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The time course of pulmonary diffusion capacity changes following maximal exercise Sheel, Andrew William 1995-12-31

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THE TIME COURSE OF PULMONARY DIFFUSION CAPACITY CHANGES FOLLOWING MAXIMAL EXERCISE by ANDREW WILLIAM SHEEL B.P.E., The University of New Brunswick, 1993 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES SCHOOL OF HUMAN KINETICS We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA August 1995 © Andrew William Sheel, 1995 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis ~for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of l40r^CirN Ne*CcS The University of British Columbia Vancouver, Canada Date rX O^Q^"l~ DE-6 (2/88) ABSTRACT Pulmonary gas transport has not been typically recognized as a limiting factor to physical exercise. Dempsey et al. (1984; 1986) have suggested that the pulmonary system remains unchanged despite chronic aerobic training. Adaptations to other physiological systems may impose metabolic demands which the respiratory system can not meet. In essence, the lung's capacity for gas exchange becomes surpassed by other training adaptations. Supporting evidence is seen as decreases in arterial oxygenation at near maximal work rates in highly trained male endurance athletes (Dempsey et al., 1984; Powers et al., 1988; 1989; Hopkins and McKenzie 1989). Decreased arterial oxygenation has been termed exercise-induced arterial hypoxemia (EIH), and has direct consequences on V02max (Lawler et al., 1988; Powers et al., 1989; Martin and O'Kroy, 1993) and maximal performance capacity (Koskolou and McKenzie, 1994). It is estimated that approximately fifty percent of highly trained male endurance athletes exhibit EIH (Powers et al., 1988; 1993; Martin et al., 1992b). One mechanism that has been advanced to explain this phenomenon is a diffusion limitation. Diffusion capacity of the lung (DL) may be depressed during exercise and not allow for complete gas equilibrium to occur. If a structural alteration were present during exercise, it would continue to depress DL during recovery. To investigate the time course of change in pulmonary diffusion capacity for carbon monoxide (DLco) ten (N=10) highly trained male cyclists (HT) and ten (N=10) moderately (MT) male subjects were selected for this study. Subjects cycled to exhaustion to determine maximal oxygen consumption (V02max) on an electronically braked cycle ergometer (Mijnhardt KEM-3) (mean ± SD: HT V02max = 68.0 ± 4.9; MT V02max = 51.6 ± 4.7 mL-kg-Emin-1). Percent arterial oxygen saturation (%Sa02) was monitored by a pulse oximeter (Ohmeda Biox 3740) to determine if subjects demonstrated exercise-induced arterial hypoxemia (defined as %Sa02 ^ 91%) (%Sa02tnin HT = 91.4 ± 1.6; MT = 94.6 ± 1.1). At a second data collection period, pulmonary function testing was performed. All subjects demonstrated normal pulmonary function. Initial diffusion measurements were made to obtain resting DLco. diffusion capacity of the alveolar membrane (DM), and pulmonary capillary blood volume (Vc). Both spirometry and diffusion ii measurements were made using the same apparatus (Collins PLUS DS II). DM and Vc were calculated by measuring DLco at two inspired O2 concentrations using the technique of Roughton & Forster (1957). Subjects then cycled to fatigue at a workrate that corresponded to the highest workrate attained during the VC»2max test. Expired gases and %Sa02 data were collected during the time to fatigue cycle test. Five additional measurements of pulmonary diffusion were made at 1, 2, 4, 6 and 24 hours following the cycle test. One hour post-exercise, DLco was significantly decreased in both groups compared to baseline. The decrease reached a minimum value at 6 hrs and approached normal values 24 hrs after the exercise. Only HT subjects exhibited EIH yet both groups experienced similar changes in DLco The correlation between %Sa02min and change in DLco was l°w 0--0.3), implying that EIH can not be explained by post exercise decrease in DLco- The change in DLco can be explained primarily by a parallel decrease in Vc. Vc decreased below baseline values in both groups, perhaps indicating a compensatory shunting mechanism. A smaller degree of change was observed in DM, and played less of a role in the decreased DLco-The results of this study are the first to compare diffusion capacity in two separate groups, based on training status, following maximal exercise. Both moderately trained and highly trained subjects exhibited similar decreases in pulmonary diffusing capacity. This supports the theory that the lung may not adapt to aerobic training and behaves in a similar manner regardless of training status. iii TABLE OF CONTENTS Abstract ii Table of Contents v List of Tables vList of Figures viiList of Abbreviations and Symbols ix Acknowledgment xi Introduction 1 Methods 5 SubjectsMaximal Cycle Ergometer Test 5 Experimental Protocol 6 Time to Fatigue TestPulmonary Diffusion Data Collection 7 Calculation of Diffusion Capacity 8 Calculation of DM and VcStatistical Analyses 11 Results 12 General DataMaximal Cycle Ergometry 13 Time to Fatigue Cycle Ergometry 4 Pulmonary Diffusion Capacity for Carbon Monoxide 15 Pulmonary Diffusion Capacity per Alveolar Volume 7 Membrane Diffusion Capacity 19 Pulmonary Capillary Blood Volume 21 DLco 90% 02 23 Alveolar Volume, [Hb], and Mass 5 %Sa02min and DLcoDiscussion 7 Exercise Testing 2Maximal Cycle ErgometryTime to Fatigue Cycle Ergometry 28 Pulmonary Diffusion Capacity for Carbon Monoxide 29 Pulmonary Capillary Blood Volume 30 Membrane Diffusion Capacity 1 iv Adaptability of the Pulmonary System 32 Summary 34 References 5 Appendix A Review of Literature: Exercise Induced Arterial Hypoxemia 40 Appendix B Raw Data 5Appendix C Statistical Analyses 62 Appendix D Reliability Data 5 v LIST OF TABLES Table 1 Age, height and mass, group data 12 Table 2 Pulmonary function, group dataTable 3 Heart rate, V02max, peak power and %Sa02min during maximal cycle ergometer test, group data 13 Table 4 Heart rate, V02max, time to fatigue and %Sa02min during time to fatigue cycle ergometer test, group data 14 Table 5 Pulmonary diffusing capacity for carbon monoxide during rest and following time to fatigue cycle ergometry, group data 15 Table 6 Pulmonary diffusion capacity per alveolar volume during rest and following time to fatigue cycle ergometry, group data 18 Table 7 Membrane diffusing capacity during rest and following time to fatigue cycle ergometry, group data 19 Table 8 Pulmonary capillary blood volume (Vc) during rest and following time to fatigue cycle ergometry, group data 21 Table 9 Pulmonary diffusing capacity for carbon monoxide and 90%O2 during rest and following time to fatigue cycle ergometry, group data 23 Table 10 Mass during rest and following time to fatigue cycle ergometry, group data 25 Table 11 Correlation for %Sa02min and DLco 26 Table 12 Change in pulmonary diffusion capacity following exercise 49 Table 13 Age, height and mass, individual subject data for moderately trained subjects 50 Table 14 Age, height and mass, individual subject data for highly trained subjectsTable 15 Pulmonary function, individual subject data for moderately trained subjects 51 Table 16 Pulmonary function, individual subject data for highly trained subjectsTable 17 Maximal heart rate, (V02max), peak power and %Sa02min during maximal cycle ergometer test, individual subject data for moderately framed subjects 52 Table 18 Maximal heart rate, (V02max), peak power and %Sa02min during maximal cycle ergometer test, individual subject data for highly trained subjectsvi Table 19 Maximal heart rate, (VC^max), time to fatigue and %Sa02min during time to fatigue cycle ergometer test, individual subject data for moderately trained subjects 53 Table 20 Maximal heart rate, (VO^max), time to fatigue and %Sa02min during time to fatigue cycle ergometer test, individual subject data for highly trained subjects ' 53 Table 21 Pulmonary diffusion capacity data pre and post time to fatigue cycle ergometer test, individual subject data for moderately trained subjects 54 Table 22 Pulmonary diffusion capacity data pre and post time to fatigue cycle ergometer test, individual subject data for highly ttained subjects 56 Table 23 Hemoglobin, mass, alveolar volume, and diffusion/alveolar volume (D/VA) pre- and post- time to fatigue cycle ergometer test, individual subject data for highly trained subjects 58 Table 24 Hemoglobin, mass, alveolar volume, and diffusion/alveolar volume (D/VA) pre- and post- time to fatigue cycle ergometer test, individual subject data for moderately trained subjects 60 Table 25 Subject characteristics and pulmonary diffusion capacity measurements, reliability data 67 vii LIST OF FIGURES Figure 1 Overall pulmonary diffusing capacity for carbon monoxide during rest and following time to fatigue cycle ergometry 16 Figure 2 Group pulmonary diffusing capacity for carbon monoxide during rest and following time to fatigue cycle ergometry 17 Figure 3 Pulmonary diffusion capacity per alveolar volume (D/VA) during rest and following time to fatigue cycle ergometry 18 Figure 4 Membrane diffusing capacity (DM) during rest and following time to fatigue cycle ergometry 20 Figure 5 Group membrane diffusing capacity (DM) during rest and following time to fatigue cycle ergometryFigure 6 Pulmonary capillary blood volume (Vc) during rest and following time to fatigue cycle ergometry 22 Figure 7 Group pulmonary capillary blood volume (Vc) during rest and following time to fatigue cycle ergometryFigure 8 Pulmonary diffusing capacity for carbon monoxide and 90%O2 during rest and following time to fatigue cycle ergometry 24 Figure 9 Group pulmonary diffusing capacity for carbon monoxide and 90%O2 during rest and following time to fatigue cycle ergometry 24 viii LIST OF ABBREVIATIONS AND SYMBOLS A-aD02 Alveolar-arterial oxygen difference BHT Breath hold time DL Diffusion capacity of the Lung DLco Diffusion capacity of the lung for carbon monoxide DM Diffusion capacity of alveolar membrane D/VA Diffusion capacity per alveolar volume EIH Exercise-induced arterial hypoxemia FEF25-75% Forced expiratory flow at 25-75% of forced vital capacity FVC Forced vital capacity FEVi Forced expired volume in first second FEFmax Maximal expiratory flow rate HT Highly trained endurance athletes Hb Hemoglobin [Hb] Concentration of hemoglobin He insp Fraction of helium inspired Heexp Fraction of helium expired MT Moderately trained subjects PACO2 Alveolar partial pressure of carbon dioxide PaC02 Arterial partial pressure of carbon dioxide PAO2 Alveolar partial pressure of oxygen Pa02 Arterial partial pressure of oxygen PB Barometric pressure Pcap02 Capillary partial pressure of oxygen Q Cardiac output Cc Capillary Perfusion ix PvBG Red blood cell RER Respiratory exchange ratio %Sa02 Percentage of arterial oxyhemoglobin saturation %Sa02min Minimal percentage of arterial oxyhemoglobin saturation during exercise 9 Reaction rate of hemoglobin and carbon monoxide VA Alveolar ventilation VA Alveolar volume VA/Qc Ventilation-perfusion ratio Vc Pulmonary capillary blood volume VE Expired ventilation per minute VE/VO2 Ventilatory equivalent for oxygen VI Inspired volume VO2 Rate of oxygen uptake VC^mrax Maximal rate of oxygen uptake x ACKNOWLEDGMENT This thesis is the result of support and encouragement from many individuals. I would like to thank all those who have lent a hand along the way, specifically: Dr. Don McKenzie My Committee Diana Jesperson Iris and Jim My Parents Jen Phillips My advisor, who provided inspiration through example. He has made a great impression on me that will last a lifetime. Dr. Ken Coutts, Dr. Pierce Wilcox, Dr. Pat Neary whose contributions made this thesis possible. Without Diana, NOTHING would ever get done in the lab. Many mistakes were avoided by listening to her, as she has made most of them. My diffusion buddies. Who always let me fall, but were there to pick me up. Who stood by me, from afar. xi INTRODUCTION Exercise physiologists have generally accepted the conventional view that oxygen (O2) delivery to working muscle is the primary determinant of maximal oxygen uptake (V02max) and exercise performance (McArdle et al., 1991). Pulmonary gas transport has not been typically recognized as a limiting factor to physical exercise. This belief is based on data which shows that arterial blood gases are maintained during exercise (Asmussen and Nielson, 1960; Saltin et al., 1968). It is well known that endurance training produces adaptations to both the cardiovascular and the musculoskeletal systems. However, Dempsey et al. (1984; 1986) have suggested that the pulmonary system remains unchanged despite chronic aerobic training. Adaptations to other physiological systems may impose metabolic demands which the respiratory system can not meet. In essence, the lung's capacity for gas exchange becomes surpassed by training adaptations to separate organ systems. Supporting evidence has been documented by several authors who have reported decreases in arterial oxygenation at near maximal work rates in highly trained (V02max ~ 5 L-mur1) male endurance athletes (Dempsey et al., 1984; Powers et al., 1988; 1989; Hopkins and McKenzie 1989). These studies demonstrate that the pulmonary system may not be capable of maintaining blood gas homeostasis during maximal exercise. Decreased arterial oxygenation has been termed exercise-induced arterial hypoxemia (EIH). This phenomenon has direct consequences for competitive athletes as a lower percentage of arterial oxyhemoglobin saturation (%Sa02) can lower V02max (Lawler et al., 1988; Powers et al., 1989; Martin and O'Kroy, 1993) and impair maximal performance capacity (Koskolou and McKenzie, 1994). It is estimated that approximately fifty percent of highly trained male endurance athletes exhibit EIH (Powers et al., 1988; 1993; Martin et al., 1992b). Several mechanisms have been advanced to explain this phenomenon: relative hypoventilation, veno-arterial shunts, ventilation (VA) to pulmonary capillary blood perfusion (Qc) heterogeneity (VA/Qc), and diffusion limitations. Athletes with high aerobic capacities may have an inappropriate hyperventilatory response to maximal exercise (Dempsey et al., 1984; Wagner, 1992). This would result in a lower alveolar PO2 (PAO2) reducing the driving 1 force of O2 transfer across the blood-gas barrier. Inadequate exercise hypemea in athletes may be the result of diminished response to humoral factors by peripheral and/or central chemoreceptors. VA/Qc mismatch may also contribute to EIH, where the ratio becomes less uniform with increasing exercise intensity (Gale et al., 1985; Hammond et al., 1991; Hopkins et al., 1994). During maximal exercise, cardiac output (Q) increases to ~ 33 L-mhr1 (Hopkins et al., 1994) and may reach values as high as 40 L-min-1 (Ekblom et al., 1968). Pulmonary capillary blood volume expands with increases in Q and exercise intensity, but may reach its anatomic limit despite further increases in Q. Capillary transit time may therefore be decreased such that diffusion equilibrium does not occur (Dempsey et al, 1984; Hopkins et al., 1994). The formation of pulmonary edema is another possible diffusion limitation. The mechanism for the accumulation of extravascular water, or pulmonary edema, could be caused by increased capillary hydrostatic pressure, increased capillary permeability, increased capillary surface area or a lymphatic insufficiency (West, 1977). The process of gas diffusion through tissues is proportional to the tissue area and the difference in gas partial pressure between the two sides, and inversely proportional to the tissue thickness. Pulmonary edema would increase the distance across the gas exchange barrier, impairing diffusion. Pulmonary edema may occur during exercise as a result of stress failure of the pulmonary capillary membrane (Tsukimoto et al., 1991; West et al.,1993) related to the extreme pressures associated with high Q which are known to occur in highly trained athletes (Reeves et al., 1988). Given the thinness of the blood-gas barrier (~ 0.3 pm), it seems highly possible that the integrity of the membrane could be compromised when extremely high Q are achieved. A number of authors have reported a decrease in the diffusing capacity of the lung (DL) following a period of maximal exercise (Miles et al., 1983; Rasmussen et al., 1988; Manier et al., 1993; Hanel et al., 1994). If sufficient pulmonary edema accumulates during exercise to widen the alveolar-arterial difference, there should be a necessary time period for fluid clearance. During recovery from maximal exercise, relative homeostasis is observed in a short time. If a structural alteration were present it would continue to depress DL, despite a return to normal of heart rate and other exercise-induced disturbances. However, data examining DL 2 have been conflicting. Diffusing capacity of the lung for carbon monoxide (DLco) was reduced 2% twenty-four hours following a marathon run (Miles et al., 1983); was depressed by 10.5% two and one-half days after a short duration maximal rowing effort (Rasmussen et al., 1988); and was at baseline values 0.5 hours following maximal cycle ergometry (Manier et al., 1993). Despite these divergent results, it appears that a change occurs to the diffusion capacity of the lung following maximal exercise. By partitioning DL into its two components: 1) the diffusion capacity of the alveolar membrane (DM) and 2) the reaction rate of the gas with Hb within the red blood cell (6) and pulmonary capillary blood volume (Vc), a more detailed view of DL can be obtained. To date, there have been few studies that have followed and separated DL for an extended period post-exhaustive exercise. Studies that have successfully divided DL have also produced variable results. Miles et al. (1983) found DLco and DM to be significandy lower than baseline values, while Vc had returned to normal 24 hours after a marathon run. In contrast, Hanel et al. (1994) have reported that six hours following maximal rowing subjects had significantly lower DLco. normal DM, and Vc had dropped significantly below resting values. Highly trained endurance athletes that develop EIH may do so by the accumulation of interstitial fluid due to capillary stress failure, and DL decreases following maximal exercise for up to 24 hours. The time course of change in DL post-exercise is unclear. Therefore, this study investigated the changes in DL following a bout of maximal exercise and compared highly trained endurance athletes to moderately trained subjects. The relationship between the lowest %SaC«2 (%SaC»2min) during exercise and DL post-exercise was also investigated. The hypothesis tested were: (1) DLco wm be depressed significandy in highly trained endurance cyclists following a time to fatigue maximal cycle ergometry test when compared to baseline values, and remain depressed for 2 hours post exercise. (2) Moderately trained subjects will not show a significant decrease in DLco following a time to fatigue maximal cycle ergometry test when compared to baseline values. 3 (3) There will be a positive correlation between %Sa02min during the time to fatigue cycle ergometer test and the greatest A DLco post-exercise. 4 METHODOLOGY Subjects Ten highly trained (HT) male endurance cyclists and ten moderately trained (MT) non smoking male subjects were recruited to participate in this study. HT subjects were from local competitive cycling clubs and MT subjects were university students not involved with regular aerobic training. Prior to any testing, subjects received a verbal description of the experiment, and completed a written informed consent form. This study was approved by the Clinical Screening Committee for Research and Other Studies Involving Human Subjects of the University of British Columbia. Upon giving written consent, all subjects performed two separate sessions of data collection. Criteria for participation was a maximal oxygen consumption (V02max) < 55 mL-kg^-min"1 or < 4 L-min"1 in the MT group, > 60 mL-kg" i-min"1 or > 5 L-min-1 in the HT group. Additionally, all subjects were required to have normal pulmonary function with no history of respiratory disease. Subjects who satisfied these criteria were included in the study. Maximal Cycle Ergometer Test Subjects reported to the laboratory after a 24-hour period of no intense exercise and performed a 5 minute self-selected cycling warm-up (50-100 watts) immediately prior to a maximal cycle ergometer test. All cycling was completed on an electronically braked cycle ergometer (Mijnhardt KEM-3) equipped with a racing saddle and pedals. During the maximal test subjects pedaled at a self-chosen cadence at an increasing workload which started at 0 watts and increased 30 watts-min"1 until volitional fatigue was achieved. While cycling, subjects breathed through a two-way non-rebreathing valve (Hans-Rudolph, #2700B). Analysis of expired respiratory gases and minute ventilation (VE) was performed using an automated metabolic system (Rayfield System). Heart rate was recorded every 15 seconds using a heart rate monitor (Polar Vantage XL). Percent arterial oxygen saturation (%Sa02) was measured by a validated (Martin et al., 1992a) pulse oximeter (Ohmeda Biox 3740) and averaged every 15 seconds. Prior to placement of the oximeter ear sensor, a topical vasodilator cream 5 (Finalgon®, Boehringer/Ingeheim) was applied to the lobe of the ear to increase local perfusion. Additional indicators for achieving V02max, beyond volitional fatigue were a plateau in VO2 with increasing work rate, heart rate > 90% of predicted maximum heart rate, and a respiratory exchange ratio (RER) > 1.15. Other descriptive physical information was also obtained, including age, height, body mass, and peak power output during the cycle test. Experimental Protocol The maximal cycle ergometer test and the experimental protocol were separated by at least 72 hours in all subjects. Upon arrival at the laboratory subjects sat and rested for 30 minutes to stabilize the pulmonary system for measurement of the diffusing capacity of carbon monoxide (DLco) (Billiet, 1974). Initially subjects performed at least 3 flow:volume maneuvers to determine forced vital capacity (FVC), forced expired volume in 1 second (FEVi), forced expiratory flow at 25-75% of FVC (FEF25-75%), and maximal forced expiratory flow rate (FEFmax). Following completion of spirometry, baseline values of DLco were obtained. Both spirometry and diffusion measurements were collected using the same commercial apparatus (Collins PLUS DS II). A time to fatigue cycling test was then performed. A total of six diffusion measurements were made, including baseline and 5 measurements at 1, 2, 4, 6, and 24 hours following the time to fatigue cycling test. Subjects did not participate in any physical activity following the time to fatigue cycling test beyond light walking. At all diffusion measurement periods hemoglobin concentration was measured using a direct reading hemoglobinometer (HemoCue, Helsingborg, Sweden) to correct DLco measures (Cotes et al., 1972). Time to Fatigue Test All subjects completed a 5-10 minute cycling warm-up at a workload equivalent to 25-50% of the subject's V02max obtained from the preliminary test. The test began when workrate was manually increased to correspond to the highest workrate achieved during the maximal cycle ergometer test. Changes in saturation are known to occur when high metabolic 6 rates are achieved by endurance-trained athletes (Dempsey et al:, 1984; Powers et al., 1988; 1989). Subjects were instructed to cycle to complete exhaustion, and time was recorded. All subjects received the same degree of verbal encouragement but were not informed of elapsed time during the test. Expired gases, heart rate and %Sa02 were monitored as detailed above. Following the test, subjects recovered by cycling for 5 minutes at a self-selected workrate and cadence. Before the time to fatigue test, and at each DLco measurement, subjects were weighed. Throughout all testing subjects were encouraged to consume fluids to prevent dehydration and shifts in plasma volume. Pulmonary Diffusion Data Collection Pulmonary diffusing capacity was determined by the single-breath method of Roughton and Forster (1957) as modified by Ogilvie et al. (1957). The single-breath technique was chosen over a steady-state method because of its ability to represent the true characteristics of the membranes and pulmonary capillary bed of the ventilated parts of a subject's lungs. The steady-state technique requires analysis of arterial PCO2, where slight errors can lead to large errors in calculating the diffusing capacity for carbon monoxide (Forster et al., 1986). Seated subjects made a maximal inspiration from residual volume of a gas mixture containing 20.9% O2, 9.7% He, 0.3% CO balanced with N2. The breath was held for approximately 10 seconds, and then expired. The first litre of expired gas was discarded, and the next 750 mL was considered to be an alveolar sample uncontaminated by dead space gas. Concentrations of CO were measured using an infrared analyzer. For all measurements of DLco subjects were encouraged to relax against a closed glottis and remain calm during the breath-hold in order to avoid performing a Valsalva or Muller maneuver which could decrease or increase DLco respectively. Each diffusion measurement was examined to ensure that the inspired volume was always at least 90% of FVC, the total time of inspiration was less than 2 seconds and breath-hold time was between 9 and 11 seconds as determined by the methods of Ogilvie et al. (1957). Measurements were made in duplicate separated by 5 minutes. Both tests were within 7 3 mL-min'i-mmHg"1 or a third test was performed. The average of the two closest values was recorded. The diffusion apparatus was calibrated daily for both volume and carbon monoxide. Calculation of Diffusing Capacity Diffusion measurements were calculated automatically by the Collins system using the following equations: Alveolar Volume (single breath) VA (sb) = He insp x VI x 1.05 x BTPS He exp VA = alveolar volume VI = volume inspired He insp = Fraction of inspired Helium 1.05 = constant He exp = Fraction of expired Helium BTPS = body temperature and pressure saturated Diffusion of the Lung/Alveolar Volume DL/VA = (60/BHT) x (1000/PB-47) x Ln [He exp/CO exp] x (STPD/BTPS) BHT = breath-hold time Ln = natural logarithm PB = barometric pressure CO exp = carbon monoxide expired STPD = standard temperature and pressure dry Diffusion of the Lung (single breath) DL (sb) = VA (sb) x DL/VA Calculation DM of and Vc In order to calculate diffusion of the membrane (DM) and pulmonary capillary blood volume (Vc), a second DLco (DLco 90% O2) test was performed similar to the methods of Roughton and Forster (1957) and Ogilvie et al. (1957). Subjects breathed for 5 minutes through a low resistance valve (Hans Rudolph, #2700B) attached to a Douglas bag filled with a gas mixture of approximately 90% O2, 10% N2. The DLco 90% O2 test was immediately 8 performed in the same manner as the 21% O2. The 10 second breath hold was comprised of a gas mixture of 90% O2,10% He, and 0.3% CO. The reciprocal of DLco (1/DLcoX or resistance, is the sum of two resistances: (1) the resistance to diffusion of CO from the alveoli through the alveolar epithelium, basement membrane and capillary endothelium and then through a plasma layer to the surface of the red blood cell (1/DM) and (2) the resistance dependent on the rate of chemical reaction of CO with hemoglobin (9), and the total volume of red blood cells in the pulmonary capillary bed (Vc). By adding the resistances, an overall relationship is observed: 1 = _J + 1 DLco DM 9 • Vc By measuring DLco at two different inspired O2 concentrations (DLco 21% O2, and DLco 90% O2) and plotting each value of 1/DLco against each 1/9, a linear regression line can be formed. The slope of the line estimates 1/Vc, and the Y-intercept represents 1/DM. Each value of 1/9 was calculated as described by Forster et al. (1986) where mean capillary oxygen (Pcap02) tension can be estimated by using the alveolar gas equation assuming a respiratory exchange ratio (RER) of 0.8 and that arterial pressure of carbon dioxide (PaC02) is equal to an alveolar PCO2 (PACO2) of 40 mm Hg. Alveolar Gas Equation PA02 = [ FI02 x (PB - 47) ] - PAC02 [ FI02 + ( 1 - FIQ2 ) 1 RER FIO2 = fraction of inspired oxygen End Pcap02 is typically the same as PAO2, while mean Pcap02 is approximately 15 mm Hg lower. Therefore, mean Pcap02 is expressed as PAO2 - 15. Theta, or 9, depends on the number of red cells present or hemoglobin concentration, [Hb] . It is then necessary to take [Hb] into account when calculating 1/9. The calculated value becomes: 9 1/0 = 0.034 + r 0.006 x (PA02 -15)1 15 This technique was observed to be highly reliable between test and re-test during preliminary data collection (Appendix D). Pearson product-moment correlations for DLco 21%02, DLco 90%O2, DM and Vc were .98, .96, .84, and .92 respectively. 10 Statistical Analyses Data was examined using a 2 (group) by 6 (time) factorial analysis of variance (ANOVA) with repeated measures across time periods. Time effects were analyzed using the Dunnet Test for multiple comparisons to a control group, where post-exercise means were compared to resting values. If a significant interaction occurred, Scheffe's post-hoc procedure was applied for further comparison. Student's Mests were used to compare descriptive data. Pearson product-moment correlations were used to determine the relationship between %Sa02min and changes in DLco- The level of significance was set at P < 0.05 for all statistical comparisons. 1 1 RESULTS General Data Subjects in both groups were similar in age and height (Table 1). MT subjects had a higher mean body mass than HT (t=2.53, df=9, P=0.0322). Individual anthropometric data can be found in Tables 13 and 14. Table 1. Age, height and mass, group data. GROUP AGE HEIGHT MASS (yrs) (cm) (kg) HT (N=10) 25.4 178.6 73.6* (4.8) (4.3) (4.6) MT (N=10) 25.8 179.2 81.3 (2.6) (4.7) (6.9) Values are means (± SD). HT, highly trained endurance athletes; MT, moderately trained. * significandy different compared with MT (P < 0.05). Resting pulmonary function data was normal for all subjects (Table 2). Both MT and HT subjects had similar values for FVC, FEVi, FEF25-75%, FEVi/FVC, and FEFmax. Pulmonary function data for individual subjects can be found in Tables 15 and 16. Table 2. Pulmonary function, group data. GROUP FVC FEVi FEF25-75% FEVi/FVC FEFmax (L) (L) (L-sec-1) (%) (L-sec-1) HT(N=10) 5.81 4.78 4.75 82.40 10.60 (.56) (.53) (1.29) 6.57 (1.80) MT(N=10) 5.63 4.78 5.00 84.91 10.04 (.51) (.47) (.98) (4.86) (1.77) Values are means (± SD). HT, highly trained endurance athletes; MT, moderately trained. 12 Maximal Cycle Ergometry Results from the maximal cycle ergometer test (Table 3) show that absolute maximal VO2 was significantly higher in HT (t=4.40, df=9, P=0.0017) as was relative V02max (t=8.89, df=9, P<0.0001). HT subjects achieved a significantly lower %SaC»2min (t=6.27, df=9, P<0.0001), and a higher peak power (t=6.51, df=9, P<0.0001). Maximal heart rate was similar between groups. Using the criteria %Sa02min < 91% (Powers et al., 1988), 3 of 10 HT subjects exhibited EIH. No MT subjects attained a %Sa02min that would qualify them as demonstrating EIH. Individual data obtained from the maximal cycle ergometer test is found in Table 17 and 18. Table 3. Maximal oxygen consumption (VO^max), peak power, minimal percentage of arterial oxyhemoglobin saturation (%Sa02min) and maximal heart rate (HRmax) during maximal cycle ergometer test, group data. GROUP V02max V02max PEAK %Sa02min HRmax (L-min-1) (mL-kg-l-min-1) POWER (%) (bpm) (watts) HT (N=10) 4.99* 68.0* 446.5* 91.4* 186.1 (.31) (4.9) (17.3) (1.6) (5.3) MT (N=10) 4.24 51.6 359.6 94.6 189.6 (.44) (4.7) (30.4) (1.1) (11.6) Values are means (± SD). HT, highly trained endurance athletes; MT, moderately trained. * significantly different compared with MT (P < 0.01). 13 Time to Fatigue Cycle Ergometry Table 4 shows a comparison between HT and MT subjects during the time to fatigue cycle test. Absolute (t=6.13, df=9, P=0.0002) and relative f> 10.05, df=9, P<0.0001) VO2 were higher in HT. %Sa02min was significantly lower in HT (t=2.67, df=9, P=0.026). Time to fatigue and maximal heart rate were not different between groups. Individual subject information from the time to fatigue test can be found in Table 19 and 20. VO2 values were similar for both groups between maximal cycle ergometry (HT V02max = 68.0±4.9; MT = 51.6±4.7 mL-kg-i-min"1) and time to fatigue cycling (HT VC^max = 68.0±3.9; MT = 50.3±4.4 mL-kg'i-min"1). Mean %SaC»2min was higher for HT during time to fatigue (92.9+1.9) than maximal cycling (91.4 ±1.6). MT %Sa02min was similar between both exercise tests (94.6 ±1.1 and 94.8 ±1.1). Table 4. Maximal oxygen consumption (VC«2max), time to fatigue, minimal percentage of arterial oxyhemoglobin saturation (%SaC»2min) and maximal heart rate (HRmax) during time to fatigue cycle ergometer test, group data. GROUP V02max V02max (L-mhr1) (mL-kg^-mur1) PEAK POWER (watts) TIME (s) %Sa02min (%) HRmax (bpm) HT (N=10) 4.89* 68.0* 446.5* 113.9 92.9* 178.3 (.39) (3.9) (17.3) (29.8) (1.9) (8.9) MT (N=10) 4.03 50.3 359.6* 127.6 94.8 183.9 (.38) (4.4) (30.4) (25.6) (1.1) (13.7) Values are means ± (SD). HT, highly trained endurance athletes; MT, moderately trained. * significantly different compared with MT (P < 0.05). 14 Pulmonary Diffusing Capacity for Carbon Monoxide Pulmonary diffusing capacity for carbon monoxide was not significantly different between groups (F=1.507, df=l/18, P=0.2354) nor was there a significant group x time interaction (F=2.068, df=5/90, P=0.0766). A significant time effect was found, indicating that DLco measures were different between time periods (F=18.495, df=5/90, P<0.0001). DLco was decreased 1 hr after exercise and attained a minimum value at 6 hrs. The Dunnett test for multiple comparisons was applied to the means across time. DLco was statistically different from baseline values at 1, 2, 4, 6 (P<0.01) and 24 hours (P<0.05) (Table 5). Figure 1 shows overall values over time. Figure 2 displays group means over time. Individual measures of diffusion can be found in Tables 21 and 22. Table 5. Pulmonary diffusing capacity for carbon monoxide (mL-min'^-mrnHg"1) during rest (BASE) and following time to fatigue cycle ergometry, group data. GROUP BASE 1 hr 2 hrs 4 hrs 6 hrs 24 hrs HT (N=10) 34.88 32.21 31.80 31.10 29.78 33.62 (5.03) (4.37) (3.80) (4.13) (4-22) (3.65) MT (N=10) 32.47 29.53 29.00 29.23 29.11 29.97 (5.50) (4.51) (4.56) (4.41) (4.48) (5.12) Mean (± SD) 33.67 30.87* 30.40* 30.17* 29.44* 31.79t (5.27) (4.53) (4.33) (4.27) (4.25) (4.71) Values are means (± SD). HT, highly trained endurance athletes; MT, moderately trained. * Significantiy different from BASE (P < 0.01). t Significantly different from BASE (P < 0.05) 15 Figure 1. Overall pulmonary diffusing capacity for carbon monoxide during rest (BASE) and following time to fatigue cycle ergometry (Mean ± S.E.). * significantly different from BASE (P < 0.01). t significantly different from BASE (P < 0.05) 35 -r 34 J 28 • ' • i i 1 BASE 1 HR 2 HRS 4 HRS 6 HRS 24 HRS Time 16 Figure 2. Group pulmonary diffusing capacity for carbon monoxide during rest (BASE) and following time to fatigue cycle ergometry (Mean ± S.E.). BASE 1 HR 2 HRS 4 HRS 6 HRS 24 HRS Time Pulmonary Diffusion Capacity per Alveolar Volume Pulmonary diffusion capacity per alveolar volume (D/VA) was similar to the results of DLco- D/VA was not different between groups (F=.123, df=l/18, P=.7299) and a group x time interaction was not observed (F=1.044, df=5/90, P=.3967). Means across time were significantly different (F= 12.623, df=5/90, P<0.0001). A subsequent Dunnett test for multiple comparisons showed that D/VA was different from baseline at 1, 2, 4, 6 (P < 0.01) and 24 hours (P < 0.05) (Table 6). Means over time are shown in Figure 3. 1 7 Table 6. Pulmonary diffusion capacity per alveolar volume (D/VA) during rest (BASE) and following time to fatigue cycle ergometry, group data. GROUP BASE 1 hr 2 hrs 4 hrs 6 hrs 24 hrs HT (N=10) 4.07 3.79 3.74 3.64 3.51 3.91 (.84) (.63) (.60) (.51) (-53) (.44) MT(N=10) 4.20 3.82 3.72 3.83 3.71 3.88 (.62) (.48) (.46) (.49) (-48) (.53) Mean (± SD) 4.14 3.81* 3.73* 3.73* 3.61* 3.89t (.72) (.55) (.52) (.52) (.50) (-47) Values are means (± SD). HT, highly trained endurance athletes; MT, moderately trained. * Significantly different from BASE (P < 0.01). t Significantly different from BASE (P < 0.05) Figure 3. Pulmonary diffusion capacity per alveolar volume (D/VA) during rest (BASE) and following time to fatigue cycle ergometry (Mean ± S.E.). * significantly different from BASE (P < 0.01). t significantly different from BASE (P < 0.05) 4.4 -r 4.3 -4.2 -34 BASE 1 HR 2 HRS 4 HRS 6 HRS 24 HRS Time 18 Membrane Diffusing Capacity HT and MT subjects did not differ significantly with regards to membrane diffusing capacity (F=1.778, df=l/18, P=0.1990). It was found that means for DM changed significantly over time (F=3.016, df=5/90, P=0.0146). Further analyses showed that DM was significantiy lower at 6 hours post-exercise (43.0 ± 7.3) than while at rest (46.55 ± 7.7) (P < 0.05). Overall mean changes are summarized in Table 7. No interaction was detected for group x time (F=.406, df=5/90, P=0.8434). The trend is visually depicted in Figures 4 and 5. Table 7. Membrane diffusing capacity (mL-min^-mmHg"1) during rest (BASE) and following time to fatigue cycle ergometry, group data. GROUP BASE 1 hr 2 hrs 4 hrs 6 hrs 24 hrs HT (N=10) 48.4 45.2 45.9 46.0 44.0 46.0 (6.9) (6.5) (5.3) (6.9) (7.8) (6.9) MT (N=10) 44.7 41.3 41.5 41.6 41.9 41.6 (8.4) (5.9) (7.3) (7.4) (6.9) (8.4) Mean (± SD) 46.5 43.3 43.8 43.8 43.0* 43.9 (7.7) (6.4) (6.6) (7.3) (7.3) (7.9) Values are means (± SD). HT, highly trained endurance athletes; MT, moderately trained. * Significamly different from BASE (P < 0.05). 1 9 Figure 4. Membrane diffusing capacity (DM) during rest (BASE) and following time to fatigue cycle ergometry (Mean ± S.E.). * Significantly different from BASE (P < 0.05). 49 -r 48 -47 -41 J . . 1 1 1 1 BASE 1HR 2 HRS 4 HRS 6 HRS 24 HRS Time Figure 5. Group membrane diffusing capacity (DM) during rest (BASE) and following time to fatigue cycle ergometry (Mean ± S.E.). 52 -j j 50 - T 38 'IIII 1 • BASE 1 HR 2 HRS 4 HRS 6 HRS 24 HRS Time 20 Pulmonary Capillary Blood Volume A non-significant group effect was observed, indicating that mean Vc values did not differ significantly between HT and MT (F=.570, df=l/18, P=0.4601). Mean Vc averaged over time was different among groups (F=20.601, df=5/90, P<0.0001). At 1, 2, 4, and 6 hours post- time to fatigue cycling Vc was different from resting values (P < 0.01) (Table 8). Figure 6 demonstrates the overall change in Vc over time. Although Vc was lower 24 hrs post-exercise (66±12.0 mL) compared to rest (71.8+14.7 raL), the difference was not statistically significant. A significant group x time interaction (F=3.688, df=5/90, P=0.0044) was detected. The interaction indicates that the groups were heterogeneous over time (Figure 7). Scheffe's procedure was applied and revealed that Vc was significantly different between HT (72.0+10.0) and MT (60.0+11.1) 24 hrs post-exercise (P<0.05). Table 8. Pulmonary capillary blood volume (Vc) (mL) during rest (BASE) and following time to fatigue cycle ergometry, group data. GROUP BASE 1 hr 2 hrs 4 hrs 6 hrs 24 hrs HT (N=10) 74.6 66.2 61.2 57.4 53.3 72.0 (14.0) (12.8) (13.0) (10.4) (11.0) (10.0) MT (N=10) 69.1 60.8 58.0 56.6 56.9 60.0 (15.6) (15.5) (14.7) (11.0) (12.0) (11.1) Mean (± SD) 71.8 63.5* 59.6* 57.0* 55.1* 66.0 (14.7) (14.1) (13.6) (10.5) (1L4) (12.0) Values are means (± SD). HT, highly trained endurance athletes; MT, moderately trained. * Significandy different from BASE (P < 0.01). 21 Figure 6. Pulmonary capillary blood volume (Vc) during rest (BASE) and following time to fatigue cycle ergometry (Mean ± S.E.). * Significantly different from BASE (P < 0.01). 80 50 J . . . . . . BASE 1 HR 2 HRS 4 HRS 6 HRS 24 HRS Time Figure 7. Group pulmonary capillary blood volume (Vc) during rest (BASE) and following time to fatigue cycle ergometry (Mean ± S.E.). * Significantly different between MT and HT (P < 0.05). 80 45 BASE 1 HR 2 HRS 4 HRS 6 HRS 24 HRS Time 22 DLco 90% 02 No group effect was observed for pulmonary diffusing capacity for the 90%02 mixture (F=.526, df=l/18, P=0.4778). Means were significantly different over time (F=27.967, df=5/90, P<0.0001) (Table 9). DLco 90% O2 was significantly lower than baseline at 1, 2, 4 and 6 hours (P<0.01) (Figure 8). A significant time x group interaction was detected (F=2.929, df=5/90, P=0.0170). However, Scheffe's post-hoc test failed to detect a significant difference between group means at any of the individual time periods. Figure 9 shows an interaction plot. Table 9. Pulmonary diffusing capacity for carbon monoxide and 90%C>2 (mL-min^-mmHg"1) during rest (BASE) and following time to fatigue cycle ergometry, group data. GROUP BASE 1 hr 2 hrs 4 hrs 6 hrs 24 hrs HT (N=10) 14.16 12.90 12.19 11.60 11.20 13.97 (2.24) (1.86) (1.77) (1.74) (1.74) (1.08) MT (N=10) 13.53 12.10 11.55 11.57 11.32 12.29 (2.61) (2.70) (2.34) (1.73) (1.92) (1.94) Mean (+ SD) 13.84 12.50 11.87 11.58 11.26 13.13 (2.39) (2.29) (2.05) (1.69) (1.79) (1.75) 23 Figure 8. Pulmonary diffusing capacity for carbon monoxide and 90%O2 (mL-min^-mmHg" 1) during rest (BASE) and following time to fatigue cycle ergometry. * Significantly different from BASE (P<0.01). 14.5 -r 14 J 10.5 J . . . . . • 1 BASE 1HR 2 HRS 4 HRS 6 HRS 24 HRS Time Figure 9. Group pulmonary diffusing capacity for carbon monoxide and 90%C<2 (mL-min~ i-mrnHg-1) during rest (BASE) and following time to fatigue cycle ergometry. 10.5 -1 1 . . . . . BASE 1HR 2 HRS 4 HRS 6 HRS 24 HRS Time 24 Alveolar volume, [Hb], and mass. There were no time, group, or group x time interactions observed for alveolar volume and hemoglobin concentration (Appendix C). Body mass was significantly different between groups (F=6.288, df=l/18, P=0.0220) and over time (F=20.186, df=5/90, P<0.0001). Overall and group means are presented in Table 10. No group x time interaction was found indicating that change in weight over time was similar between groups. Table 10. Body mass (kg) during rest (BASE) and following time to fatigue cycle ergometry, group data. GROUP BASE 1 hr 2 hrs 4 hrs 6 hrs 24 hrs HT (N=10) 73.3 73.8 1 73.9 74.5 74.8 74.2 (4.3) (4.0) (4.2) (4.1) (4.3) (4.3) MT (N=10) 80.5 80.6 80.7 81.2 81.2 81.0 (7.6) (7.6) (7.5) (7.4) (7.4) (7.2) Mean (± SD) 76.9 77.2 77.3* 77.8t 77.8t 77.6t (7.0) (6.9) (6.9) (6.8) (6.9) (6.7) Values are means (± SD). HT, highly trained endurance athletes; MT, moderately trained. ^Significantly different from BASE (P < 0.05). t Significantly different from BASE (P < 0.01) %Sa02min and DLco The greatest change in DLco (A DLco) observed for each subject was correlated with %Sa02min achieved during the time to fatigue cycling test (Table 11). HT and MT groups were also analyzed seperately and correlated with A DLco and the lowest obtained (DLco LO) 25 Table 11. Correlation Matrix for %Sa02min and DLco-A DLco ADLCQLO Overall %Sa02min - 0.335 0.028 MT %Sa02min 0.038 0.240 HT %Sa02min - 0.504 0.094 26 DISCUSSION Exercise-induced hypoxemia which occurs in approximately 50% of highly trained male endurance athletes (Powers et al., 1988) can negatively affect V02max (Lawler et al., 1988; Powers et al., 1989; Martin and O'Kroy, 1993) and exercise performance (Koskolou and McKenzie, 1994). Despite numerous investigations the cause of EIH remains unresolved. The possible mechanisms are: VA/Qc mismatch, veno-arterial shunts, hypoventilation, shortened pulmonary transit time and pulmonary edema. A diffusion limitation, specifically due to pulmonary edema, may contribute to the hypoxemia observed in elite athletes at sea level (Younes and Burks, 1985; Caillaud et al., 1993; Schaffartzik et al., 1992) and should be reflected in measurements of pulmonary diffusion capacity. The time course of DL following exercise has previously been described in an attempt to quantify the changes in diffusion (Miles et al., 1983; Rasumussen et al., 1988; Hanel et al., 1994). However, data from these studies have been conflicting, possibly due to varied exercise protocols and a wide range of subject training status. To date it has been unclear if the changes observed in DL are exclusive to elite athletic populations. This study represents the first attempt to examine changes in DL in two separate subject populations based on aerobic capacity. Exercise Testing Maximal Cycle Ergometry / Highly trained subjects in the present study attained V02max values that were comparable to other EIH investigations (Dempsey et al., 1984; Warren et al., 1991) as did moderately trained subjects (Powers et al., 1988). MT subjects had a somewhat high absolute V02max (4.24 ± 4.4 Lmhr1) compared to their relative value (51.6 ± 4.7 mL-kg'i-min"1). This discrepancy may be a reflection of their body composition. The incidence of EIH in the HT group was 30%. This result is lower than previously reported for endurance athletes (Powers et al., 1988; Powers et al., 1993). The criteria for determining EIH was %Sa02min < 91.0% (Powers et al., 1988). This is derived from 27 findings that healthy, untrained individuals reduce their saturation to ~ 95% during maximal exercise (Astrand and Rodahl, 1986) and that 91% is approximately 1 SD below normal. Mean HT values (%Sa02min = 91.4 ± 1.6) are comparable to other hypoxemia studies (Dempsey et al., 1984; Hopkins and McKenzie, 1989). An observed desaturation of 92-93% is severe enough to negatively affect VO^max (Powers et al., 1989). In this study, 9 out of 10 HT subjects had a %Sa02min < 93.0%. Six HT subjects ranged in %Sa02min from 91.1-93.0%, with 4 of these being less than 92.0%. As with other EIH studies, the range of desaturation responses was varied but decrements below the normal range (95%) were consistently observed in HT subjects. MT subjects maintained a normal arterial oxygenation (94.6 ± 1.1%) during the maximal test. None of the MT group demonstrated EIH, which is consistent with the theory that only highly trained athletes develop hypoxemia resulting from exercise (Dempsey et al., 1984; Powers et al., 1988). Peak power output was statistically different between subject groups, emphasizing the difference in training status (MT = 359.6 ± 30.4; HT = 446.5 ± 17.3 watts). Time to Fatigue Cycle Ergometry Oxygen consumption was similar between the maximal and the time to fatigue cycling for all subjects. This is in agreement with other reports where exercising at 100% of V02max workrate for 5 minutes elicits a similar V02max value as an incremental test to exhaustion (Hopkins and McKenzie, .1989). Subjects in this study cycled, on average, for approximately 2 minutes at the highest workrate (peak power output) achieved during the maximal test. The fatigue test workrate was higher than that at 100% V02max, as oxygen consumption usually plateaus during an incremental test while workrate continues to increase. MT subjects cycled for a slightly longer time than HT subjects, however, the difference was not significant despite peak power output being significantly higher for HT. Both cycling tests elicited the same %Sa02min in the MT group. As expected, HT subjects had a significantly lower %Sa02min than MT during the time to fatigue test. HT 28 subjects achieved a slightly higher %Sa02min during the time to fatigue (92.9 ± 1.9%) than maximal testing (91.4 ± 1.6%). Ten of 10 HT subjects experienced decrements in %Sa02, ranging from 89.9 to 95.5, and 20% experienced EIH. Interestingly, the HT group lowered their mean %Sa02min to the range considered to impair V02max. The discrepancy in %Sa02min between the maximal and time to fatigue test is possibly related to the rapid onset of metabolic acidosis during the time to fatigue test when compared to the maximal test. Pulmonary Diffusion Capacity for Carbon Monoxide It is known that DLco is reduced following endurance activity (Miles et al., 1983; Manier et al., 1991) and short-term maximal exercise (Rasumussen et al., 1992; Hanel et al., 1994). This study confirms that DLco is decreased during recovery from short-term maximal exercise. DLco reached a minimum value at 6 hrs post-exercise and approached baseline at 24 hrs. These findings are in agreement with Rasmussen et al. (1992), where DLco normalized 20 hrs post exercise. The minimum DLco observed in the present study was 87% of pre-exercise, comparable to ~ 90% at 6 hrs observed by Hanel et al. (1994). The current study does not support the observation that DLco remains depressed 2.5 days following short-term exercise (Rasmussen et al., 1988). Other data has indicated that DLco returns to normal 30 minutes post-exercise (Manier et al., 1993), however subjects were not specifically endurance trained and 3 subjects were smokers making interpretation and comparison of these data difficult. The most striking DLco finding is that both groups demonstrated a similar time course of change in DLco- Despite a lack of statistical significance (P=0.08) it is interesting to note that MT subjects reached their lowest value at 2 hrs, while HT subjects attained their lowest DLco at 6 hours. Figure 2 demonstrates the group changes over time. These data support the original hypothesis that highly trained endurance athletes experience a decrease in DLco following maximal exercise. The change in DLco seen in the MT group was not expected. Changes in DLco could be due to differences in body size and lung surface area available for diffusion. However, when D/VA was examined the changes were identical to those of DLco 29 (Figure 3), indicating that a discrepancy in lung size did not affect the pattern of change between groups. Elevated blood concentration of carboxyhemoglobin (COHb) impedes the transfer of CO from alveolar gas to pulmonary capillary blood during a DLco measurement. COHb was not measured in this study. However, Hanel et al. (1994) measured DLco at similar time periods as this study and found that COHb levels were not at a level that would alter DLco (Brody and Coburn, 1970). In non-smokers, the effect of blood COHb concentrations are small, so that the effect of COHb on DLco hi these individuals is inconsequential (Mohsenifar and Tashkin, 1979). The changes in DLco observed in this study were therefore not a result of carbon monoxide back pressure. The technique used in this study to obtain DLco> DM, and Vc has been found to be highly reliable in preliminary testing (Appendix D). Pulmonary Capillary Blood Volume Resting Vc was slightly lower than values previously reported (McNeil, 1958; Miles et al., 1983; Hanel et al., 1994). Mean Vc was decreased 1 hr after cycling in all subjects and reached a minimum value after 6 hrs. At 24 hrs Vc had returned to 92% of resting values, and was not significantly different from baseline. The decrease in Vc corresponded to the changes in DLco- These results (78% baseline) corroborate those of Hanel et al. (1994) where Vc was 74% of baseline at 6 hrs. Others have found contradicting results where Vc was normalized 1/2 hr post (Manier et al., 1993) 24 hrs post (Miles et al., 1983), and elevated 1/2 hr following exercise (Manier et al., 1991). Twenty-four hours after exercise HT subjects in this study had returned to 97% baseline, while MT were significantly lower at 87% baseline. The degree of change in Vc parallels the changes in DLco suggesting that the majority of decrease in DLco can be attributed to a lower capillary blood volume. With less blood flow and volume in the pulmonary capillaries, DLco would be reduced, as it is perfusion limited. A reduction in central blood volume following exercise has been previously described using trans-thoracic electrical impedance (Rasumussen et al., 1992; Hanel et al.,1994) and by a decrease in Vc (Hanel et al., 1994). These data are contrary to the findings of Buono et al. 30 (1983), but are in agreement with the current results. A loss of fluid resulting from exercise could potentially alter the calculation of Vc. Subjects were weighed at each diffusion measurement and no significant reduction was observed. It is not known why a reduction of central blood volume would occur following maximal exercise, but a compensatory shunting mechanism may play a role. Membrane Diffusion Capacity Reductions in DM have been observed to persist for 2 hours following exercise (Manier et al., 1991; 1993; Miles et al., 1983). In this study the majority of change in DM occurred within the first hour and reached a statistically significant minimum at 6 hrs (P < 0.05). This is slightly different compared to the findings of Hanel et al. (1994) where DM reached it's lowest value 2 hrs after rowing and was restored by 4 hrs. Manier et al. (1991) found that DM decreased 29%. The present study found less of a decrease (8%) similar to a more recent study by Manier et al. (1993). MT and HT subjects did not differ in their DM response over time. No obvious explanation is available to describe the pattern of change in DM. Stress failure due to high pressures in the pulmonary vasculature may have occurred and allowed the leakage of fluid into the interstitial space. Mean pulmonary arterial pressure and capillary wedge pressures can reach values greater than ~ 40 and 27 torr, respectively (Wagner et al., 1986; Reeves et al., 1988). When pressures develop in this range, the vascular endothelium may be injured allowing the movement of fluid from the vascular space to the interstitium of the lung. This effect has been observed in racehorses who achieve high pulmonary pressures (Jones et al., 1992; West et al., 1993) and in exercising pigs (Schaffartzik et al., 1993). Permeability of the pulmonary capillaries may have also been altered and allowed fluid accumulation, similar to high altitude pulmonary edema (Schoene et al., 1986). A final possibility is that the lymphatic system could not maintain the same fluid clearance rate during the later stages of recovery. It is possible that edema first presented itself as a result of a change to the peribronchial plexus and leaky bronchial venules. A change in DM would occur 31 later as fluid accumulated in the interstitial space. This hypothesis is consistent with the change in DM seen in the present study. Normally the pathway for diffusion is short. Several factors exist to increase the distance, or DM: (i) thickening of the alveolar wall, (ii) thickening of the capillary endothelium, (iii) cell layers may be separated by interstitial edema, (iv) intra-alveolar edema, and (v) the intracapillary path may be increased if capillaries contain several red blood cells abreast (Forster et al., 1986). It is not known what degree of edema, or alteration to DM, impairs diffusion during exercise. A small amount of edema present during exercise may cause a decrease in %Sa02irrm> as an increase in the above factors, coupled with increased Q (i.e. shortened transit time), would present a diffusion limitation and impair diffusion equilibrium. A structural alteration such as pulmonary edema could contribute to a VA/Qc inequality during exercise and during recovery. However, the time course of recovery of VA/Qc following exercise is short (~ 20 min) compared to the results of this study (Schaffartzik et al., 1992). A mismatch of VA/Qc may have played a role in the observed decrements in %SaC»2, but was likely not responsible for the changes seen in diffusion measurments post-exercise. Pulmonary edema has been implicated as a potential cause of EIH in HT athletes (Younes and Burks, 1985; Wagner et al., 1986; Caillaud et al., 1993). However, data from this study demonstrate a similar change in DM for HT and MT subjects, yet only HT experienced EIH, suggesting that the change in DM was not responsible for decreases in %SaC«2 seen in the HT group. These results are in agreement with those of Hanel et al.(1993), where pulmonary diffusion capacity decreased following mild exercise (60% VChmax), making a change in DM, or edema, seem unlikely. Adaptability of the Pulmonary System The pulmonary system has traditionally been viewed as ideally designed to regulate ventilation and gas exchange at rest and at high metabolic rates. Dempsey et al. (1985; 1986) propose that the pulmonary system remains unchanged from it's original state despite regular aerobic training. Aerobic training produces increases in aerobic capacity through effects on the 32 heart, systemic vasculature, and the metabolic capacity of skeletal muscle. As the lung remains unchanged, it can no longer meet the demands of the other adapted systems. The authors further suggest that the pulmonary system may become a limiting factor to oxygen transport and utilization in the highly trained. If this theory is correct, and no training adaptations occur within the lung, then the time course of change in DL should be similar between different groups, regardless of training status. The parallel changes seen in HT and MT DLco support this theory. The correlation between %Sa02min and A DLco was l°w (r=-0.3) suggesting that the two variables were mildly related and that the change in diffusion capacity was not responsible for the decline in HT %SaC«2. When groups were analyzed seperately, the correlations between variables remained moderate. The current results confirm another low correlation (r=0.3) observed between A DLco and A %SaC»2 (Turner, 1992). An untrained group (V02max < 45 mL-kg^-min-1) was not examined in this investigation, but may offer a valuable comparison to the two trained groups. Examination of exercise at different metabolic rates may also provide useful information to explain the pattern of change in pulmonary diffusion capacity. 33 Summary The results of this study corroborate other findings that pulmonary diffusion capacity is reduced following short-term maximal exercise in highly trained male athletes. These are the first data to indicate that moderately trained and highly trained athletes experience the same changes in DL post-maximal exercise. Diffusion reaches a minimum value 6 hours post exercise and approaches resting values within 24 hrs. Decrements in arterial oxygenation during exercise could not be explained by decreases in DL following exercise. The change in DL appears to be primarily due to a decrease in Vc and partially caused by a decrease in DM. Although this has been observed by other authors, mechanisms responsible for the decrease in Vc post-exercise remain unknown. 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Breathing pattern during and after exercise of different intensities. J. Appl. Pysiol. 59(3):898-908, 1985. 39 APPENDIX A REVIEW OF LITERATURE EXERCISE-INDUCED HYPOXEMIA Limitations to Exercise There are numerous factors which may restrict athletic performance. The traditional view is that oxygen (O2) delivery to working muscle represents the primary limiting factor to exercise performance, and that the oxygen content of arterial blood is adequate to meet all exercise imposed metabolic demands. Most normal healthy individuals who engage in strenuous activity at sea-level maintain normal blood gas homeostasis for both O2 and CO2. Their pulmonary system is able to supply muscle with O2 and eliminate excess CO2. In contrast, several authors have challenged the pulmonary system's adequacy by showing decreases in arterial pressure of O2 (Pa02) in exercising elite aerobic athletes (Rowell et al., 1964; Dempsey et al., 1984; Powers et al, 1988, 1989; Hopkins & McKenzie, 1989). This phenomenon, exercise-induced arterial hypoxemia (EIH), has been found to occur in 50% of highly trained runners and cyclists and is defined as a 4% decrement in %Sa02 from resting values (Powers et al., 1988). It is not certain to what extent a decrease in %Sa02 can negatively affect endurance performance, however a %Sa02 of 92-93% may affect VOmiax (Lawler et al., 1988; Powers et al., 1989; Martin and O'Kroy, 1993) and %Sa02 < 90% may impair maximal performance capacity (Koskolou and McKenzie, 1994). Elite athletes undergo training adaptations in skeletal muscle and the cardiovascular system which may eventually surpass the capabilities of their pulmonary system (Dempsey and Fregosi, 1985). Therefore, the athlete's pulmonary system may become the 'weak link' to maximal exercise capacity. Dempsey et al. (1986) have speculated that this occurs because of the pulmonary system's inability to adapt to training despite many years of aerobic exercise training. If this supposition holds true, then the respiratory system becomes a constraint to maximal exercise performance because of its inability to match the athlete's metabolic requirements brought about by adaptations to other systems. 40 Mechanisms of Exercise Induced Hypoxemia (EIH) Despite considerable research efforts the mechanism responsible for EIH remains controversial. Four primary explanations have been discussed in the literature: hypoventilation, veno-arterial shunts, ventilation-perfusion inequalities, and diffusion limitations. Hypoventilation Hypoventilation is an alveolar ventilation below the rate metabolically required to maintain arterial blood gases at normal values. Dempsey et al. (1984, 1986) have suggested that a deficient hyperventilatory response during exercise may contribute to EIH in elite athletes by decreasing PAO2, thereby reducing the driving force of O2 transfer across the blood-gas barrier. Minimal compensatory hyperventilation was observed during near maximal exercise in a group whose PaC>2 decreased to approximately 70 torr (Dempsey et al, 1984). Conversely, Hopkins and McKenzie (1989) observed a similar decrease in Pa02 (~78 torr) with a high alveolar PO2. Dempsey et al.(1984,1986) have also proposed that hypoventilation can occur despite the presence of stimuli to increase ventilation, such as increases in arterial carbon dioxide tension (PaC02), body temperature, blood catecholamines, metabolic acidosis or a decrease in PaC«2. This was supported recently whereby athletes who exhibited EIH had reduced peripheral chemoresponsiveness to hypercapnia (Cooper, 1993). Perrault et al. (1991) examined endurance athletes who desaturated (%SaC«2min < 91%), and demonstrated that hypoventilation was significantly correlated with those subjects who desaturated. It is necessary to note that an elevated PaC02 is regarded as the cardinal marker of hypoventilation, while in this study hypoventilation was determined by the ventilatory equivalent for oxygen (VE/VO2). Caillaud et al. (1993) found reduced PAO2 and elevated levels of PaCC»2 in highly trained subjects as compared to untrained subjects during maximal exercise. It was concluded that a lack of compensatory hypernea during exercise in the highly trained group was a major factor in the observed decrease in Pa02- In contrast, Powers et al., (1992) detected a decrease 41 in PaCC«2 during maximal exercise in subjects who developed EIH making hypoventilation seem unlikely. Further study is required to completely examine the role of hypoventilation and the complex ventilatory control mechanisms involved, however the current consensus in the literature is that hypoventilation does not play a significant role in the development of EIH (Powers et al., 1993). Veno-arterial Shunt A veno-arterial shunt is an anatomical phenomenon that allows the mixture of venous blood with arterial blood causing a decrease in Pa02. Early work suggests that fifty percent of the alveolar-arterial difference (A-aD02) in resting humans may be explained by veno-arterial shunts (Whipp & Wasserman, 1969; Gledhill et al., 1977) and could possibly account for as much as 49% of the A-aD02 during moderate exercise (Asmussen & Nielson, 1960). The role of shunts in the formation of EIH was later investigated by Dempsey et al. (1984) and Powers et al. (1992), who showed that breathing hyperoxic gas (24-26% O2) at maximal exercise intensities, caused PaC«2 to return to normal levels. If veno-arterial shunts were the cause of EIH, breathing such a gas mixture would have little effect on Pa02 because of the venous and arterial blood mixture. Based upon these findings, veno-arterial shunts have been ruled out as a major contributor to the formation of EIH. Ventilation-Perfusion Mismatch In normal healthy lungs, the ventilation-perfusion ratio (VA/Qc) is reasonably well matched and allows for adequate pulmonary gas exchange at rest and exercise, while an inequality in VA/Qc hinders pulmonary gas exchange. Dispersion of VA/Qc can occur when ventilation to an area of the lung is compromised and blood passing by this area does not participate in gas exchange. Blood flow increases at the base of the lung due to gravity while ventilation increases at a slower rate. Consequently, the alveoli at the apex of the lung have little blood flow but are well ventilated, while the base of the lung is well perfused but less well 42 ventilated. This concept has been related to the development of EIH, where a worsening of this ratio could occur during maximal exercise (Gale et al., 1985; Torre-Bueno et al., 1985; Wagner et al., 1986; Hammond et al., 1986). Data from Hammond et al. (1986), showed that a VA/Qc mismatch increased with exercise intensity, to an oxygen consumption of approximately 3.5 L-mhr1. When VO2 increased beyond this level no further dispersion of VA/Qc occurred, yet the A-aDC«2 continued to widen. Most recently, Hopkins et al. (1994) found that VA/Qc heterogeneity is the most important contributor (>60%) to the A-aD02 during high intensity cycle ergometry. Why an increase in the VA/Qc ratio occurs during exercise is unclear, but may be caused by non-uniform pulmonary vasoconstriction, reduced gas mixing in the large airways and the development of interstitial pulmonary edema (Schaffartzik et al., 1993). To determine the role of VA/Qc inequality, Schaffartzik et al. (1992) exercised subjects at near maximal intensities while breathing a hypoxic gas mixture (inspiratory PO2 = 91 torr). Approximately 50% (N = 7) of subjects developed a significant VA/Qc mismatch during exercise which persisted for 20 minutes post-exercise. This time frame is beyond the period necessary for the recovery of ventilation and cardiac output, and is indicative of another mechanism. It appears that VA/Qc inequality accounts for part of EIH but is not solely responsible. Diffusion Limitations Veno-arterial shunts and hypoventilation have been excluded as large contributors to EIH, and a VA/Qc mismatch does not completely explain decreases in PAO2 seen in high aerobic capacity athletes. By elimination this implies that a diffusion limitation is at least partly responsible for EIH (Powers et al., 1993). By using an exercising horse model, Wagner et al. (1989) suggest that approximately two-thirds of EIH can be related to diffusion limitations. Two possible diffusion limitations have been pursued: increased pulmonary capillary transit time and the accumulation of interstitial pulmonary edema. 43 Pulmonary Capillary Transit Time During exercise there are several mechanisms which exist to help maintain adequate pulmonary gas exchange. Pulmonary capillary blood volume (Vc) increases through a 3 fold recruitment of capillaries above resting values. The rise in Vc accommodates exercise related increases in cardiac output and allows for adequate transit time of RBC in the pulmonary capillaries. In normal exercising individuals this is sufficient for diffusion equilibrium to occur. It has been theorized that when elite athletes exercise at high intensities cardiac output may continue to increase, while Vc plateaus because it has reached its anatomical limit (Dempsey et al., 1984; Dempsey and Fregosi, 1985). When pulmonary capillary blood flow continues to increase with exercise intensity, transit time will be compromised and complete diffusion equilibrium may not occur. Under normal conditions the RBC remains in the pulmonary capillary for ~ 0.75 s (Johnson et al., 1960), while during intense exercise transit time has been estimated to be reduced to ~ 0.25 s (West, 1979). When examining highly trained cyclists and runners, Warren et al. (1991) observed that Vc did not plateau, nor did mean transit time fall below 0.46 s despite further increases in exercise intensity. Hopkins (1993) observed that a decrease in Pa02 during high intensity cycling could be partially explained by shortened pulmonary transit time, but that other factors may contribute more significantly. Although the results of these studies are not definitive, they do suggest that EIH originates elsewhere. Pulmonary Edema One of the primary factors which limits the rate of 02 transfer through the alveolar membrane is the distance between the membrane and the RBC. An increase in this distance would decrease the diffusion capability of the respiratory system. It has been postulated that elite athletes could possibly enlarge the diffusion distance through the formation of interstitial pulmonary edema. 44 The mechanism for the accumulation of extravascular water remains to be deteirnined, but is likely related to increases in capillary hydrostatic pressure, capillary permeability, capillary surface area or a lymphatic insufficiency (West, 1977). Mean pulmonary arterial pressure and capillary wedge pressures can reach values greater than ~ 40 and 27 torr, respectively (Wagner et al., 1986; Reeves et al., 1988). Stress failure of the pulmonary capillaries at these elevated pressures may cause leakage of fluid and temporary pulmonary edema. When pressures develop in this range, the vascular endothelium may be injured allowing the movement of fluid from the vascular space to the interstitium of the lung. Accumulation of interstitial fluid is usually removed by lymph flow, but highly trained athletes may accumulate more fluid than the lymphatic system can clear. Pulmonary lymph flow has been shown to increase approximately 3 fold in exercising sheep (Coates et al., 1984). A final possibility relates to the distention of the lung capillaries during exercise, where an increased blood volume could increase permeability and promote fluid shifts (Rasmussen et al., 1988). These results, in combination with increased vascular pressures, add to the circumstantial evidence for the accumulation of pulmonary edema. Transthoracic electrical impedance (TEI) has been used in an attempt to quantify the accumulation of extravascular water. Buono et al. (1983) found that TEI was decreased for 30 minutes following exercise and postulated that this finding was related to the accumulation of lung water. However, data on the training status of the subjects was not reported nor was a measure of arterial oxygenation during exercise making interpretation of their results difficult. The physiological importance of these findings remains unclear because the measurement of TEI is non-specific and can not explain the exact source of hindered impedance. It is important to note that the decrease in TEI may have been due to an increase in thoracic intravascular volume and not interstitial edema. More recent results (Rasmussen et al., 1992) showed that TEI was increased following maximal exercise. These conflicting studies, and the non-specific nature of TEI, demonstrate the limitation of using TEI as a tool to evaluate interstitial pulmonary edema. 45 Circulating vascular proteins may also act to alter capillary permeability. Histamine has been implicated as a humoral contributor to increased lung water permeability. A significant positive correlation (r=.80) was observed between the increase in percentage of histamine released and the drop in Pa02 (Anselme et al., 1994). However, it is unknown if increased histamine levels are a response to injury or the cause of decreased arterial oxygenation. The most direct evidence for edema was observed during high-intensity short-term exercise in pigs (Schaffartzik et al., 1993). A higher percentage of pulmonary arteries with perivascular edema was found in exercised than in non-exercised animals. The etiology of pulmonary extravascular fluid accumulation remains unclear, yet indirect evidence shows that some degree of pulmonary edema likely occurs in elite athletic populations following strenuous exercise. Diffusion Capacity of the Lung Measurement of the diffusing capacity of the lung (DL) with carbon monoxide (CO) is based on the early work of Krogh (1914), and was later modified by Roughten and Forster (1957) and Ogilvie et al., (1957). The process of diffusion through tissues is governed by Fick's law, where the rate of transfer of gas through a sheet of tissue is proportional to the tissue area and the difference in gas partial pressure between the two sides, and inversely proportional to the tissue thickness. The diffusion capacity from the alveoli to the pulmonary capillary blood is partitioned into two separate components. The membrane diffusing capacity (DM) is the transfer of gas from the alveoli to the RBC, including plasma. Once added to the blood, the combination of gas (02 or CO) with Hb is represented by 6, and the amount of blood in the vascular bed (Vc). The total resistance of the lung is represented as: 1/DL = 1/DM + 1/6-Vc During strenuous exercise, DL increases 2-3 fold due to recruitment of pulmonary capillaries and an increase in cardiac output (Ayers et al., 1975). Paradoxically, several studies have shown that DLco is significantly reduced following strenuous short-term exercise 46 (Manier et al., 1993; Rasmussen et al., 1991, 1992) and long-term exhaustive exercise (Miles et al., 1983). These findings are in agreement with Dempsey et al.'s (1984) hypothesis that a diffusion limitation could partially account for a decrease in arterial oxygenation. If sufficient pulmonary edema accumulates during exercise to cause a decrease in PaC«2, there should be a necessary time period for fluid clearance. During recovery from maximal exercise, relative homeostasis is observed; heart rate and Vc return to normal resting values in a short time (Manier et al., 1993). If a structural alteration were present it would continue to depress DL, despite a return to normal of heart rate and Vc. Early work by Maron et al., (1979) failed to show a change in DLco following a marathon run. However, these results should be interpreted cautiously, as a significant correlation was observed between the change in DLco and heart rate at the time of the post-race measurement. An elevated cardiac output, as reflected by a high heart rate, likely caused an overestimation of DLco- Conversely, others have shown statistically significant decreases in DLco post-exercise. Miles et al., (1983) using two DLco measures at different gas mixtures found that DLco and DM decreased following a marathon race. This occurred despite the return of Vc and heart rate to normal 1-2 hrs post-race. These results were supported by Manier et al., (1991) who measured both DLco and DLNO (nitric oxide) pre- and post-marathon. Both post-race measures were depressed when compared to pre-race values. Mean DM decreased 29% while Vc had returned to near control values suggesting that the endurance exercise had altered DL. It was concluded that the decreases in DLco and DLNO were due to a modification in the membrane component of the DL equation. Table 12 summarizes the results of studies that have measured DLco Pre_ and post-exercise. It is interesting to observe the range of data in those investigations which have determined DM and Vc post-exercise, particularly those results of Hanel et al. (1994) which show a decrease in Vc (26%) 6 hours post-exercise compared to baseline values. Reductions in central blood volume, as measured by TEI, were described as the cause of reduced DLco and Vc. This study also investigated the effects of multiple bouts of exercise on DLco- A second session of exercise did not influence DLco or DM beyond values observed following 47 the first bout, indicating that changes to diffusion capacity had plateaued. To date, only one study has examined changes to diffusion and decreases in arterial oxygenation. Turner (1992) measured DLco 1 hr post exhaustive exercise in a placebo trial group. A non-significant positive correlation (r = .30) was observed between the change in DLco and %SaC»2min. The relationship between %Sa02 and DL following maximal exercise remains to be determined. 48 Table 12 Change in pulmonary diffusion capacity following exercise. STUDY SUBJECTS A DLco A DM A Vc Rasmusen et al. (1986) canoeists - 6.7% (2.1 hrs) Rasmusen et al. (1988) rowers - 10.5% (2.5 days) Rasmusen et al. (1992) rowers - 15% (2-3 hrs) Hanel et al. (1993) rowers - 5% (2 hrs) Turner (1992) cyclists - 6.8% (1 hr) Miles et al. (1983) marathon runners -2% - 9% baseline (24 hrs) (24 hrs) (24 hrs) Manier et al. (1991) marathon runners -10% (.5 hrs) -29% (.5 hrs) + 10% (.5 hrs) Manier et al. (1993) handball players - 12.9% (.5 hrs) - 13.3% (.5 hrs) baseline (.5 hrs) Hanel et al. (1994) rowers -19% (6 hrs) baseline (6 hrs) -26% (6 hrs) A = percent change compared to baseline values, DLco = diffusion capacity of the lung for carbon monoxide, DM = membrane diffusing capacity, Vc = capillary blood volume. Time of measurement post exercise shown below reported values. 49 APPENDIX B RAW DATA Table 13 Age, height and mass, individual subject data for moderately Uained subjects. SUBJECT AGE HEIGHT MASS (yrs) (cm) (kg) MT-01 26 181.0 69.9 MT-02 27 181.2 82.9 MT-03 24 175.0 76.0 MT-04 28 176.6 84.8 MT-05 24 177.4 76.4 MT-06 24 173.4 87.5 MT-07 21 180.1 73.8 MT-08 30 190.4 87.6 MT-09 28 179.0 91.2 MT-10 26 178.3 82.5 Table 14 Age, height and mass, individual subject data for highly trained subjects. SUBJECT AGE HEIGHT MASS (yrs) (cm) (kg) HT-01 28 174.5 74.0 HT-02 33 177.4 68.8 HT-03 23 180.0 74.1 HT-04 26 174.1 68.4 HT-05 32 180.2 78.3 HT-06 20 182.8 76.1 HT-07 23 182.6 79.4 HT-08 20 170.8 65.3 HT-09 28 180.0 75.3 HT-10 21 184.1 76.2 50 Table 15 Pulmonary function, individual subject data for moderately trained subjects. SUBJECT FVC FEVi FEF25-75% FEVi/FVC FEFmax (L) (L) (L-sec-1) (%) (L-sec1) MT-01 6.31 4.78 3.61 75.68 12.17 MT-02 5.06 3.96 3.29 78.26 8.13 MT-03 4.99 4.43 5.40 88.87 9.24 MT-04 6.31 5.30 5.40 84.00 10.49 MT-05 5.86 5.29 5.84 90.12 10.42 MT-06 4.97 4.19 4.55 84.32 7.99 MT-07 6.05 5.25 5.23 86.87 9.03 MT-08 5.73 4.80 4.59 83.79 11.41 MT-09 5.51 4.76 5.64 86.69 8.41 MT-10 5.54 5.01 6.41 90.49 13.09 Table 16 Pulmonary function, individual subject data for highly trained subjects. SUBJECT FVC FEVi FEF25-75% FEVi/FVC FEFmax (L) (L) (L-sec1) (%) (L-sec1) HT-01 6.15 4.88 4.15 79.41 9.97 HT-02 5.53 4.66 4.70 84.25 11.99 HT-03 5.97 5.28 6.38 88.45 14.16 HT-04 5.57 4.22 3.43 75.79 9.66 HT-05 4.67 3.66 2.99 78.41 10.98 HT-06 6.10 4.95 4.47 81.21 10.16 HT-07 5.84 4.65 4.38 79.65 7.49 HT-08 5.39 5.00 6.51 92.82 11.13 HT-09 6.78 4.95 3.95 73.00 11.42 HT-10 6.11 5.56 6.55 91.02 9.04 51 Table 17 Maximal heart rate (HRmax), maximal oxygen consumption (VC»2max), peak power and minimal percentage of arterial oxyhemoglobin saturation (%Sa02inin) during maximal cycle ergometer test, individual subject data for moderately trained subjects . SUBJECT HRmax (bpm) MT-01 190 MT-02 197 MT-03 174 MT-04 215 MT-05 183 MT-06 190 MT-07 186 MT-08 184 MT-09 198 MT-10 179 VO^max VC^max (L-min"1) (mL-kg-rnhr1) 3.96 56.6 4.58 55.2 3.66 48.3 4.07 48.0 3.84 50.3 4.44 43.7 4.05 54.9 4.35 49.7 5.09 55.8 4.08 49.5 PEAK %Sa02min POWER (%) (watts) 348 94.8 390 92.1 324 93.5 381 94.7 339 95.5 323 94.0 361 94.1 376 93.1 414 94.7 337 95.9 Table 18 Maximal heart rate (HRmax), maximal oxygen consumption (V02max), peak power and minimal percentage of arterial oxyhemoglobin saturation (%Sa02min) during maximal cycle ergometer test, individual subject data for highly trained subjects . SUBJECT HRmax (bpm) V02max (L-min-1) V02max (mL-kg-min-1) PEAK POWER (watts) %Sa02i (%) HT-01 181 5.22 70.5 451 92.9 HT-02 187 4.94 71.8 445 89.4 HT-03 188 4.93 66.5 443 91.9 HT-04 177 4.80 70.2 431 91.6 HT-05 180 4.65 60.1 451 91.8 HT-06 188 4.46 60.3 418 93.5 HT-07 186 5.45 68.6 454 91.0 HT-08 194 4.81 73.7 430 91.4 HT-09 189 5.51 73.2 476 92.7 HT-10 191 4.98 65.4 466 88.3 52 Table 19 Maximal heart rate (HRmax), maximal oxygen consumption (V02max), time to fatigue and minimal percentage of arterial oxyhemoglobin saturation (%Sa02min) during time to fatigue cycle ergometer test, individual subject data for moderately trained subjects . SUBJECT HRmax VC^max VC^max TIME %SaC»2min (bpm) (L-mhr1) (mL-kg-'-mhr1) (s) (%) MT-01 189 3.74 55.5 117 95.8 MT-02 189 4.46 55.6 169 92.9 MT-03 177 3.96 53.6 149 95.1 MT-04 208 3.90 46.2 117 93.1 MT-05 185 3.75 49.8 136 95.6 MT-06 188 4.13 46.93 151 94.3 MT-07 178 3.76 51.0 105 95.6 MT-08 159 3.86 43.5 79 94.2 MT-09 196 4.92 54.6 126 94.9 MT-10 170 3.85 46.5 127 96.1 Table 20 Maximal heart rate (HRmax), maximal oxygen consumption (V02iriax), time to fatigue and minimal percentage of arterial oxyhemoglobin saturation (%Sa02min) during time to fatigue cycle ergometer test, individual subject data for highly trained subjects . SUBJECT HRmax VC^miax V02max TIME %Sa02min (bpm) (L-min-1) (mL-kg^-mur1) (s) (%) HT-01 163 4.54 61.9 59 95.5 HT-02 188 5.10 74.7 136 90.2 HT-03 173 4.95 67.6 107 94.8 HT-04 168 4.48 63.7 96 93.6 HT-05 174 5.16 66.5 173 89.8 HT-06 181 4.23 69.4 111 94.7 HT-07 179 5.32 67.8 119 91.8 HT-08 181 4.69 71.6 95 92.9 HT-09 192 5.40 71.4 130 94.4 HT-10 184 4.99 65.3 113 92.0 53 Table 21 Pulmonary diffusion capacity data pre and post time to fatigue cycle ergometer test, individual subject data for moderately trained subjects. SUBJECT TEST DLco 21% DLco 90% DM VC MT-01 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-02 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-03 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-04 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-05 baseline 1 hour 2 hours 4 hours 6 hours 24 hours 39.1 16.02 37.67 15.6 36.75 14.78 35.5 14.03 35.86 14.02 38.45 14.52 28.46 11.15 25.57 8.89 25.15 10.16 28.23 10.58 27.18 10.1 26.77 11.18 31.45 14.49 26.54 11.77 23.37 11.15 22.1 10.22 22.43 11.1 22.96 10.89 36.2 12.4 30.72 11.99 31.39 10.72 32.62 11.33 31.86 10.99 32.68 11.52 36.48 15.95 32.2 15.07 31.16 13.25 31.04 13.64 31.31 11.71 32.56 14.31 53.8 85.1 51.5 71.4 51.2 81.0 50.0 77.6 50.8 73.1 55.8 67.0 40.5 52.4 39.9 40.0 35.0 50.4 41.5 46.9 40.2 50.1 36.5 49.3 40.4 81.9 34.8 63.6 29.5 64.1 28.3 53.7 27.8 60.8 29.0 56.9 56.9 54.0 43.7 57.0 49.5 46.7 50.7 49.4 49.8 48.1 50.2 50.1 48.2 80.9 41.0 80.8 41.9 65.8 40.9 69.0 45.8 53.3 42.9 71.9 54 MT-06 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-07 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-08 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-09 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-10 baseline 1 hour 2 hours 4 hours 6 hours 24 hours 23.16 10.91 24.11 10.01 24.33 10.44 23.22 10.32 24.79 9.73 24.71 10.46 24.05 8.82 23.56 7.67 23.92 6.92 25.54 8.42 23.88 7.75 24.15 8.9 34.94 16.88 29.84 15.07 31.94 14.67 30.5 12.61 34.11 14.22 34.95 13.36 35.26 14.5 32.51 11.81 29.32 11.1 30.19 11.86 28.82 11.5 31.19 13.93 35.58 14.16 32.61 13.14 32.7 12.3 33.32 12.67 30.84 12.11 31.25 13.85 29.5 57.2 33.0 52.4 32.6 49.2 30.5 54.2 35.2 44.7 33.4 51.7 35.7 45.9 38.8 37.5 44.7 32.1 41.5 39.6 39.4 38.1 35.8 44.6 43.8 90.0 36.7 84.9 41.1 76.7 41.7 57.8 46.4 72.0 50.3 63.5 48.4 73.7 48.7 59.5 42.6 61.3 42.7 63.6 40.3 68.7 40.7 78.2 49.9 69.7 45.3 60.8 47.7 52.9 48.2 54.2 43.6 60.4 41.0 66.6 DLco 21% = pulmonary diffusion for 0.3% carbon monoxide, 21%02? 10% He, balance N2 (mL-min^-mmHg'1); DLco 90% = pulmonary diffusion for 0.3% carbon monoxide, 90%C»2, 10% He (mL-min-i-mmHg-1); DM = membrane diffusing capacity (mL-mur i-mmHg-1); Vc = pulmonary capillary blood volume (mL). 55 Table 22 Pulmonary diffusion capacity data pre and post time to fatigue cycle ergometer test, individual subject data for highly trained subjects. SUBJECT TEST DLco 21% DLCo 90% DM Vc HT-01 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-02 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-03 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-04 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-05 baseline 1 hour 2 hours 4 hours 6 hours 24 hours 34.73 13.54 31.53 11.94 30.94 10.54 32.52 10.8 30.59 9.14 33.69 12.85 31.18 12.98 27.31 12.47 31.15 12.00 26.86 11.57 26.17 10.83 28.92 13.73 32.51 12.60 31.56 11.92 28.40 10.92 29.03 10.84 28.30 11.93 30.42 14.08 26.37 9.81 23.67 9.51 26.22 9.62 23.31 7.91 20.76 7.96 29.23 14.28 44.86 18.43 38.48 16.68 39.52 15.88 36.05 14.03 33.12 12.6 36.93 15.23 49.4 73.7 45.8 54.4 48.9 50.1 52.6 47.6 55.2 38.9 48.7 59.2 42.3 71.0 35.2 74.0 44.5 63.5 35.7 57.6 35.7 50.4 36.6 76.8 46.5 58.1 46.0 55.1 40.9 48.3 42.7 56.3 38.3 60.9 39.0 73.9 38.9 50.8 33.1 48.8 39.1 43.9 37.1 39.4 29.9 35.6 36.5 75.5 61.6 87.6 51.1 83.0 55.0 76.6 51.3 66.3 47.9 60.0 50.6 75.1 56 HT-06 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-07 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-08 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-09 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-10 baseline 1 hour 2 hours 4 hours 6 hours 24 hours 37.77 14.97 35.69 13.98 35.75 13.13 35.54 13.59 35.66 13.27 39.33 15.29 34.92 14.17 32.20 12.26 29.87 11.35 30.57 11.00 30.23 11.10 31.74 12.53 34.62 14.99 35.08 13.92 32.68 13.46 31.4 12.9 33.18 13.49 35.96 15.09 39.48 15.69 35.68 13.64 33.56 12.82 35.86 12.21 31.57 10.92 37.41 14.12 32.35 14.39 30.93 12.65 29.91 12.15 29.94 11.14 28.23 10.73 32.52 12.42 53.0 99.4 50.5 84.5 53.0 82.5 51.2 71.4 52.4 68.6 55.9 93.3 48.4 75.9 46.6 60.4 43.3 56.2 46.2 51.6 45.0 52.7 44.8 63.1 46.0 85.4 49.2 78.0 44.7 74.5 43.0 71.7 45.8 66.9 48.7 76.0 55.5 72.3 51.6 58.8 48.5 54.9 56.9 51.8 49.4 48.2 54.5 63.1 42.4 71.7 42.7 64.9 41.4 61.6 44.1 59.9 40.9 50.4 47.0 47.0 DLco 21% = pulmonary diffusion for 0.3% carbon monoxide, 21%02, 10% He, balance N2 (mL-min_1-mmHg_1); DLco 90% = pulmonary diffusion for 0.3% carbon monoxide, 90%C»2, 10% He (mL-min_1-mmHg-1); DM = membrane diffusing capacity (mL-min-i-mmHg"1); Vc = pulmonary capillary blood volume (mL). 57 Table 23 Hemoglobin (Hb), mass, alveolar volume (VA), and diffusion/alveolar volume (D/VA) pre- and post- time to fatigue cycle ergometer test, individual subject data for highly trained subjects. SUBJECT TEST Hb Weight VA D/VA (g-dL-l) (kg) (L) HT-01 baseline 13.4 73.3 9.89 3.51 1 hour 15.7 74.1 9.18 3.44 2 hours 14.2 74 9.4 3.24 4 hours 15.1 74.8 9.74 3.34 6 hours 14.9 74.6 9.69 3.16 24 hours 15.6 73.3 9.74 3.46 HT-02 baseline 13.6 68.3 8.35 3.73 1 hour 13.5 70 8.25 3.31 2 hours 13.4 70 8.39 3.71 4 hours 15.4 70.5 8.35 3.22 6 hours 16.0 70 8.32 3.15 24 hours 15.0 69.9 8.59 3.37 HT-03 baseline 15.8 73.2 8.14 3.99 1 hour 15.5 73.3 7.9 3.99 2 hours 16.4 73.4 7.93 3.58 4 hours 13.7 74.2 7.98 3.64 6 hours 15.1 74.2 7.86 3.60 24 hours 15.8 73.9 7.88 3.86 HT-04 baseline 13.8 69.7 7.54 3.5 1 hour 14.6 69.9 7.55 3.14 2 hours 15.5 70.1 7.48 3.51 4 hours 13.6 70.8 7.55 3.09 6 hours 16.2 70.8 7.31 2.84 24 hours 16.4 71 6.92 4.23 HT-05 baseline 15.8 77.6 7.13 6.29 1 hour 15.7 77.9 7.39 5.21 2 hours 15.3 79 7.54 5.25 4 hours 15.3 79 7.58 4.76 6 hours 15.0 79.3 7.59 4.36 24 hours 15.3 79.4 7.77 4.76 58 HT-06 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-07 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-08 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-09 baseline 1 hour 2 hours 4 hours 6 hours 24 hours HT-10 baseline 1 hour 2 hours 4 hours 6 hours 24 hours 11.0 75.3 12.0 75.7 11.1 75.5 13.6 76.2 13.6 76.5 11.8 76.8 14.0 75.3 14.6 75.7 14.5 75.5 14.8 76.2 14.8 76.5 14.6 76.8 13.6 65.5 13.0 65.9 13.5 65.9 13.4 66.3 14.9 66.1 15.1 65.9 16.1 75.6 16.8 76.1 16.9 76.7 16.0 77.3 15.5 77.2 16.0 76.1 16.1 76.4 14.7 76.8 14.8 76.7 13.2 76.8 15.3 76.9 14.0 77.3 9.95 3.80 9.67 3.69 9.75 3.67 9.92 3.58 9.71 3.67 9.88 3.98 9.95 3.80 9.67 3.69 9.75 3.67 9.92 3.58 9.71 3.67 9.88 3.98 7.96 4.35 8.12 4.31 7.96 4.11 7.81 4.02 8.07 4.11 8.44 4.26 11.12 3.55 10.89 3.28 10.76 3.12 10.86 3.30 10.66 2.96 11.11 3.37 8.96 3.61 8.88 3.48 8.83 3.39 8.75 3.42 8.78 3.22 8.61 3.78 59 Table 24 Hemoglobin (Hb), mass, alveolar volume (VA), and diffusion/alveolar volume (D/VA) pre- and post- time to fatigue cycle ergometer test, individual subject data for moderately trained subjects. SUBJECT TEST Hb Weight VA D/VA (g-dL-1) (kg) (L) MT-01 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-02 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-03 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-04 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-05 baseline 1 hour 2 hours 4 hours 6 hours 24 hours 14.1 67.4 16.5 67.5 13.5 67.6 13.2 68 13.9 68.1 15.3 68.8 15.7 80.2 15.3 81.1 15.2 80.9 16.2 81.7 14.4 81.1 17.5 80.4 14.5 73.9 14.7 74.1 14.7 74.1 15.6 74.3 15.9 74 16.0 74.5 15.5 84.5 15.3 84.7 15.5 84.7 15.6 84.8 15.5 85 15.8 84.9 15.5 75.3 15.5 75.4 15.5 75.4 15.6 76 15.5 76 15.7 75.6 9.23 4.23 9.24 4.08 9.34 3.93 9.11 3.9 9.22 3.89 9.57 4.02 6.73 4.23 6.66 3.84 6.68 3.76 6.71 4.21 6.62 4.11 6.66 4.02 6.64 4.73 6.41 4.15 6.55 3.57 6.29 3.51 6.71 3.35 6.63 3.47 9.16 3.95 8.9 3.45 8.76 3.58 8.37 3.90 8.58 3.54 8.62 3.92 8.67 ' 4.21 8.53 3.78 8.65 3.60 8.54 3.64 8.7 3.60 8.58 3.79 60 MT-06 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-07 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-08 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-09 baseline 1 hour 2 hours 4 hours 6 hours 24 hours MT-10 baseline 1 hour 2 hours 4 hours 6 hours 24 hours 16.1 88.0 14.6 87.8 16.6 87.8 15.3 88.1 16.0 88.1 15.7 87.9 13.4 73.8 13.4 73.8 13.4 74.8 14.0 75.8 13.3 75.3 14.0 75.3 16.1 88.8 15.9 88.5 15.7 88.5 16.5 89.4 15.0 90.2 15.0 88.3 14.8 90.1 13.8 90.5 12.9 90.5 13.6 90.6 12.3 90.6 14.2 90.8 14.9 82.8 16.0 82.9 16.5 82.9 16.7 83.2 14.6 83.5 16.6 83 5.39 4.29 5.89 4.09 5.84 4.16 5.30 4.38 5.98 4.15 5.57 4.43 9.01 2.61 9.05 2.71 9.16 2.61 9.3 2.75 9.22 2.59 9.18 2.63 8.04 4.34 8.41 3.55 8.5 3.76 8.51 3.58 8.82 3.87 9.04 3.87 7.27 4.85 7.58 4.29 7.4 3.96 7.53 4.01 7.54 3.82 7.5 4.16 7.74 4.60 7.68 4.25 7.67 4.26 7.57 4.40 7.39 4.17 7.01 4.46 61 APPENDIX C STATISTICAL ANALYSES ANOVA table for DLCo 21% 02 DF Sum of Squares Mean Square F-Value P-Value TRAINING STATUS 1 165.464 165.464 1.507 .2354 Subject(Group) 18 1975.821 109.768 TIME 5 224.812 44.962 18.495 <.0001 TIME * TRAINING ST... 5 25.143 5.029 2.068 .0766 TIME * Subject(Group) 90 218.795 2.431 ANOVA table for DLco 90% 02 DF Sum of Squares Mean Square F-Value P-Value TRAINING STATUS 1 11.023 11.023 .526 .4778 Subject(Group) 18 377.559 20.975 TIME 5 97.210 19.442 27.967 <.0001 TIME * TRAINING ST... 5 10.179 2.036 2.929 .0170 TIME * Subject(Group) 90 62.566 .695 ANOVA table for D/VA DF Sum of Squares Mean Square F-Value P-Value TRAINING STATUS 1 .200 .200 .123 .7299 Subject(Group) 18 29.283 1.627 Time 5 3.295 .659 12.623 <.0001 Time * TRAINING STA... 5 .273 .055 1.044 .3967 Time * Subject(Group) 90 4.699 .052 62 ANOVA table for DM DF Sum of Squares Mean Square F-Value P-Value TRAINING STATUS 1 445.060 445.060 1.778 .1990 Subject(Group) 18 4504.919 250.273 TIME 5 161.559 32.312 3.016 .0146 TIME* TRAINING ST... 5 21.761 4.352 .406 .8434 TIME * Subject(Group) 90 964.298 10.714 ANOVA table for Hb DF Sum of Squares Mean Square F-Value P-Value Training Status 1 5.504 5.504 .942 .3447 Subject(Group) 18 105.209 5.845 TIME 5 4.161 .832 1.279 .2801 TTME * Training Status 5 5.679 1.136 1.745 .1324 TIME * Subject(Group) 90 58.584 .651 ANOVA table for VA DF Sum of Squares Mean Square F-Value P-Value Training Status 1 18.873 18.873 2.198 .1555 Subject(Group) 18 154.565 8.587 TTME 5 .095 .019 .478 .7919 TTME * Training Status 5 .245 .049 1.238 .2982 TTME * Subject(Group) 90 3.561 .040 ANOVA table for Vc DF Sum of Squares Mean Square F-Value P-Value TRAINING STATUS 1 448.417 448.417 .570 .4601 Subject(Group) 18 14168.266 787.126 TIME 5 3868.056 773.611 20.601 <.0001 TIME * TRAINING ST... 5 692.392 138.478 3.688 .0044 TTME * Subject(Group) 90 3379.634 37.551 63 ANOVA table for Weight DF Sura of Squares Mean Square F-Value P-Value Training Status 1 1391.964 1391.964 6.288 .0220 Subject(Group) 18 3984.742 221.375 TIME 5 13.599 2.720 20.186 <.00()1 TIME * Training Status 5 .705 .141 1.047 .3952 TIME * Subject(Group) 90 12.127 .135 64 APPENDIX D RELIABILITY DATA Nine (5 female, 4 male) healthy, non-smoking subjects participated in data collection and repeated the experimental protocol at the same time on separate days. All subjects performed spirometry and diffusion measurements as described in the methods section. A pearson-product moment correlation coefficient was used to obtain the degree of correlation between pulmonary diffusion variables. Values obtained during the diffusion trials are presented in Table 25. Pearson product-moment correlations between test and re-test measures of pulmonary diffusion data. Measurement Con-elation DLco 21% O2 r = .98 DLco 90% O2 r = -96 DM r = .84 Vc  = .92 DLco 21% 02 = pulmonary diffusion for 0.3% carbon monoxide, 21%02, 10% He, balance N2; DLco 90% O2 = pulmonary diffusion for 0.3% carbon monoxide, 90%O2, 10% He; DM = membrane diffusing capacity; Vc = pulmonary capillary blood volume. These correlation values can be considered high, where a high correlation between two trials of a test is an indication of good test reliability. The results suggest that the measurement of DLco and the calculation of DM and Vc are reliable among non-smoking males and females aged 23-37. Pulmonary capillary blood volume values appear to be low in the present study when compared to other reported values of approximately 90 mL (Wan-en et al., 1991; Manier et al., 1993; Hanel et al., 1994). However, these studies used an exclusively male, athletic population. The discrepancy seen in Vc values may be a reflection of differences in gender, size and training status. Subjects in this investigation included both males and females, as well as highly trained and moderately trained individuals. The variety of subjects and the high 65 correlation coefficients emphasizes the reliability of the experimental measurements. In summary, the Collins diffusion system was found to be highly reliable when measuring pulmonary diffusion capacity and calculating DM and Vc. Table 25 Subject characteristics and pulmonary diffusion capacity measurements. SUBJECT AGE (yr) GENDER DLco 21% O2 DLco 90% 02 DM Vc 1 37 male 28.38 14.38 52.6 82.2 29.80 15.07 55.3 86.6 2 25 male 32.68 14.95 74.3 77.7 32.56 13.53 97.9 64.5 3 26 male 38.44 15.93 115.4 76.9 38.29 16.90 96.2 83.6 4 24 male 39.22 17.47 97.3 85.3 37.23 16.19 98.2 78.3 5 36 female 19.76 8.98 45.6 46.5 18.72 8.10 49.7 39.5 6 23 female 25.25 10.67 71.2 52.2 22.74 9.98 58.0 49.3 7 34 female 22.02 9.33 61.6 45.6 18.52 8.02 49.6 38.4 8 27 female 24.88 11.92 51.5 63.4 21.5 9.23 59.3 43.8 9 25 female 23.17 8.68 116.0 37.6 21.03 8.02 93.4 35.4 Values are from test 1, with test 2 values directly below. DLco 21% 02= pulmonary diffusion for 0.3% carbon monoxide, 21%02, 10% He, balance N2 (mL-min-LmmHg-1); DLco 90% O2 = pulmonary diffusion for 0.3% carbon monoxide, 90%O2, 10% He (mL-min-LmmHg"1); DM = membrane diffusing capacity (mL-min-LmmHg-1); Vc = pulmonary capillary blood volume (mL). 67 

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