Attachment for Automated Single Breath Diffusing Capacity Measurement

CLINICAL INVESTIGATIONS Attachment for Automated Single Breath Diffusing Capacity Measurement* Edward A. Caensler, M.D., F.G.G.P.,.· and Arthur A. Smith, M.S., E.E.t

The single breath CO diffusing capacity hlM proved valuable for screening, particularly in situations in which altered mechanics of breathiug do not reflect the degree of pulmonary impairment. Although simple in concept, the method has proved technically difficult both for patients and operators. Also, results are modified by the volumes of breatbholding, of wash-out and of sampling and by the manner and timing of breatbholding. A device is described that eliminates these variables. It is virtually error-proof, simple to operate, inexpensive and easy to construct, has less deadspace, and can be attached to any box-balloon spirometer. Because all swikhiDg and sampling is controlled electrically, it is weD suited for computer-controlled testing and analysis. Routine use of the instrument for the past two years in our laboratory and during two indnstrial surveys has greatly reduced the time required for testing and for operator instruction, and the coefficient of variation for test and retest has been reduced from ±8.3 percent to ±1.4 percent.

The single breath carbon monoxide diffusing capacity, here called DL, was devised by Krogh in 1914.1 It was not used clinically until 40 years later when Forster et al 2 introduced helium as a tracer gas for calculation of the initial CO concentration in the lungs, and when nondispersion infrared spectrometers became available for CO analysis." With the conventional technique.' the subject breathes room air through tap no. 1 of a manually operated rotating four-way valve (Fig 1). On command, he expires fully and then inspires to total lung capacity (TLC) through tap no. 2 a mixture of 0.3 percent CO, 10 percent helium, 21 percent 02, ·From the Thoracic Services, Departments of Medicine and Surgery, Boston University School of Medicine, Boston. ··Professor of Surgery, . tSenior Fellow, Thoracic Services, Boston University School of Medicine and Instructor in Electrical Engineering, Massachusetts Institute of Technology. This study was supported in part by a SCOR award (HL15063), a Research Grant (HL-05933), a Career Award (HL-1l73) and a Training Grant (HL-5562), all from the National Heart and Lung Institute, N.I.H., USPHS. Reprint requests: Dr. Gaensler, Boston University School of Medicine, 15 Stouehtor: Street, Boston 02118

136

balance N2. The breath is held for about 10 seconds followed by rapid expiration through tap no. 3 to flush the apparatus and anatomic deadspace. An "alveolar" sample is then collected in a small bag through tap no. 4, and finally the subject breathes room air once more through tap no. 1. The inspiratory gas is stored in a balloon within a box to which Ii spirometer is attached so that the inspired and wash-out volumes can be read from the kymograph. Calculation of D L requires knowledge of the lung volume, VA, at which the breath was held as well as initial and final CO concentrations in the lung.' The final CO concentration comes from analysis of the "alveolar" bag. The initial CO concentration in the lungs is calculated from the dilution ratio of expired to inspired helium because essentially no helium is lost from the lungs during breathholding," We have examined D L in over 3,000 patients and in several surveys and we have found it to be a valuable screening method, particularly in situations in which altered mechanics of breathing do not reflect the degree of pulmonary impairment.v" It also became apparent that the results were

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AUTOMATED SINGLE BREATH DIFFUSING CAPACITY o

#1 Air

construct," had less deadspace than the conventional valves, and can be attached to any boxballoon spirometer. Because all switching and sampling are controlled electrically, it is also well suited for computer controlled testing, sample analysis and calculation.P PRINCIPLE OF OPERATION

The spirometer is prepared in a conventional manner: the balloon is filled with the CO-He mixture, the CO and He meters are adjusted to

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°The required parts for the attachment can be obtained for about $200. Assembly may require eight hours of electronic technician time and one week of machine shop work. The breathing assembly, the wash-out box, or the entire apparatus wiII be available from Warren E. Collins Co., Braintree, Mass.

FIGURE 1. Conventional manual system for D t, , slightly modified from Ogilvie, et al4 , used in our laboratory since 1954. During test four-way valve is rotated clockwise from room air ( # 1) to inspire (#2), deadspace wash-out (#3), alveolar sampling (#4) and back to room air. Bag B within box contains CO-He mixture to be inspired. Bag b, which is manuaIly evacuated before test, is for coIlection of alveolar gas. Spirometer records volume of inspiration, adequacy of breathholding, breathholding time and wash-out volume. Inspiratory tubing may be guarded by one-way valve and, before test, is flushed with inspiratory gas by turning valve to position #2 and pressing on spirometer beIl.

modified by the lung volume, VA, at which the breath is held,I.5,l.U5 by variations in volume during breathholding;" by the wash-out volume for the patient's and apparatus deadspace," the sample colIection volume,17-19 the breathholding time2.4.19.20 and the manner of breathholding.! These variables are related to proper patient instruction, split-second timing in the operation of the conventional four-way valve, the speed of response to command, and the respiratory flow rates. Initially, with experienced observers and trained subjects, differences between multiple determinations were small,··15.21 but subsequently, as the number of patients and laboratory staff increased, with rapid turnover unavoidable in a teaching setting, and especially in screening situations, these diHerences have become larger, and more time has been required for instruction and repeated testing. Details in technique appear to be particularly important in the determinations of the diffusing capacity of the pulmonary membrane (D M ) and the pulmonary capillary blood volume Vc) .17 With these considerations in mind, and especially for screening, we constructed an attachment for automated performance of the test. It is virtually error-proof, requires but a few minutes for operator instruction, is inexpensive and simple to CHEST, VOL. 63, NO.2, FEBRUARY, 1973

FIGURE 2. New device is shown attached to conventional boxballoon spirometer. CO and He meters are mounted side by side on front panel on right; immediately below is control panel for our device. Cord connects this panel to remote control of kymograph. Also on front panel, below to left, are oush buttons which control sampling valves V-5, V-6 and V-7 (see Fig 3). In center of figure, supported by adjustable rod, is breathing assembly with mouthpiece and solenoid valve, V-I. "Flush" valve is shown immediately above mouthpiece. Behind "flush" valve is solenoid valve, V-2, and, suspended from it, is sample bag, B-1, and its adjustable cage. Switch, S-l, is on back of this cage and not visible. Just to right of cage is Henderson-Haggard valve, V-F, which prevents expiration during breath-holding maneuver. Tube with V-F leads to balloon within box inside of spirometer console. Other tube, to right of V-F, for expiration, leads to valve V-3 which guards wash-out bag, B-2. This is shown in lower left comer, encased by its plastic box. On top right of this plastic box is corrugated tube which leads to box around balloon within spirometer console (compare Fig 1). On top left of plastic box is adjustable rod, connected to switch, S-2, and scale for adjusting wash-out volume. Valve, V-3, has been modified to permit automatic emptying of bag when valve is closed. Two corrugated tubes in upper left of figure are used for conventional spirometry.

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GAENSLER, SMITH

"zero" with room air and to "100" with balloon gas, and the spirometer bell is raised. The desired Bushout volume, collection volume and breathholding time are preselected on the new attachment. It has four breathing positions (Fig 2, 3) like the conventional four-way valve (Fig 1). Step 1

In this resting position the patient breathes room air. A spring-loaded push-button valve ("Bush") permits Bushing of the inspiratory circuit with the

CO-He mixture (Fig 3). When the patient is ready, he exhales maximally and signals with his hand when "his lungs are empty." The operator then pushes a button which initiates the test (step 2) and all further sequencing proceeds automatically. Step 2

The inspire and hold position is started by pushing the button; at this moment the following changes occur: 1) A buzzer, which signals to the patient to

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Washout Box 3. Schematic of automated DI. device. Before test, inspiratory circuit is flushed with COHe mixture from balloon through valve V-F by elevating valve marked "flush" on top. Meanwhile, patient breathes room air through "Mouth" orifice. When start button is activated, solenoid V-I closes, patient then inspires from balloon through valve V-F but cannot exhale. At same time kymograph is turned on and buzzer begins to sound. At end of breathholding period, valve V-3, shown at bottom, opens and patient exhales, into B-2, flush-out volume that is predetermined on scale attached to microswitch S-2. Cas thereby displaced from wash-out box goes through opening on top, marked by arrow, into box surrounding CO-He balloon within spirometer console. Thus, actual washout volume can be read on kymograph. When bag B-2 is filled, V-3 closes and solenoid valve V-2 on top opens for collection of alveolar sample in B-1. Volume of alveolar sample can he regulated on scale attached to microswitch S-1. When B-1 is filled to predetermined volume, valve V-2 closes, valve V-I opens once more and patient again breathes room air. At this time kymograph is turned off automatically. Large solenoid valve V-3 has been modified so that, when test is completed, flush gas from bag B-2 is automatically evacuated to wash-out box. Optional sampling circuit, shown to left, is located behind push-button panel of spirometer (Fig 1). This circuit provides for automatic evacuation of bag B-1 during breathholding period. Evacuation occurs when three-way miniature valve V-4 is directed to miniature three-way valve V-8 and pump is automatically turned on. Alveolar gas is analyzed when V-4 is turned towards V-.'5 and pump draws sample through drying tubes, flow meter and analytic meters. Sampling circuit also provides for zero setting of meters with "air" and "100" setting of meters with "balloon" gas, FIGURE

CHEST, VOL. 63, NO.2, FEBRUARY, 1973

AUTOMATED SINGLE BREATH DIFFUSING CAPACITY

inspire maximally and hold his breath is activated; it remains on for a preset time interval, usually 9.5 seconds. 2) Valve V-I closes permitting inspiration of the CO-He mixture from the balloon; unintentional exhalation is prevented by a one-way 6utter valve, V-F. 3) The kymograph is turned on; it remains on during steps 2, 3 and 4, and is turned off at the end of the test. 4) A small pump is turned on to evacuate the sampling bag, B-1, through valves V-4 and V-

8.

Step 3 The wash-out period begins automatically at the end of the breathholding interval. At the moment of initiation the following occurs: 1) The buzzer stops. 2) Evacuation of the sampling bag stops; the bag is sealed in the evacuated condition by valves V-4 and V-5. 3) Valve, V-3, opens, permitting exhalation into the wash-out bag, B-2. 4) An electronic timer, Rel-5, adjusted to approximately two seconds, is started. Step 4. The collection period is normally initiated automatically when the patient has exhaled the present wash-out volume into B-2, closing switch, S-2; if, unexpectedly, he fails to exhale the selected volume within two seconds, then the timer, Rel-5, causes Step 4 to begin. As Step 4 begins, the following occurs: 1) Valve, V-2, opens permitting expiration into the sampling bag, B-1. 2) Valve, V-3, closes, preventing further expiration into B-2; this also opens a small leak in the bottom of V-3, permitting B-2 to empty into the surrounding box thus preparing it for the next test. 3) An electronic timer, Rel-6, adjusted to approximately two seconds, is started. Return to Step 1 is achieved normally when the patient has exhaled the preset collection volume into B-1, closing switch S-I; if, unexpectedly, he fails to exhale the preselected volume within two seconds, the timer, Rel-6, causes return to Step 1. On returning to Step 1 the following occurs: 1) Valve, V-I, opens permitting the patient to breathe room air once more. 2) The kymograph stops. 3) Valve, V-2, closes sealing the collected sample in B-1. CHEST, VOL. 63, NO.2, FEBRUARY, 1973

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At the completion of the test, the sampling pump and V-5 are activated by a push button on the spirometer. This slowly evacuates bag B-1 through filters and analyzers; when He and CO readings have become steady the pump is turned off and final readings are recorded. The actual percentage of CO removed is obtained from a calibration curve; the effective breathholding time is read from the spirogram according to Ogilvie et al" or Jones and Meade.!" The inspired volume is read from the spirogram and the alveolar volume, VA is calculated by addition of the previously determined residual volume and corrected to standard temperature and pressure dry ( STPD ), 4 or it can be calculated from the single breath He dilution ratio.l" DL, and perhaps D M and Vc, are calculated in the usual manner," except that the suggested meter adjustments simplify the calculation. DESCRIPTION OF ApPARATUS

The attachment consists of a breathing assembly, a washout box mounted near the box-balloon system and a control box (Fig 2).

The Breathing Assembly This apparatus consists of a main breathing tube (1.5" ID) with a center opening for the rubber mouthpiece ("mouth") (Fig 3). On top of the tube is a normally closed, spring-loaded valve ("flush") which, when opened manually, causes a large leak so that the spirometer bell can be lowered; this forces balloon gas into the inspiratory tubing and breathing assembly. To the left is a solenoid with a plunger, V-I, which functions as a three-way valve: in the deenergized position (step 1), shown in Figure 3, the patient breathes air through a series of openings; when V-I is energized (steps 2, 3, 4), the patient breathes to the right of the mouthpiece. A large-bore, normally closed solenoid valve, V-2, has a side inlet attached to the main breathing tube and an outlet attached to bag, B-1, for collection of the alveolar sample; it is open only during step 4. The deadspace for alveolar sampling, that is, the internal volume of V-2 and the bag attachment, is 7 mI. To either side of B-1 are two metal plates, one hinged and with a microswitch, S-1. An alveolar sample from 300 to 1,500 ml can be selected by adjusting the distance between the two plates. Inflation of B-1 closes S-2, which returns the instrument to step 1. The main breathing tube branches to the right: the tube nearer the center is connected to solenoid valve, V-3 which guards the wash-out box (Fig 3); the tube at the end is connected to the balloon containing the inspiratory gas, and it is guarded by a low resistance Henderson-Haggard type flutter valve.

The Sampling Circuit Prior to the test, the sampling bag, B-1, can be evacuated by twisting and clamping; or, it can be attached to a sampling system designed for survey work)! It is shown in Figure 3 to the right of the broken line and consists of three two-way normally closed miniature solenoid valves, V-5, V-6 and V-7, two similar three-way valves, V-4 and V-8, and a small pump. The upper inlet of V-5 samples alveolar gas from

140

GAENSLER, SMITH Analy.i. 01 Duplicate Determination. by Manual and Automated D,_ Method. 20 Normal Volunteers

27 Pipe Coverers A

Manual Mean S.D.

Automatic Mean S.D.

Manual (1966) Mean S.D.

Breath holding time, sec Combined trials (test and retest) Test-retest difference Coefficient of variation

10.08 0.56 -0.25 0.63 ±6.3

9.70 0.27 -0.07 0.35 ±3.6*

10.20 1.44 -0.04 1.05 ±1O.3

9.21 0.43 0.09 0.46 ±5.0*

Inspired volume (VA), L Combined trials (test and retest) Test-retest difference Coefficient of variation

3.53 0.67 -0.04 0.26 ±7.2

3.64 0.75 0.18 -0.50 ±4.8

3.58 0.58 0.03 0.23 ±6.6

3.20 0.53 0.20 -0.01 ±6.4

Washout volume, L Combined trials (test and retest) Test-retest difference Coefficient of variation

1.69 0.55 0.32 0.64 ±37.9

0.92 0.13 0.01 0.14 ± 15.3*

2.30 1.10 -0.38 0.55 ±24.2

0.95 0.21 -O.oI 0.11 ± 11.3*

DL, ml/min/torr Combined trials (test and retest) Test-retest difference Coefficient of variation

33.5 7.0 0.6 2.8 ±8.3

32.7 6.4 0.2 0.8 ±2.4*

27.2 6.7 -0.7 3.8 ±14.0

23.8 5.8 0.4 1.4 ±5.8*

Automatic (1970) Mean S.D.

*P
The Wash-out Box This apparatus is made of plastic tubing, with an internal diameter of 4~ inches (Fig 2 and 3) . The expired gas enters a 3 L anesthesia bag, B-2, within the box through a large, normally closed solenoid valve, V-3, which is open only during step 3. Resting on top of the bag, and hinged at the right end of the box, is a plastic plate which moves upwards as the bag fills. When the plate impinges on microswitch, S-2, step 4 is reached. The height of S-2 can be adjusted with a plunger and calibrated scale for wash-out volumes from 500-1,500 ml. The wash-out box is connected to the main box of the box-balloon system so that the

spirometer rises as B-2 fills, and the actual wash-out volume can be read from the spirogram. Valve, V-3, was modified by drilling a hole through the bottom of its housing. Inside the valve we placed a spring-loaded plunger which closes the hole when the valve is energized (open); when the valve returns to its normally closed position, the hole opens, in effect, converting V-3 into a three-way valve. The small hole is connected to the box with a tube so that the Hush-out gas within B-2 empties into the box around the bag without affecting the spirometer, and thus prepares B-2 for the next test.

The Control Circuit This mechanism is shown in Figure 4. It is attached to a standard 19" X 3*" relay rack panel which fits the front of the spirometer (Fig 2). For safety, all relays, pilot lights and solenoid valves operate on 24 volts DC because some are within the patient's reach or near his mouth (Fig 2). Both the AC line neutral, and the 25 volt B- are grounded to the spirometer and breathing assembly. Simple, commercial control relays were used for switching rather than sophisticated logic circuits, because the latter are more expensive and have insufficient power for the heavy solenoid valves. The unit is turned on by S-4 which also connects the remote control of the spirometer kymograph via a receptacle, Hee-L, mounted on the front panel. The heart of the unit is a four-pole stepping relay, Bel-L, an inexpensive unit which "steps-on-break" and requires ReI2. With a relay which "steps-on-make," Rel-2 is not needed and the alternative connection shown in Figure 4 is made. The four poles of Rel-l are connected to pilot lights L-l, L-2, L-3 and L-4 on the front panel so that the active step can be seen. The test is started by depressing S-5 on the front panel which switches from step I to step 2. All other steps proceed automatically. However, each next step can be actuated manually by depressing S-5 once more. If the instrument is left in any step other than 1, then timing circuits in steps 2, 3 and 4 automatically return the instrument to step 1 to prepare

CHEST, VOL. 63, NO.2, FEBRUARY, 1973

141

AUTOMATED SINGLE BREATH DIFFUSING CAPACITY

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FIGURE 4. Diagram of control circuit. For detailed description see text. In addition to sequencing of breathing circuit, device also sounds buzzer during breathholding period, operates kymograph for period of test and operates panel lights for visual inspection of sequencing. Entire circuit, including all solenoid valves shown in Figure 2, is operated by 25 volts DC supplied by T-I rated at 4 amps. Relays Rel-2 and Rel-3, Lamps L-I to L-4, microswitches S-I and S-2, toggle switches S-3 and S-4, buzzer and connectors are all standard, inexpensive industrial parts. Rel-4, which controls breathholding time, adjusted by R-I, and ReI-6, which controls sample collection time and is adjusted by R-3, are precision electronic time delay relays (Potter and Bromfield CUH-42-300IO). ReI-5, which controls wash-out period, is thermal time delay tube (Amperite 26-NO-5T). S-5 is normally open momentary push button which initiates test sequence. Relay contacts are protected against arcing by industrial spark suppressors or diodes as indicated. ReI-I, main sequencer, is special four position stepping relay (Potter and Bromfield) which steps-on-break. This requires ReI-2. Note #1: If step-on-make relay were available, Rel-2 could be eliminated as indicated by broken line. for the next test and to prevent overheating of the solenoid valves. The circuit design is such that all electric contacts which could switch to the next step are active only during that step. This is important because S-I and S-2 remain closed for as long as the bags are filled. During step I, double-pole relay, Rel-3, is energized. Therefore, in this "resting" position, Rec-I, which activates the remote control of the kymograph drum, is disconnected and valve, V-I, is de-energized (Fig 3). During all other steps Rec-I and V-I are energized. With step 2, the kymograph is turned on via Rec-l. V-I is activated, switching the patient from room air to the other circuits (Fig 3); and an electronic time delay circuit and the normally closed circuit of Rel-4 are energized. CAUBRATION

Calibration of Volume Scales for Wash-Out and Alveolar Bags The two bags, B-1 and B-2, were allowed to empty and the

tube at the bottom of V-3 and rubber nipple of B-1 were

clamped (Fig 3). The spirometer was then emptied. Step 3 was activated manually, and air was blown slowly into the

CHEST, VOl. 63, NO.2, FEBRUARY, 1973

"Mouth" orifice. Switches S-2 and S-I were allowed to activate steps 4 and I, respectively, then the gas volumes contained in B-1 and B-2 were measured with a graduated I L syringe, and the scales were marked accordingly. This procedure was repeated a number of times at different settings of switches S-I and S-2. REsULTS

Accuracy of Preselected Wash-Out and Alveolar Bag Volumes For the following experiments the wash-out volume was adjusted to 750 ml, then later to 1,500 ml on the now calibrated scale, and the bag volume to 500 ml and later to 1,000 mi. Steady "expiratory" flow rates at the "mouth" were achieved by connecting compressed air with a flow regulator to the mouthpiece. The actual flow rates were calculated from the slope of the spirometer tracing, and the actual bag volumes were measured with the graduated syringe.

142

GAENSLER, SMITH

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S. Two curves marked by solid dots show actual volume in flush-out bag when its control was set to 0.75 and 1.5 L, respectively. Circles indicate alveolar bag volume with adjustments to 0..5 and 1.0 L.. respectively. At expiratory flow rates to about 1 Lisee actual volumes are identical to preselected volume. At faster flow rates bags contain slightly more gas but even at flow rates of 3 Lisee error was insignificant in terms of testing procedure. FIGURE

Figure 5 shows that up to Bow rates of 1 LI sec, the actual bag volumes were the same as the volumes preselected on the scales of S-1 and S-2. At higher flow rates, the time required for closure of microswitches, relays and large solenoid valves became significant. Theoretically, at a Bow rate of 3 Llsec, a delay of only 30 msec would cause an "overfill" of 100 ml. Actually, at about this Bow rate the bag volumes exceeded the preselected volume by about 90-120 ml. However, this was an insignificant error in practical terms. Effect on Variability of DL The effectiveness of the control unit in reducing variability was evaluated in two ways. First, 20 normal volunteers were tested in duplicate in randomized fashion by experienced operators both with a conventional manual four-way valve and with the automated device. The same box-balloon spirometer and analytic instruments were used. Second, 27 pipe coverers who had had duplicate D L determinations with our manual instrument in 1966, were tested again in duplicate in 1970 with the automatic system by briefly trained operators. The results are summarized in the Table. Data were analyzed using the T and F tests for paired observations.P:" In the normal subjects, there were no important differences between the mean of duplicate determinations performed with the manual and with the automatic system in regard to breathholding time, inspired volume and D L • The mean wash-out vol-

ume of 1.69 L with the manual method was much larger than the 0.92 L with the automatic attachment, even though we tried for a wash-out of 1 L at all times. This was because with large vital capacities and rapid expiratory Bow rates of normal subjects, the manual valve could not. be turned fast enough. A similar difference in wash-out volumes was observed in the pipe coverers (manual 2.30 L, automated 0.95 L), but in those workers there were also differences in inspired volume and D L , both of which were significantly lower in 1970. This was, in part, the result of aging of the subjects and, more important, because of progressive asbestosis in many workers,u·12 The variability between duplicate tests, as measured by the coefficient of variation, was reduced to one-half, both with regard to breathholding time and to wash-out volume, when the automatic attachment was used (see the table). This had the effect of reducing the coefficient of variation of the DL from 8.3 percent to 2.4 percent in the normal subjects and from 14.0 percent to 5.8 percent in the pipe coverers. Our instrument, unlike that of others,25.26 does not limit or control the inspired volume, and therefore the coefficient of variation for this was unchanged (see the table). During the past two years we have used the attachment routinely in our laboratory in more than 200 patients. There have been no technical problems, coefficients of variation between triplicate tests have remained low when inspired volumes were similar, and repeated testing has become unnecessary. More important, the time required for operator instruction has been greatly reduced and the instrument has been used successfully by medical students and residents with minimal training. And for technicians a test that formerly was considered a chore, has become a matter of simple routine. Also, during the last two years, this version of the instrument, and another in which the test and all calculations are performed by a small dedicated computer," have been used in two surveys. One concerned 186 paper workers who had a history, chest examination, spirometry and DL in four days and the other included 65 asbestos workers who were studied at our laboratory. In each instance, with the new attachment, duplicate D L determinations required less time than any of the other screening procedures. DISCUSSION

The technical details of the D L measurement have received a great deal of attention. Although simple in conception, the test has proved more difficult in

CHEST, VOL. 63, NO.2, FEBRUARY, 1973

AUTOMATED SINGLE BREATH DIFFUSING CAPACITY

practice. In experienced hands the coefficient of variation within laboratories has ranged from 5 to 18 percent,4.15.21.24 and results between laboratories have varied from 46 to 171 percent of the expected value." This has been of concern particularly when D L was used to monitor the natural course of infiltrative lung disease or the results of therapy, and when it was part of a screening program for epidemiologic studiesY·12.14.27-29 Review of our D L data obtained between 1954 and 1970 in 1,840 subjects showed that erroneous reading of analytic meters and errors in the use of calibration curves for the CO meter were the most important sources of observer variation. The former have been virtually eliminated by subsitution of digital meters.P and the latter have been avoided by simple methods for construction and use of calibration curves. Among the other technical variables, the following must be considered: the lung volume (VA) at which the breath is held, the possible effect of a Valsalva maneuver during breathholding, the CO "back pressure," the breathholding time, the washout volume and the volume of the alveolar sample. Concerning VA, Krogh' found that D L decreased progressively with decreasing VA until functional residual capacity (FRC) was reached, and she attributed this to a progressive decrease in the size of the membrane. With the revival of her technique, this factor initially was ignored because Forster, Ogilvie and their associates2.4.3 0 did not find a significant effect of VA on DL. Subsequently, however, data from our laboratories":" and from othersI4.25.31-33 have amply confirmed Krogh's findings. For example, in 98 normal subjects a 50 percent decrease in VA from total lung capacity (TLC) resulted in a mean decrease in D L of 40 percent, and control of VA importantly affected repeatability; in 67 patients with uncontrolled multiple D L determinations the coefficient of variation was reduced from ± 10.7 to ±2.6 percent when only those DL values were considered in which the breath had been held at between 95 and 100 percent of TLC. 15 Furthermore, the large numerical difference between steady state D L and single breath DL was largely explained by the difference in the lung volume at which the two determinations were made. When the single breath DL was determined at FRC,15 or when the steady state test was done near TLC,34 then this difference disappeared. Two previous devices for semiautomated DL determinations were designed primarily to prevent variations of D L resulting from variability of inspired volume. The instrument described by Meade et al 25 is an elaborate and costly spirometer system CHEST, VOL. 63, NO.2, FEBRUARY, 1973

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in which volume changes are detected by a light beam which is interrupted by blanks in the pulley wheel of the spirometer. For proper adjustment, the anticipated volume of inspiration must be dialed ahead of time on the instrument. This volume is selected so that, presumably, inspiration will be limited by solenoid valves to about 300 ml less than the anticipated maximal inspiratory volume. In the attachment by DeGraff and Romans'" inspired volume is detected by a potentiometer on the pulley, and this volume is similarly adjusted before the test to 100-300 ml less than anticipated inspiration. This instrument which uses electric chronometers for timing and a complex electronic circuit for sequencing was not useful for us because the alveolar sample that could be trapped-no more than 75 ml-was too small for our infrared and catharometer analyses. We have purposely avoided any limitation of the anticipated inspired volume in our instrument for the following considerations: 1.) A significant number of patients, during the first or all D L tests, did not reach the inspired volume which was anticipated from previously performed spirometry, usually because of failure to expire fully before inspiring the CO-He mixture. For example, 12 percent of 710 survey subjects failed to reach 95 percent of the best VC from spirometry during duplicate D L tests. If VA had been preselected at 100 to 300 ml less than VC, then in all these instances the instrument would not have triggered. However, this failure would not have been noticed until the subject had taken a deep breath of the gas; a waiting period of at least five minutes would then be required before another test could be tried. 2.) The change of D L with decreasing VA is not a linear function in most subjects; rather, there is usually an abrupt fall of DL until a VA of 80 to 90 percent of TLC is reached. and then there is only a slight further decline as V A declines from 80 to 50 percent of TLC.15 Therefore, any artificial limitation of the VA near TLC may cause a considerable artefactual reduction of D L. Actually, 6 percent of our survey subjects achieved a VA during the Dr. tests that was larger than the best VC determined separately. In these, DL would have been severely underestimated if V A had been artificially limited. We have circumvented the problem of varying VAin two ways. In our routine calculation program that is largely used for statistical purposes, any Dr. that was obtained at a VA less than 90 percent of the best V A is discarded and we have devised regression equations for Dr. based upon performance of 98 normal subjects each of whom held his breath at at least four different VA values between

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50 and 100 percent of TLO'·ls: men: D L = 3.75 X VA (STPD) - 0.153 X age + 19.93 women: D L = 5.38 X VA (STPD) - 0.083 X age + 7.72 Inasmuch as these equations include VA as a variable, two types of predicted values can be calculated. If a VAis inserted that is derived from a predicted TLC, then the normal predicted D L is obtained. If the patient's actual VA during the D L test is inserted, then a D L is predicted that would correspond to that particular VA for a subject of given sex, age and height. Thus, the actual DL can b~ evaluated, even though VAwas abnormally low, either because of inadequate effort or because of restrictive lung disease. Other expressions such as DL/V A or Krogh's K are based upon similar considerations. An increase in intrathoracic pressure occurs during breathholding, if the subject relaxes at TLC against a closed glottis or with an open glottis against valve V-F (Fig 3). This might decrease venous return, cardiac output and hence D L. One of the devices previously described contains provisions for monitoring the alveolar pressure if the glottis is open or to detect closure of the glottis." We have not considered such an elaboration because the actual decline of D L is very small, even with a forceful Valsalva maneuver.t and we have been unable to detect any significant change in D L with "normal" relaxation against an inspiratory valve, which may result in a 15 to 25 torr pressure elevation. Conventional calculations of D L are based on the assumption that CO in the pulmonary capillary blood exerts no significant 'back pressure." With steady state diffusing capacity measurements, particularly during exercise, there is a significant CO uptake, and appropriate corrections for back pressure must be made. With the DL as performed here, CO uptake is in the order of only 8 ml for each test, which would increase COHb saturation by less than I percent; this is not enough to measurably affect duplicate or triplicate determinations. IS Variations in breathholding time were significantly reduced by our attachment, in part because of automatic sequencing at a predetermined time interval and, in part, because of an audible signal to the patient indicating the end of breathholding. However, this decreased variation (see the table) had little effect on reducing the variability of the DL, because the relationship of the natural logarithm of the alveolar CO concentration to the breathholding time is virtually linear for breathholding periods that range from 5 to 15

GAENSLER, SMITH

seconds.v':" Therefore, insertion of any actual breathholding time within these limits, as measured from the spirogram, properly corrects for failure of the patient to hold the breath for exactly the predetermined time interval. Standardization of the expired volume prior to sampling, and of the alveolar sample volume appear to be much more important and were largely responsible for improved results with our sequencer (see the table). This is largely because the ratio of DL/VA is not the same throughout the lung," and because the earlier portions of the expirate are derived from the better ventilated alveoli. A constant wash-out volume appears to be most important because D L is significantly lower when an alveolar sample is collected early, rather than late. 4 •17 Such standardization is especially important to obtain reproducible values for the diffusing capacity of the pulmonary membrane, D M , and the pulmonary capillary blood volume, Vc; neglect of such standardization has led to a reversal of the relationship of Vc to lung volume." The variability of various alveolar fractions has been analyzed in detail with mathematical models" and in animals." The importance of a constant wash-out volume and early alveolar sampling have been emphasized. Both are most difficult to achieve with a manual four-way valve, particularly in subjects with large expiratory flow rates. They are assured, however, with the automatic device here described. More important than all of these factors has been the automation of the procedure itself which forces the subject to perfrom the right maneuver at the right time and frees the operator from such manual tasks as signaling the patient, activating the kymograph, observing a clock and turning a valve, all at more or less the same time. As a result of automation, testing time has been reduced, fewer samples have been lost, results are more reliable and repeatable, there is less operator fatigue and mass screening has been greatly simplified. The device is inexpensive and easily constructed from readily available components. 0 A~KNOWLEDGMENT: The authors are grateful for the assistance of Mr. Paul L. Swanson and Mr. Richard D. SmaIl in the design and construction of the mouth and wash-out assemblies.

REFERENCES

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18 Marshall R: A comparison of methods of measuring the diffusing capacity of the lungs for carbon monoxide. Investigation by fractional analysis of the alveolar air. J Clin Invest 37 :394-408, 1958 19 Jones RS, Meade F: A theoretical and experimental analysis of anomalies in the estimation of pulmonary diffusing capacity by the single breath method. Q J Exp Physiol46:131-143,1961 20 Anderson TW, Shephard RJ: A theoretical study of some errors in the measurement of pulmonary diffusing capacity. Respiration 26: 102-115, 1969 21 Cotes JE, Hall AM: The transfer factor for the lung; normal values in adults. In Normal Values for Respiratory Function in Man. (Arcangeli P, ed ) Panminerva Medica 1970, pp 327-343 22 Smith AA, Gaensler EA: Lung function mini-computer. Scientific Exhibits, 11th International Congress on Diseases of the Chest, American College Chest Physicians, Lausanne, Switzerland, Aug 3-7,1970 23 Natrella MG: Experimental Statistics. National Bureau of Standards Handbook 91. Washington, D.C. US Government Printing Office, 1963, pp 3.38-3.40 & 4.9-4.14 24 Heinone AO, Karvonen MJ, Jarvinen E: The reliability of the pulmonary diffusing capacity determination. Scand J Clin Lab Invest 14:307-310,1962 25 Meade F, Saunders MJ, Hyatt F, et all Automatic measurement of lung function. Lancet 2:573-575, 1965 26 DeGraff AC Jr, Romans W: Programmed valve sequence and alveolar gas sampler for DLCO measurements. J Appl PhysioI23:415-418, 1967 27 Cotes JE: Effect of variability in gas analysis on the reproducibility of the pulmonary diffusing capacity by the single breath method. Thorax 18: 151-154, 1963 28 Hunt R: Routine lung function studies on 830 employees in an asbestos processing factory. Ann NY Acad Sci 132:406-420, 1965 29 Ferris BG [r, Ranadive MV, Peters JM, et all Prevalence of chronic respiratory disease. Asbestosis in ship repair workers. Arch Environ Health 23:220-225, 1971 30 Forster RE II, Briscoe WA, Bates DV: Pulmonary diffusing capacity at different lung volumes. Fed Proc 13:46, 1954 31 Mittman C, Burrows B: Uniformity of pulmonary diffusion: Effect of lung volume. J Appl Physiol 14:496, 1959 32 Hamer NAJ: Variations in the components of the diffusing capacity as the lung expands. Clin Sci 24:275-285, 1963 33 Miller JM, Johnson RL Jr: Effect of lung Inflation on pulmonary diffusing capacity at rest and exercise. J Clin Invest 45:493-500,1966 34 Sikand RS, Piper J: Pulmonary diffusing capacity for CO in dogs by the single-breath method. Resp Physioll:172192, 1966