuvers, at least two of these efforts must be repeatable; results are repeatable when there is a difference of no more than 0.15L between the largest and next-largest FVC and between the largest and next-largest FEV₁. In patients who have an FVC of 1L or less, a difference of 0.10L or less is used. The largest values for both FEV₁ and FVC, whether or not they are from the same attempt, are reported as the test result.

Table 1.

The response to inhaled bronchodilators may be assessed by repeating the FVC maneuver following drug administration. According to ATS/ERS guidelines, four puffs of any acute bronchodilator (e.g., Albuterol or Ipratropium) may be administered by metered dose inhaler (MDI), or an equivalent dose may be delivered via a nebulizer. The study is repeated after fifteen minutes. Once again, three acceptable maneuvers, with at least two repeatable measurements, are obtained, and the highest FVC and FEV₁ are reported.

Spirometry is associated with many potential sources of error and variability, so scrupulous care must be exercised in its performance. Factors related to equipment, the environment, and the operators play roles. Quality control, regular maintenance, and equipment calibration help eliminate errors attributable to faulty equipment. Patient coaching through explanation, demonstration of the technique, and enthusiastic encouragement while the patient is performing the maneuver are essential to obtaining accurate results. Training workshops in coaching technique are especially important for staff that conduct testing in primary care practices, as such workshops increase the percentage of tests that meet ATS/ERS criteria for acceptability and repeatability.

Lung Volumes

Two of the three techniques used to measure lung volumes–helium dilution and nitrogen washout–are based on the principle of conservation of mass: [initial gas concentration] x [initial volume of the system] = [final gas concentration] x [final volume of the system]

In the helium dilution method, a known volume and concentration of helium are added to the patient’s respiratory system. Helium, which is inert and is not absorbed significantly from the lungs, is diluted in proportion to the lung volume to which it is added. The final concentration of helium is then measured and the conservation of mass equation solved for the initial volume of the system, which is FRC.

The nitrogen washout method is based on the fact that nitrogen is present in the air we breathe. The patient is given 100 percent oxygen to breathe, and the expired gas, which contains nitrogen in the lung at the beginning of the test, is collected. When no more nitrogen is noted in the expirate, the volume of air expired and the entire amount of nitrogen in that volume are measured. The amount of nitrogen in ambient air is assumed to be relatively constant. With three of the four components of the conservation of mass equation in hand, the initial volume of the system (FRC) can be calculated.

Body plethymography (also known as the “body box” method) for determining lung volumes is based on Boyle’s law, which dictates that the product of the pressure and volume of a gas is constant at a constant temperature. The patient is placed in an air-tight box that incorporates a pressure transducer and a pneumotachograph to measure airflow. At the end of quiet expiration, a shutter on the pneumotach is closed, and the patient is asked to pant against the closed circuit. Pressure changes at the mouth (which, in a closed system, equals alveolar pressure) and in the box are measured. Based upon measurements of changes in pressure and volume, the initial lung volume (FRC) can be calculated.

The helium dilution method, the nitrogen washout method, and the body plethymography method each have advantages and disadvantages. The two techniques that are based on gas equilibration may underestimate lung volumes in patients with advanced airways obstruction because equilibration may take a long time. Plethysmography is fast and allows for repetitive measurements in quickly assessing the reproducibility of results, and the results do not vary with the severity of underlying airway obstruction. However, since plethysmography measurements are based on all gas in the chest, large bullae or hiatal hernias may be included in lung volume estimates. Furthermore, plethysmographs are expensive, and some patients cannot tolerate plethysmography because of their body size, skeletal abnormalities, or claustrophobia.

Diffusing Capacity

Diffusing capacity (DLCO) is most commonly measured using the single-breath technique. The patient takes a full inspiration of a gas mixture containing 0.3 percent carbon monoxide and 10 percent helium (the dilution of which provides an index of lung or “alveolar” volume). After a ten-second breath-hold, the patient exhales. The first portion of the exhaled breath, which is composed of dead-space ventilation, is discarded, and the next liter is collected and analyzed. The difference between the original and final concentrations of carbon monoxide is assumed to represent the gas transported across the lung alveolar surface and to reflect the diffusion capacity.

Interpretation of results

Interpreting pulmonary function test results is a multi-step process of assessing the adequacy of the study, comparing the results to an appropriate reference standard, defining the pattern of abnormality, determining the degree of abnormality, assessing response to bronchodilators, and evaluating changes in measurements over time (Figure 3).

Figure 3.

Spirometry and Lung Volumes

Assuming the test is adequate, the use of appropriate reference standards is critical. ATS/ERS recommend using NHANES III in the United States as the spirometry reference standard. Each laboratory should ensure that the race/ethnicity of the subjects tested is represented in the reference population. Furthermore, because reference values often derive from populations with few members at the extremes of age and size, use of appropriate standards for the elderly, the very young, the very small, and the very tall can be problematic. Finally, geographic considerations, such as urban versus suburban populations or high-altitude versus low-altitude dwelling, may significantly impact the comparability of reference populations.

The most recent (2005) ATS/ERS guidelines recommend an interpretation algorithm that differs from prior schemes (Figure 4). The most notable changes are the use of a lower limit of normal (LLN) based on normal value distributions, rather than a fixed cutoff of percent predicted, and the use of vital capacity (VC), rather than forced vital capacity (FVC), as the denominator of the term, FEV₁/VC, to determine the presence of obstruction. The use of LLN is believed to do a better job of incorporating age-related changes in spirometry, while the use of VC is thought to be more sensitive in diagnosing obstruction. LLN is defined as the fifth percentile of the normal population for a particular age, height, gender, and race. VC is defined as the largest of the measurements of FVC, slow vital capacity (SVC), and the forced inspiratory vital capacity (FIVC).

Figure 4.

Alternately, the method espoused by the Global Initiative on Obstructive Lung Disease (GOLD) for the diagnosis of obstruction is based on a fixed cut-off of 0.70 for the post-bronchodilator FEV₁/FVC. Both approaches have limitations, the most important among them being that spirometry values must be interpreted in clinical context.

Once the nature of the abnormality has been defined (typically as obstructive or restrictive), its severity is determined. According to ATS/ERS guidelines, the level of severity is defined by the reduction in percent of predict FEV₁ for both obstruction and restriction. Obstruction is considered bronchodilator-responsive if, following the administration of bronchodilator, there is an increase of at least 12 percent in FEV₁ or FEV and an absolute increment of at least 200cc.

Serial pulmonary function testing over time has demonstrated significant variation in spirometry, both in normals and in patients with pulmonary disease. The variability is due to the complex requirements of the tests, variations of the disease state in individuals (e.g., diurnal variation), and the inherent error of the machines employed in an effort-dependent test. Therefore, defining “significant change” in results is challenging.

In this regard, a conservative approach, which is supported by ATS/ERS guidelines, is to consider a significant a change of at least 15 percent and 200cc. However, the clinician must consider the clinical context. For instance, a change of 10 percent over two months following a hospitalization for pneumonia is likely to be important, even though the change falls short of the 15 percent mark.

DLCO

Many pathologic conditions are associated with changes in DLCO [Table 2]. Since DLCO is affected by the lung surface area available for gas diffusion, any condition that reduces the number of functioning alveolar units lowers the DLCO. Examples include prior lobectomy, cystic lung disease, pulmonary consolidation, atelectasis, pulmonary fibrosis, and alveolar filling processes (e.g., pulmonary edema).

Table 2.

Incomplete expansion of alveoli secondary to muscle weakness or chest wall abnormalities, and uneven distribution of the inspired helium and CO gas mixture used in the test as a result of airway obstruction also reduces DLCO. Changes in pulmonary blood flow may reduce the surface area available for gas exchange. Therefore, loss of the pulmonary microvasculature, as seen in emphysema or pulmonary fibrosis, or changes in blood volume, may affect DLCO. In addition, increased membrane thickness, like that which occurs in interstitial lung disease or pulmonary edema may also reduce DLCO.

An elevated DLCO is usually associated with circumstances in which more hemoglobin-binding sites for CO available; such circumstances include the presence of polycythemia, alveolar hemorrhage, and increased pulmonary blood flow. Obesity and asthma have also been associated with elevations in DLCO.

Although abnormalities in DLCO occur most often in conjunction with impairments in pulmonary mechanics, they may also occur in isolation. If the patient does not have anemia or an elevated carboxyhemoglobin level, an isolated reduction in DLCO suggests loss of the pulmonary capillary bed from pulmonary vascular disease (e.g., pulmonary emboli or pulmonary hypertension) or an early parenchymal lung disease that has not yet affected lung volumes or spirometry.

Measurement of DLCO is particularly useful in assessing patients at risk for desaturation with exercise, who would benefit from additional testing. The test may also be useful in making distinctions within a pathophysiologic group of disorders. For example, obstruction associated with a reduced DLCO is more likely to be due to COPD than to asthma.

DLCO has more inherent variability over time than other pulmonary function tests do. Several well-established causes of fluctuations in DLCO, other than changes in lung function, include increased depth of inspiration during the test, exercise, changes in altitude, and changes in hemoglobin concentration. Elevations in carboxyhemoglobin reduce DLCO by limiting the available CO-binding sites and by increasing the “back pressure” for CO diffusion. Measured values for DLCO in heavy smokers or those exposed to heavy exhaust may be spuriously low because of elevated CO levels. A conservative approach to interpreting serial measurements of DLCO over time is to consider significant a change of at least 10percent and 3 units.

In addition to encompassing single, numerical measurements of flow, such as FEV₁ or FVC, contemporary spirometry measurements yield graphic depictions of flow over time. These flow-volume loops provide additional insight into both test quality and the underlying disease process (Figure 5). In addition to evaluating rates of flow, flow-volume loops should be inspected as part of interpreting the pulmonary function test.

Figure 5.

Performance characteristics of the procedure

Spirometric results from multiple studies reveal an association with mortality from both respiratory and non-respiratory causes. A longitudinal survey from the 1970s of more than fifteen thousand adults in Scotland demonstrated that relative FEV₁ correlated with all-cause mortality, as well as with death from ischemic heart disease, cerebrovascular disease, lung cancer, and respiratory disease, when controlled for age, smoking history, blood pressure, body mass index (BMI), cholesterol, social class, and respiratory symptoms. Thus, significant correlations were also present in lifelong non-smokers and in individuals who had no respiratory symptoms.

Other studies have shown that FEV₁ predicts respiratory or overall mortality; whether this finding reflects an association or causality remains unclear. Based on these results, some experts recommend routine screening for airflow obstruction.

Since spirometric results do not significantly increase smoking cessation rates, the United States Preventive Services Task Force (USPSTF) does not recommend spirometry for COPD screening.

Outcomes (applies only to therapeutic procedures)

Not applicable.

Alternative and/or additional procedures to consider

For some patients, cardiopulmonary exercise testing (CPET may provide additional diagnostic information in the evaluation of dyspnea.

Complications and their management

Complications of pulmonary function testing are rare.

What’s the evidence?

Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005;26:319-38.

(The statement of the ATS and ERS on the correct performance of spirometry.)

Wanger J, Clausen JL, Coates A, et al. Standardisation of the measurement of lung volumes. Eur Respir J 2005;26:511-22.

(2005 ATS/ERS statement on the appropriate performance of lung volumes.)

Enright PL. How to make sure your spirometry tests are of good quality. Respir Care 2003;48:773-6.

(A review of the most common errors in spirometry testing that can lead to bad data and misinterpretations. Patient coaching, grading test efforts, using a centralized spirometry quality assurance program, daily equipment testing, and use of appropriate corrections for temperature and pressure are discussed.)

Guberan E, Williams MK, Walford J, Smith MM. Circadian variation of FEV in shift workers. Br J Ind Med 1969;26:121-5.

(An older study that examines the effect of time of day on the results of spirometry.)

Lung function testing: selection of reference values and interpretative strategies. American Thoracic Society. Am Rev Respir Dis 1991; 114:1202-18.

(An earlier version of the ATS statement on spirometry that includes reference values.)

Eaton T, Withy S, Garrett JE, Mercer J, Whitlock RM, Rea HH. Spirometry in primary care practice: the importance of quality assurance and the impact of spirometry workshops. Chest 1999;116:416-23.

(Randomized, controlled, prospective, interventional study conducted in primary care practices in Auckland City, New Zealand. The study compares spirometry performed in practices that were either “trained” or “usual” groups. Although a significant training effect was demonstrated after the workshop, the quality of spirometry in clinical practice in neither group generally satisfied full ATS criteria for acceptability and reproducibility. The trained group was better, but results were acceptable in only a minority of cases.)

D’Angelo E, Prandi E, Marazzini L, Milic-Emili J. Dependence of maximal flow-volume curves on time course of preceding inspiration in patients with chronic obstruction pulmonary disease. Am J Respir Crit Care Med 1994;150:1581-6.

(A study that examines the impact of the preceding inspiratory effort on FEV1 and FVC.)

Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J 2005;26:948-68.

(The new ATS/ERS statement on the appropriate interpretation of pulmonary function testing, including spirometry.)

Kreider ME, Grippi MA. Impact of the new ATS/ERS pulmonary function test interpretation guidelines. Respir Med 2007;101:2336-42.

(Pulmonary functions tests from 319 patients are analyzed according to four different interpretation schemes. Although a similar proportion of patients were identified as having a restrictive disorder using either the “GOLD” scheme or the 2005 ATS/ERS algorithm, significantly more (44% vs. 33%) were defined as having obstruction using the newly proposed scheme. In addition, 36 percent of subjects defined as obstructed using either the traditional or new schemes were classified differently using the new approach. This study suggests that the new algorithm leads to a diagnosis of obstruction in a higher proportion of patients who undergo pulmonary function testing.)

Enright P. Flawed interpretative strategies for lung function tests harm patients. Eur Respir J 2006;27:1322-3; author reply 3-4.

(An editorial that describes potential flaws in the 2005 ATS/ERS statement on appropriate interpretation of pulmonary function testing.)

Hole DJ, Watt GC, Davey-Smith G, Hart CL, Gillis CR, Hawthorne VM. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ 1996;313:711-5; discussion 5-6.

(Prospective general population study of 7058 men and 8353 women in Scotland who were followed from 1972-6 onward. A trend toward increasing risk with diminishing FEV1 was observed for both sexes for all causes of mortality, even after adjustment for age, cigarette smoking, diastolic blood pressure, cholesterol concentration, body mass index, and social class. The authors concluded that impaired lung function was a major clinical indicator of increased mortality in men and women for a wide range of diseases.)

Peto R, Speizer FE, Cochrane AL, et al. The relevance in adults of air-flow obstruction, but not of mucus hypersecretion, to mortality from chronic lung disease: results from 20 years of prospective observation. Am Rev Respir Dis 1983;128:491-500.

(From 1954 to 1961, pulmonary function was assessed in 2,718 British men. In 20 to 25 years of follow-up, 104 men (all of whom had smoked) died of chronic obstructive pulmonary disease (COPD). The risk of death from COPD was strongly correlated with the initial degree of reduction in FEV₁.)

Schunemann HJ, Dorn J, Grant BJ, Winkelstein W Jr., Trevisan M. Pulmonary function is a long-term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health Study. Chest 2000;118:656-64.

(Prospective study (with 29-years of follow-up) of the Buffalo Health Study cohort. Except for men who survived for more than twenty-five years, a statistically significant negative association between FEV1 percent predicted, and all-cause mortality was noted. Participants in the lowest quintile of FEV1 percent predicted experienced significantly higher all-cause mortality compared to participants in the highest quintile. The authors concluded that pulmonary function is a long-term predictor for overall survival rates in both genders and that it could be used as a tool in general health assessment.)

Young RP, Hopkins R, Eaton TE. Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes. Eur Respir J 2007;30:616-22.

(A review of the predictive power of the FEV1 in smokers. The authors posit that a reduced FEV1 identifies undiagnosed COPD, has comparable utility to that of serum cholesterol in assessing cardiovascular risk, and defines those smokers who are at greatest risk of lung cancer. They argue that FEV1 screening in smokers should be performed routinely.)

Friedman GD, Klatsky AL, Siegelaub AB. Lung function and risk of myocardial infarction and sudden cardiac death. N Engl J Med 1976;294:1071-5.

(This study finds that, compared with controls, VC was reduced in patients who subsequently had a myocardial infarction. Heavy smoking, productive cough, exertional dyspnea, and cardiac enlargement were associated with diminished VC. However, excluding subjects with these findings did not reduce the predictive value of the VC. The authors postulate that a reduced VC may be a risk factor for CAD.)

Buffels J, Degryse J, Decramer M, Heyrman J. Spirometry and smoking cessation advice in general practice: a randomised clinical trial. Respir Med 2006;100:2012-7.

(This study examines the effects on quit rate of adding spirometry to smoking cessation counseling. No increment in smoking cessation rate was observed among those who had spirometry performed.)

Screening for chronic obstructive pulmonary disease using spirometry: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008;148:529-34.

(In this document, the USPSTF weighed the benefit and harm of screening for COPD that were identified in an accompanying review of the evidence. The recommendation was that practitioners not screen adults for COPD using spirometry (Grade D recommendation).)

Hsia CC, McBrayer DG, Ramanathan M. Reference values of pulmonary diffusing capacity during exercise by a rebreathing technique. Am J Respir Crit Care Med 1995;152:658-65.

(A study of the components of the DLCO and their variations.)

Kelley MA, Panettieri RA Jr., Krupinski AV. Resting single-breath diffusing capacity as a screening test for exercise-induced hypoxemia Am J Med 1986;80:807-12.

(Results of exercise studies are examined in 106 patients consecutively referred to an exercise laboratory. Arterial desaturation is seen in all patient disease categories and is closely associated with reduced diffusing capacity. A diffusing capacity less than 50 percent of predicted is associated with substantial arterial desaturation during exercise. The results suggest that resting diffusing capacity may serve as a useful screening test for exercise-induced hypoxemia in an unselected population.)

SPECIALIZED TESTS OF PULMONARY FUNCTION

General description of procedure, equipment, technique

In selected clinical circumstances, less commonly performed tests of pulmonary function may provide additional diagnostic information. Three such specialized tests are considered below: tests of respiratory muscle function, bronchoprovocation testing, and hypoxia altitude simulated testing.

Tests of Respiratory Muscle Function

Restrictive pulmonary physiology or small lung volumes may result from disorders that cause increased elastic recoil (e.g., pulmonary fibrosis), abnormalities of the chest wall (e.g., kyphoscoliosis), or neuromuscular weakness. Selected pulmonary function tests may be helpful in sorting out respiratory muscle weakness from the other causes of restriction. These include the VC (vital capacity), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and maximal voluntary ventilation (MVV). VC may also be affected disproportionately by body position in patients with diaphragmatic dysfunction; hence, measurement of VC in the upright and supine positions may be useful in elucidating this underlying cause of restrictive physiology.

Six-minute Walk Test

There are several types of “field-walking” tests of exercise capacity in adults with chronic respiratory disease (including but not limited to COPD, interstitial lung disease, pulmonary vascular disease) including the incremental shuttle walk test (ISWT), the endurance shuttle walk test (ESWT) and the 6-minute walk test (6MWT). Different institutions/pulmonary function labs may prefer one to another. The 6MWT is the most commonly used, and has been demonstrated to be a valid and reliable test to measure exercise capacity. Patients are asked to walk as far as possible in 6 minutes. The primary outcome of the 6MWT is distance walked (meters or feet), also known as the 6-minute walking distance (6MWD).

Bronchoprovocation Testing

One of the defining characteristics of asthma is an increase in the responsiveness of the airways to a number of stimuli. If lung function is normal but the patient experiences intermittent episodes of cough, dyspnea, or wheezing, the demonstration of bronchial hyper-responsiveness may be useful in establishing a diagnosis of asthma. Two general types of bronchoprovocation studies may be performed: direct and indirect. Direct testing employs pharmacologic agents that directly stimulate airway smooth muscle receptors to cause bronchoconstriction. The most commonly utilized drugs in direct testing are methacholine and histamine.

Indirect testing incorporates agents that stimulate release of pro-inflammatory mediators, which ultimately induce bronchoconstriction. Indirect tests employ hypertonic saline or mannitol or are based on exercise protocols used to elicit exercise-induced asthma or eucapnic voluntary hyperpnea.

Hypoxia Altitude Simulated Testing

Some large pulmonary function laboratories offer Hypoxia Altitude Simulated Testing (HAST), a test designed to assess patient risk for hypoxia during commercial air flight. Commercial aircraft generate cabin pressures equivalent to a maximum altitude of about eight thousand feet, which corresponds to an oxygen concentration of approximately 15.1 percent. In most travelers, this oxygen concentration is associated with normal oxygen saturation. However, in those with underlying cardiopulmonary disease, significant hypoxemia may arise.

HAST identifies patients whose arterial partial pressure of oxygen may fall onto the steep part of the hemoglobin dissociation curve and, who, therefore, may experience significant desaturation and symptoms during flight. HAST has been demonstrated to be equally predictive of oxygenation as a hypobaric chamber, which is the gold standard for determining the risk of hypoxemia at high altitudes. In addition, HAST provides an opportunity not only to assess for flight-related changes in PaO₂ but also to assess for potential symptoms and arrhythmias.

Indications and patient selection

Tests of Respiratory Muscle Function

Tests of respiratory muscle function are used to differentiate neuromuscular causes of dyspnea and reduced lung function from pulmonary parenchymal abnormalities. Like all pulmonary function tests, they require a compliant patient who is able to follow commands. The tests are extremely effort-dependent, and they require a maximal and consistent patient effort and a technician who is capable of producing a maximally accurate study using appropriate coaching.

6-Minute Walk Test

Results, which are reported in distance (meters or feet), but may also include oxygen desaturation, heart rate, dyspnea, and fatigue, can be used not only to help understand exercise capacity, but to guide prognosis and to assess response to therapies. It is important to recognize that 6-minute walk distance (6MWD) is dependent upon factors such as encouragement, track layout/length, use of supplemental oxygen, and use of rolling walkers, and for this reason, these factors must be kept as constant as possible, especially when the test is used over time. Space is an important practical consideration; there must be a length of at least 30 m. If this is not possible, then the previously mentioned shuttle walk tests could be considered.

Bronchoprovocation Testing

Patients are appropriately referred for bronchoprovocation testing to improve the accuracy of a diagnosis of asthma, to assess their response to therapy (largely limited to drug studies), or to identify asthma triggers (when a specific provocative agent is used).

Hypoxia Altitude Simulated Testing

The British Thoracic Society recommends further testing of patients with lung disease if the SpO₂ at rest is 92-95 percent; if they have other identifiable risk factors, such as hypercapnia, an FEV₁ less than 50 percent predicted, underlying lung cancer, or restrictive lung disease; or if they require ventilatory support, have cardiac or cerebrovascular disease, or have had a recent hospitalization for an exacerbation of chronic lung or cardiac disease. Those with a SpO₂ above 95 percent do not require further testing and may be permitted to travel without supplemental oxygen.

The Aerospace Medical Society suggests that further testing should be performed on any patient with a sea level PaO₂ of less than 70 mm Hg. Several recommendations on which patients should undergo HAST testing have been proposed.

Contraindications

Tests of Respiratory Muscle Function

There are no contraindications to performing these tests. The greatest risk may be that, because they are so effort-dependent, false positive or negative results may lead to inappropriate further testing and therapy.

Bronchoprovocation Testing

Patients with known significant airway obstruction (FEV₁ < 50% predicted), recent myocardial infarction or stroke, uncontrolled hypertension, or a known aortic aneurysm should not be referred for bronchoprovocation testing. Care should be used in testing patients with mild obstruction and pregnant women. In methacholine challenge testing, concomitant use of a cholinesterase inhibitor is a relative contraindication.

6-Minute Walk Test

Absolute contraindications to performing a 6MWT are similar to those for any cardiopulmonary testing: recent myocardial infarction, unstable angina, significant valvular disease, symptomatic arrhythmias, thrombosis (PE or lower extremity), uncontrolled asthma, mental illness precluding following instructions. Relative contraindications include, but are not limited to, moderate valvular disease, severe untreated hypertension, pulmonary hypertension, orthopaedic disease.

Hypoxia Altitude Simulated Testing

Typically, airlines (and portable oxygen concentrators and tanks utilized by airlines) allow patients to use, at most, 4-5 LPM. Therefore, patients who are already using more than 4-5LPM derive no benefit from testing and should not be tested. Patients who cannot tolerate brief desaturation, such as those with recent MI or unstable angina, should not undergo testing.

Details of how the procedure is performed

Tests of Respiratory Muscle Function

How the VC is measured is described above in the section on spirometry. Maximal inspiratory and expiratory pressures (MIP/MEPs) are measured by having the patient perform maximal inspiratory and expiratory efforts against a closed valve and measuring the static pressures that are generated. The maximal voluntary ventilation is often coupled with spirometry by having the patient breathe in as deeply and as quickly as possible for ten to fifteen seconds and then extrapolating that volume to one minute.

6-minute Walk Test

The patient is asked to walk as far as possible in 6 minutes. Distance markers are pointed out and patients are instructed to walk back and forth as many times as possible in 6 minutes. Testers let patients know when each minute passes and are asked not to provide significant encouragement during the test. Patients are permitted to stop and rest as often as needed, but are asked to resume walking as soon as able. Oxygen saturation, heart rate, dyspnea (Borg scale) are assessed at time zero and at 6 minutes. Patients may use supplemental oxygen if they are on long-term oxygen therapy, and should use at their standard flow rate.

Bronchoprovocation Testing

In performing a methacholine challenge test, following the performance of baseline spirometry, increasing concentrations of methacholine are administered through either a nebulizer or a hand-held dosimeter. Shortly after each dose, three FVC maneuvers are performed that must be timed appropriately in order to assess the effect of the maximal dose of the drug before it wears off. ATS criteria for acceptability and repeatability that apply to any spirometry maneuver are followed. At any point in testing, a 20 percent or greater fall in FEV₁ compared with baseline is a signal for cessation of testing and bronchodilator administration. If no significant fall is noted after the highest dose is administered, the test is terminated.

Testing for Exercise-Induced Bronchoconstriction

Evaluation for exercise-induced bronchoconstriction is conducted using either a bicycle ergometer or treadmill. The patient breathes cool, dry air (< 25^o C and < 50% humidity) and then exercises for four to six minutes at 80-90% of predicted maximal heart rate (which should correspond to a minute ventilation of about 80-85% predicted). FVC maneuvers are performed at baseline and at three, five, ten, fifteen, and thirty minutes following cessation of exercise.

Hypoxia Altitude Simulated Testing

The patient is monitored for symptoms and continuous ECG monitoring is performed. An arterial blood gas is obtained before and during the simulation. The patient usually wears a nasal cannula underneath the reservoir mask so, if the PaO₂ drops, the test can be repeated using supplemental oxygen. If the PaO₂ falls below 50 mmHg during the simulation, the patient is asked to use supplemental oxygen (usually at 2 liters per minute), and the arterial blood gas is repeated. If a patient’s PaO₂ is borderline with regard to hypoxemia, he or she may be asked to walk in place in order to simulate ambulation within the aircraft cabin as a means of further assessing the risk for hypoxemia.

Interpretation of Results

Tests of Respiratory Muscle Function

The evaluation of maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) is challenging. In general, the lower limit of normal for MIP is less than -70cm H₂O in young men and less than -35cm H₂O in young women. The corresponding values for persons older than age sixty-five are less than -40cm H₂O in men and less than -25cm H₂O in women. The lower limit of normal for MAP is greater than 90cm H₂O in men and greater than 50cm H₂O in women.

While advancing age has no significant impact on the lower limits, these measurements are plagued by multiple potential limitations and technical considerations. The test is often difficult to perform, and its accuracy depends heavily on patient motivation. A tight seal at the mouthpiece, which may be difficult to achieve in patients with bulbar weakness, is essential. In addition, the maximal pressures obtainable depend on the lung volume at which the measurements are made so the pressures must be measured at maximal inspiration and expiration, which requires an experienced technician who can ensure that the timing is correct. What’s more pre-existing lung disease that alters lung volume can affect measured pressures, and finally, the true “normal” values for subjects have not been well established.

The maximal voluntary ventilation (MVV) has been touted as a measure of both strength and endurance. However, like the MIP and MEP, the MVV is an effort-dependent test that requires maximal effort and a reliable technical measurement. In addition, the test is affected by underlying lung function, as one would not expect patients with diminished lung function to be able to produce the same maximal liter flow as normals. In general, patients should be able to generate an MVV of thirty-five to forty times their FEV₁. If the measured MVV is less than the calculated MVV, neuromuscular weakness or fatigue may be contributing. Notation should be made of any comments by the performing technician regarding the quality of the patient’s effort.

6-Minute Walk Test

The minimally important difference between tests is considered to be 30 m, and does not appear to vary between diseases. Among patients with COPD, ILD and PAH, 6MWD is responsive to treatment effects.

Bronchoprovocation Testing

Methacholine challenge testing

Results of methacholine challenges are normally expressed either as the provocative dose (PD) or the concentration (PC) of a stimulus that produces a 20 percent decline in the FEV₁. The lower the PD₂₀, the greater the degree of responsiveness. For methacholine challenges, PCs of 16 mg/ml or lower are considered abnormal.

Certain substances and behavior should be avoided prior to testing, as they can lead to either false positives or false negatives. Recent upper respiratory tract infection and cigarette smoking can elevate bronchial hyper-responsiveness, and use of bronchodilators, leukotriene receptor antagonists, and anti-histamines and recent consumption of coffee, chocolate, or other substances that contain caffeine can reduce bronchial hyper-reactiveness. In addition, disease processes other than asthma, including food allergies, allergic rhinitis, sarcoidosis, COPD, smoking, bronchiectasis, inflammatory bowel disease, rheumatoid arthritis, and smoking, can lead to bronchial hyper-responsiveness.

Testing for Exercise-Induced Bronchoconstriction

A fall in FEV₁ of 10 percent post-exercise is considered abnormal, and a fall of 15 percent or more is considered diagnostic of exercise-induced bronchoconstriction.

Bronchoprovocation studies appear to be most useful in excluding the diagnosis of asthma (high negative predictive value), rather than in making a diagnosis (poor positive predictive value).

Hypoxia Altitude Simulated Testing

If the PaO₂ during HAST is above 55 mmHg, no supplemental oxygen is recommended. If the PaO₂ is between 50 and 55 mmHg, the test is considered borderline, and measurements with patient activity may be warranted. If the PaO₂ is below 50 mmHg, oxygen supplementation during air travel is recommended at the level of FIO₂ used during HAST that resulted in adequate oxygenation. Some authors have suggested that simple measurement of SpO_{2 ,}rather than PaO₂, may be sufficient, but no comparative trials are available.

A study of fifteen healthy adults compared results of HAST with in-flight SpO₂ measurements. Although there was no difference between the final HAST results and the mean flight SpO₂, a significant difference was noted between the lowest in-flight SpO₂ (88 + 2%) and the lowest HAST SpO₂ (90 + 2%). Exercise at high altitude, such as moving around the cabin or shifting luggage, may explain the difference between the in-flight measurements and the HAST results.

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