Diffusing Capacity Tests

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Chapter 3

Diffusing Capacity Tests

The chapter describes measurement of diffusion in the lungs. Diffusing capacity (also referred to as transfer factor) is usually measured using small concentrations of carbon monoxide (CO) and is referred to as Dlco or Dco. Dlco is used to assess the gas-exchange ability of the lungs, specifically oxygenation of mixed venous blood. Various methods, all of which use CO, have been described. The most commonly used method is the single-breath, or breath-hold technique. The single-breath method is also the most widely standardized. The techniques section focuses on the single-breath method but also describes some of the other methods that are used for specific applications.

Dlco measurements are used in the diagnosis and management of most pulmonary disorders. The importance of standards and guidelines in the performance of Dlco tests and in the overall interpretation of results is highlighted. Interpretive strategies are presented in a format similar to those in previous chapters.

Carbon monoxide diffusing capacity

Description

Dlco measures the transfer of a diffusion-limited gas (CO) across the alveolocapillary membranes. Dlco is reported in milliliters of CO/minute/millimeter of mercury at 0°C, 760 mm Hg, dry (i.e., standard temperature, pressure, dry [STPD]).

Techniques

CO combines with hemoglobin (Hb) approximately 210 times more readily than oxygen (O₂). In the presence of normal amounts of Hb and normal ventilatory function, the primary limiting factor to diffusion of CO is the status of the alveolocapillary membranes. This process of conductance across the membranes can be divided into two components: membrane conductance (Dm) and the chemical reaction between CO and Hb (Figure 3-1). Dm reflects the process of diffusion across the alveolocapillary membrane. Uptake of CO by Hb depends on the reaction rate (θ) and the pulmonary capillary blood volume (Vc). These two components occur in series, so the diffusion conductance can be expressed as:

Figure 3-1 Diffusing capacity is performed to evaluate the alveolar capillary interface where gas exchange occurs.

< ?xml:namespace prefix = "mml" />1DLCO=1Dm+1θVc D

Diffusing capacity can be affected by factors that change the membrane component, as well as by alterations in Hb and the capillary blood volume.

A small amount of CO in inspired gas produces measurable changes in the concentration of inspired versus expired gas. Because little or no CO is normally present in pulmonary capillary blood, the pressure gradient causing diffusion is basically the alveolar pressure (P_Aco). If the partial pressure of CO in the alveoli and the rate of uptake of the gas can be measured, the Dlco of the lung can be determined. There are several methods for determining Dlco (Table 3-1). All methods are based on the following equation:

Table 3-1

Advantages and Disadvantages of Dlco Testing Methods

Method	Technique	Advantages	Disadvantages	Applications
Dlcosb (breath hold)	CO and tracer gas analysis relatively simple; 10-sec breath hold	Easy calculations, simple, fast; highly standardized and automated; minimal COHb back-pressure effect	Sensitive to distribution of ventilation and /matching; “nonphysiologic”; not practical for exercise testing	Screening and clinical applications
Dlcorb (rebreathing)	Rapid analysis of CO and tracer gas required; rebreathing must be controlled	Less sensitive to V_A than Dlcosb; less sensitive to /abnormalities; can be used with NO to measure Dlno	Complex calculations (computerized); rapidly responding analyzers required; sensitive to COHb back-pressure	Clinical and research applications; provides most accurate Dlco
Dlcoib (intrabreath)	Rapid analysis of CO and tracer gas during single controlled exhalation	Breath holding not required; can be used during exercise	Complex calculations (computerized); flow must be controlled; sensitive to uneven /; not standardized	Screening and clinical applications; may be useful in patients who cannot hold their breath
1/Dm + 1/θV_c (membrane diffusing capacity)	Dlcosb repeated at two different levels of alveolar PO₂	Differentiates membrane transfer resistance from red cell uptake	Complex calculations; estimates of alveolar PO₂ are critical	Research with limited clinical applications

Dlco

DLCO=V·COPACO-PCCO

where:

co milliliters of CO transferred/minute (STPD)

P_Aco = mean alveolar partial pressure of CO

P_Cco = mean capillary partial pressure of CO, assumed to be 0

Dlco is expressed in milliliters of gas/minute/unit of driving pressure at STPD conditions.

3-1How To…

Perform a Dlcosb Maneuver

1. Tasks common to all procedures

a. Calibrate and prepare equipment

b. Review order

c. Introduce yourself and identify patient according to institutional policies

d. Describe and demonstrate procedure

2. Review spirometry data and adjust expired volume criteria if appropriate (VC < 2.0 L).

3. Enter recent Hgb and adjust for COHb if available.

4. Have the subject sit upright with feet flat on the floor and adjust the mouthpiece to the proper height.

5. The mouthpiece should rest on top of the tongue. Have the subject gently bit down with his or her teeth and seal lips firmly around the mouthpiece. Emphasize the need for tight lips without a leak. Place the noseclip securely.

6. Have them breathe quietly for several breaths and then empty completely to RV (verbal cues such as “keep blowing,” or “push, push until empty”).

7. Once empty, have subject inhale rapidly as much as possible (verbal cues, “up, up, up”) and hold their breath (verbal cues, “keep holding or hold it”). Counting down the last few seconds can be very helpful.

8. Have subject blow their air out until empty or the system terminates the maneuver.

9. A wait period of 4 minutes is required between maneuvers.

10. Perform until acceptability and repeatability criteria are achieved or a maximum of five maneuvers. (See Criteria for Acceptability 3-1)

11. Note comments related to test quality.

Single Breath-Hold Technique (Modified Krogh’s Technique)

The patient exhales to RV and then inspires a vital capacity breath (referred to as the IVC or V_I) from a system such as that in Figure 3-2. A special diffusion gas mixture is delivered either from a spirometer, a reservoir bag, or by means of a demand valve. The diffusion mixture usually contains 0.3% CO, a “tracer” gas, 21% O₂, and the balance is N₂. The tracer gas is usually an insoluble, inert gas such as helium (He), methane (CH₄), or neon (Ne). The tracer used depends on the type of analyzer implemented to analyze the exhaled gas. The traditional method used He (usually about 10%) as the tracer gas. Rapidly responding infrared analyzers (see Chapter 11) have been used for continuous analysis of the small changes in CO. The same type of infrared analyzer can use CH₄ as the tracer gas, so that a single analyzer can rapidly detect changes in both CO and the tracer. Another method uses gas chromatography (see Chapter 11) to detect changes in CO with neon used as the tracer gas.

Figure 3-2 Dlco apparatus. Basic equipment for performing a Dlco test (specifically the Dlcosb). Gas is delivered to the automated valve from a reservoir bag (not shown), the spirometer, or a demand valve (not shown). The automated valve allows the patient to inhale the test gas rapidly. A computer usually displays a volume-time tracing along with signals from the gas analyzer(s) (see Figures 3-3, 3-4, and 3-5). Timing of the maneuver is usually performed by the computer.

After inspiring the VC breath, the patient holds the breath at total lung capacity (TLC) for approximately 10 seconds. The patient then exhales. After a suitable washout volume (750–1000 mL) has been discarded, a sample of alveolar gas is collected. The alveolar sample may be collected in a small bag (approximately 500 mL or less) or by continually aspirating a sample of the exhaled gas.

The sample is analyzed to obtain the fractional CO and tracer gas concentrations in alveolar gas, F_Aco_T (where T is the time of the breath hold), and F_Atracer, respectively. The concentration of CO in the alveoli at the beginning of the breath hold (F_Aco₀) must be determined as well. It is calculated as follows:

FACO0=F1CO×FAtracerFI tracer

where:

F_Aco₀ = fraction of CO in alveolar gas at beginning of breath hold (time = 0)

F_Ico = fraction of CO in reservoir (usually 0.003)

F_Atracer = fraction of tracer in alveolar gas sample

F_Itracer = fraction of tracer in inspired gas (varies with tracer gas used)

The change in tracer gas concentration reflects dilution of inspired gas by the gas remaining in the lungs (i.e., RV). This change is used to determine the CO concentration at the beginning of the breath hold, before diffusion from the alveoli into the pulmonary capillaries. The Dlcosb (single-breath) is then calculated as follows:

DLCOsb = VA × 60(PB−47) × (T) × LnFACO0FACOT

where:

V_A = alveolar volume, mL (STPD)

60 = correction from seconds to minutes

P_B = barometric pressure, mm Hg

47 = water vapor pressure at 37 °C, mm Hg

T = breath-hold interval, seconds

Ln = natural logarithm

F_Aco₀ = fraction of CO in alveolar gas at beginning of breath hold

F_Aco_T = fraction of CO in alveolar gas at end of breath hold

V_A may be calculated from the single-breath dilution of the tracer gas:

VA=(VI−VD)×FItracerFAtracer×STPD correction factor

where:

V_I = volume of test gas inspired, mL (see Figure 3-3)

Figure 3-3 Dlcosb maneuver tracing. Tracing of a single-breath Dlco maneuver proceeding from left to right *(heavy line)*. After exhaling to RV (0 L on the volume axis), the patient rapidly inspires a vital capacity breath (V_I) of the test gas, then holds the breath at TLC for approximately 10 seconds. At the end of the breath hold, the patient exhales rapidly. The dead space washout volume is discarded, an alveolar gas sample is collected, then analyzed. The recommended timing method is the Jones and Meade method.

V_D = dead space volume (anatomic and instrumental), mL

F_Atracer = fraction of tracer in alveolar gas sample

F_Itracer = fraction of tracer in inspired gas (depends on tracer used)

Note that the V_A, usually expressed in BTPS units, must be converted to STPD for the single-breath calculation. The dilution of tracer gas is used twice to determine the CO concentration at the beginning of the breath hold and to determine the lung volume (i.e., V_A) at which the breath hold occurred.

A simplification of the single-breath method described earlier is widely used. The tracer gas and CO analyzers may be calibrated to read full scale (100% or 1.000) when sampling the diffusion mixture, and to read zero when sampling air (no tracer or CO). If the analyzers have a linear response to each other, the fractional concentration of the tracer gas in the alveolar sample is equal to the F_Aco₀. This technique assumes that both the tracer gas and CO are diluted equally during inspiration. Because no tracer gas leaves the lung during the breath hold, its concentration in the alveolar sample approximates that of the CO before any diffusion occurred. The exponential rate of CO diffusion from the alveoli can then be expressed as follows:

Ln(FAtracerFACOT)

where:

F_Atracer = fraction of tracer in alveolar gas, equal to F_Aco₀

F_Aco_T = fraction of CO in alveolar gas at end of breath hold

Ln = natural logarithm of the ratio

This technique avoids the necessity of analyzing the absolute concentrations of the two gases. However, it requires that the analyzers be linear with respect to each other. Analysis of CO is often done using infrared analyzers (see Chapter 11), and their output is nonlinear. Care must be taken to ensure that corrected CO readings are used in the computation. These corrections are easily accomplished either electronically or via software in computerized systems. Systems that use the same detector for both CO and the tracer gas (e.g., infrared, gas chromatography) also need to provide linear output. The linearity of the system should be within 0.5% of full scale. This means that any drift or nonlinearity should cause no more than a 0.5% error when analyzing a known gas concentration (See Chapter 12).

Dlco gas analysis is commonly performed with either a rapidly responding multigas analyzer or gas chromatography. Multigas analysis uses specialized infrared analyzers capable of detecting several gases simultaneously. These systems use methane (CH₄) as a tracer gas. One advantage of multigas analysis is that CO and CH₄ are measured rapidly and continuously (Figure 3-4) so that the calculated Dlco is available as soon as the exhalation has been completed. Gas chromatography (see Chapter 10) can also be used for Dlco gas analysis. Neon (Ne) is used as the tracer gas (Figure 3-5). Helium is used as a “carrier” gas for the chromatograph. Although gas analysis using chromatography is slow (60–90 seconds), it is extremely accurate.

Figure 3-4 Dlcosb maneuver using continuous gas analysis. Changes in gas concentrations are shown *(top)*. Test gases (CO and CH₄) rise rapidly to their initial values of 0.3% during the breath hold. During exhalation, both gas concentrations fall as dead space is washed out. The tracer gas, CH₄, shows a plateau as alveolar gas is exhaled. CO shows a similar pattern, but with a lower concentration because of uptake (diffusion). Gas concentration measurements are made from an alveolar window *(gray lines)* that can be adjusted. Simultaneous changes in lung volumes are shown on the bottom tracing. IVC indicates inspiratory volume (V_I). In this test, the patient failed to inspire at least 85% of the VC *(dashed gray line)*. BHTs and BHTe indicate the breath-hold timing scheme. Calculated Dlco and related measurements are displayed allowing for inspection of changes as the alveolar sample “window” is adjusted. (Courtesy CareFusion Healthcare Critical Care Division, Palm Springs, Calif.)

Figure 3-5 Dlcosb test using gas chromatography. Volume-time tracing with inspiration, breath-hold, and alveolar sampling is shown *(left graph)*. In this scheme, inspiration causes a downward deflection. Output of the gas chromatograph is shown *(right graph)*. Neon (the tracer gas) and CO show distinct peaks on the gas chromatograph tracing. The alveolar sample is superimposed over a pre-analysis (calibration) curve of the test gas. Ne_I is the initial tracer concentration, and Ne_A is the concentration after the breath hold. CO concentrations of the undiluted test gas (CO₀) and end of the breath hold (CO_T) are superimposed. Calculated Dlco and related values for multiple efforts are shown at the top. (Courtesy Medical Graphics, Inc., St. Paul, Minn.)

The resistance of the breathing circuit should be less than 1.5 cm H₂O/L/sec, at a flow of 6 L/sec. This is important in allowing the patient to inspire rapidly from RV to TLC. A demand valve may be used instead of a reservoir bag for the test gas. In a demand-flow system, the maximal inspiratory pressure to maintain a flow of 6 L/sec should be less than 10 cm H₂O. Increased resistance, in either a reservoir or a demand valve system, may cause the patient to produce large subatmospheric pressures during inspiration. This has the effect of increasing pulmonary capillary blood volume and may falsely increase Dlco.

The timing device for the maneuver should be accurate to within 100 msec over a 10-second interval (1%). Most computerized systems time the maneuver automatically. However, a means of verifying the accuracy of the breath-hold time should be available. The Jones and Meade method of timing the breath hold should be used (see Figure 3-5). The Jones and Meade method measures breath-hold time from 0.3 of the inspiratory time to the midpoint of the alveolar sample collection.

Corrections must be made for the patient’s anatomic dead space (V_D) and for dead space in the valve (and sample bag, if used). Anatomic V_D should be calculated as 2.2 mL/kg (1 mL/lb) of ideal body weight. The equipment manufacturer should specify instrument V_D. Instrument V_D should not exceed 350 mL for adult subjects, including mouthpiece and any filters that might be used. Smaller instrument V_D may be necessary for pediatric patients. Anatomic and instrument V_D are subtracted from inspired volume (V_I) before the alveolar volume (V_A) is calculated.

All gas volumes must be corrected from ATPS to STPD for the Dlco calculations. However, when the V_A is used to calculate the ratio of Dlco to lung volume (Dl/V_A), it is normally expressed in BTPS units. Accurate measurement of inspired volume during the maneuver requires that the spirometer have an accuracy of 3.5% (3% + 0.5% for the calibration syringe itself) over a range of 8 L. Volume-based spirometer systems must also be free from leaks.

Gas analyzers that are affected by carbon dioxide (CO₂) or water vapor require appropriate absorbers. Absorption of CO₂ is usually accomplished with a chemical absorber using Ba(OH)₂ (baralyme) or NaOH (soda lyme). Each of these reactions produces water vapor. Therefore, CO₂ absorbers should be placed upstream of an H₂O absorber. Anhydrous CaSO₄ is commonly used to remove water vapor. Selectively permeable tubing (PERMA PURE®) can also be used to establish a known water vapor content. Gas-conditioning devices must be routinely checked to ensure accurate gas analysis. Chemical absorbers typically add an indicator that changes color as the absorber becomes exhausted.

PF Tip 3-1

Watch the patient carefully during the Dlcosb effort to detect either a Valsalva or Müller maneuver. Widely varying results in two or more Dlco measurements are often caused by the patient failing to relax during the breath hold. Some pulmonary function systems provide a pressure monitor to detect large positive or negative pressures during the breath hold.

Dlcosb maneuvers should be performed after the patient has been seated for at least 5 minutes. The patient should refrain from exertion immediately before the test; exercise increases cardiac output, which increases Dlco. The patient should be instructed about the requirements of the maneuver and the technique demonstrated. Expiration to RV should be of a reasonable duration, usually 6 seconds or less. Patients who have airway obstruction may have difficulty exhaling completely in this interval. Inspiration to TLC should be rapid but not forced. Healthy subjects and patients with airway obstruction should be able to inspire at least 85% of their VC within 4 seconds (Criteria for Acceptability 3-1). The single-breath calculation assumes instantaneous filling of the lung. Prolonged inspiratory times will decrease the actual time of breath holding at TLC, typically resulting in a lower Dlco. The breath hold should be relaxed, against either the closed glottis or a closed valve. The patient should avoid excessive positive intrathoracic pressure (Valsalva maneuver) or excessive negative intrathoracic pressure (Müller maneuver). A Valsalva maneuver reduces pulmonary capillary blood volume and may produce a falsely low Dlco. A Müller maneuver increases pulmonary capillary blood volume and may falsely increase Dlco. Expiration after the breath hold should be smooth and uninterrupted. Exhalation should take less than 4 seconds, and alveolar gas sampling should occur in less than 3 seconds (again because the calculations assume instantaneous emptying of the lung). Patients who have moderate or severe airway obstruction may have difficulty achieving these criteria. The breath-hold time, measured using the Jones and Meade method (see Figure 3-3), should be 10 seconds ± 2 seconds. Prolonged inspiratory or expiratory times may result in breath-hold times greater than 12 seconds and should be noted on the report.

Criteria For Acceptability 3-1 Dlco_sb

1. System has passed calibration and quality control procedures.

2. Inspiration from RV to TLC should be rapid and should occur within 4 seconds or less.

3. The volume inspired (V_I or IVC) should be at least 85% of the best previously recorded VC.

4. Breath-hold time should be between 8 and 12 seconds, with no evidence of leaks, or Valsalva or Müller maneuver.

5. Exhalation should be rapid with total exhalation lasting 4 seconds or less with appropriate clearance of VD and proper sampling/analysis of alveolar gas

6. An interval of at least 4 minutes should elapse between repeated tests. No more than five single-breath maneuvers should be performed.

7. The V_A is consistent with the clinical presentation. In a normal subject, the TLC–V_A relationship should be very close, if not the same, and TLC performed by any method in any disease state should be larger than V_A.

8. The average of two or more acceptable tests should be reported. Duplicate determinations should be within 3 mL/min/mm Hg of each other or within 10% of the largest observed value.

PF Tip 3-2

One of the most common problems encountered when performing the Dlcosb maneuver is failure of the subjects to inspire at least 85% of their previously measured VC. Careful instruction or reinstruction of the subject usually helps eliminate the problem, including making sure they expire completely before taking the maximal inhalation of test gas. Patients who have airway obstruction may have difficulty inspiring maximally after exhalation to residual volume (RV).

PF Tip 3-3

Dlco is affected by both Hb and COHb levels in the patient’s blood. A low Hb (anemia) or high COHb reduces the measured Dlco. A high Hb (polycythemia) causes the Dlco to appear elevated. As a “rule of thumb,” a 10% COHb will reduce the measured Dlco by 10%.

To obtain an alveolar sample, dead space gas needs to be washed out (i.e., discarded). A washout of 0.75–1.0 L is usually sufficient to clear the patient and sampling device dead space. For patients with small vital capacities (>2.0 L), the washout volume may be reduced to 0.5 L. A sample volume of 0.5–1.0 L should be collected, but a smaller sample may be necessary in patients whose VC is less than 1 L. In Dlcosb systems that analyze expired gas continuously (see Figure 3-4), inspection of the washout of the tracer gas may be used to select an appropriate alveolar sample. Rapidly responding gas analyzers that measure the CO and tracer gas simultaneously allow adjustment of washout volume (i.e., dead space) and sample volume after completion of the maneuver. These adjustments may be particularly useful in subjects who have very small vital capacities (e.g., pediatric patients or adults with severe restrictive disease). Such adjustments assume that both the CO and tracer gas concentrations reflect changes occurring at the mouth. Alveolar sampling may be adjusted to begin at the point where the tracer gas and CO indicate an “alveolar plateau” (see Figure 3-4). In patients who have uneven mixing or emptying of the lungs, there may not be a clear demarcation between dead space and alveolar gas. Adjustments to either washout (dead space) volume or sample volume should be noted on the report.

Two or more acceptable Dlcosb maneuvers (see Criteria for Acceptability 3-1) should be averaged. Duplicate determinations should be within 3 mL CO/min/mm Hg of each other, or within 10% of the largest value obtained from an acceptable effort. No more than five repeated maneuvers should be performed because of the effect of increasing carboxyhemoglobin (COHb) from inhalation of the test gas. There should be a 4-minute delay between repeated maneuvers to allow for washout of the tracer gas from the lungs.

Corrections for abnormal hemoglobin (Hb) concentrations should be applied with a current Hb value. The predicted Dlco should be corrected so that it reflects the Dlco at an Hb value of 14.6 g% for adult and adolescent males, and to an Hb value of 13.4 g% for women and children of either sex younger than 15 years of age. The Hb-corrected predicted value for males may be calculated as follows: