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Pulmonary diffusing capacity and exercise-induced hypoxemia in highly trained athletes Lama, Iris L. 1996

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PULMONARY DIFFUSING CAPACITY AND EXERCISE-INDUCED HYPOXEMIA IN HIGHLY TRAINED ATHLETES by Iris L. Lama B.Sc, The University of British Columbia, 1981 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 January 1996 © Iris L. Lama, 1996 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 h'ooyiO^ kU'/l&fa'cZ The University of British Columbia Vancouver, Canada Date DE-6 (2788) iv Table of Contents ABSTRACT ii TABLE OF CONTENTS iv TABLE OF TEXT TABLES vii TABLE OF TEXT FIGURES viii LIST OF SYMBOLS ix ACKNOWLEDGEMENTS X /. INTRODUCTION 1 1.1 HYPOTHESES 4 2. METHODS 6 2.1 SUBJECTS: SELECTION 6 2.2 EXPERIMENTAL PROTOCOL 6 2.3 EXPERIMENTAL MEASURES 7 2.4 STATISTICAL ANALYSES 10 3. RESULTS 12 3.1 SUBJECT DESCRIPTIVE DATA 12 3.2 MAXIMAL EXERCISE TEST DATA 12 THE RELATIONSHIP BETWEEN EXERCISE AND PULMONARY DIFFUSING CAPACITY 14 5.4 THE RELATIONSHIP BETWEEN CHANGES IN PULMONARY DIFFUSING CAPACITY AND ARTERIAL BLOOD OXYGEN SATURATION 17 3.5 THE RELATIONSHIP BETWEEN EXERCISE AND BREATHING PATTERN 20 * DISCUSSION 24 4.7 ALTERATIONS IN PULMONARY DIFFUSING CAPACITY FOLLOWING MAXIMAL EXERCISE 24 4.2 ALTERATIONS IN ARTERIAL OXYGEN HEMOGLOBIN SATURATION FOLLOWING MAXIMAL EXERCISE 31 4.J THE PHYSIOLOGICAL SIGNIFICANCE OF REDUCED PULMONARY DIFFUSING CAPACITY 34 4.4 ALTERATIONS IN BREATHING PATTERN FOLLOWING MAXIMAL EXERCISE 35 5. CONCLUSIONS 37 Abstract The purpose of this study was to determine whether a reduced post-exercise pulmonary diffusing capacity (DL) had a physiological effect on subsequent exercise. Thirteen endurance-trained male athletes (age = 27 ± 3 yrs; ht = 179.6 ± 5.0 cm; mass = 71.8 ± 6.9 kg; VChmax = 67.0 ± 3.6 ml-kg -min ) performed two consecutive V02max exercise tests, separated by 60 min of recovery. Testing was on an electronically-braked cycle ergometer (Quinton, Excalibur) using a ramp protocol (30 W-min"1). Arterial oxygen saturation (%Sa02) was measured via ear oximetry (Ohmeda Biox 3740 pulse oximeter), and resting D L was measured by a single-breath carbon monoxide diffusing capacity test (Collins Survey Tach Pulmonary Function Testing Unit), prior to exercise and 60 min following each exercise bout. In order to partition the membrane diffusing capacity (DM) and pulmonary capillary volume (Vc) from D L , two test gases were used (21% 0 2 and 90% 0 2 with 0.3% CO). Athletes that exhibited a decrease in %Sa02 ^91 during exercise were grouped as desaturaters (D) all others were grouped as nondesaturaters (ND). There was a significant difference in %Sa02 between D and N D (p = 0.0001); however, all other measures between the two groups were not significantly different. There were no significant differences in VOimax or %Sa02min between exercise bouts. A 1.7% decrease (p = 0.003) in peak power output occurred during the second exercise test (Ex2). Significant decreases occurred in D L (p< 0.0001), D M (p = 0.02) and Vc (p < 0.0001) post-exercise, as compared to pre-exercise. D L decreased 11% following iii the initial exercise bout (p < 0.05) and a further 6% (p < 0.05) from post-exercise 1 (Exl) to post-Ex2. Similarly, Vc showed an overall decrease of 20% with a 10% decrease (p < 0.05) between exercise bouts. D M showed a significant (p < 0.05) 11% decrease from pre-exercise to post-Exl and a further 2% decrease (p > 0.05) between post-Ex 1 and post-Ex2. A strong positive linear relationship existed in D between changes in %Sa02 and changes in D L (r = 0.87, p = 0.03), and between changes in %Sa02 and changes in D M (r = 0.85, p = 0.03) consequent to Exl. No linear relationship existed for changes in D during Ex2 or during either exercise bout for ND. Rapid shallow breathing (RSB) was observed during recovery (R) following both exercise bouts. No significant differences in breathing pattern existed between Exl - Rl and Ex2 - R2, or between D and N D . The development of RSB and decreases in D M following exercise support the presence of pulmonary edema. Because no further changes were observed following the second exercise bout and no differences existed between D and ND, alternate mechanisms in addition to diffusion limitations, must contribute to the final decrease in %Sa02. V APPENDIX A: REVIEW OF THE LITERATURE 38 A. l ASSESSMENT OF EXERCISE-INDUCED HYPOXEMIA 38 A. 2 INCIDENCE OF EIH AND CONSEQUENCES ON PERFORMANCE 39 A. 3 PHYSIOLOGICAL MECHANISMS OF EXERCISE-INDUCED HYPOXEMIA 41 A.3.1 HYPOVENTILATION . 4 1 A.3.2 VENTILATION PERFUSION MISMATCH 42 A.3.3 PULMONARY.DIFFUSION LIMITATIONS 43 A.3.3. i) Inadequate RBC Transit Time 43 A.3.3. ii) Accumulation of Interstitial Pulmonary Fluid 44 A.4 PULMONARY CAPILLARY STRESS FAILURE HYPOTHESIS 48 A. 5 CONCLUSIONS 50 REFERENCES 52 APPENDIX B: INDIVIDUAL SUBJECT DATA 59 TABLE Bl: DESCRIPTIVE PHYSIOLOGICAL DATA 59 TABLE B2: MAXIMAL AEROBIC TEST DATA - EXERCISE 1 60 TABLEB3: MAXIMAL AEROBIC TEST DATA - EXERCISE 2 61 TABLE B4: PULMONARY DIFFUSING CAPACITY AND %SA02 PRE- AND POST-EXERCISE 1 62 TABLE B5: PULMONARY DIFFUSING CAPACITY AND %SA03 PRE- AND POST-EXERCISE 2 63 TABLE B6: PERCENT CONTRIBUTION OF DM AND VC TO DL PRE-EXERCISE AND POST-EXERCISE 1 AND 2 64 TABLE B7: HEART RATE, HEMOGLOBIN CONCENTRATION AND BODY MASS DURINGDLco MEASUREMENTS 65 TABLE B8: CHANGES IN TIDAL VOLUME AT GIVEN RATES OF VENTILATION MEASURED AT EACH MINUTE OF RECOVERY DURING RECOVERY 1 - EXERCISE 1 AND RECOVERY 2 - EXERCISE 2 66 TABLE B9: T-TEST COMPARISONS OF PHYSIOLOGICAL VARIABLES BETWEEN SUBJECTS DURING TWO EXERCISE BOUTS 67 TABLE BIO: TWO-WAY ANALYSIS OF VARIANCE OF DIFFERENCES BETWEEN DESATURATERS AND NON-DESATURATERS ACROSS 3 DIFFERENT MEASUREMENT TIMES (PRE-EXERCISE, POST-EXERCISE 1, POST-EXERCISE 2) 68 TABLEBll: CORRELATIONS OF PERCENT CHANGE IN %SA02 BETWEEN DESATURATERS AND NON-DESATURATERS ACROSS BOTH EXERCISE SESSIONS 69 vi TABLE B12: THREE-WAY ANALYSIS OF VARIANCE (2X2X5) OF DIFFERENCES BETWEEN DESATURATERS AND NON-DESATURATERS ACROSS 2 PERIODS OF EXERCISE AND RECOVERY FOR DIFFERENCES IN VT AT A GIVEN VE MEASURED AT EACH MINUTE DURING RECOVERY 70 FIGURE Bl: SUBJECT SJBREATHING PATTERN DURING EXERCISE AND RECOVERY 71 FIGURE B2: SUBJECT CJ BREATHING PATTERN DURING EXERCISE AND RECOVERY 72 FIGURE B3: SUBJECT MB BREATHING PATTERN DURING EXERCISE AND RECOVERY 73 FIGURE B4: SUBJECT BB BREATHING PATTERN DURING EXERCISE AND RECOVERY 74 FIGURE BS: SUBJECT JF BREATHING PATTERN DURING EXERCISE AND RECOVERY 75 FIGURE B6: SUBJECT MM BREATHING PATTERN DURING EXERCISE AND RECOVERY 76 FIGURE B7: SUBJECT TS BREATHING PATTERN DURING EXERCISE AND RECOVERY 77 FIGURE B8: SUBJECT JC BREATHING PATTERN DURING EXERCISE AND RECOVERY 78 FIGURE B9: SUBJECT AS BREATHING PATTERN DURING EXERCISE AND RECOVERY 79 FIGURE BIO: SUBJECTSC BREATHING PATTERN DURING EXERCISE AND RECOVERY 80 FIGURE Bll: SUBJECT CB BREATHING PATTERN DURING EXERCISE AND RECOVERY 81 FIGURE B12: SUBJECT TB BREATHING PATTERN DURING EXERCISE AND RECOVERY 82 FIGURE B13: SUBJECT MP BREATHING PATTERN DURING EXERCISE AND RECOVERY 83 Table of Text Tables TABLE l: PHYSICAL CHARACTERISTICS OF SUBJECTS. TABLE 2: MAXIMUM AND MINIMUM VALUES FOR BLOOD, VENTILATORY AND POWER OUTPUT DATA DURING MAXIMAL EXERCISE TESTING. TABLE 3: MAXIMUM AND MINIMUM VALUES FOR BLOOD, VENTILATORY AND POWER OUTPUT DATA DURING MAXIMAL EXERCISE TESTING GROUPED FOR DESATURATERS AND NONDESATURATERS. TABLE 4: PULMONARY DIFFUSING CAPACITY MEASUREMENTS PRE- AND POST-EXERCISE. TABLE 5: PHYSIOLOGICAL MEASURES DURING PULMONARY DIFFUSING CAPACITY MEASUREMENTS PRE- AND POST-EXERCISE. TABLE 6: MEAN PERCENT DECREASE IN DL, DM, VC, AND %SA02 DURING EACH EXERCISE BOUT. TABLE 7: MEAN PERCENT CHANGE IN AVT DURING EACH MINUTE OF RECOVERY. Table of Text Figures FIGURE 1: CHANGES IN PULMONARY DIFFUSING CAPACITY PRE-AND POST-EXERCISE. FIGURE 2: CORRELATIONS BETWEEN ADL, ADM, AVC AND A%SA02 IN ATHLETES WHO DESATURATED DURING THE FIRST EXERCISE BOUT. FIGURE 3: OVERALL CORRELATIONS (BASELINE TO POST-EXERCISE 2) BETWEEN ADL, ADM, AVC AND A%SA02 IN ATHLETES WHO DESATURATE FIGURE 4: TIDAL VOLUME AS A FUNCTION OF VENTILATION NORMALIZED FOR VITAL CAPACITY FOR ONE SUBJECT (MP) FIGURE 5: AVT DURING THE FIRST 5 MIN OF RECOVERY 1 AND RECOVERY 2. IX List of Symbols (A-a)DO 2 : alveolar-arterial P0 2 difference EIH: exercise-induced hypoxemia D : desaturaters; minimum arterial 0 2 hemoglobin saturation < 91 % D L : pulmonary diffusing capacity D M : membrane diffusing capacity FEVi 0 : forced expiratory volume in the first second of expiration FVC: forced vital capacity HT: highly trained athletes V 0 2 >60 ml-kg"1-min"1 N D : non desaturaters; minimum arterial 0 2 hemoglobin saturation > 9 1 % RSB: rapid shallow breathing RV: residual volume %Sa02: percentage arterial oxygen-hemoglobin saturation 0 (theta): reaction rate of gas with hemoglobin V A / Q : ventilation/perfusion ratio i/02max: maximal oxygen consumption Vc: pulmonary capillary blood volume V E / V C : ventilation normalized for vital capacity VT (%VC): tidal volume expressed as a percentage of vital capacity AVT: change in vital capacity (measured at a given rate of ventilation) Ackno wledgements I would like to acknowledge the outstanding support and guidance provided by Dr. Don McKenzie in helping to make this research and my master's work an enjoyable and fulfilling experience. I would also like to extend my gratitude to committee members Dr. Ken Coutts and Dr. Jeremy Road. Many thanks to all the volunteers who contributed countless hours towards the completion of this project. Special thanks to Diana Jespersen whose patience and humour were invaluable. Thanks also to Bill Sheel, Lynneth Wolski, Sherri Niesen and Jim Potts for sharing their time and the physiology lab. Particular thanks to my family for their exceptional confidence in me. Finally, I would like to express my never-ending gratitude to my life partner Mike Rankin, for his love and support. 1 /. Introduction Highly trained athletes working at metabolic rates in excess of 4-5 1-min"1 are frequently unable to maintain arterial oxygen tension (Pa02) and arterial oxygen hemoglobin saturation (%Sa02) homeostasis. Dempsey et al. (1984) were the first to provide conclusive evidence for the development of exercise induced hypoxemia (EIH) in some elite athletes (V02ma.x = 72 ml-kg -^min"1 or ~ 5 1-min"1), demonstrating significant reductions in %Sa02, (below 91%) and decreases in Pa02 (— 75 mmHg). Blood gas measurements obtained from subjects running at maximal and near maximal exercise levels indicated an alveolar-arterial 0 2 difference [(A-a)D02] in excess of 40 mmHg. These findings have been confirmed by others who have detected EIH by direct measure of arterial blood gas tension (Hopkins and McKenzie 1989; Martin et al. 1992b; Pedersen et al. 1992b; Powers et al. 1992; Warren et al. 1991), and by non-invasive estimates of %Sa02 via ear oximetry (Lawler et al. 1988; Martin and O'Kroy 1993; Powers et al. 1988, 1989b; Williams et al. 1986). The development of oxygen-hemoglobin desaturation occurs gradually as work rates increase. In all cases, subjects who demonstrate EIH are highly trained and exercising at extreme levels. Individuals demonstrating EIH show otherwise normal pulmonary function, indicating that EIH represents a pulmonary limitation at high metabolic rates. It has been estimated (Martin et al. 1992b; Powers et al. 1988) that approximately 50% of HT male endurance athletes may experience a significant decrement in %Sa02 (4% decrease from resting values) during maximal exercise. A 2 decreased arterial oxygen content due to reduced %Sa02 has a direct effect on maximal oxygen consumption (V02max) and possibly reduces endurance performance (Koskolou and McKenzie 1994; Lawler et al. 1988; Martin and O'Kroy 1993; Pedersen et al. 1992a; Powers et al. 1989a). Studies have shown that the level of arterial desaturation is inversely related to V0 2max during heavy exercise (Williams et al. 1986). However, VChmax is not a good predictor of endurance performance since there are many other contributing factors (Allen et al. 1985). When performance is assessed by total work output, a linear relationship exists between maximal exercise performance and %Sa02, indicating that maximal performance capacity is significantly impaired in HT athletes demonstrating arterial desaturation (Koskolou and McKenzie 1994). The etiology of EIH remains unclear. Earlier studies (Hammond et al. 1986a) demonstrated that at exercise levels of VO2 > 3.0 1-min"1, the most significant contributor to widening of the (A-a)D02 appeared to be diffusion limitation. More recently Hopkins et al. (1994) have shown that although athletes develop diffusion * 1 limitations during maximal exercise (VO2 > 5 1-min"), the most important contributor to the widening (A-a)D02 is V A / Q mismatch. Although several mechanisms are possible, current theory suggests the mechanism for both increased V A / Q mismatch and increased diffusion limitations is the accumulation of interstitial pulmonary fluid (Buono et al. 1981, 1982; Caillaud et al. 1995; Hammond et al. 1986a; Schaffartzik et al. 1992; Wagner et al. 1986). 3 A technique for the direct assessment of subclinical perivascular and/or peribronchial edema has yet to be established. Indirect evaluation can be made by measurement of pulmonary diffusing capacity (DL), and by assessment of alterations in breathing pattern. At the onset of exercise, D L increases due to increases in membrane (alveolar-capillary) diffusing capacity (DM) and pulmonary capillary volume (Vc) (Billiet 1970; Fisher and Cerny 1982; Johnson et al. 1960). Following exercise, there is a decrease in D L and D M below pre-exercise levels, which may persist for up to 48 hours (Rasmussen et al. 1992). The decrease in D M is an outcome of an increased distance between the gas and blood phase of lung tissue resulting from a thickening of the alveolar-capillary membrane (Staub et al. 1967). Breathing patterns pre- and post-exercise are similarly altered. At low levels of exercise, ventilation is enhanced by increases in tidal volume. As exercise intensity increases, changes in respiratory frequency dominate (Hey et al. 1966). During recovery from very high levels of exercise, rapid shallow breathing (RSB) has been observed in HT athletes (Caillaud et al. 1993; Younes and Burks 1985). Persistent exercise-induced interstitial edema during recovery may be responsible for both the decrease in D M and development of RSB. The development of EIH in HT athletes is highly reproducible; Powers et al. (1988) have demonstrated a test/retest correlation of 0.95 (p < 0.05). Although it is well documented that EIH can occur in the healthy HT male athlete, the mechanisms remain obscure. It has been hypothesized that changes that occur during one exercise bout could be compounded in subsequent exercise sessions. In moderately trained 4 athletes, repeat exercise has resulted in decreases in D L which appear to be a consequence of a fall in central blood volume (Clifford et al. 1991; Hanel et al. 1993). To date no studies have assessed the effect of repeat exercise in HT athletes on the development of EIH. 1.1 Hypotheses The purpose of this study was to assess the changes in D L , D M and Vc following exercise. Pulmonary fluid accumulation can not be measured directly, but is associated with RSB and decreases in D L and D M , which may result in decreased %Sa02 during exercise. It was reasoned that if decreases occur following one bout of high intensity exercise, a second bout of exercise would precipitate even greater changes. Additionally, the percent change in %Sa02 should correspond with the percent changes in D L and D M . Thus, it was hypothesized that a second maximal exercise challenge (Ex2), following an initial maximal exercise effort (Exl) would result in further decreases in D L , D M and %Sa02. Because of these changes, it was hypothesized that there would be a decrease in VChmax and peak power output (Ppeak) during Ex2, even though a previous study from this lab failed to demonstrate decreased VChmax in association with decreased Ppeak (Koskolou and McKenzie 1994). It was felt that no changes would occur in Vc consequent to Ex2. Additionally, it was hypothesized that there would be a difference in the degree of RSB between the two exercise bouts. Therefore, the following null hypotheses were tested: 5 H : There will be no significant difference in D L , D M , or Vc in HT athletes between pre-exercise and post-exercise measurements (post-exercise measurements preceded by 60 min of recovery). H 0 2 : There will be no significant difference in the minimum value of %Sa02 in HT athletes between measurements during Exl and measurements during Ex2 (Exl and Ex2 separated by 60 min of recovery). H 0 3 : There will be no significant difference in the VChmax and Ppeak attained between Exl and Ex2. H 0 4 : There will be no significant correlation between the percent change in %Sa02 and the percent change in D L , D M , and Vc between Exl and Ex2. H 0 5 : There will be no significant difference between breathing pattern during exercise (Exl, Ex2) and recovery (Rl, R2). 6 2. Methods 2.1 Subjects: Selection Thirteen non-smoking endurance-trained male athletes between the ages of 21 and 33 years were recruited. All subjects were screened for inclusion in the study, and met the following criteria: (i) V02max > 60 ml-kg"1-min"1 or 5 1-min"1, and (ii) normal resting pulmonary function. VOimax was determined using a cycle ergometer as described in the experimental protocol. Subjects were grouped according to the minumum degree of arterial oxygen hemoglobin saturation during exercise. Desaturaters (D) were those subjects who demonstrated a minumum %Sa02 ^ 91%, nondesaturaters (ND) demonstrated a minimum %Sa02 > 91% at maximal exercise. Pulmonary function tests to ensure normal spirometry were examined by measurement and assessment of the following: forced vital capacity (FVC), forced expiratory volume in one second (FEVi 0), and the ratio of FEV, 0 / F V C . All subjects were familiarized with the experimental protocol prior to giving informed consent. 2.2 Experimental Protocol The protocol was approved by the University of British Columbia Clinical Screening Committee for Research and Other Studies Involving Human Subjects. Prior to all testing, subjects were required to avoid exhaustive exercise for 24 hr; abstain from ingestion of food or fluid, except water for 2 hr; and refrain from consuming alcohol and caffeine for 12 hr. 7 Pulmonary diffusing capacity was assessed prior to initial exercise (pre-exercise) and 60 min after the completion of each exercise test by means of the single breath carbon monoxide diffusing capacity test ( D L c 0 , ml-min^-mmHg"1). All D L C O measurements were preceded by 30 min of seated rest, to ensure stabilization of measurement (Billiet 1970). Blood hemoglobin concentration ([Hb]) was measured prior to all diffusing capacity measurements. Prior to maximal exercise testing, subjects warmed up on the cycle ergometer using a pyramid step protocol to a maximum work load of 200 watts. Following the 10 min warm-up, resting data was collected for 3 min while the subject remained seated on the ergometer. VChmax was determined using a ramp protocol beginning at 0 watts, with increments of 30 watts-min"1. The criteria for maximal aerobic capacity was attainment of three of the following: (i) a plateau in V C h with increasing work load, (ii) RER > 1.10, (iii) 90% of age-predicted maximal heart rate, or (iv) volitional fatigue. An active cool-down period of 7 min at a work load of 75 watts was followed by 60 min of seated rest, followed by a post-exercise D L c o measurement (post-exercise 1). The entire testing sequence from pre-test warm up to post-test cool down was repeated with a final D L c o measure (post-exercise 2) made following 60 min of seated rest after the second maximal exercise bout. 2.3 Experimental Measures Spirometry and D L c 0 were measured and analysed using a Collins Survey Tach Pulmonary Function Testing Unit (Warren E. Collins Inc., Braintree MA). The 8 method used for D L C 0 was that of Roughton and Forster (1957) as modified by Ogilvie et al. (1957). The rate of disappearance of carbon monoxide (CO) from alveolar gas was assessed during a 10 sec breath hold. Duplicate trials were performed in order to ensure that values differed by less than 3 ml-min"1-mmHg"1, using a test gas of 21% 0 2 , 10% He, 0.3% CO, in a balance of N 2 . In order to partition the components of D L , the rate of disappearance of CO from a second test gas of 10% He, 0.3% CO, in a balance of 0 2 was measured following a 5 min wash out period. During the washout period, subjects breathed a mixture of 90% 0 2 (balance N2) through a low resistance, non-rebreathing Hans Rudolph valve. Plots from the 2 gas concentrations of 1/DL VS the inverse of the reaction rate of CO with Hb (1/0), enabled the determination of 1/DM from the y-intercept. Values for 6 pre- and post-exercise were corrected for deviations from normal [Hb] (Cotes et al. 1972). 1/0 = [0.34 + (0.006 x Pca PQ2)l ([HB] / 15) The mean tension of oxygen in the alveolar capillaries (Pcap02) was estimated using the alveolar air equation assuming RER = 0.8 and P A C 0 2 = 40 mm Hg, less 15mm Hg (Forster et al. 1986). The test-retest correlation for both test gas measures was assessed previously in this lab and was found to be very high (r = 0.98 and r = 0.96 respectively) (Sheel 1995a, unpublished). Prior to D L c 0 measurement, [Hb] and subject body mass were measured in order to ascertain that sufficient liquids were 9 consumed to replace lost fluids between exercise bouts. A lancet was used to produce capillary samples for analysis of [Hb] using a hemoglobinometer (HemoCue, LeoDiagnostics AB, S-251 09 Helsingborg, Sweden). The maximal exercise tests were performed on an electronically-braked cycle ergometer (Quinton, Excalibur). Subjects breathed room air through a low resistance, non-rebreathing mouth valve (Hans Rudolph). Expired gases were measured and analysed continuously by an automated gas analysis system (Rayfield), to determine oxygen consumption ( V O 2 ) , carbon dioxide production ( V C O 2 ) , and respiratory exchange ratio (RER). Breathing frequency was assessed by pneumotach and integration with the Medical Graphics, CPX-D. The CPX-D pneumotach was calibrated with a 3-1 syringe and the Rayfield gas analysers were calibrated with air and calibration gases prior to each test. Arterial oxygen saturation was measured with an ear oximeter (Ohmeda Biox 3740 pulse oximeter). To improve perfusion, the ear lobe was rubbed with vasodilatory nicotine cream (Finalgon, Boehringer Ingelheim). To determine the minimum level of % S a 0 2 for statistical analysis, 15 sec averages of % S a 0 2 during exercise were calculated and graphed. All external devices were integrated with an IBM computer utilizing a data collection software package (LABTECH Notebook; Laboratory Technologies Corporation, Maryland). V 0 2 ° i a x for data analysis was determined by averaging the 4 highest consecutive values (15 sec averages) of V 0 2 - Heart rate was monitored and recorded every 15 s throughout the entire testing protocol using a portable heart rate monitor (Polar Vantage XL, Finland). 10 2.4 Statistical Analyses A two-way multivariate repeated measures analysis of variance was used to analyse the mean differences in the physiological variables between the three test conditions (pre-exercise, post-exercise 1, and post-exercise 2), and between desaturaters (D, %Sa02 ^ 91.0) and non-desaturaters (ND, %Sa02 > 91.0). When significant differences were observed, post-hoc comparisons were performed using a Bonferroni t-procedure. Differences were tested for the following: D L , D M , Vc, HR(resting), [Hb], and body mass. A matched pairs t-test was used to analyse the mean differences in the physiological variables between the two bouts of exercise and between the two groups (D and ND). Differences were tested for the following: V02max, %Sa02min, respiratory frequency (JR), peak pulmonary ventilation (VEpeak), peak power output (Ppeak), and HRpeak. In order to assess alterations in breathing pattern consequent to exercise, V E was normalized for vital capacity ( V E / V C ) and plotted as a function of tidal volume (VT) expressed as a percentage of vital capacity (%VC). The difference in VT (%VC) between exercise and recovery (AVT) at the same level of V E / V C was read from the graph at each of the first 5 min of recovery. When recovery points lay to the left of exercise points, a positive value was given to AVT, if they lay to the right, a negative value was assigned. A three-way repeated measures ANOVA (2x2x5) was used to determine if the mean AVT was significantly different between exercise-recovery 1 and exercise-recovery 2, and if differences existed between D and ND. 11 Regression analyses were used to determine the relationship between the percent change in %Sa02, D L , D M , and Vc between measurements. The level of significance for each test was set at p < 0.05. All data was computer analysed using BMDP Statistical Software (BMDP/Dynamic Release 7.0). 12 3. Results 3.1 Subject Descriptive Data Subject descriptive information is presented in Table 1. All data are expressed as means ± SD. Subjects were all highly trained cyclists or triathletes (VChmax = 67.0 ± 3.6 ml-kg"1-min"1). All resting pulmonary function test results showed no abnormalities and represented expected values for an athletic population of healthy individuals. Table 1: Physical characteristics of subjects. All Desaturaters Non-Desaturaters (n=13) (n=6) (n=7) Age (yr) 27±3 26±3 2 8 ± 4 Height (cm) 179.6 ± 5 . 0 180.2 ± 6 . 9 179.0 ± 3 . 2 Mass (kg) 7 1 . 8 ± 6 . 9 71.6 ± 8 . 8 7 1 . 9 ± 5 . 5 F V C (litres) 5.7 + 0.5 5.6 ± 0 . 5 5.8 ± 0 . 5 F E V L 0 (litres) 4.7 ± 0 . 4 4.7 ± 0 . 6 4.7 ± 0 . 3 F E V L Q / F V C 0.8 ± 0 . 0 0.8 ± 0 . 1 0.8 ± 0 . 0 3.2 Maximal Exercise Test Data The mean physiological measures (± SD) are presented in Table 2. No significant differences were found between the 2 exercise bouts for maximum values of fR (p = 0.10), V E (P = 0.53), and V 0 2 (p = 0.08), or minimum values of %Sa02 (p = 0.21). There was a significant decrease (p = 0.003) in peak power output (1.7%) during the second exercise test. 13 Table 2: Maximum and minimum values for metabolic, ventilatory and power output data during maximal exercise testing. Asterisks (*) identify exercise 1 measurements significantly different from exercise 2 measurements (p = 0.003) (breaths-min"1) v E i (1-min") V02max (1-min1) %Sa02min HRpeak (b-min") Ppeak (watts) n=13 Exercise 1 69 176.5 4.8 91.4 187 454* ± 17 ± 15.4 ± 0 . 3 ± 2 . 1 ± 7 ± 3 4 Exercise 2 66 177.9 4.7 91.6 186 * 446 ± 14 ± 15.7 ± 0 . 3 ± 1.7 ± 7 ± 3 5 When subjects were grouped according to the minimum degree of arterial saturation at maximal exercise (Table 3), no significant differences were found between D and ND for any of the variables measured, except for the minimum degree of arterial saturation (p = 0.0001). The minimum level of %Sa02 was approximately 3.5% lower in D than in ND. Table 3: Maximum and minimum values for metabolic, ventilatory and power output data during maximal exercise testing grouped for desaturaters and nondesaturaters. Small letters (a,b) indicate those measurements which are significantly different from one another between desaturaters and non-desaturaters during the same exercise session (p = 0.0001). fR (breaths-min") V E x (1-min") V02max (1-min1) %Sa02min Ppeak (watts) Group: Desaturaters (n=6) Exercise 1 68 174.9 4.8 89.6a 451 ± 2 0 ±21 .5 ± 0 . 3 ± 1.1 ± 4 4 Exercise 2 65 173.9 4.7 90.0* 443 ± 2 0 ± 2 2 . 9 ± 0 . 3 ± 0 . 8 ± 4 6 Group: Non-Desaturaters (n=7) Exercise 1 69 178.0 4.8 93.0" 457 ± 15 ± 9.2 ± 0 . 2 ± 1.0 ± 2 7 Exercise 2 66 181.3 4.8 92.9* 449 ± 8 ± 5.4 ± 0 . 3 ± 1.0 ± 2 6 14 3.3 The Relationship Between Exercise and Pulmonary Diffusing Capacity Mean values (± SD) for pulmonary diffusing capacity for each measurement period are presented in Table 4. There was no significant difference for any variable between those athletes that desaturated and those that did not. Table 4: Pulmonary diffusing capacity measurements pre- and post-exercise. Asterisks (*) indicate post-exercise measurements which are significantly different from pre-exercise; small letters (a,b) indicate post-exercise 2 measurements significantly different from post-exercise 1 (p< 0.05). D L D M % D M / D L Vc %Vc/ D L (ml-min"1 •mmHg"1) (ml) All (n=13) Pre-Exercise 36.3 63.3 58.1 77.6 41.9 ± 4 . 6 ± 10.4 ± 7.7% ± 19.6 ± 7.7% Post-Exercise 1 32.4* 55.6* 58.7 69.7* 41.3 ± 6 . 0 ± 10.9 ± 5.4% + 17.1 ± 5.4% Post-Exercise 2 30.4*'° 54.4* 56.1 62.2*'" 43.9 ± 5 . 4 ± 10.0 ± 4.9% ± 13.3 ± 4.8% Desaturaters (n=6) Pre-Exercise 33.8 58.5 57.9 69.6 42.1 ± 5 . 6 ± 9.6 ± 3.9% ± 13.6 ± 3.9% Post-Exercise 1 30.0 53.2 57.3 61.2 42.7 ± 5 . 7 ± 13.6 ± 5.3% ± 9.8 ± 5.3% Post-Exercise 2 28.4 52.7 54.7 56.0 45.3 ± 5 . 8 ± 13.5 ± 4.6% ± 9.2 ± 4.6% Non-Desaturaters (n =7) Pre-Exercise 38.4 67.4 58.3 84.4 41.7 ± 2 . 2 ± 9.9 ± 10.3% ±22 .3 ± 10.3% Post-Exercise 1 34.5 57.6 59.8 77.0 40.2 ± 5 . 8 ± 8.4 ± 5.6% ± 19.2 ± 5.6% Post-Exercise 2 32.1 55.9 57.3 67.4 42.7 ± 4 . 8 ± 6.5 ± 5.0% ± 14.6 ± 5.0% % D M / D L = [(1/DM) / (1/DL)] x 100 % V C / D L = [[(1/Vc) x (1/0)] / (1/DL)] x 100 15 Approximately 60% of diffusing capacity could be attributed to the membrane component while 40% was dependent upon pulmonary capillary blood volume and the reaction rate of CO with Hb. These components remained constant between D and ND and between measurement periods. There was a significant difference in D L (p < 0.0001), D M (p = 0.02) and Vc (p < 0.0001) between pre-exercise and post-exercise measurements. Figure 1 depicts these changes. Diffusing capacity decreased approximately 17% below pre-exercise values. There was a significant 11% decrease (p < 0.05) from pre-exercise following the first bout of exercise, and a further 6% decrease (p < 0.05) following the second bout of exercise. There was an 11% decrease (p < 0.05) in D M from pre-exercise to post-exercise 1; however, the further 2% decrease between the first and second exercise bouts was non significant (p > 0.05). The changes in Vc were the greatest with a 10% reduction (p < 0.05) from pre-exercise measures following the first exercise bout. A further 10% reduction in Vc between the first and second exercise bouts was also significant (p < 0.05). 16 Figure 1: Changes in pulmonary diffusing capacity pre- and post-exercise (n = 13). Small letters (a,b) identify post-exercise measurements which are significantly different from one another; asterisks (*) identify post-exercise measurements significantly different from pre-exercise (p < 0.05). 100.0 - -90.0 --80.0 --70.0 --D L , DVI 6 0 0 -(ml/min/mmHg) VC(ml) 50.0 40.0 -30.0 20.0 10.0 0.0 ^ Pre-Exercise Post-Exercise 1 Post-Exercise 2 Measurement condition To ensure that D L C 0 measures were performed under the same physiological conditions, body mass, [Hb] and resting HR were monitored (Table 5). There were no significant differences in body mass (p = 0.15) or [Hb] (p = 0.05) between any of the measurement conditions; however, there was a significant difference (p < 0.0001) in HR. Post-exercise 1 HR was significantly (p < 0.05) elevated compared with pre-exercise HR. Additionally, there was a non significant 3% (p > 0.05) increase in HR 17 during the second post-exercise measurements compared to the first post-exercise measurements. Table 5: Physiological measures during pulmonary diffusing capacity measurements pre- and post-exercise (n = 13). Asterisks (*) indicate post-exercise measurements significantly different from pre-exercise (p < 0.05). Pre-Exercise Post-Exercise 1 Post-Exercise 2 HR (beats-min"1) 56 ± 5 61* ± 6 63* ± 5 Hb (g-dL1) 15.0 ± 1.0 14.8 ± 0 . 9 14.6 ± 1.2 Mass (kg) 71.8 ± 6 . 9 71.6 ± 7 . 0 7 1 . 6 ± 6 . 8 3.4 The Relationship Between Changes in Pulmonary Diffusing Capacity and Arterial Blood Oxygen Saturation When analysed as a whole, there was no evidence to indicate that a linear relationship existed between the percent decrease in %Sa02 from resting to minimum exercise values (A%Sa02) and percent decrease from pre-exercise to post-exercise values in D L (ADL) , D M (ADM) or Vc (AVc). However, when subjects were grouped according to the degree of arterial desaturation, significant relationships were evident in athletes that desaturated (Table 6). 18 Table 6: Mean percent decrease in D L , D M , V C , and %Sa02 during each exercise bout. Small letters (a,b,c) indicate significant linear relationships between variables (p = 0.03). A D L A D M AVc A%Sa02 Exercise 1 All (n=13) 10.9 11.0 9.7 4.9 ± 9.3% ± 17.7% ± 6.0% ±2.0% Desaturaters (n=6) 11.2 a 9.4" 11.5 6.6 ± 8.8% ± 15.8% ± 5.5% ± 1.0% Non-Desaturaters (n =7) 10.7 12.4 8.2 3.4 ± 10.4% ±20.3% ± s 6.4% ± 1.3% Exercise 2 All (n=13) 6.2 1.7 9.7 4.7 ± 3.6% ± 9.2% ± 9.9% ± 1.8% Desaturaters (n=6) 5.7 0.7 7.7 6.3 ± 2.4% ± 12.1% ± 12.4% ±0.8% Non-Desaturaters (n =7) 6.7 2.6 11.5 3.5 ± 4.6% ± 6.8% ± 7.7% ± 1.2% Overall All (n = 13) 16.6 13.0 18.4 4.8 ± 8.4% ± 15.9% ± 10.9% ± 1.8% Desaturaters (n=6) 16.7 c 10.6 18.2 6.2 c ± 9.0% ± 14.9% ± 13.0% ±0.9% Non-Desaturaters (n =7) 16.8 15.1 18.6 3.5 ± 8.6% ± 17.7% ± 9.8% ± 1.2% Figure 2 depicts a strong positive linear relationship (r = 0.87, p = 0.03) in D between A%Sa02 and A D L , and between A%Sa02 and A D M (r = 0.85, p = 0.03) consequent to Exl. This indicates that there was the tendency for D who demonstrated a large decrease in arterial saturation as a result of exercise, to have a large decrease in D L and D M . Approximately 73% of the variability in A%Sa02 could be accounted for by differences in the membrane component of diffusing capacity during the first exercise bout. There was no evidence to indicate that a linear relationship existed in D 19 between A%Sa02 and A D L or A D M during the second exercise bout or A%Sa02 and AVc during either exercise bout. Figure 2: Correlations between A D L , A D M , AVc and A%Sa02 in athletes who desaturated during the first exercise bout (n = 6). Closed diamond. A D L ; closed square. A D M ; open triangle. AVc. 3 5 . 0 T -20.0X A %SaQ2 (%) Figure 3 depicts the relationships found when data was analysed for overall changes from baseline to post-exercise 2. A positive linear relationship between A D L and A%Sa02 in D was evident (r = 0.86, p = 0.03); however, no other overall relationships were found. 20 Figure 3: Overall correlations (baseline to post-exercise 2) between A D L , A D M , AVc and A%Sa0 2 in athletes who desaturate (n = 6). Closed diamond. A D L ; closed square. A D M ; open triangle. AVc. 35.0 30.0-25.0-20.0 15.0 A D L (%) A D M (%) 1 0 0 A V C (%) 5.0 0.0 -5.0 + -10.0 AVC : r = 0.70; p = 0.12 A ADL : r = 0.86; p = = 0.35; p = 0.49 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 A %Sa02 (%) 3.5 The Relationship Between Exercise and Breathing Pattern Ventilation ( V E ) was normalized to vital capacity (VC), and tidal volume (VT) was expressed as a percentage of V C and plotted during exercise and recovery. Differences in tidal volume (AVT) between exercise and recovery were compared at the same levels of V E - Comparisons were made at each minute of recovery and differences read from the graph. When exercise exceeded recovery V T , a positive value was assigned; similarly, when recovery exceeded exercise values a negative sign was assigned. 21 Figure 4 depicts the changes observed in breathing pattern between exercise and recovery in one subject. A tachypneic effect is evident, as the recovery breathing pattern is displaced to the left of the exercise breathing pattern. This typifies the pattern observed in most of the subjects. Figure 4: Tidal volume as a function of ventilation normalized for vital capacity for one subject (MP). Closed diamonds, exercise values; open diamonds, recovery values. 30.0-25.0-20.0-VE/VC 15.0-10.0-5.0-0.0 -0.0 10.0 20.0 30.0 40.0 50.0 60.0 VT(%VC) The average width of the breathing pattern loop (to 5 min of recovery) was determined from the means of the 5 AVT values. A large positive mean AVT was observed in 11 of 13 subjects during the first exercise-recovery bout and in all subjects during the second exercise-recovery bout. A mean AVT significantly greater than zero has been described as rapid shallow breathing (Younes and Burks 1985) and may indicate fluid accumulation. Table 7 summarizes the changes observed when comparisons were made. No significant differences in breathing pattern were observed between exercise-recovery 1 and exercise-recovery 2 (p = 0.55) or between D and ND (p =0.16). Table 7: Mean percent change in AVT during each minute of recovery. 1-min 2-min AVT 3-min 4-min 5-min AVT (Mean) Exercise-Recovery 1 All (n=13) 12.1 10.0 9.5 8.4 6.6 9.3 ± 6 . 9 ± 6 . 1 ± 7 . 9 ± 8 . 2 + 11.1 ± 7 . 1 Desaturaters (n=6) 9.4 7.8 5.1 4.0 1.2 5.5 ± 6 . 2 ± 5 . 3 ± 7 . 3 ± 7 . 0 ± 13.7 ± 6 . 9 Non-Desaturaters (n= =7) 14.4 11.9 13.2 12.2 11.1 12.6 ± 7 . 0 ± 6 . 5 ± 6 . 6 ± 7 . 7 ± 6.1 ± 5 . 7 Exercise-Recovery 2 All (n=13) 10.3 10.9 10.2 9.4 9.0 10.0 ± 4 . 9 ± 4 . 5 ± 5 . 0 ± 5 . 0 ± 5.8 ± 4 . 4 Desaturaters (n=6) 10.0 10.7 9.6 8.8 7.8 9.4 ± 5 . 6 ± 4 . 6 ± 5 . 6 ± 4 . 9 ± 6.8 ± 4 . 6 Non-Desaturaters (n= =7) 10.6 11.0 10.8 10.0 10.0 10.5 ± 4 . 6 ± 4 . 8 ± 4 . 8 ± 5 . 3 ± 5.1 ± 4 . 6 Figure 5 depicts the mean AVT for all subjects, plotted for the first 5 min of recovery when comparisons were made. The results show that a large positive AVT was observed at each of the comparisons. 23 Figure 5: AVT during the first 5 min of recovery 1 and recovery 2. 25 i Recovery Time (min) [Rl= recovery 1; R2 = recovery 2] 24 4. Discussion The main findings of this study confirm that there is a decrease in pulmonary diffusing capacity following short term intense exercise. There is a further decease when exercise is repeated after 60 min of recovery. The decrease in D L is due to a decrease in D M and V c and is accompanied by the development of rapid shallow breathing. Together, these suggest the development of pulmonary edema. The strong positive correlation between the change in D L and the change in D M with the change in arterial oxygen hemoglobin saturation in athletes that desaturate, indicates that oxygen transport across the alveolar-capillary membrane is compromised as a result of these changes during heavy exercise. This is the first study to date to demonstrate this relationship. 4.1 Alterations in Pulmonary Diffusing Capacity Following Maximal Exercise There was a significant decrease in pulmonary diffusing capacity following short term intense exercise. The 11% reduction in D L measured 60 min following one exercise bout and 6% reduction following a second exercise bout, is similar to the findings of other studies that have examined the effects of short term, high intensity exercise on post-exercise pulmonary diffusing capacity. Hanel et al. (1994) reported a 10% reduction in D L 120 min following 6 min of maximal rowing, but no further reductions following a second exercise bout. Turner et al. (1992) found a 7% reduction in D L 60 min following 5 min of cycling at 90% of VChmax. Manier et al. (1993) demonstrated a 9% decrease in D L 30 min following a ramped VChmax test (cycle ergometer), and 25 Rasmussen et al. (1992) reported a 15% decrease in D L 2.4 hr following 6 min of maximal arm cranking, rowing or running. Similar results are also apparent following exercise of long duration. Manier et al. (1991) reported an 11 % decrease in D L 28 min post-marathon, while Miles et al. (1983) demonstrated a 28% decrease in D L 60 min post-marathon. Most recently, Caillaud et al. (1995) have reported a 5% decrease in D L 95 min post triathlon. The variations in the decrease in D L between studies may be a function of a number of factors. The duration and intensity of exercise may be important in determining the degree of change. Manier et al. (1991, 1993) found that the most significant decreases in diffusing capacity occurred following a long duration exercise bout compared to a short term maximal exercise bout. However, Hanel et al. (1993) maintain that decreases in pulmonary diffusing capacity are independent of the duration and intensity of exercise, referring to comparisons made between 1 to 6 min of exercise at submaximal and maximal exercise intensities. Diffusing capacity may also vary with changes in HR. Since HR and cardiac output (Q) demonstrate a linear relationship and D L increases with increasing Q (Andrew and Baines 1974), decreases in D L may be masked by elevated HR at the time of measurement. The time of measurement post-exercise may also affect the values obtained. An unpublished study from this lab (Sheel 1995b) followed the time course of changes in diffusing capacity following short term intense exercise. D L continued to decrease to a minimum value 6 hrs post-exercise; however, by 24 hrs baseline values were restored. Thus, values between 26 studies may differ depending upon whether measurements are made 30, 60 or 120 min post-exercise. Finally, the resting state immediately prior to measurement will affect D L values. Billiet (1970) has demonstrated that rest causes some decrease in pulmonary diffusing capacity, even if the degree of previous physical activity is low. Therefore, if subjects are not restricted in their post-exercise activity prior to D L measurement, higher values may result. Since D L reflects the sum of its series components (1/DM and 1/9-Vc), changes in membrane resistance or capillary blood volume will determine the degree of change in D L (Roughton and Forster 1957). In the current study the proportion contributed by the membrane component to D L remained close to 60% during all measurement periods. This is unlike the study by Miles et al. (1983), where the proportion of resistance offered to diffusion by the alveolar capillary membrane increased significantly from a control value of 56% to 65% post-marathon. The difference between the two studies reflects the differences observed between short term and long term exercise in changes in post-exercise D L and D M . Significant decreases in post-exercise D M have been observed following short term exercise. The 11% decrease in the current study is comparable to the 9% decrease observed by Manier et al. (1993). Although D M showed an additional 2% decrease following a second exercise bout, this value was not statistically different from D M following one exercise bout. Despite the lack of significance, the contribution of D M toward decreases in D L remained close to 60%. This apparent discrepancy may be explained by the great variability in measurements of D M . The equation describing the 27 relationship between D L , D M and Vc can be rearranged as follows: Vc = [ D M - D L ] / [6-(DM - D L ) ] . Possible values of Vc and D M that satisfy this equation, at fixed values of D L and 0, fall on a rectangular hyperbola. This means that when a point falls on the horizontal asymptote, as do most points for normal subjects, a small change in Vc causes a large change in the values of D M (Lewis et al. 1958). This reasoning can be also applied to the findings of Hanel et al. (1994) who found a larger (24%) decrease in D M following one exercise bout and a non-significant 4% decrease following a second exercise bout. Decreases in D M have also been observed following long term exercise. Manier et al. (1991) and Miles et al. (1983) observed reductions in D M of 29% and 22% respectively, post-marathon. Decreases in D M have been interpreted to be as a result of perivascular and/or alveolar wall edema (Buono et al. 1983; Lewis et al. 1958; Manier et al. 1991; Miles et al. 1983; Rasmussen et al. 1986; Schaffarzik et al. 1992; Staub et al. 1967). The earliest form of pulmonary edema is characterized by engorgement of the peribronchial and perivascular spaces and is known as interstitial or high pressure edema. Interstitial edema is described as tissue swelling and results from a disturbance in the normal fluid exchange between plasma and tissue (Prichard 1982). Normally the total path for diffusion is very short (O.lu). The thickening of the alveolar-capillary membrane causes an increase in the distance between the gas and blood phase of the lung tissue (Staub et al. 1967), resulting in a persistent decreased membrane diffusing capacity. In the latter stages of pulmonary edema, fluid crosses the alveolar epithelium into the 28 alveolar spaces and is known as alveolar or permeability edema. Alveolar edema results in the replacement of air spaces with fluid. Since the alveoli are unventilated, no oxygenation of the blood passing through them is possible, resulting in a dangerous interference with pulmonary gas exchange (West 1984). How could fluid accumulate during exercise? Mean pulmonary artery pressure (PAP) and presumably pulmonary capillary pressure increase during exercise. As pulmonary capillary blood volume increases during exercise, total capillary surface area for fluid exchange increases. According to the Starling hypothesis for capillary fluid exchange, pulmonary edema may result from elevated capillary hydrostatic pressure, increased capillary permeability to plasma proteins, increased capillary surface area, and decreased lymphatic drainage (Staub et al. 1967). When left atrial pressures exceed 24 mmHg, fluids have been shown to accumulate in the lung (Guyton and Lindsey 1959). Alternatively, the increase in PAP during exercise may be of sufficient magnitude to cause disruptions of the endothelium of the capillary wall and epithelium of the alveolar membrane (Tsukimoto et al. 1991). Studies have shown that PAP can exceed 40 mmHg under high intensity exercise (Schaffartzik et al. 1992; Wagner et al. 1986). The end result by either mechanism is an accumulation of pulmonary fluid. Studies have shown that the amount of fluid accumulation in the lung resulting from exercise is minimal. Approximately 5 ml of interstitial edema corresponding with a 17% increase in alveolar wall thickness has been calculated to be required to elicit a 7% decrease in pulmonary diffusing capacity (Rasmussen et al. 1986). These changes are of insufficient magnitude for detection using thoracic electrical impedence. 29 Similarly, Caillaud et al. (1995) were unable to identify obvious images of acute interstitial or alveolar pulmonary edema by computerized tomography (CT) scanning in post-exercise measurements of the thorax. However, significant increases in opacitites and lung density suggested an increase in pulmonary interstitial fluid accompanied by a significant decrease in D L . Animal studies involving pigs exercised at near maximal intensity for short duration (6-7 min) have demonstrated that perivascular edema can occur during short-term exercise (Schaffartzik et al. 1993). Perivascular cuffing indicates an early stage in the development of interstitial edema. The most perplexing finding in the current study was the change in pulmonary capillary volume following exercise. A significant 10% reduction in Vc was observed following each of the two exercise bouts. This finding is consistent with that of Hanel et al. (1994) who found a significant 4% decrease in Vc following one exercise bout and a further 10% decrease following a second exercise bout. The decrease in Vc has been shown to continue up to 6 hr post-exercise, paralleling decreases in D L (Sheel 1995b). Further evidence in support of a reduction in central fluid volume following short term maximal exercise, is the finding of an increase in thoracic electrical impedence (Hanel et al. 1994; Rasmussen et al. 1992). These findings are contrary to results following long term exercise. Manier et al. (1991) found a significant 10% increase in Vc 28 min post-marathon while Miles et al. (1983) found a non-significant 4% increase in Vc 60 min post-marathon. The differences between the long duration (marathon) studies may be attributed to the time of post-exercise data collection. In the Manier study, measurements were made 28 min post-exercise when Vc may still have 30 been elevated as a consequence of exercise. When comparing the two studies, it would appear that Vc was decreasing with time. However, this reasoning does not appear to follow when analysing the differences in short term exercise. The mechanism for change between the two types of exercise is possibly different. Why would there be a decrease in Vc when measured 60 min to 6 hr following short intense exercise? In the current study, HR and presumably cardiac output were significantly elevated from pre-exercise values. However, in the Hanel study, no significant changes were observed in Q between measurement periods. These findings appear contrary to the observed decrease in Vc. Previous studies have demonstrated a strong positive correlation between D L , D M , Vc and Q (r = 0.92, r = 0.71, r = 0.92 respectively) during exercise (Johnson et al. 1960). Although pulmonary blood flow and D L , D M and Vc increase during exertion, they are not necessarily associated under other conditions. For example, Ross et al. (1959) have demonstrated that D L does not increase when cardiac output is increased by means other than exercise (epinephrine). A lack of association between HR and presumably Q, and Vc appears to occur during recovery from heavy exercise. The observed decreases in Vc may be a reflection of compensatory shunting consequent to heavy exercise, as blood flow is shunted away from the thorax to clear metabolic waste products from exercised muscle. Decreases in Vc contributed approximately 40% to the decrease in D L observed post exercise. 31 4.2 Alterations in Arterial Oxygen Hemoglobin Saturation Following Maximal Exercise Arterial oxygen hemoglobin saturation decreased to a minimum value at maximal exercise. Two groups were evident based upon the minimum values attained for %Sa02. Athletes with a reduction in %Sa02 to 91% or less were grouped as desaturaters (D), while those with a minimum %Sa02 greater than 91% were grouped as non desaturaters (ND). The 6.5% decrease demonstrated by D and 3.4% decrease demonstrated by ND is in agreement with other studies (Turner et al. 1992). Additionally, the minimum %Sa02 attained was the same during the first and second exercise bouts, which is in agreement with the findings of Hanel et al. (1994). Exercise induced hypoxemia (EIH) has been defined as an arterial oxygen hemoglobin saturation < 91%, based upon a physiologically significant decline in %Sa02 of 4% (Powers et al. 1988). The incidence of EIH in the current study was similar to the findings of others, with six athletes (46%) comprising the D group and 7 athletes the ND group. Powers et al. (1988) and Martin et al. (1992b) have reported that between 46 and 52% of elite cyclists studied exhibit EIH during heavy exercise. The Ohmeda Biox 3740 pulse oximeter has been shown to be a valid and reliable tool for assessing arterial oxygen saturation during intense exercise in subjects with exceptional V02max. The oximeter used in this lab has been validated with arterial blood gas measures using HT athletes exercising at maximal aerobic capacity (r = 0.87, p < 0.001). Similarly, Martin et al. (1992a) have demonstrated a strong positive relationship (r = 0.94, p < 0.05) between pulse oximeter estimates of %Sa02 32 and measured arterial oxygen hemoglobin saturation over a wide range of saturation levels and exercise intensities (> 81% \02max). The mechanism for the development of EIH is unclear. EIH occurs in elite endurance athletes (VChmax = 68-70 ml-kg"1-min"1) (Williams et al. 1986). Not surprisingly, the fitness level of athletes in the current study (VOimax = 67.0 ± 3.6 ml-kg"1-min"1) was comparable to that of other studies that have assessed EIH. Mechanisms for the development of EIH which have been assessed include an inadequate hyperventilatory response (Hopkins et al. 1989; Powers et al. 1984), and venoarterial shunts (Dempsey et al. 1984; Powers et al. 1992); however, the latter has been rejected as a possible mechanism. The widening of the (A-a)D02 observed in EIH may be partially explained as a consequence of V A / Q mismatch (Gale et al. 1985; Hammond et al. 1986a; Hopkins et al. 1994). Hammond et al. (1986a) have demonstrated an increased V A / Q mismatch with increasing exercise intensity up to a moderate work load ( V 0 2 = 3 1-min"1). When moderately trained subjects exercised beyond this intensity, the (A-a)D02 continued to increase but V A / Q remained constant. It was hypothesized that the major contributor to the continued increase in (A-a)D02 was diffusion limitation. Recently Hopkins et al. (1994) have demonstrated that V A / Q mismatch increases significantly with increasing exercise intensity at heavy and maximal exercise levels (VO2 > 5 1-min"1). Because the observed exceeded the predicted (A-a)D02, the 33 results suggested that V A / Q mismatch contributed more than 60% towards the increased (A-a)D02, while diffusion limitations contributed the remainder. The mechanisms responsible for the V A / Q mismatch may be due to the accumulation of interstitial fluid, mucus in the airways, or a continuing effect of vasoactive or bronchoactive mediators released during exercise (Hammond et al. 1986a). Diffusion limitations are a consequence of incomplete pulmonary gas exchange. Arterial hypoxemia may result because of reduced erythrocyte transit time along pulmonary capillaries due to high Q during heavy exercise (Dempsey 1986, Reeves et al. 1988). Dempsey (1986) proposes that pulmonary blood flow is capable of increasing beyond the point at which pulmonary capillary blood volume has reached its maximum morphological limits. The result is an abrupt decrease in RBC transit time. However, Warren et al. (1991) has demonstrated that mean capillary blood volume does not plateau with increasing exercise intensity, thus mean transit time is maintained within an adequate range. Therefore, a decrease in mean transit time does not seem to explain the development of an increased (A-a)D02 in athletes experiencing EIH. Alternatively, diffusion limitation may result when there is an increased diffusion distance between the alveolar membrane and the RBC. These increased distances may be as a result of low grade pulmonary edema resulting from increased hydrostatic pressures consequent to high Q . The hypothesis of exercise-induced pulmonary extravascular water accumulation has been developed in several studies, as previously discussed. 34 4.3 The Physiological Significance of Reduced Pulmonary Diffusing Capacity In order to assess whether a decreased post-exercise pulmonary diffusing capacity had any physiological effect, subjects performed a second maximal exercise test. No significant differences were observed in VChniax or %Sa02min between the first and second exercise bouts, consistent with the study of Hanel et al. (1994). There was a significant decrease in peak power output, which can be a consequence of hypoxemia (Koskolou and McKenzie 1994). The reduced power output in the current study was most likely due to the development of peripheral fatigue, since the decrease was demonstrated by both groups regardless of the degree of arterial desaturation. During exercise both D L and %Sa02 demonstrated an overall parallel decrease of similar magnitude. Significant positive correlations were observed between changes in D L with changes in %Sa02 in athletes that desaturated. These correlations were evident during the first exercise bout and between changes from rest to the final D L C O measurement, when significant decreases occurred in D L . Significant positive correlations were also observed in D during the first exercise bout between changes in D M with changes in %Sa02. These findings support the hypothesis that decreases in D L post-exercise indicate the accumulation of pulmonary fluid as a consequence of physical disruption of the alveolar-capillary membrane or due to increased hydrostatic pressure. The contribution of these changes to the drop in %Sa02 during exercise was high. During the second exercise bout when D L was already depressed, the contribution of decreases in D L and D M to decreases in %Sa02 was low, indicating that 35 a secondary mechanism may be involved in the development of EIH. Additionally, the contribution of decreased D L and D M to decreases in %Sa02 in N D was low. 4.4 Alterations in Breathing Pattern Following Maximal Exercise The speculation of the development of minimal pulmonary edema was further supported by observed changes in breathing pattern during recovery from high intensity exercise. Breathing patterns were compared between exercise and recovery to assess any rate altering influences. By plotting ventilation against tidal volume during exercise and recovery, comparisons between vital capacity at similar levels of ventilation could be made. Large differences were observed during the first five minutes of recovery where the tidal volume during exercise exceeded the tidal volume during recovery by approximately 10%. These changes have been described by Younes and Burks (1985) as rapid shallow breathing and are consistent with the findings of Caillaud et al. (1993). The development of RSB has been attributed to the accumulation of interstitial pulmonary fluid. When there is a rise in pulmonary capillary pressure resulting in increased fluid in the interstitial space, the resulting physical enlargement activates the J pulmonary receptors. Weak or gradual stimulation of these interstitial stretch receptors cause respiratory acceleration (Paintal 1973). The development of RSB is a phenomenon that occurs only after very high levels of exercise (Younes and Burks 1985). Additionally, RSB occurs with a persistence of a widened (A-a)D02 during recovery from heavy exercise (Caillaud et al. 1993). The continued reduction in D L and D M following exercise, in conjunction with the 36 development of RSB futher supports the hypothesis that pulmonary edema appears to be the most plausible mechanism for the development of EIH. 37 5. Conclusions This study has provided strong indirect evidence in support of the hypothesis that the accumulation of pulmonary fluid contributes to the development of EIH, by the demonstration of decreases in D L in combination with the development of RSB. Decreased D L following one bout of exercise and a continued decrease following a second bout of high intensity work indicate that the changes consequent to heavy exercise are persistent. The decrease in D L was due to decreased membrane diffusing capacity and decreased pulmonary capillary volume. Significant correlations between changes in D L and D M with changes in %Sa02 in athletes who demonstrated a reduction in arterial oxygen hemoglobin saturation below 91%, indicate that the contributions of these changes toward the development of EIH was high. The lack of significant decrease in D M and lack of significant correlation between changes in D M and changes in %Sa02 following the second exercise bout, indicates that a secondary mechanism may also contribute to the development of EIH. Further evidence in support of multiple or alternate mechanisms is the lack of difference in D L , D M , Vc and RSB between athletes that desaturated and athletes that did not. This may be a reflection of the mechanism involved in the development of pulmonary edema, or the minute amount of fluid involved. It would appear that fluid accumulation is a consequence of heavy exercise in HT athletes, reflected in the decrease in D L and D M and development of RSB in both groups. Whether athletes experience EIH may depend upon the degree of fluid accumulation, the efficiency of the clearance pathway during the resolution of edema or alternate mechanisms. 38 Appendix A: Review of the Literature In recent years the lung has been shown to be a factor in limiting athletic performance in highly trained (HT) athletes, resulting in a phenomenon termed exercise-induced hypoxemia (EIH) (Dempsey et al. 1984). During high intensity exercise, many endurance trained athletes experience a decrease in arterial oxygen hemoglobin saturation (%Sa02) below 91% (Martin et al. 1992b; Powers et al. 1988), which may affect athletic performance Although the mechanism of EIH is unclear, current theory suggests that the widening of the alveolar-arterial P0 2 difference [(A-a)D02] is exacerbated by an accumulation of interstitial pulmonary fluid (edema). Increased pulmonary capillary pressures resulting from the high cardiac output and aerobic capacity (VOimax) of these HT athletes may be responsible for the development of edema. Pulmonary edema results in altered distributions of ventilation and blood flow ( V A / Q), and diffusion limitations. A. 1 Assessment of Exercise-Induced Hypoxemia Highly trained athletes working at metabolic rates in excess of 4-5 1-min"1 are sometimes unable to maintain Pa02 and %Sa02 homeostasis. Dempsey et al. (1984) were the first to provide conclusive evidence for the development of EIH in some elite athletes (V02max = 72 ml-kg -^min"1 or ~ 5 1-min"1), demonstrating significant reductions in %Sa02, (below 92%) and decreases in Pa02 (~ 75 mmHg). Blood gas 39 measurements obtained from subjects running at maximal and near maximal exercise levels indicated an increased alveolar-arterial difference in excess of 40 mmHg. The findings of Dempsey et al. (1984) have been confirmed by others who have detected EIH by direct measure of blood gas tension (Hopkins and McKenzie 1989; Martin et al. 1992b; Pedersen et al. 1992b; Powers et al. 1992; Warren et al. 1991), and by non-invasive estimates of %Sa02 via ear oximetry (Lawler et al. 1988; Martin and O'Kroy 1993; Pedersen et al. 1992b; Powers et al. 1988, 1989b; Williams et al. 1986). In all cases, subjects who demonstrated EIH were highly trained and exercising at extreme levels. A. 2 Incidence of EIH and Consequences on Performance It has been estimated (Martin et al. 1992b; Powers et al. 1988) that 46-52% of HT male endurance athletes may experience a significant decrement in %Sa02 (4% decrease from resting values) during maximal exercise. In addition, EIH has been demonstrated to occur in HT "master" (—65 yr) athletes (Prefaut et al. 1994). The mechanism of EIH may or may not be the same in older as in younger athletes, since it is well known that lung function declines with aging. There has been only one study to document the occurrence of EIH in female athletes (McCusker and Br ilia 1992). It had been hypothesized that female athletes would not demonstrate EIH because of their inability to consume volumes of oxygen as large as males. However, McKusker and Brilla (1992) found that during high intensity exercise, 8 endurance-trained female athletes desaturated in a manner similar to male HT athletes. Although ear oximetry 40 measures of %Sa02 can be lower than blood sample measurements (Pedersen et al. 1992b), further study is required to confirm the high degree of desaturation measured in McKusker's study (%Sa02 = 85.25). Individuals demonstrating EIH show otherwise normal pulmonary function, indicating that EIH represents a pulmonary limitation at high metabolic rates. A decreased arterial oxygen content due to reduced %Sa02 has a direct effect on maximal oxygen consumption, possibly reducing endurance performance (Koskolou and McKenzie 1994; Lawler et al. 1988; Martin and O'Kroy 1993; Pedersen et al. 1992a; Powers et al. 1989a; Williams et al. 1986). Williams et al. (1986) have quantified the relationship between %Sa02 and VChmax during heavy exercise, showing that the level of arterial desaturation is inversely related to VC»2max. This relationship may be extrapolated to indicate an association between maximal cardiac output (Qmax) and %Sa02, suggesting that individuals with high Qmax may desaturate more readily than those with lower Qmax. However, V0 2 max may not be a good predictor of endurance attainment since other factors such as fatigue also contribute to performance (Allen et al. 1985). Arterial saturation has also been found to be inversely related to capillary blood lactate (Rasmussen et al. 1991). Using total work output as a measure of performance, Koskolou and McKenzie (1994) demonstrated that a linear relationship exists between %Sa02 and maximal exercise performance. In this study, alterations in the percentage of inspired 0 2 simulated mild and moderate hypoxemia. 41 Thus, it is likely that maximal performance capacity is significantly impaired in HT athletes demonstrating arterial desaturation. A. 3 Physiological Mechanisms of Exercise-Induced Hypoxemia Only recently has the pulmonary system been implicated as a limiting factor in the maximal oxygen uptake of healthy trained individuals exercising at sea level. The mechanisms of exercise-induced hypoxemia are not clear. A. 3.1 Hypoventilation It has been hypothesized that a decrease in Pa02 is a consequence of an inadequate hyperventilatory response (Bebout et al. 1989; Dempsey 1986; Dempsey et al. 1984). Dempsey et al. (1984) observed that the most severe hypoxemia during heavy exercise was associated with little or no alveolar hyperventilation. Measures of end-tidal P0 2 (< 110 mmHg) and arterial PaC02 (> 35 mmHg) seemed to indicate that the development of the large alveolar-to-arterial difference (> 40 mmHg) was due to an inadequate hyperventilatory response. Hopkins and McKenzie (1989) have investigated the relationship between ventilatory response to hypoxia, exercise ventilation and arterial desaturation in HT athletes, and found no significant correlation between hypoxic drives and ventilation-to-02 uptake ratio or %Sa02. More recently Powers et al. (1992) have confirmed these findings. Arterial desaturation during maximal exercise appears to be due to some mechanism other than inadequate pulmonary ventilation. 42 A3.2 Ventilation Perfusion Mismatch Exercise-induced hypoxemia is closely associated with an increased (A-a)D02. Ventilation-perfusion inequality at sea level contributes to the (A-a)D02 at rest and at low levels of exercise up to V 0 2 of 3 1-min"1 (Hammond et al. 1986a; Torre-Bueno et al. 1985). As minute ventilation and cardiac output increases, recruitment and expansion of pulmonary capillaries increase, causing V A / Q to become more uniform. By means of the multiple inert gas elimination technique, estimations of V A / Q distributions of blood flow and ventilation have been determined in humans (Gale et al. 1985; Hammond et al. 1986a; Hopkins et al. 1994; Schaffartzik et al. 1993; Torre-Bueno et al. 1985; Wagner et al. 1986) as well as in horses (Wagner et al. 1989). Mismatching occurs when some alveoli that are ventilated with air are not perfused with pulmonary capillary blood flow; alternatively, perfused alveoli may not be ventilated (Rasmussen and Ryan 1990). Using the gas elimination technique under hypoxic conditions, Schaffartzik et al. (1992) have demonstrated that recovery from exercise-induced V A / Q mismatch may be prolonged. The V A / Q mismatch observed may be as a result of higher pulmonary arterial pressures due to hypoxic vasoconstriction causing transvascular fluid flux. Pulmonary arteries with perivascular edema have been observed in exercised pigs, indicating that perivascular edema can occur during short-term heavy exercise (Schaffartzik et al. 1993). However, it remains unclear whether this contributes to the increased V A / Q inhomogeneity seen at high 43 levels of exercise at sea level. Recently Hopkins et al. (1994) have demonstrated that V A / Q mismatch increases significantly with increasing exercise intensity at heavy and maximal exercise levels ( V 0 2 > 5 1-min"1). Because the observed exceded the predicted (A-a)D02, the results suggested that V A / Q mismatch contributed more than 60% towards the increased (A-a)D02, while diffusion limitations contributed the remainder. A.3.3 Pulmonary Diffusion Limitations An observed alveolar-to-arterial oxygen tension difference at a higher exercise intensity can not be explained by ventilation-perfusion inequality alone; presumably, diffusion limitations exist at higher exercise intensity. In moderately trained subjects exercising at levels of VO2 > 3.5 1-min"1, the most significant contributor to a widening of the (A-a)D02 appears to be a diffusion limitation (Hammond et al. 1986a). Currently, two theories are proposed to explain the development of diffusion limitations: an incomplete equilibration of 0 2 between alveolar gas and pulmonary capillary blood as a result of inadequate RBC transit time (Dempsey 1986; Reeves et al. 1988) and/or accumulation of interstitial pulmonary fluid (Hammond et al. 1986a; Rasmussen et al. 1986; Staub et al. 1967; Wagner et al. 1989; Younes and Burks 1985). A.3.3. i) Inadequate RBC Transit Time During high cardiac outputs RBC transit time may decrease in some parts of the lung. Transit time may decrease to the point where 0 2 equilibrium of end-capillary blood 44 with alveolar gas is not permitted (Dempsey 1986; Dempsey and Fregosi 1985; Rowell et al. 1964). The pulmonary capillary blood volume reaches its morphologic limit near 25 1-min1 (Dempsey and Fregosi 1985). Individuals demanding cardiac output beyond this level as a result of increased oxygen consumption, may experience diffusion limited EIH (Dempsey and Fregosi 1985; Dempsey et al. 1984). Warren et al. (1991) measured an increase in capillary blood volume ( V C ) and a decrease in mean RBC transit time in HT athletes who demonstrated arterial hemoglobin desaturation during heavy exercise. Although mean RBC transit time ( V C / Q ) reached a plateau at moderate exercise, it remained unchanged with increasing exercise intensity. There was no relation between mean RBC transit time and (A-a)D02. It was concluded that the (A-a)D02 increases and Pa02 decreases observed in these HT athletes, were not caused by a plateau in capillary blood volume and a consequent reduction in mean RBC transit time. A.3.3. ii) Accumulation of Interstitial Pulmonary Fluid The accumulation of interstitial pulmonary fluid has been proposed as the mechanism responsible for changes in diffusion and V A / Q > which could be responsible for the deterioration of pulmonary gas exchange during heavy exercise (Buono et al. 1981, 1982; Hammond et al. 1986a, 1986b; Torre-Bueno et al. 1985; Wagner et al. 1986). EIH has also been demonstrated in racehorses (Wagner et al. 1989); however, exercise 45 in horses has little effect on V A / Q relationships, and most of the hypoxemia in racehorses during heavy exercise appears to be due to diffusion limitations. The presence of perivascular and/or peribronchial edema has been assessed indirectly by measuring pulmonary diffusing capacity (DL) and calculating its components; membrane (alveolar-capillary) diffusing capacity (DM), and pulmonary capillary volume (Vc). Decreased pulmonary diffusing capacity due primarily to a significant reduction in D M , has been observed following the running of a marathon (Manier et al. 1991; Miles et al. 1983) and after short, intense exercise bouts (Hanel et al. 1991; Manier et al. 1993; Turner et al. 1992). The significant increase in membrane resistance to diffusion (1/DM), indirectly supports the occurrence of perivascular and/or alveolar wall edema, reflecting an increased distance between the gas and blood phase of the lung tissue, due to a thickening of the alveolar-capillary membrane (Staub et al. 1967). Although pulmonary diffusing capacity is reduced following exercise, Hanel and associates (Clifford et al. 1991; Hanel et al. 1993, 1994) suggest this may be caused by a fall in central blood volume. They support this conclusion with the finding that (DL) is decreased up to 2 hours after exercise regardless of the duration or intensity of exercise performed. However, Goresky et al. (1975) have measured an increase in central blood volume by 50% with a tripling of cardiac output during a steady-state maximum work load. Lung water as measured by means of dilution methodology increased, while both D L c 0 and exercise increased. In addition, Gallagher et al. (1988) have been unable to find radiographic evidence of interstitial pulmonary edema after maximal exercise. These discrepancies may be 46 because EIH and the associated increased (A-a)D02 do not occur in all individuals. Individuals demonstrating EIH are highly trained and exercising at very high levels of oxygen consumption, conditions which may not have been met in these studies. Finally, the amount of fluid present may be too small to be detected by X-ray measures or computerized tomography scans (Caillaud et al. 1995). Further evidence for the accumulation of pulmonary fluid has been assessed by observations of changes in pulmonary function following exercise. Following maximal exercise, increases occur in residual volume (RV), and total lung capacity (TLC) (Buono et al. 1981). TLC and RV may remain elevated up to 30 min during recovery. Decreased trans-thoracic impedance measures (Buono et al. 1982) indicate the presence of sub-clinical edema following exercise, which may be responsible for the post-exercise increases in TLC and RV. In addition, forced vital capacity (FVC) decreases, following high-intensity exercise of short duration (O'Kroy et al. 1992), or moderate-intensity exercise of long duration (Farrell et al. 1983). It appears that the duration and intensity of the exercise are significant in determining the magnitude of pulmonary function changes observed. In a comparison of marathon running and prolonged treadmill running, greater changes in lung volume occur with exercise at a marathon race pace and duration, than in a shorter less-intense prolonged treadmill run (Farrell et al. 1983; Maron et al. 1979). The mechanism for changes in lung volume remains unclear, but reduction in airway diameter (Cosio et al. 1978) resulting from an accumulation of interstitial pulmonary fluid may be a factor. The hypothesized efflux of fluid into the pulmonary interstitium may reflect an elevated 47 driving pressure at the capillary level due to an increase in pulmonary blood flow during exercise (Miles et al. 1985). High-altitude pulmonary edema (HAPE) has also been associated with changes in pulmonary function. Reductions in vital capacity and expiratory flow rate in association with a decrease in trans-thoracic electrical impedance, precedes the radiographic appearance of edema in some individuals experiencing HAPE (Selland et al. 1993). These findings indicate that measurements of vital capacity may be useful in following the development and resolution of pulmonary edema. The accumulation of peribronchial fluid has been hypothesized as the mechanism of airway obstruction causing the pulmonary function changes associated with HAPE. Since lymphatic fluid travels in the peribronchiolar space, lymphatic engorgement or interstitial edema could compress small airways and contribute to diminished volumes. Changes in breathing pattern following exercise may also indicate an accumulation of interstitial pulmonary edema. The onset of HAPE is characterized by tachycardia or rapid shallow breathing at rest and during exercise (Selland et al. 1993). In addition, rapid shallow breathing is observed during recovery from very high exercise levels at sea level (Caillaud et al. 1993; Younes and Burks 1985). Interstitial pulmonary edema is well known to be associated with rapid shallow breathing. When there is increased fluid in the interstitial space, the resulting physical enlargement activates the J pulmonary receptors. Weak or gradual stimulation of these interstitial receptors cause respiratory acceleration (Paintal 1973). 48 A. 4 Pulmonary Capillary Stress Failure Hypothesis The mechanism by which pulmonary edema may occur during exercise, has been hypothesized to be as a result of a failure in the integrity of the pulmonary capillary membrane (West and Mathieu-Costello 1993a). It is not surprising that membrane disruption does occur, given that the thickness of the blood-gas barrier is only 0.3u (Gehr et al. 1978). Stress failure of pulmonary capillaries results in high-permeability edema or frank hemorrhage, and appears to be the mechanism of high altitude pulmonary edema, as previously discussed, and neurogenic pulmonary edema. It may also explain the exercise-induced pulmonary hemorrhage that occurs in all racehorses (O'Callaghan et al. 1987). The common factor that may lead to capillary failure is the tremendous increase in pulmonary arterial pressure. During intense exercise, cardiac output increases, causing increases in the amount of blood that flows through the lung. There is also a large increment in the wedge pressure (left atrial). This is an important adaptation for increasing the pulmonary diffusing area. An examination of the pulmonary blood flow and pressures associated with exercise, has indicated that initial increases in exercise intensity, occur without any increase in driving pressure (Reeves et al. 1988a). The recruitment of pulmonary capillaries explains this finding. Additionally, an increase in wedge pressure also causes distension of previously open vessels. The consequence of an increased diffusing area is the development of high pulmonary arterial and pulmonary capillary pressures. Fluid filtration occurs at pressure values midway between pulmonary arterial and left atrial pressures. In the dog lung, filtration pressure 49 will exceed the threshold for edema formation during heavy exercise (Younes et al. 1987). It is likely that humans experience similar effects during intense exercise. Tsukimoto et al. (1991) have observed damage to the capillary membrane as a result of increased capillary pressure in rabbit lungs. The ruptures occur above 40 mmHg, and result in disruption of the endothelial layer while the basement membrane remains intact, or by complete disruption of all layers. Three forces act on the capillary membrane, including: (i) the circumferential tension resulting from capillary transmural pressure; (ii) the surface tension of the alveolar lining; and (iii) longitudinal tension in the alveolar wall consequent with lung inflation (West et al. 1991a). The degree of wall stress (tension/wall thickness) in the capillary, determines whether disruption will occur. Incredibly, stresses at 40 mmHg in the rabbit lung are approximately equal to those observed in the normal aorta (Tsukimoto et al. 1991). Although capillary pressures of 40 mmHg that are necessary to cause stress failure in the rabbit lung may seem high, there is evidence that during maximal exercise, pulmonary capillary pressures in the human lung may rise above 30-35 mmHg (Reeves et al. 1988a; West et al. 1991a). When pulmonary capillary pressures in the rabbit are raised from normal low values to high values, initially fluid moves from the capillary lumen into the alveolar wall interstitium and alveolar spaces. At these moderate pressures, fluid clearance can be maintained by lymph flow (Coates et al. 1984). As pressure increases, it has been hypothesized that pore stretching may result. At the highest pressures, stress failure occurs causing either high-permeability 50 edema characterized by a high protein content in the edema fluid, or hemorrhage (West and Mathieu-Costello 1992b). The incidence of exercise-induced pulmonary hemorrhage (EIPH) is well documented in racehorses (Jones et al. 1992; O'Callaghan et al. 1987; West et al. 1993b). EIPH may be a consequence of the high pulmonary capillary pressures that are generated as a result of enormous maximum oxygen consumption (up to 180 ml-kg^-min"1). Selective breeding of racehorses has developed the cardiovascular systems of these animals to the point where pulmonary capillary pressures often exceed the strength of the capillary membranes (West and Mathieu-Costello 1992b). A similar condition may occur in the human athlete. West et al. (1991b) have documented one such incidence in a 35-year-old rugby player during the extreme physical exertion of the game. It is hypothesized that the increase in capillary pressure resulted in bleeding rather than high-permeability edema because of an extremely abrupt rises in pressure. A. 5 Conclusions Although the mechanism of EIH remains unclear, it is certain that respiratory factors may limit performance in some highly trained athletes. It would appear that the mechanism is multi-factorial with the accumulation of interstitial pulmonary fluid contributing to ventilation-perfusion inequality and diffusion limitations. The pulmonary capillary stress failure hypothesis best explains this development of edema. High pulmonary pressures, cardiac outputs, and oxygen consumption generated by the requirements of HT athletes are factors contributing to edema formation. 51 The blood-gas barrier must meet conflicting requirements. It must be thin enough to allow for rapid diffusion of gases, yet it must be strong enough to withstand the pressures associated with the metabolic demands of exercise at maximal capacity. It appears this requirement has not been fully satisfied in racehorses who exhibit EIPH. As a result of selective breeding, the respiratory system in horses has been surpassed by the cardiovascular system. Pressures greater than those that the pulmonary vasculature are able to withstand are generated during maximal exercise. 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