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Peripheral chemoresponsiveness and exercise induced arterial hypoxemia in highly trained endurance athletes 1993

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Peripheral Chemoresponsiveness and Exercise Induced Arterial Hypoxemia in Highly Trained Endurance Athletes. by Trevor Kenneth Cooper Bachelor of Physical Education 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 November, 1993 (c) Trevor Kenneth Cooper, 1993 In presenting this thesis in partial fulfillment 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. School of Human Kinetics The University of British Columbia 2075 Wesbrook Mall Vancouver, Canada V6T 1W5 Thursday, November 25, 1993 ABSTRACT To determine whether highly trained endurance athletes (HT) who develop exercise induced arterial hypoxemia (EIH) also demonstrate reduced peripheral chemoresponsiveness (PC) during exercise, twelve (N=12) HT male cyclists were selected for study. Basic pulmonary function data (FEV1 = 4.69 ± 0.66 L, PVC = 6.12 ± 0.82 L, FEV1 /FVC = 0.77 ± 0.08, FEFmax = 10.52 ± 1.57 L•sec’ , and MVV = 194 ± 21 L.min’) were obtained on all subjects. Subjects exercised on a cycle ergometer to exhaustion to determine their maximal aerobic capacity (“O2max = 5.08 ± 0.32 Lmin1, 66.6 ± 4.7 mL.min1•kg),and ventilatory threshold (VO2TH = 3.29 ± 0.12 Lmin1, 44.3 ± 4.2 mL.minl.kg).Oxygen saturation of arterial hemoglobin (SaO2max) was monitored with an ear oximeter (Hewlett-Packard, 47201A), to determine whether subjects exhibited EIH (SaO2max 91%) during the maximal cycle ergometer test. Subjects with SaO2max 93% were placed in the normal saturation group (NOS, Sa°2max = 93.4 ± 0.4 %) while subjects whose SaO2max 91% were placed in the low saturation group (LOS,5a°2max = 89.9 ± 0.9 %). Ventilatory responses to hypercapnic (13% C02, 21% 02, 66% N2) and hyperoxic (100% 02) gas mixtures were determined at rest, and during exercise on a cycle ergometer at approximately 25% VO2max, 50% VO2max, V02Th. Hypercapnic peripheral chemoresponsiveness was lower in LOS subjects than NOS subjects and increased in both groups from rest to 50 % VO2max. Hyperoxic peripheral chemoresponsiveness was not different in LOS and NOS subjects and did not change with exercise. Pre-stimulus SaO2 fell significantly during exercise in all subjects with LOS having lower SaO2 than NOS at VO2during the hypercapnic chemoresponse tests only. No evidence for a relationship between pre-stimulus SaO2 and either hypercapnic or hyperoxic peripheral chemoresponsiveness was found. The results 11 of this study provide information which may help explain variations in the ventilatory response to exercise in athletes. Additionally, data from this study suggest a role of altered ventilatory control in highly trained endurance athletes who do and do not demonstrate exercise induced arterial hypoxemia. 111 TABLE OF CONTENTS Abstract ii Table of Contents iv List of Tables vii List of Figures ix List of Abbreviations and Symbols Xi Acknowledgment xv Introduction 1 Methods 6 Subjects 6 Resting Pulmonary Function Tests 6 Maximal Cycle Ergometer Test 7 Chemoresponse Tests 8 Apparatus 9 Hypercapnic Chemoresponse 11 Hyperoxic Chemoresponse 11 Saturation 12 Statistical Analysis 12 Results 14 Subject Selection 14 Anthropometric Data 16 Resting Pulmonary Function Data 16 Maximal Cycle Ergometry 17 Exercise Workloads 19 Hypercapnic Peripheral Chemoresponse 21 Pre-Stimulus Arterial Hemoglobin Saturation 25 Hypercapnic Peripheral Chemoresponse and Pre-Stimulus Arterial Hemoglobin Saturation 26 iv Hyperoxic Chemoresponse.27 Pre-Stimulus Arterial Hemoglobin Saturation 30 Hyperoxic Peripheral Chemoresponse and Pre-Stimulus Arterial Hemoglobin Saturation 32 Discussion 33 Resting Pulmonary Function, Maximal Exercise Tests, and Subject Selection.... 34 Measurement of Peripheral Chemoresponses 35 Hypercapnic Peripheral Chemoresponse 36 Hyperoxic Peripheral Chemoresponse 36 Effect of Training Status on Peripheral Chemoresponsiveness 37 Effect of Exercise on Peripheral Chemoresponsiveness 38 Peripheral Chemoresponsiveness and Exercise Induced Arterial Hypoxemia 39 Peripheral Chemoresponsiveness and Pre-Stimulus Arterial Hemoglobin Saturation 40 Implications for Ventilatory Control 40 Summary 41 Bibliography 43 Appendix A 48 The Pulmonary System: a Limiting Factor In Exercise Performance 48 Normal, Healthy, Untrained Individuals 48 Highly Trained, Endurance Athletes 49 Exercise Induced Arterial Hypoxemia 50 Definition of Exercise Induced Arterial Hypoxemia 50 Causes of Exercise Induced Arterial Hypoxemia 50 Ventilation-Perfusion Heterogeneity and Veno-Arterial Shunt 51 Diffusion Disequilibrium 51 Relative Hypoventilation 52 V Mechanical Limitation of Ventilation and Respiratory Muscle Fatigue.52 Ventilatory Control 53 Control Mechanisms 53 Central Control of Ventilation 54 Supra-Pontine Control 54 Central Chemoreception 55 Spinal Motor Neuron Interaction 55 Peripheral Control of Ventilation 55 Peripheral Mechanoreceptors 56 Peripheral Chemoreceptors 56 Aortic Body Chemoreceptors 56 Carotid Body Chemoreceptors 56 Appendix B 58 Appendix C 83 Appendix D 94 vi LIST OF TABLES Table 1 Age, height, mass and body surface area of subjects, group data 16 Table 2 Resting Pulmonary Function, group data 17 Table 3 VO2max, peak power output, and SaO2max of subjects, group data 18 Table 4 VO2TH, and power output at VO2,group data 18 Table 5 Power outputs maintained during chemoresponse tests, group data 20 Table 6 Age, height, mass, and body surface area, individual subject data 58 Table 7 Pulmonary function, individual subject data 59 Table 8 VO2max , peak power output, and SaO2max , individual subject data 60 Table 9 VO2TH, and power output at VO2Ti-j, individual data 61 Table 10 Workloads during chemoresponse tests, individual subject data 62 Table 11 Hypercapnic peripheral chemoresponse, individual subject data 63 Table 12 Hypercapnic peripheral chemoresponse, group data 64 Table 13 Pre-hypercapnic peripheral chemoresponse SaO2, individual subject data 65 Table 14 Pre-hypercapnic peripheral chemoresponse SaO2, group data 66 Table 15 Hyperoxic peripheral chemoresponse, group data 67 Table 16 Hyperoxic peripheral chemoresponse, individual subject data 68 Table 17 Pre-hyperoxic peripheral chemoresponse SaO2, group data 69 Table 18 Pre-hyperoxic peripheral chemoresponse SaO2, individual subject data 70 Table 19 RMANOVA, Hypercapnic Chemoresponse 71 Table 20 Polynomial Contrasts, Hypercapnic Chemoresponse 72 Table 21 RMANOVA, Pre-Hypercapnic Chemoresponse SaO2 73 Table 22 Polynomial Contrasts, Pre-Hypercapnic ChemoresonseSaO2 74 Table 23 RMANOVA, Hyperoxic Chemoresponse 75 vii Table 24 Polynomial Contrasts, Hyperoxic Chemoresponse 76 Table 25 RMANOVA, Pre-Hyperoxic Chemoresponse SaO2 77 Table 26 Polynomial Contrasts, Pre-Hyperoxic Chemoresponse SaO2 78 Table 27 Linear Regression, Hypercapnic Chemoresponse and Pre Hypercapnic Chemoresponse SaO2, NOS subjects 79 Table 28 Linear Regression, Hypercapnic Chemoresponse and Pre Hypercapnic Chemoresponse SaO2, LOS subjects 80 Table 29 Linear Regression, Hyperoxic Chemoresponse and Pre-Hyperoxic Chemoresponse SaO2, NOS subjects 81 Table 30 Linear Regression, Hyperoxic Chemoresponse and Pre-Hyperoxic Chemoresponse SaO2, LOS subjects 82 Table 31 Age, height, mass, and body surface area, individual subject data 94 Table 32 Age, height, mass, and body surface area, group data 96 Table 33 VO2max, peak power output, and SaO2max, individual subject data 97 Table 34 VO2max, peak power output, and SaO2max, group data 99 Table 35 VO2TH, and power output at /O2m, individual subject data 100 Table 36 VO2TH, and power output at VO2TH, group data 102 vrn LIST OF FIGURES Figure la PCO2, P02, and Vj of single hypercapnic peripheral chemoresponse 21 Figure lb PETCO2, ETO2, and Vj for a single hypercapnic peripheral chemoresponse 23 Figure 2 Hypercapnic peripheral chemoresponse at various exercise intensities, group data 24 Figure 3 Pre-C02 response SaO2 at various exercise intensities, group data 25 Figure 4a PCO2, P02, and VI of a single hyperoxic peripheral chemoresponse 27 Figure 4b PETCO2, ETO2, and Vj for a single hyperoxic peripheral chemoresponse 29 Figure 5 Hyperoxic peripheral chemoresponse at various exercise intensities, group data 30 Figure 6 Pre-02 response SaO2 at various exercise iiitensities, group data 31 Figure 7 Power output at various exercise intensities, group data 83 Figure 8 Power output at various exercise intensities, NOS subjects 84 Figure 9 Power output at various exercise intensities, LOS subjects 85 Figure 10 Hypercapnic peripheral chemoresponse at various exercise intensities, NOS subjects 86 Figure 11 Hypercapnic peripheral chemoresponse at various exercise intensities, LOS subjects 87 Figure 12 Pre-C02 response SaO2 at various exercise intensities, NOS subjects 88 Figure 13 Pre-C02 response SaO2 at various exercise intensities, LOS subjects 89 Figure 14 Hyperoxic peripheral chemoresponse at various exercise intensities, NOS subjects 90 ix Figure 15 Hyperoxic peripheral chemoresponse at various exercise intensities, LOS subjects 91 Figure 16 Pre-02 response SaO2 at various exercise intensities, NOS subjects 92 Figure 17 Pre-O2 response SaO2 at various exercise intensities, LOS subjects 93 x LIST OF ABBREVIATIONS AND SYMBOLS (A-a)D02 Alveolar-arterial oxygen difference. [H+]a Arterial hydrogen ion concentration. EIH Exercise induced arterial hypoxemia. F(x,y)group Omnibus F ratio for RMANOVA group main effect with x numerator degrees of freedom, and y denominator degrees of freedom. F(x,y)thals Omnibus F ratio for RMANOVA trials main effect with x numerator degrees of freedom, and y denominator degrees of freedom. F(x,y)int Omnibus F ratio for RMANOVA trials x group interaction with x numerator degrees of freedom, and y denominator degrees of freedom. F(1,y)lin Omnibus F ratio for linear polynomial contrast with 1 numerator degree of freedom, and y denominator degrees of freedom. F(1,y)lin mt Omnibus F ratio for group interaction of linear polynomial contrast with 1 numerator degree of freedom, and y denominator degrees of freedom. F(1,y)quad Omnibus F ratio for quadratic polynomial contrast with 1 numerator degree of freedom, and y denominator degrees of freedom. F(1,y)quad mt Omnibus F ratio for group interaction of quadratic polynomial contrast with 1 numerator degree of freedom, and y denominator degrees of freedom. fR Respiratory frequency. FVC Forced vital capacity. xi FEV1 Forced expired volume in first second. FEFmax Maximal expiratory flow rate. GDiC Line of general direction of change. HT Highly trained endurance athletes. [Kia Arterial potassium ion concentration. LPO Low power output, 50% of maximal aerobic power. MPO Moderate power output, aerobic power at ventilatory threshold. MVV Maximal voluntary ventilation. PACO2 Alveolar partial pressure of carbon dioxide. PAO2 Alveolar partial pressure of oxygen. PaCO2 Arterial partial pressure of carbon dioxide. a°2 Arterial partial pressure of oxygen. PC Peripheral chemoresponsiveness. PCO2 Partial pressure of carbon dioxide. PETCO2 End-tidal partial pressure of carbon dioxide. PETO2 End-tidal partial pressure of oxygen. pH Negative logarithm of hydrogen ion concentration. pHa Negative logarithm of hydrogen ion concentration in arterial blood. xli P02 Partial pressure of oxygen. Qc Perfusion. RMANOVA Repeated-measures analysis of variance. SaO2 Oxygen saturation of arterial hemoglobin. SaO2max Minimal oxygen saturation of arterial hemoglobin during maximal cycle ergometer test. VA Alveolar ventilation. VA:QC Ventilation-perfusion ratio. VCO2 Rate of carbon dioxide elimination. VE Volume of air expired. VE Expired ventilation, or volume of air expired per minute. VE/VCO2 Ventilatory equivalent for carbon dioxide elimination. VE/V02 Ventilatory equivalent for oxygen consumption. Vj Volume of air inspired. Vj Inspired ventilation, or volume of air inspired per minute. VLPO Very low power output, 25% of maximal aerobic power. V02 Rate of oxygen uptake. VO2max Maximal rate of oxygen uptake. x1u VO2 Rate of oxygen consumption at the ventilatory threshold. xiv ACKNOWLEDGMENT I would like to thank all the students, faculty, friends and relatives who encouraged me during my studies, especially during the data collection of “the thesis that wouldn’t die”. Specifically: Dr. Don McKenzie, my advisor. Don taught me how to do “real” research, and gave me encouragement and support, both emotional and financial when I needed it. He exposed me to some of the better things in life (Surf on!), gave me memories I will never forget (Cape North, Tuk, etc....), and occasionally led me astray (with the help of Howie and James)! Diana Jespersen, my lab buddy. Diana was primary source of emotional “enlightenment” in the lab and was never, well almost never, short of smiles and laughs that made even the worst moments seem like they weren’t all that bad. She also taught me everything I know about equipment. Dr. Ken Coutts, whose unparalleled problem solving ability and handiness with duct tape (MacGyver) frequently solved problems even Diana gave up on. Ken also taught me how to be cool under pressure when everything in the lab breaks down in a sequential serenade to Murphy. Pat, Dave, Tiz, Maria and Jim, my lab-mates and fellow combatants who humored me by watching me “go through the motions”, who all managed to avoid the traps I fell into, and finished their theses before me even though I was the first to start. If they hadn’t broken everything I would have finished first! and finally... Sue Hopkins, my “soul” mate. Sue was the only person in the lab I could regularly argue with and actually learn something in the end as she was usually right. Many of Sue’s ideas have subconsciously and mysteriously appeared in my research (Actually I think she used to plant thoughts into my subconscious when I was sleeping and then....) and as a result I owe most of “this” to her. NOT ALL.. .but most. Thanks again everyone...see you at the beach! xv INTRODUCTION A number of authors (11, 20, 39-41, 43) have reported a decrease in partial pressure of oxygen in arterial blood and/or desaturation of hemoglobin during intense exercise in highly trained endurance athletes. This phenomenon has been called exercise induced arterial hypoxemia and its incidence has been reported to be between 40 (42) and 52 percent (39) in highly trained male endurance athletes. The occurrence of exercise induced arterial hypoxemia in highly trained athletes is reproducible with at least one group (39) finding a testlretest correlation of 0.95, p<.O5 The most likely causes of exercise induced arterial hypoxemia are: alveolar ventilation (VA) to perfusion (Qc) heterogeneity (VA:Qc ), veno-arterial shunt, diffusion disequilibrium, and the absence of adequate compensatory hyperventilation (10, 20, 49). In normal individuals and those highly trained athletes who do not demonstrate exercise induced arterial hypoxemia, ‘/A:C heterogeneity and veno-arterial shunt account for the widening of the alveolar-arterial 02 difference from less than 5 torr at rest to approximately 30 torr during heavy exercise(9). Athletes with high cardiac outputs ( 33 L•min1)and maximal pulmonary blood volumes ( 1.6 L) are likely to have very short red blood cell pulmonary transit times (10, 19). In addition, the absence of adequate exercise hyperpnea would result in a lowering of alveolar P02 on a breath by breath basis. The rate of equilibration of 02 would then decrease on a breath by breath basis due to a lowering of the 02 driving pressure across the gas exchange barrier. This results in a subsequent fall in arterial P02 accompanied by the maintenance of a constant alveolar arterial 02 difference. Another mechanism which may be related to the high cardiac outputs and maximal pulmonary blood volumes seen in the highly trained athletes who exhibit exercise induced arterial hypoxemia, is pulmonary edema. There may be a 1 decrease in diffusion of 02 across the alveolar membrane which is caused by an increase in the diffusion distance associated with the extravascular lung water accompanying pulmonary edema (33, 44, 45, 52, 53). Thus, shortened red blood cell pulmonary transit time and pulmonary edema may result in a significant diffusion disequilibrium at the end of the pulmonary capillary. These mechanisms, together with ventilation-perfusion heterogeneity and relative hypoventilation, are likely to explain the additional widening of the alveolar-arterial 02 difference to approximately 45 torr in highly trained athletes who develop exercise induced arterial hypoxemia (9). Conflicting data have been reported regarding the level of compensatory hyperventilation associated with heavy exercise and the influence it may have on exercise induced arterial hypoxemia. Relative hypoventilation has been associated with hypoxemia during exercise at 75 - 90 % VO2max (11) while another group (20) did not find evidence for such a hypoventilation accompanying a similar level of exercise induced arterial hypoxemia during exercise at essentially VO2max. The difference between methodologies in these studies could explain the disagreement in their results. At maximal exercise intensities the accumulated ventilatory drive associated with the demand for C02 elimination may become so strong that hypoventilation is not present under these circumstances when it may have been present at lower exercise intensities. In a subsequent study (19), a relationship was found between Pa02 and ventilatory equivalent for C02 (‘JEIVCO2) supporting the hypothesis that hypoventilation plays a role in exercise induced arterial hypoxemia. The ultimate goal of the respiratory system is the maintenance of blood homeostasis with respect to a°2, partial pressure of carbon dioxide (C02) in arterial blood (PaCO2), and hydrogen ion concentration in arterial blood ([Hja). Studies 2 involving carotid body resection in human subjects (17, 18, 50, 56) have shown that the peripheral chemoreceptors play an important role in the control of the acute ventilatory response to hypoxia and hypercapnia. The responsiveness of the peripheral chemoreceptors or the integration of their feedback in the brain stem are responsible, in part, for the inter-individual differences in the ventilatory response to changes in a°2, PaCO2, [Hia, exercise (9), and possibly potassium (37). Studies investigating the ventilatory responses of trained and untrained individuals have reported conflicting results. One study reported the chemoresponsiveness of individuals to increase with training (25), while other authors have reported that highly trained athletes have similar (29) and lower (5, 54) chemoresponsiveness than untrained individuals. Studies comparing the chemoresponsiveness of humans and animals at rest and exercise have also reported conflicting results. One group (31) found a correlation between VE and hypercapnic peripheral chemoresponse in man while another (1) did not find such a relationship in the cat. It is clear that chemoresponsiveness is highly variable between individuals and it is this variability that could explain some of the differences in the results of these studies. However, like the incidence of exercise induced arterial hypoxemia, chemoresponsiveness at rest and mild exercise has been relatively reproducible, with reported mean coefficients of variation (V) ranging from 23 ± 15% (46) to 25±6%(32). It is interesting to note that reductions in a°2 and/or SaO2 have been found at exercise intensities below maximum and near the ventilatory threshold (11, 19). A relative hypoventilation, possibly mediated through reduced peripheral chemoresponsiveness could explain the development of exercise induced arterial hypoxemia at these workloads in some athletes. For this reason this study was designed to 3 investigate the peripheral chemoresponsiveness of highly trained athletes, who do and do not develop exercise induced arterial hypoxemia, during very light, light, and moderate exercise. The relationship between peripheral chemoresponsiveness and the development of exercise induced arterial hypoxemia during exercise was also examined. Our general research questions were: 1. Is there a significant difference in peripheral chemoresponsiveness between rest, very light, light, and moderate exercise in subjects who do and do not demonstrate exercise induced arterial hypoxemia? 2. Is there a significant difference in the pattern of change of peripheral chemoresponsiveness, across exercise levels, between subjects who do and do not demonstrate exercise induced arterial hypoxemia? 3. Is there a significant decrease in SaO2 from rest to very light, light, and moderate exercise in subjects who do and do not demonstrate exercise induced arterial hypoxemia? 4. Is there a significant difference in the pattern of change of SaO2 , across exercise levels, between subjects who do and do not demonstrate exercise induced arterial hypoxemia? 5. Is there a relationship between peripheral chemoresponsiveness and SaO2 measured at each exercise level in subjects who do and do not demonstrate exercise induced arterial hypoxemia. Our hypotheses with regards to the research questions we were interested in were: 1. There is a reduction in peripheral chemoresponsiveness from rest to very light, light, and moderate exercise in subjects who do and do not demonstrate exercise induced arterial hypoxemia. 4 2. Subjects who demonstrate exercise induced arterial hypoxemia have lower peripheral chemoresponsiveness than subjects who do not demonstrate exercise induced arterial hypoxemia at all exercise levels. 3. There is a reduction in SaO2 from rest to very light, light, and moderate exercise in subjects who do and do not demonstrate exercise induced arterial hypoxemia. 4. Subjects who do not demonstrate exercise induced arterial hypoxemia will demonstrate an initial fall in SaO2 from rest to light and perhaps very light exercise but will not demonstrate a further fall in SaO2 at moderate exercise intensities. Subjects who do demonstrate exercise induced arterial hypoxemia will demonstrate a fall in Sa°2 from rest to light, very light, and moderate exercise. 6. Regression analysis of SaO2 and peripheral chemoresponsiveness, measured at each exercise level in subjects who do and do not demonstrate exercise induced arterial hypoxemia, will have a positive correlation coefficient. 5 METHODS SUBJECTS Highly trained male cyclists were recruited through personal contact or through advertisements in the Cycling British Columbia monthly newsletter and gave informed consent prior to participation in any experiments. Prior to participation in the study, subjects answered questions that increased the likelihood that they would satisfy the inclusion criteria which were: 1) normal pulmonary function with no history of pulmonary disease and 2) <lO2max 5.0 L•min1 or 60.0 mL•min1•kg RESTING PULMONARY FUNCTION TESTS Pulmonary function was tested using a MedGraphics CPXID system equipped with pulmonary function software. The CPX/D system was calibrated prior to each testing session by withdrawing and injecting a known volume (5 x 3.00 Liters) through the pneumotach (MedGraphics, disposable) at various flow rates. Each subject performed a minimum of three flow:volume maneuvers in order to obtain a reproducible measurement (according to ATS standards) of forced vital capacity (FVC), forced expiratory volume in one second (FEV1), ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and maximal forced expiratory flow rate (FEFmax). In addition, subjects performed at least two maximal voluntary ventilation (MVV) maneuvers. Data obtained were compared to normative values generated by the MGC CPXID software. If subject values for FVC, FEVi0, FEV1Q!FVC, FEFmax or MVV fell below the normal range, then subjects were excluded from further study. 6 MAXIMAL CYCLE ERGOMETER TEST Subjects completed a progressive intensity test to volitional fatigue on an electronically braked cycle ergometer (Mijnhardt, KEM-3). Subjects used their own pedals and cycling shoes on the cycle ergometer and adjustments were made to the saddle and handlebars to approximate their normal riding position. Prior to testing subjects warmed-up either by riding at a slow pace to the testing facility on their bicycle or by pedaling on the cycle ergometer until they felt ready to begin. During the progressive intensity test subjects pedaled at their preferred pedal frequency (between 30 and 100 revolutions•min1)at a steadily increasing work rate (30 Watts•min’ ramp) from zero load until they discontinued the test, or their pedaling frequency fell below 30 revolutions•min-1.During the test subjects breathed through a two-way, non-rebreathing valve (Hans-Rudolph, #2700B). The inspired gas volume (Vacumetrics, #17 150 air flow meter), and expired gas 02 (Applied Electrochemistry, Oxygen Sensor N-22M and Oxygen Analyzer S-3A11) and CO2 (Beckman, LB-2) contents were monitored and recorded by a personal computer for analysis (Rayfield system). Every fifteen seconds the computer system calculated and displayed the expired minute ventilation (‘/E) and the rates of oxygen consumption (V02)and carbon dioxide elimination (VO2).After the test was completed the VO2 at the ventilatory threshold (VO2TH) was determined according to a previously documented computer technique (6). In summary, for each subject, a third order polynomial curve was fitted to a plot of ‘CO2 versus VO2 using least-squares regression. In addition, a straight line indicating the general direction of change (GDiC) was fitted between the endpoints of the polynomial curve fit. Beginning at the lowest measured V02 the computer calculated the distance between the predicted value of the polynomial curve fit and the GDiC perpendicular to the GDiC. This 7 calculation was repeated at 10 mL V02 intervals with the largest difference (Dmax) producing the VO2for that subject. Work rates at approximately 25% of VO2max, 50% of VO2max and VO2TH were determined from linear least squares regression analysis of VO2 and power output. Percent saturation of hemoglobin in arterial blood (SaO2) was measured with an ear oximeter (Hewlett-Packard, 47201A) and recorded on another personal computer (1 Hz) for later analysis. Prior to placement of the ear sensor a topical vasodilator cream (Finalgon®, Boehringer/Ingetheim) was applied to the pinna of the ear to enhance perfusion. The SaO2 data obtained during the progressive intensity test was smoothed as a 30 second moving mean with the lowest value chosen as SaO2max. The level of SaO2max chosen for inclusion into the LOS group (SaO2max 91.0 %) was based on the definition of exercise induced arterial hypoxemia reported previously (39). The level of SaO2max chosen for inclusion into the NOS group (SaO2max 93.0 %) was chosen to differentiate the NOS subjects as much as possible from subjects in the LOS group. Subjects satisfying these criteria who could not be assigned to either the exercise induced arterial hypoxemia group (LOS) or the normal group (NOS) based upon results in the maximal cycle ergometer test were excluded from further study. CHEMORESPONSE TESTS Ventilatory responses to hypercapnia and hyperoxia were determined at rest and while the subjects exercised at approximately 25% of VO2max (very low power output, VLPO), 50% of VO2max (low power output, LPO) and VO2(moderate power output, MPO). The chemoresponse trials at rest and each exercise intensity were performed on different days at least 24 hours after training. Subjects reported to the lab at least two hours after eating or drinking caffeine. During the resting determinations, subjects 8 remained in a supine position on a cot. Prior to exercise determinations, subjects adjusted the cycle ergometer then warmed-up for 5-10 minutes at approximately 50% of their exercise work rate. During all determinations subjects listened to music from a radio or with earphones. Apparatus The same apparatus was used for the hypercapnic and hyperoxic chemoresponse tests. The subjects breathed through the pneumotach of the CPXJD system which was connected to a differential pressure transducer (MedGraphics, disposable; Validyne, DP250). The flow measurement system of the CPX/D was calibrated by withdrawing and injecting a known volume through the pneumotach at various flow rates. A sample of inspired and expired gas was continuously taken from the CPX/D pneumotach and was analyzed by the fast response CPXID gas analyzers (Medical Graphics Corporation, 02 - zirconia fuel cell, C02 - infrared absorption). The CPX/D gas analyzers were calibrated with test gases of known composition. This enabled the approximate monitoring of V02, VCO2,and VE on a breath-by-breath basis as well as an accurate record of end-tidal 02 and C02 pressures (PETO2 and PETCO2) during the steady-state period preceding the chemoresponse tests. The V02,VCO2,and VE data obtained and displayed in real time on the CPX/D system were not accurate due to the variations in inspired and expired gas composition that accompanied the chemoresponse tests. This was primarily due to the effect of gas density on flow measurements but was also a factor of the inability of the CPXID software to accommodate the input from the gas analyzers during and after chemoresponse trials (see Figures la and 5a). The raw analyzer outputs of the CPXID analyzers were channeled through an AID board to a personal computer where the 9 appropriate offset and scale factors were applied to the raw signals enabling the real time display of P02 and PCO2 during the chemoresponse tests. The CPXID flow signal was used to confirm the timing of the flow signal on the inspiratory side of the breathing circuit (see below). The distal end of the CPXID pneumotach was connected to a two- way non-rebreathing valve (Hans-Rudolph, #2700B). The inspiratory port of the non rebreathing valve was connected to the outlet of a 4-way t-type valve (Hans-Rudolph,). Three of the inlets of the 4-way valve were connected to three ports of a bag-in-box system in the following manner. One of the inlets of the 4-way valve was connected to a port that was continuous with the interior of the airtight plexiglass box (volume 250 liters). The second inlet was connected to a port that was continuous with one 60 liter Douglas bag inside the box that was partially filled with the hyperoxic gas mixture. The third inlet was connected to a port that was continuous with a second 60 liter Douglas bag inside the box that was partially filled with the hypercapnic gas mixture. The fourth port of the bag-in-box system was connected to the pneumotach and differential pressure transducer of a Medical Graphics MGC/2001 metabolic cart (Hans-Rudolph, #3 800; Validyne, DP250). The flow measurement system of the MGC/2001 was calibrated by repeatedly injecting a known volume through the pneumotach at various flow rates. The flow signal of the MGC/2001 system was channeled through the A/D board and into the personal computer where the appropriate offset and scale factors were applied, the signal was integrated and the resulting inspired volume (Vi) signal was displayed in real time. Using this system, Vj was accurately determined by measuring inspired air of constant gas composition and density during the chemoresponse trials. SaO2 was monitored throughout the testing period (Hewlett-Packard, 47201A Oximeter). The oximeter was calibrated according to the published instructions immediately before the chemoresponse 10 testing began and again halfway through the chemoresponse determinations. The SaO2 signal was channeled through the AID board and into a personal computer where appropriate offset and scale factors were applied and SaO2 was displayed in real time. Every effort was made to prevent the subjects from being aware of changes in inspired gas composition during all determinations. Subjects were allowed to adjust to the apparatus for five to ten minutes and when their VE, ETO2, and Pj’J’C0 had stabilized, data collection commenced. Hypercapnic Chemoresponse The technique used for the determination of the hypercapnic peripheral chemoresponse was modified from that previously reported by another author (32). The gas mixture used was approximately 13% C02, 21% 02 and 66% N2. After a minimum of 30 seconds of pre-stimulus data had been collected, subjects were switched to the hypercapnic gas mixture using the 4-way valve for one breath and then immediately back to room air. Data collection continued for approximately 60 seconds. A period of three to five minutes separated each of a minimum of five repeated trials. The hypercapnic chemoresponse for each subject was determined in the following manner. The control ‘/j was calculated as the mean ‘/j of the five breaths immediately preceding the stimulus breath. The stimulus ‘7J was chosen as the highest single breath ‘/j recorded within 20 seconds of the stimulus breath. The control PETCO2 was calculated as the mean value during the 30 second pre-stimulus period. The trial response was calculated as the ratio of the difference between the control Vi and the stimulus Vj to the difference between the control P1fC02 and the PETCO2 of the stimulus breath. The individual subject response was calculated as the mean of the five trial responses. 11 Hyperoxic Chemoresponse The technique used for the determination of the hyperoxic peripheral chemoresponse was modified from that previously reported by another author (47). The gas mixture used was 100% 02. After a minimum of 30 seconds of pre-stimulus data had been collected, subjects were switched to the hyperoxic gas using the 4-way valve. During resting studies subjects breathed the hyperoxic gas for 20 seconds (usually three breaths). During exercise studies subjects breathed the hyperoxic gas for the same number of breaths as they had in the resting studies. Once the period of hyperoxic gas breathing was completed subjects again inspired room air. Data collection continued for approximately 60 seconds. A period of three to five minutes separated each of a minimum of five repeated trials. The hyperoxic chemoresponse for each subject was determined in the following manner. The control ‘/j was calculated as the mean over the 30 second, pre-stimulus period. After hyperoxic breathing had begun ‘1j data was smoothed using a three breath moving mean. An individual subject response was calculated as the ratio of the lowest three breath ‘/j value averaged across trials to the average control period Vj value. Saturation For both the hypercapnic and hyperoxic responses the pre-stimulus SaO2 was determined in the same manner. For each trial the SaO2 was determined to be the mean value of the fifteen seconds immediately preceding the stimulus breath or breaths. The subject SaO2 was calculated as the mean of the five trial SaO2 values. 12 STATISTICAL ANALYSIS The Students’ T-test was used to compare group means of the descriptive subject data. The hypercapnic and hyperoxic responses as well as the pre-stimulus SaO2 values were analyzed as 2 x 4 RMANOVA’s. In addition, the correlation between both sets of peripheral chemoresponse data and their associated pre-stimulus Sa02 was determined with linear regression analysis. The level of significance for all statistical comparisons was set at p = 0.05. 13 RESULTS SUBJECT SELECTION A total of 36 male cyclists were recruited for the study through advertisements in the Cycling British Columbia newsletter, and through word of mouth from previous subjects. Of the initial 36 subjects, 2 were excluded from further study because their results in the pulmonary function tests were substantially below predicted, 10 were excluded because their VO2max was less than 5.00 L•min’ or 60.0 mL•min1.kg, and 12 were excluded because either they did not satisfy the SaO2max criteria or the were not needed as the group they qualified for was complete. Using the criteria, SaO2max 91.0 %, the first six subjects accepted into the study qualified for the low SaO2max (LOS) group. The reported incidence of exercise induced arterial hypoxemia of 52 % in highly trained endurance athletes (39, 42) makes this a highly unlikely occurrence. However, at least three of the subjects selected for the LOS group had been examined previously for exercise induced arterial hypoxemia in our lab and had tested positive. Based upon the reported incidence of exercise induced arterial hypoxemia in highly trained endurance athletes only twelve more subjects should have been required to complete the selection of subjects for the NOS group. This, however, was not the case. The upper limit of the SaO2max criteria, SaO2m 94.0 %, was originally chosen in an attempt to create as large a separation between subjects in the two groups as possible. Using this criteria to select subjects for the normal SaO2max (NOS) group resulted in only two subjects qualifying for that group out of the next fifteen subjects tested. A number of the subjects not qualifying for the NOS group did qualify for the LOS group but were not studied further as that group was complete. The remaining subjects had SaO2max values which 14 fell between the upper and lower limits of the SaO2max selection criteria. The upper limit of the SaO2max criteria was then lowered to SaO2max 93.0 % (1 SD below the mean decrease in Sa°2 found in normal subjects during exercise (39)) and three more subjects were found for the NOS group as well as one additional subject for the LOS group. The additional LOS subject was accepted because he demonstrated the highest degree of exercise induced arterial hypoxemia of all subjects tested. Initially it was thought that the apparent low number of subjects qualifying for the LOS group was indicative of an incidence of exercise induced arterial hypoxemia that was much higher than previously reported. However, examination of data from all subjects indicated an incidence of exercise induced arterial hypoxemia in subjects with VO2max 5.00 L•min1 or 60.0 mL•min’ •kg1 of 31 % (8 subjects out of 26) which is substantially lower than values reported by Powers et al. (39) and is slightly lower than values reported in more recent studies (41, 42) even though the subjects in this study had lower VO2max values. Interestingly, two subjects that did not satisfy the fitness selection criteria (VO2max = 4.69 ± 0.19 L•min’, 53.8 ± 3.5 mL.minLkg) did demonstrate mild exercise induced arterial hypoxemia (SaO2max = 90.3 ± 0.1 %). Individual subject descriptive data and VO2max, peak power, SaO2max and VO2TH data for subjects not qualifying for complete study can be found in Appendix D. Of the subjects selected for complete study, six were competitive road cyclists (LOS, three; NOS, three), three were competitive off-road cyclists (LOS, one; NOS, two), one was a competitive duathlete (LOS), one was a recreational triathiete (LOS), and one was a recreational athlete who had previously competed as an Olympic class oarsman (LOS). 15 ANTHROPOMETRIC DATA Subjects in both groups were similar in height, weight, and body surface area (BSA) (Table 1). Individual subject values for all descriptive variables can be found in Table 6. Table 1 Age, height, mass and body surface area of subjects, group data. AGE HEIGHT MASS BSA GROUP (yrs) (cm) (kg) (m2) LOS (n=7) 28.9 ± 8.1 180.1 ± 5.9 74.9 ± 7.3 1.94 ± 0.10 NOS (n=5) 25.4 ± 5.3 185.3 ± 5.0 79.0 ± 2.5 2.03 ± 0.06 Values are means ± SD. LOS, low oxygen saturation; NOS, normal oxygen saturation. RESTING PULMONARY FUNCTION DATA Resting pulmonary function data were compared with normative values generated by the testing apparatus. Subjects in both groups had similar values for FVC, FEVi, FEVi/FVC, and MVV. Subjects in the LOS group had significantly higher FEFmax values than NOS subjects (tio = 2.24, p = 0.025). Individual subject data can be found in Table 7. All subjects demonstrated normal or supra-normal pulmonary function. The highest values for any pulmonary function variable, when compared to individual predicted values, were found in the FEFmax data with values ranging as high as 152% of predicted. 16 Table 2 Resting Pulmonary Function, group data. FVC FEV1 FEV1/FVC FEFmax MVV GROUP (L) (L) (L•sec’) (L.min’) (% Pred.) (% Pred.) (% Pred.) (% Pred.) LOS (n=7) 5.76 ± 0.78 4.51 ± 0.65 0.79 ± 0.09 11.25 ± 1.44 * 197 ± 16 104± 12 98±7 132± 14 109± 10 NOS (n=5) 6.60 ± 0.63 4.95 ± 0.65 0.75 ± 0.07 9.49 ± 1.18 188±27 107±4 97±6 107±11 104±12 Values are means ± SD. LOS, low oxygen saturation; NOS, normal oxygen saturation. Value indicated by (*) is significantly higher than NOS (p <0.05). MAXIMAL CYCLE ERGOMETRY There were no significant differences between groups in VO2max, or peak power output (Table 3). Results from the VO2max test for all subjects are listed in Table 8. The mean VO2max of all subjects was 5.08 ± 0.32 L•min’ or 66.6 ± 4.7 mL•min1•kg, indicating the high training status of the subjects. Values for VO2max for subjects in both groups are comparable to data reported in previous studies (20, 41) but are lower, on average, than those reported by Dempsey et al. (11). There was substantial overlap in the range of VO2max for subjects in each group (LOS, 59.6 - 74.5; NOS, 62.6 - 69.9 mL.min1.kg) As a result there was not a significant relationship between VO2max and SaO2max in these subjects (r = 0.138, F(1,10)reg = 0.193, p = 0.669). This remained the case when subjects were separated into groups (LOS, r = 0.392, F(1 1O)reg = 0.909, p = 0.384; NOS, r = 0.592, F(1,10)reg = 17 1.62 1, p = 0.293). These results are contrary to those reported previously by other authors (39, 42). Table 3 VO2max , peak power output, and SaO2max of subjects, group data. VO2max VO2max Peak Power SaO2max GROUP (L.minl) (mL.min1.kgi) (Watts) (%) LOS (n=7) 4.96 ± 0.26 66.8 ± 6.0 458 ±31 89.9 ± 0.9 * NOS (n=5) 5.24 ± 0.34 66.4 ± 2.9 453 ±23 93.4 ± 0.4 Values are means ± SD. SaO2m is lowest arterial oxygen saturation during the maximal cycle ergometer test. Value denoted by (*) is significantly lower than NOS (p < 0.05). The VO2TH of subjects in the LOS group was higher than in the NOS group although the difference did not reach statistical significance (tio = 1.79 1, p = 0.052) (Table 4). As a result LOS subjects had higher power outputs at their VO2mthan NOS subjects (tio = 3.346, p = 0.004). Individual subject values for VO2are listed in Table 9. Table 4 VO2TH, and power output at VO2TH, group data. Group VO2TH VO2 Power at VO2TH (L.min’) (mL.min1.kg’) (Watts) LOS (n=7) 3.26 ± 0.14 46.0 ± 4.7 300 ± 26 * NOS (n=5) 3.31±0.11 42.0± 1.8 259 ± 9 Values are means ± SD. Value denoted by (*) is significantly higher than NOS (p <0.05). 18 EXERCISE WORKLOADS The workloads for the chemoresponse trials were selected for two reasons: to extend the measurement of peripheral chemoresponsiveness during exercise to the highest intensities possible, hoping to elicit a hypoxemic response in the LOS subjects, and to choose as the highest workload an intensity that would allow completion of the peripheral chemoresponse data collection. Thus, the highest workload that could be practically used corresponded to the power output at VO2TH. Since this was thought to average around 75 % of VO2max in highly trained endurance cyclists the absolute workloads of 25 % and 50 % of VO2max and VO2TH were chosen for the lower exercise levels. This would have resulted in a roughly linear increase in power output from the very low power output to the moderate power output exercise levels. The power outputs in both LOS and NOS increased in a linear fashion from the very low power output to moderate power output exercise levels (F(1,1o)lin = 846.883, p <0.001). However, not only was the rate of increase in power output in the NOS group lower than that of the LOS group (F( 1,1 0)lin mt = 14.756, p 0.003), but the pattern of change in the increase in power output was different in the two groups (F(3,30)jnt = 12.858, p <0.001) (Figure 7). Specifically, subjects in both groups had similar power outputs at the very low power output and low power output exercise levels, but the NOS subjects had a substantially lower power output at moderate power output exercise level than the LOS subjects (Table 5). This was because the VO2TH of LOS subjects was higher than NOS subjects and as a result the moderate power output workload, which was approximately the ventilatory threshold workload, was higher in the LOS subjects. Consequently, the two lower workloads were effectively absolute workloads while the highest workload was a relative workload. The 19 workloads derived by regression analysis for each subject, based upon their individual V02/power output relationship, are listed in Table 10. Table 5 Power outputs maintained during chemoresponse tests, group data. Exercise Level GROUP VLPO LPO MPO LOS(n=7) 70±11 194±19 272±28 NOS(n=5) 77±13 199±10 232±11 Units are Watts. Values are means ± SD. LOS, low oxygen saturation; NOS, normal oxygen saturation. VLPO, very low power output; LPO, low power output; MPO, moderate power output. 20 HYPERCAPNIC PERIPHERAL CHEMORESPONSE The results of a typical hypercapnic peripheral chemoresponse trial can be seen in Figure la and Figure lb. Figure la PCO2 , P02 , and Vj of single hypercapnic peripheral chemoresponse. 80- 60- I I I I I 180 140 120 100 100 90 80 ‘ 70 > 60 50 40 I I I I I I -10 -5 0 5 10 15 20 Time (sec) Subject, PT. Exercise level, MPO. Traces are offset and scaled data sampled at 20 Hz. Stimulus breath occurs at t=0. The response shown in Figure la and Figure lb is of an LOS subject at the moderate power output exercise intensity. The offset and scaled analyzer output traces are 21 shown in Figure la and the breath-by-breath values derived from the offset and scaled traces are shown in Figure lb. In these figures the switching of inspired gas from room air to the test gas occurs at t=tO. Prior to the stimulus breath are shown five breaths used to calculate the pre-stimulus control Vj, and the pre-stimulus control PETCO2. Following the stimulus breath are shown the breaths occurring in the next twenty seconds, from which the breath with the highest VJ was chosen as the response breath. The response breath in this particular trial occurred two breaths after the stimulus breath (less than 5 seconds after the stimulus). This was the case in most trials with the response breath being the second or third breath after the stimulus breath, the time decreasing with increasing exercise intensity. At lower exercise levels, or at rest, the Vj trace shows an obvious increase in slope following the stimulus breath. At the higher exercise levels this slope increase is less visible in the raw Vj trace and is only seen in the breath-by-breath plot of Vj. 22 Figure lb PETCO2, ETO2, and Vj for a single hypercapnic peripheral 120 E 116 114 ‘ 112 1 60 140 120 100 80 chemoresponse. Exercise level, MPO. Subject, PT. Plot shows values extracted from raw data shown in Figure la. Vj calculated from Vj and R on a breath-by-breath basis. 50 - 9- 40 0 0 00O00 0 0000 0 — I I I I - 0 00 0 -000 0 0 0 0 0 0 0 0 0 — I I I I - 0 0 0,0 0 0• 0 0 ,0 0 0,0 0 0, I I I — -10 -5 0 5 10 15 20 Time (sec) 23 E E - C CM C U Figure 2 Hypercapnic peripheral chemoresponse at various exercise intensities, group data. 2- 1.5: 1— 0.5 - 0- I I I Rest VLPO MPO Values are means ± SD. Open circles, LOS; Open squares, NOS. VLPO, very low power output; LPO, low power output; MPO, moderate power output. The hypercapnic peripheral chemoresponse was significantly higher in NOS than in LOS (F(1,10)group = 13.652, p 0.004) and it increased significantly in both groups (F(3,30)trjals = 10.446, p <0.001) from rest to exercise (Figure 2). In addition, while hypercapnic peripheral chemoresponse as a function of exercise level had a significant linear component in both groups (F(1,1O)ljn = 13.413, p = 0.004), there was also a significant plateauing of hypercapnic peripheral chemoresponse near the higher LPO 24 workloads in both groups (F(1,10)quad = 8.197, p = 0.017). Individual subject, averaged, hypercapnic chemoresponses are listed in Table 11. Figure 3 Pre-C02 response SaO2 at various exercise intensities, group data. Values are means ± SD. Open circles, LOS; Open squares, NOS. output; LPO, low power output; MPO, moderate power output. VLPO, very low power Pre-Stimulus Arterial Hemoglobin Saturation The pre-stimulus Sa02during hypercapnic peripheral chemoresponse trials was not different in LOS and NOS averaged across exercise levels (F(1,10)group = 0.019, p = 0.894), however a significant fall in SaO2 was seen in both groups (F(3,30)trials = 15.12, 100 99 - 98 - 97 - 96 - 95 - 94 Rest VLPO LPO MPO 25 p <0.0001). The fall in SaO2 in the LOS group was larger than that of the NOS group (F(3,30)jnt = 3.2 13, p = 0.037) and it occurred mostly from the low power output to moderate power output exercise intensities. The fall in SaO2 in both groups was almost entirely a linear function of increasing exercise intensity (F( 1, 10)lin = 34.299, p < 0.000 1) with the more pronounced decrease in the LOS group at the moderate power output exercise intensity (F(J.,10)quad mt = 6.596, p = 0.028) accounting for any deviation from linearity. Hypercapnic Peripheral Chemoresponse and Pre-Stimulus Arterial Hemoglobin Saturation There was not a significant linear relationship between hypercapnic peripheral chemoresponsiveness and pre-stimulus SaO2 in either group of subjects (LOS, r2 = 0.115, p = 0.078; NOS, r2 =0.097, p = 0.181). 26 HYPEROXIC CHEMORESPONSE The results of a typical hyperoxic peripheral chemoresponse trial can be seen in Figure 4a and Figure 4b. Figure 4a PCO2, P02, and Vj of a single hyperoxic peripheral chemoresponse. 60- 800 - ; ir Time (sec) Exercise level, MPO; subject, PT. Plot shows offset and scaled data sampled at 20 Hz. Vj calculated in real-time from inspiratory flow rate. The response shown in Figure 5a and Figure 5b is of an LOS subject at the moderate power output exercise intensity. The offset and scaled analyzer output traces are 27 shown in Figure 5a and the breath-by-breath values derived from the offset and scaled traces are shown in Figure 5b. In these figures the switching of inspired gas from room air to the test gas occurs at t=O. Prior to the stimulus breath are shown a number of breaths from the 30 second pre-stimulus control period used to calculate the pre-stimulus control Vi. Following the stimulus breath are shown the breaths occurring in the next thirty seconds, from which the breath with the lowest Vi is chosen as the response breath. At lower exercise levels, or at rest, the Vj trace shows an obvious decrease in slope following the stimulus breath. At the higher exercise levels this slope decrease is less visible in the V1 trace and is only seen in the breath-by-breath plot of VT. 28 Figure 4b PETCO2, ETO2, and V1 for a single hyperoxic peripheral chemoresponse. - E 55- E 0 :popp00Co°°°,° - 800 60O- 0 40O- 0 0 0- 0200- 0000000 — I I I I 140 - 120 - pOp 100- 00 U000 0 00 1 0 0 0U- 000 60- I I I I I I -10 -5 0 5 10 15 20 25 30 Time (see) Exercise level, MPO; subject, PT. Plot shows values extracted from offset and scaled data shown in Figure 5a. VI calculated from Vj and fR on a breath-by-breath basis. The hyperoxic chemoresponse was not significantly different either between groups or across exercise levels (F(1,10)group = 0.000, p = 0.988, F(3,30)trials = 2.152, p = 0.115), nor was there a significant interaction effect (F(3,30)int 1.224, p = 0.3 18) (Figure 5). Individual subject, averaged, hyperoxic chemoresponses are listed in Table 16. 29 Figure 5 Hyperoxic peripheral chemoresponse at various exercise intensities, group data. I I I I Rest VLPO LPO MPO Values are means ± SD; open circles, LOS; open squares, NOS. VLPO, very low power output; LPO, low power output; MPO, moderate power output. Pre-Stimulus Arterial Hemoglobin Saturation The pre-stimulus SaO2 during hyperoxic peripheral chemoresponse trials was not different in LOS and NOS (F(1,10)group = 0.966, p = 0.349) averaged across exercise levels, however a significant fall in SaO2 was seen in both groups (F(3,30)trials = 18.769, p <.0001) (Figure 6). The fall in SaO2 in the LOS group was not larger than that of the NOS group (F(3,30)int = 0.456, p = 0.7 15). The fall in SaO2 in both groups was almost 30 - 25 - 20 - 15 - 10 - 5 30 C ti) C entirely a linear function of increasing exercise intensity (F( 1, 10)lin = 36.276, p <.0001) with a significant inverted sigmoid function (F(1,10)cubjc = 11.828, p = 0.006) accounting for any deviation from linearity. The pre-stimulus SaO2 data for all subjects during hyperoxic peripheral chemoresponse trials are shown in Table 18. Figure 6 Pre-02 response SaO2 at various exercise intensities, group data. 100 - 99 - 98 - 97 - 96 - 95 - 94- Values are means ± SD; open circles, LOS; open squares, NOS. VLPO, very low power output; LPO, low power output; MPO, moderate power output. Rest VLPO LPO MPO 31 Hyperoxic Peripheral Chemoresponse and Pre-Stimulus Arterial Hemoglobin Saturation There was not a significant linear relationship between hyperoxic peripheral chemoresponse and pre-stimulus SaO2 in either group of subjects (LOS, r2 = 0.015, p = 0.540; NOS, r2 = 0.002, p = 0.846). 32 DISCUSSION Exercise induced arterial hypoxemia occurs in 40 to 50 % of highly trained endurance athletes (39, 42) and has a detrimental effect on both VO2max and exercise performance (27, 42). The primary mechanisms suggested to be responsible for exercise induced arterial hypoxemia are veno-arterial shunt, diffusion disequilibrium secondary to increased pulmonary transit time or pulmonary edema, VA:Qc heterogeneity (11, 19, 49) and relative hypoventilation (11, 30). A substantial amount of research has been undertaken to elucidate the proportional importance of these mechanisms with somewhat contradictory results. Much of the work investigating the relative importance of hypoventilation in exercise induced arterial hypoxemia has involved only description or comparison of the ventilatory responses of the subjects who do and do not demonstrate exercise induced arterial hypoxemia. No studies have examined the ventilatory control mechanism directly and related any observations made to the incidence of exercise induced arterial hypoxemia. As a result some authors have excluded the hypoventilation mechanism as playing a major role in the development of exercise induced arterial hypoxemia (42). This study represents the first attempt to measure the peripheral chemoresponsiveness to hypercapnia and hyperoxia, at rest and during very light to moderate exercise, in highly trained endurance athletes. The peripheral chemoresponsiveness of these highly trained endurance athletes is compared with results obtained from previous studies on trained and untrained individuals at rest and during exercise. In addition, the relationship between peripheral chemoresponsiveness and exercise induced arterial hypoxemia is investigated by comparing the peripheral 33 chemoresponsiveness of highly trained endurance athletes who do and do not demonstrate exercise induced arterial hypoxemia. RESTING PULMONARY FUNCTION, MAXIMAL EXERCISE TESTS, AND SUBJECT SELECTION The subjects in this study all demonstrated pulmonary function values within predicted normal ranges. Interestingly, it was common for subjects to be significantly higher than predicted on FEFmax and MVV, while at the same time values for FEV1 and FEV1/FVC were only normal or slightly sub-normal. It is possible that the very high FEFmax values, as high as 152 % of predicted, were simply related to the superior development of the thoracic musculature in these athletes. However, many subjects who had very high FEFmax values also had mid-expiratory flow rates that were substantially below predicted. All subjects reached at least 90 % of their MVV during the incremental cycle ergometer test. Values for VO2max for subjects in this study are comparable to data reported in some previous studies (20, 41) but are lower, on average, than those reported by Dempsey et al. in 1984 (11). Contrary to previous reports (39), no relationship was found between VO2max and SaO2max in the subjects in this study either as a whole or when divided into groups based on the presence of exercise induced arterial hypoxemia. The incidence of exercise induced arterial hypoxemia in the highly trained endurance athletes who completed this study was 58 %. This result overestimates the actual incidence of exercise induced arterial hypoxemia observed in all subjects completing the maximal cycle ergometer test as most subjects completing that test were not studied further because: 1) they did not pass the pulmonary function criteria, 2) they did not pass the 34 VO2max criteria, or 3) they qualified for the LOS group but that group was already full. The incidence of exercise induced arterial hypoxemia in all subjects meeting the VO2max criteria for inclusion in the study was only 38 %, which agrees with lower incidences reported (41). There were two subjects who did not meet the VO2max criteria that did demonstrate exercise induced arterial hypoxemia. They would have been categorized as moderately trained in the previous study (39) that reported no cases of exercise induced arterial hypoxemia in subjects of similar VO2max. Although subjects in both groups demonstrated similar levels of aerobic power at maximal exercise, the aerobic power at the ventilatory threshold of the LOS subjects was higher than the NOS subjects. As a result the moderate power output exercise intensity was a relative work load while the very low power output and low power output exercise intensities were both relative and absolute work loads in these subjects. Comparison of the exercise intensities attained in this study with similar studies of peripheral chemoresponsiveness (30, 32, 21, 22, 47, 51) confirm that not only were higher absolute power outputs attained with these highly trained endurance athletes but higher relative exercise intensities were attained as well. MEASUREMENT OF PERIPHERAL CHEMORESPONSES Computerization of the techniques of McClean et al. (1988) and Stockley (1978) made the collection and analysis of data during both resting and the three exercise determinations of peripheral chemoresponsiveness to hypercapnia and hyperoxia possible. The automation and computerization of the data collection and analysis also permitted more reliable determination of valid responses than in the previous studies 35 since errors in the calculation of ‘1j from the slope of a chart recording of Vj were eliminated. Hypercapnic Peripheral Chemoresponse At the time that the study was undertaken the technique described by McClean et al. (1988) was the only technique that enabled measurement of the peripheral chemoresponse to hypercapnia during exercise. During the hypercapnic peripheral chemoresponse trials it was impossible to keep the subjects completely unaware of the beginning of C02 breathing. At an inspired fraction of 13 % the level of C02 in the test gas was sufficiently high to be tasted by most subjects. A sharp increase in the peak and mean expiratory flow rates during the second and third breaths after the stimulus breath, in conjunction with reports from some subjects of a perceived need to exhale forcefully, confirmed that the administration of the stimulus was not completely blind. However, a number of factors suggest that the influence of these cortical perceptions on the peripheral chemoresponse to hypercapnia, although unknown, is probably small: 1) the peripheral chemoresponse to hypercapnia was determined from ‘1j and not VE and the cortical perceptions would not be likely to increase the inspiratory drive, 2) increases in the inspiratory flow rate were much smaller in proportion to those in expiratory flow rate, and 3) subjects were naive about which test gas they were receiving in what doses during any given chemoresponse trial. The use of PETCO2 to quantify the stimulus delivered to the carotid body chemoreceptor is based upon the assumption that there is a small and constant arterial to alveolar C02 difference. This has not been documented in the literature and could be a confounding factor, especially in subjects who likely suffer from some diffusion limitation of 02. The fact that the exercise intensities used did not elicit exercise induced 36 arterial hypoxemia in any of the subjects suggests that if a significant arterial to alveolar C02 difference can exist it was not likely to be present in these studies. Hyperoxic Peripheral Chemoresponse Unlike during the hypercapnic peripheral chemoresponse tests, subjects were unaware when measurement of hyperoxic peripheral chemoresponsiveness took place. The test gas, although it was dry and was inspired for between 5 and 20 seconds, did not increase or decrease any sensations of dyspnea at rest or during exercise. Also, with the addition of on-line display of inspired and expired P02 and PCO2 to the method of Stockley (47) evidence of hypoventilation in response to the hyperoxic stimulus could easily be detected facilitating the identification of valid responses. The lack of isocapnic conditions during the hyperoxic chemoresponse tests results in a variable underestimation of the decrease in ventilation in response to hyperoxia at rest and during exercise. Thus caution is required when comparing data from this study with other studies where isocapnia was maintained. EFFECT OF TRAINING STATUS ON PERIPHERAL CHEMORESPONSIVENESS The hypercapnic peripheral chemoresponsiveness of the highly trained endurance athletes in this study was higher at rest (mean ± SD, 0.54 ± 0.30 L•minl.mmHg1)than values reported for healthy untrained males (mean ± SD, 0.38 ± 0.14 L.min.m Hg (32). This is in agreement with data indicating that peripheral chemosensitivity to hypercapnia is higher in trained versus untrained individuals (25) but is contrary to reports of others documenting a decrease in chemosensitivity to hypercapnia in individuals following prolonged exercise training (35). The results of the second study were obtained using a C02 rebreathing technique in which both central and peripheral 37 chemoreceptive mechanisms are active. The results of the study by Miyamura and Ishida (35) are not in conflict with data from this study if, while peripheral chemoresponsiveness increases with training, central chemoresponsiveness decreases with training, the net result being an overall increase in chemoresponsiveness to hypercapnia. The resting hyperoxic peripheral chemoresponsiveness of subjects in this study (mean ± SD, 20.0 ± 8.1 %) is similar to previously reported values in a group of athletes of similar aerobic capacity (mean ± SD, 22 ± 2 %) (31) and is slightly higher than a group of healthy, normal subjects (mean ± SE (n=35), 16.2 ± 2.6 %) (47). The difference between the data in this study and the data of Stockley (1978) is not significant (t45 = 0.8 13, p = 0.2 10) and would suggest that there is no difference between trained and untrained individuals in the resting contribution to normoxic of hypoxic sensitivity. This seems intuitive because at rest both trained and untrained individuals have the same SaO2 and a°2. EFFECT OF EXERCISE ON PERIPHERAL CHEMORESPONSIVENESS Subjects in this study demonstrated an increase in peripheral chemoresponsiveness to hypercapnia associated with exercise supporting previous reports of an augmentation of peripheral chemoresponsiveness to hypercapnia during exercise (21, 22). Further, this data indicates that on transition from very light to moderate exercise the rate of increase in peripheral chemosensitivity decreases with increasing exercise intensity. It would seem that as exercise intensity increases approaching and exceeding the ventilatory threshold peripheral chemosensitivity to hypercapnia plays a less important role in the development of exercise hyperpnea. 38 As others have reported (31, 47) this study did not demonstrate a statistically significant change in hyperoxic peripheral chemoresponsiveness with increasing exercise intensity. A previous report (51) indicated that hyperoxic chemoresponsiveness was augmented by exercise, however, the observations in that study were based on an extrapolation of VE to an infinitely high a°2 and are questionable in light of the more recent work by the same group (31). PERIPHERAL CHEMORESPONSIVENESS AND EXERCiSE INDUCED ARTERIAL HYPOXEMIA In the present study the peripheral chemosensitivity to hypercapnia was lower in subjects who demonstrated exercise induced arterial hypoxemia. This effect cannot be attributed to a difference in trained status because subjects in both groups had similar VO2max. Differences between the LOS and NOS subjects at the two low exercise intensities are not likely to be simple exercise effects because the subjects exercised at the same relative and absolute metabolic rate. At the moderate power output exercise level the LOS subjects were exercising at a higher metabolic rate relative to VO2max, although both groups were exercising at their VO2,and the difference in hypercapnic peripheral chemoresponsiveness present at the low power output exercise intensities was maintained. The pattern of change in peripheral chemoresponsiveness to hypercapnia as a function of increasing exercise intensity was the same in both LOS and NOS subjects. There seems to be a relationship between exercise induced arterial hypoxemia and the sensitivity of the peripheral chemoreceptors to hypercapnia. The absence of a difference in hyperoxic peripheral chemoresponsiveness between LOS and NOS subjects indicates that, at the exercise intensities studied, there is 39 no relationship between hyperoxic peripheral chemoresponsiveness and exercise induced arterial hypoxemia. This is probably due to the fact that the moderate power output exercise intensity was not high enough to induce arterial hypoxemia in the LOS subjects and the baseline activation of the peripheral chemoreceptors to hypoxia was not different from NOS subjects. A relationship between hyperoxic peripheral chemoresponsiveness and exercise induced arterial hypoxemia may become apparent at higher workloads but this study has no data to support this hypothesis. PERIPHERAL CHEMORESPONSIVENESS AND PRE-STIMULUS ARTERIAL HEMOGLOBIN SATURATION No evidence was found to support the hypothesis that peripheral chemoresponsiveness was related to exercise SaO2. Although there was a difference in peripheral chemoresponsiveness to hypercapnia in LOS and NOS subjects there was no difference between groups in pre-stimulus SaO2 averaged across exercise intensities and peripheral chemoresponsiveness was not different in LOS and NOS subjects. Again, although subjects in the LOS group had lower pre-stimulus Sa°2 values at the moderate power output exercise intensity, they did not demonstrate exercise induced arterial hypoxemia and this fact may have prevented the detection of a relationship between these variables. IMPLICATIONS FOR VENTILATOR Y CONTROL The ventilatory control mechanism suggested by some authors (48) consists of a feed-forward component that directs the initial response of the ventilatory system to increased CO2 load, and a feed-back component that is responsible for correcting errors in the feed-forward portion of the control mechanism. Other authors have expanded this 40 model and suggest that the role of the peripheral chemoreceptors is to stabilize ventilation, effectively acting as a brake to the initial hyperventilation that accompanies the onset of exercise (3). Data from this study suggest that highly trained endurance athletes, who have higher hypercapnic peripheral chemoresponsiveness than untrained individuals, control this initial increase in ventilation more effectively, maintaining tighter control on PaCO2, pHa and a°2. It would seem that highly trained endurance athletes who demonstrate exercise induced arterial hypoxemia are less able to control their ventilation, they have lower hypercapnic peripheral chemoresponsiveness, under similar conditions and are more likely to experience wider variations in PaCO2, P11a and a°2 than individuals of similar aerobic capacity who do not demonstrate exercise induced arterial hypoxemia. The mechanism of these changes in athletes with exercise induced arterial hypoxemia is unknown. It is possible that there are differences between these two groups of subjects in the physiologic response of the carotid bodies themselves, in the integration of afferent signals from the carotid bodies with other feed-back within the respiratory center or in the subsequent expression of this feed-back as a change in ventilation. SUMMARY The results of this study provide information which may help explain variations in the ventilatory response to exercise in athletes. Additionally, data from this study suggest a role of altered ventilatory control in highly trained endurance athletes who do and do not demonstrate exercise induced arterial hypoxemia. Further study is required to ascertain the specific causes of the reduced hypercapnic peripheral chemoresponsiveness 41 in highly trained endurance athletes who demonstrate exercise induced arterial hypoxemia. 42 BIBLIOGRAPHY 1. Aggarwal D., H.J. Milhom and L.Y. Lee. 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Kelley M.A., M.D. Laufe, R.P. Miliman and D.D. Peterson. Ventilatory response to hypercapnia before and after athletic training. Respir Physiol. 55(3):393-400, 1984. 26. Kelley M.A., R.J. Panettieri and A.V. Krupinski. Resting single-breath diffusing capacity as a screening test for exercise-induced hypoxemia. Am J Med. 80(5):807- 12, 1986. 27. Koskolou M.D. and D.C. McKenzie. Arterial hypoxemia and performance during intense exercise. Eur. J. Appi. Physiol. [in press], 1993. 28. Lugliani R., B.J. Whipp, C. Seard and K. Wasserman. Effect of bilateral carotid- body resection on ventilatory control at rest and during exercise in man. N Engi J Med. 285(20):1105-11, 1971. 29. Mahier D.A., E.D. Moritz and J. Loke. Ventilatory responses at rest and during exercise in marathon runners. JAppi Physiol. 52(2):388-92, 1982. 30. Martin B.J., K.E. Sparks, C.W. Zwillich and J.V. Weil. Low exercise ventilation in endurance athletes. MedSci Sports. 11(2):181-5, 1979. 31. Martin B.J., J.V. Weil, K.E. Sparks, et al. Exercise ventilation correlates positively with ventilatory chemoresponsiveness. JAppi Physiol. 45(4):557-64, 1978. 32. McClean P.A., E.A. Phillipson, D. Martinez and N. Zamel. Single breath of C02 as a clinical test of the peripheral chemoreflex. JAppi Physiol. 64(1):84-9, 1988. 33. Miles D.S., M.H. Cox, J.P. Bomze and R.W. Gotshall. Acute recovery profile of lung volumes and function after running 5 miles. J Sports Med Phys Fitness. 31(2):243-8, 1991. 34. Mines A.H. Respiratory physiology. (2nd ed.) New York: Raven Press, 1986. 35. Miyamura M. and K. Ishida. Adaptive changes in hypercapnic ventilatory response during training and detraining. Eur JAppi Physiol. 60(5):353-9, 1990. 45 36. Pan L.G., H.V. Forster, G.E. Bisgard, et al. Role of carotid chemoreceptors and pulmonary vagal afferents during helium-oxygen breathing in ponies. JAppi Physiol. 62(3):1020-7, 1987. 37. Paterson D.J. Potassium and ventilation in exercise. JAppi Physiol. 72(3):81 1-20, 1992. 38. Paterson D.J., P.A. Robbins and J. Conway. Changes in arterial plasma potassium and ventilation during exercise in man. Respir Physiol. 78(3):323-30, 1989. 39. Powers S.K., S. Dodd, J. Lawler, et al. Incidence of exercise induced hypoxemia in elite endurance athletes at sea level. Eur JAppi Physiol. 58(3):298-302, 1988. 40. Powers S.K., S. Dodd, J. Woodyard, et al. Haemoglobin saturation during incremental arm and leg exercise. Br J Sports Med. 18(3):212-6, 1984. 41. Powers S.K., D. Martin, M. Cicale, et al. Exercise-induced hypoxemia in athletes: role of inadequate hyperventilation. Eur JAppi PhysioL 65(1):37-42, 1992. 42. Powers S.K., D. Martin and S. Dodd. Exercise-induced hypoxaemia in elite endurance athletes. Incidence, causes and impact on VO2max. Sports Med. 16(1):14-22, 1993. 43. Powers S.K. and J. Williams. Exercise-induced hypoxaemia in highly trained athletes. Sports Med. 4(1):46-53, 1987. 44. Rasmussen B.S., P. Elkjaer and B. Juhi. Impaired pulmonary and cardiac function after maximal exercise. J Sports Sci. 6(3):219-28, 1988. 45. Schaffartzik W., D.C. Poole, T. Derion, et al. VA:Q distribution during heavy exercise and recovery in humans: implications for pulmonary edema. JAppi Physiol. 72(5):1657-67, 1992. 46. Shaw R.A., S.A. Schonfeld and M.E. Whitcomb. Progressive and transient hypoxic ventilatory drive tests in healthy subjects. Am Rev Respir Dis. 126(1):37- 40, 1982. 47. Stockley R.A. The contribution of the reflex hypoxic drive to the hyperpnoea of exercise. Respir Physiol. 35(1) :79-87, 1978. 46 48. Swanson G.D. Overview of ventilatory control during exercise. Med Sci Sports. 1 1(2):221-6, 1979. 49. Wagner P.D. Ventilation-perfusion matching during exercise. Chest. :192S-198S, 1992. 50. Wasserman K., B.J. Whipp, S.N. Koyal and M.G. Cleary. Effect of carotid body resection on ventilatory and acid-base control during exercise. JAppi Physiol. 39(3):354-8, 1975. 51. Weil J.V., E. Byrne-Quinn, I.E. Sodal, et al. Augmentation of chemosensitivity during mild exercise in normal man. JAppi Physiol. 33(6):813-9, 1972. 52. West J.B. and 0. Mathieu-Costello. Stress failure of pulmonary capillaries in the intensive care setting. Schweiz Med Wochenschr. 122(20):751-7, 1992. 53. West J.B., K. Tsukimoto, 0. Mathieu-Costello and R. Prediletto. Stress failure in pulmonary capillaries. JAppi Physiol. 70(4):1731-42, 1991. 54. West J.B. Respiratory physiology--the essentials. (3rd ed.) Baltimore: Williams & Wilkins, 1985:x, 183 p. : ill. ; 23 cm. 55. Whipp B.J. The hyperpnea of dynamic muscular exercise. Exerc Sport Sd Rev. 5(295):295-311, 1977. 56. Whipp B.J. and K. Wasserman. Carotid bodies and ventilatory control dynamics in man. Fed Proc. 39(9):2668-73, 1980. 47 APPENDIX A REVIEW OF LITERATURE THE PULMONARY SYSTEM: A LIMITING FACTOR IN EXERCISE PERFORMANCE There are a number of factors which are commonly considered to limit athletic performance in humans. However, which factor or combination of factors are most important remains controversial. The controversy revolves around the likelihood that as one moves along the continuum of aerobic power from untrained normal individuals (VO2max of approximately 40 mL.min1.kg)to highly trained endurance athletes (VO2max of approximately 60 to 75 mLmin1.kg)which of these potentially limiting factors becomes the most important for any specific sub-group of the population undoubtedly varies. NORMAL, HEALTHY, UNTRAINED INDIVIDUALS In healthy sedentary individuals, exercising at sea-level, the pulmonary system shows near perfect regulation of alveolar gases, distribution of alveolar ventilation (VA) and perfusion (c) and diffusion equilibrium in the lung at rest and during exercise. The capacity of the pulmonary systems of these individuals to extract oxygen from the atmosphere exceeds that of their cardiovascular and metabolic systems to deliver and use that oxygen (12). Maximal aerobic power (‘O2max) and therefore exercise performance are limited by maximal stroke volume, cardiac output, skeletal muscle vascularity and/or the oxidative capacity of the skeletal muscles (9) in these individuals . At sea level the pulmonary system is able to meet the demands placed on it for oxygen (02) extraction and carbon dioxide (C02) elimination during heavy exercise through a number of 48 mechanisms. Firstly, the hyperpnea of exercise ensures the maintenance of alveolar oxygen pressure (PAO2) above 110 mmHg maintaining arterial oxygen pressure (PaO2) near resting values (100 mmflg) and ensuring adequate elimination of C02 (2). Secondly, pulmonary capillary blood volume increases in a linear fashion up to 3 times its resting value with the 4 to 5-fold increase in pulmonary blood flow. This maintains red blood cell transit times necessary for equilibration of blood in the pulmonary capillaries with alveolar gas, a relatively uniform distribution of pulmonary blood flow and expansion of the alveolar-capillary surface area, and relatively low pulmonary vascular resistance (9). Finally, the lymphatic system is capable of adequately draining the pulmonary interstitial space of pulmonary extra vascular water. This prevents the lengthening of alveolar-capillary diffusion distances (8). HIGHLY TRAiNED, END URANCE ATHLETES In highly trained endurance athletes the physiological adaptations of the cardiovascular system and of the oxidative capacities of the skeletal muscles, accompanied by the limited scope for adaptation in the pulmonary system, may result in the pulmonary system actually becoming the limiting factor in exercise performance (9, 43). In fact, many highly trained endurance athletes demonstrate a significant and reproducible decrease in a°2 or arterial hemoglobin saturation (SaO2) during moderate to intense exercise. It is not entirely clear what level of SaO2 is required to maintain performance however some data suggests that measurable reductions in exercise performance begin to occur at Sa°2’5 of less than 90% (27). 49 EXERCISE INDUCED ARTERIAL HYPOXEMIA The reduction rn a°2 accompanying exercise was first reported by Harrop in 1919 (16) who observed a decrease in SaO2 from 95.6% at rest to 85.5% immediately following fifteen minutes of brisk exercise (heart rate = 140 beats•min’, R = 30 breaths•min’). More recent reports of reductions in a°2 and/or SaO2, a phenomenon now commonly referred to as exercise induced arterial hypoxemia, are numerous (11, 20, 39, 42, 43). DEFINITION OF EXERCISE INDUCED ARTERIAL HYPOXEMIA Exercise induced arterial hypoxemia, although previously observed, was first defined by Powers et al. in 1988 (39) as a decrease in SaO2 from a resting value of approximately 97% to a value less than or equal 91% during exercise. This definition of a critical level of SaO2, allowed the authors to document the incidence and reproducibility of exercise induced arterial hypoxemia in highly trained endurance athletes (52%, r=0.95, p<.O5). More recently the same authors have modified their definition of exercise induced arterial hypoxemia based on direct measurement of a°2 in conjunction with measures of SaO2 (41). The incidence of exercise induced arterial hypoxemia is 40 % in highly trained endurance athletes using the new definition of a decrease in SaO2 of 4 % below resting SaO2. CA USES OF EXERCISE IND UCED ARTERIAL HYPOXEMIA Although a significant amount of research is being conducted in an attempt to elucidate the mechanism underlying exercise induced arterial hypoxemia (7, 11, 20, 23, 24, 26, 39-43, 49), the causes of exercise induced arterial hypoxemia are not clearly understood and remain a topic of debate. A number of mechanisms have been identified 50 as likely contributors to the development of exercise induced arterial hypoxemia however their relative importance is currently unknown. Ventilation-Perfusion Heterogeneity and Veno-Arterial Shunt The distribution of alveolar ventilation (\o(V,\s( ))A) and pulmonary capillary perfusion (Qc) or VA:C throughout the lung is not uniform and actually becomes less uniform during heavy exercise (49). This ‘/A:C heterogeneity, accompanied by a left to right heart shunt, explains most of the widening (2.5- to 3-fold) of the alveolar to arterial P02 difference ((A-a)D02 ) in healthy, sedentary individuals (9). It should be noted that although there is a widening of the (A-a)D02 in healthy, sedentary individuals, they maintain their a°2 to within roughly 10 mmHg of resting values and therefore do not exhibit exercise induced arterial hypoxemia. Diffusion disequilibrium Abnormal widening of the (A-a)D02 or diffusion disequilibrium has been suggested to be the other major cause of exercise induced arterial hypoxemia (15, 26, 42, 43, 49). The additional widening of the (A-a)D02 beyond that seen in healthy, sedentary individuals is thought to be due to a decrease in red blood cell transit time below the level necessary for full equilibration of pulmonary blood with alveolar gas or a decrease in the diffusing capacity of the pulmonary system (12, 42, 49). The cause of this reduced transit time is an increase in pulmonary blood flow beyond the point at which pulmonary capillary blood volume has reached its maximum morphological limits (9, 19). An increased diffusion distance, due to extremely high pulmonary capillary pressures and increased plasma leakage into the interstitial spaces referred to as pulmonary edema, may also contribute further to the widening (A-a)D02 due to (7, 9, 49). 51 Relative Hypoventilation Inadequate hyperventilation has been suggested as one of the major causes of exercise induced arterial hypoxemia in highly trained endurance athletes. The lack of an appropriate hyperventilatory response to exercise causes an increased widening of the (A-a)D02 resulting in a drop in a°2 (9, 49). Mechanical limitation of ventilation and respiratory muscle fatigue The difference in maximal exercise ventilation corrected for metabolic rate between healthy, untrained individuals (/J/:/02 = 19.0 ± 0.4, V]/Vco2 22.6 ± 0.7) and highly trained endurance athletes (VE/V02= 15.7 ± 0.2, VE/VCO = 19.0 ± 0.7) at low exercise intensities suggests that mechanical limitation of ventilation or respiratory muscle fatigue might explain, at least in part, the lack of an appropriate hyperventilatory response in athletes who develop exercise induced arterial hypoxemia (30). The hypothesis regarding mechanical limitation of ventilation is supported by experiments in which the mechanical work of breathing was reduced in subjects breathing a mixture of helium (He) and 02 which resulted in an immediate and significant hyperventilation (11) as well as the observation that maximal volitional expiratory flow:volume limits may be exceeded at very high levels of exercise (14). Whatever the relative contributions of these mechanisms to the development of exercise induced arterial hypoxemia in the highly trained, endurance athlete, it seems clear that factors influencing the control of the ventilatory response to exercise must also be considered as playing a role in the development of exercise induced arterial hypoxemia. 52 VENTILATORY CONTROL Despite abundant scientific inquiry, the topic of ventilatory control is not fully understood and remains controversial. Until recently (20), ventilatory control has not been directly studied as a potential contributing factor in exercise induced arterial hypoxemia although a number of investigations of exercise induced arterial hypoxemia have included a description of the ventilatory response accompanying the exercise stimulus CONTROL MECHANISMS The current body of data has led some researchers (48) to hypothesize a system of ventilatory regulation during exercise based upon the fact that in normal individuals, exercising at moderate intensities (ranging from rest to the anaerobic threshold) PaCO2, pH and P02 are regulated at essentially their resting values. One hypothesized structure for the ventilatory controller combines feed-forward and feed-back mechanisms (48). The actual physiological mechanisms that could contribute to the feed-forward response are summarized below: 1. arterial CO2 (pH) oscillations sensed by the carotid body, 2. central neural stimulus to the respiratory center from the motor cortex, 3. afferent input from exercising muscles to the respiratory center, 4. venous return to the heart sensed by some unknown mechanism, 5. a sensor responding to pulmonary blood flow, mixed venous C02,CO2 flux to the lung, or some other unknown humoral substance, 6. an intrapulmonary chemoreceptor, also not yet identified, sensing mixed venous blood pH. 53 This feed-forward response would yield an exercise ventilation proportional to the CO2 production, with any errors in this feed-forward response being corrected by the feed back response of the arterial chemoreceptors to PaCO2 (48). CENTRAL CONTROL OF VENTILATION The central nervous system plays an important role in the regulation of the ventilatory response to exercise. The regulation is accomplished through the integration of sensory input via three basic types of mechanisms; non-chemical input from supra pontine areas of the brain, chemical input from chemoreceptive regions of the medulla, and spinal motor neuron cross innervation (13). Supra-pontine Control The supra-pontine portion of the ventilatory control equation, plays an important role in the ventilatory response of humans during exercise. Its effect is obtained through the integration of three basic influences. The traditional voluntary influence of the higher centers has obvious and significant application to the control of breathing in athletic endeavors where the ventilatory musculature in also involved in the activity directly (13). The second influence of the higher centers is effected through the sensation of ventilatory effort. A number of receptors including, but not limited to, pulmonary and airway stretch receptors, intercostal muscle spindles, and costo-vertebral joint receptors are located in such a way that they provide feedback to the motor cortex regarding lung volume, rib cage distortion, upper airway resistance, development of muscle tension, and other important determinants of ventilatory sensation (13). The third category of contributions from higher levels of the CNS involves more direct influences of supra-pontine mechanisms on medullary output and the interaction of these inputs with the more 54 traditional chemoreceptor inputs to the same areas. These mechanisms are generally classified into two groups, cortical inputs (inhibitory) and diencephalic inputs (facilatory) however the activation of these influences is not clearly understood (13). Central Chemoreception The majority of the resting ventilatory response of normal individuals at sea level is mediated by the central chemoreceptors. Medullary chemoreceptive cells on the ventral surface of the medulla are sensitive to changes in the pH of the medullary interstitial fluid and cerebrospinal fluid with decreases in pH stimulating ventilation (2). Due to the presence of the blood-brain barrier, which is more permeable to CO2 than to H ions, these receptors are not influenced by arterial pH but rather by PaCO2. These receptors are responsible for maintaining a ventilatory response adequate to maintain a resting PaCO2 of about 40 to 45 mmHg. Spinal Motor Neuron Interaction The influence of the spinal motor neurons on the control of ventilation is not clearly understood. The motor neurons do not generate rhythmic discharge but do show reciprocal inhibition. They receive input from a variety of sources including mechanoreceptor afferents, phasic command signals and tonic decending influences. They could, in combination with the above mentioned mechanisms, conceivably generate an appropriate ventilatory response to exercise without inputs arising from outside the central nervous system (13). PERIPHERAL CONTROL OF VENTILATION Peripheral influences on the ventilatory response to exercise come from primarily two sources, peripheral mechanoreceptors and peripheral chemoreceptors. The integration 55 of afferent signals from these receptors with others mentioned previously allow the close regulation of a°2, PaCO2 and pHa observed in normal individuals at sea level. Peripheral Mechanoreceptors A number of receptors have been identified that could play a role in the regulation of the ventilatory response to exercise. These receptors, some of which are skeletal muscle spindles, Golgi tendon organs, and skeletal joint proprioceptors, send afferent signals to the sensory cortex (2) and are thought to play a significant role in the neurogenic or phase 1 portion of the ventilatory response to exercise (55). Peripheral Chemoreceptors Peripheral chemoreceptors are of basically two types, aortic body chemoreceptors and carotid body chemoreceptors. Both receptors respond to changes in blood gas tensions however their relative importance in the control of ventilation is quite different. Aortic Body Chenwreceptors The aortic bodies are located around the aortic arch and between the arch and the pulmonary artery and are therefore appropriately located to respond to changes in the chemical composition of arterial blood. They are stimulated by a decreased mean a°2 and by an increased mean PaCO2, the response to 02 being greater (34). Although the aortic body chemoreceptors are involved in respiratory regulation, the role of the carotid body chemoreceptors is much greater. Carotid Body Chemoreceptors The carotid body chemoreceptors are located in the carotid bodies which are found at the bifurcation of the common carotid arteries into the internal and external carotid arteries. Like the aortic bodies, they are stimulated by decreasing Pa°2 and by increasing PaCO2, however they are also stimulated by a decrease in pHa (34) and 56 increasing blood potassium ([K]) levels (38). In addition, the carotid bodies respond quickly enough to be sensitive to the within-breath variations of pHa caused by within breath fluctuations in PACO2, possibly providing one of the more important signals used to match ventilation to metabolic rate during exercise (34). That the carotid bodies play an important role in the control of exercise ventilation is clear (4, 17, 28, 36, 50). In addition, experiments involving 100% 02 breathing during exercise have indicated that the maximal reduction in ventilation during administration of 100% 02 (i.e., ‘silencingt the carotid bodies) is greater during exercise than at rest suggesting enhancement of carotid body drive induced by exercise (55). The importance of the chemoreceptive drive to breath is clear, playing a role in both the feed-forward and feed-back portions of the respiratory control mechanism, its briskness has profound effects on the ability to maintain homeostasis during moderate to intense exercise. Variations in carotid body drives have been suggested to play a role in the control of exercise ventilation. Carotid drives have been reported to increase (25) and decrease (35) significantly with training and during exercise compared to rest (21, 22, 51). For example, carotid body chemoresponsiveness to hypercapnia has been reported to range from 0.38 ± 0.14 L•min.m Hg in healthy untrained individuals (32) to as high as 2.15 ± 0.62 L•min•m Hg’ in highly trained endurance athletes at rest (25). Thus, individual differences in variations in carotid body drives during exercise could explain some of the variation in the ventilatory response to exercise and development of exercise induced arterial hypoxemia in highly trained endurance athletes. 57 (yrs) 28 31 27 24 24 46 28 25 33 21 20 22 (cm) 177 183 190 184 174 179 184 178 184 191 189 174 182± 6 (kg) 65.7 84.0 76.3 81.4 69.8 79.7 78.6 74.7 79.9 80.8 80.8 67.2 76.6 ± 6.0 (m2) 1.81 2.06 2.03 2.04 1.84 1.98 2.01 1.93 2.03 2.09 2.08 1.80 1.98 ±0.11 APPENDIX B TABLES Table 6 Age, height, mass, and body surface area, individual subject data. AGE HEIGHT MASS BSA SUBJECT TM PT DB GA HT BT RR SF MF DH ME JF MEAN±SD 27±7 58 Table 7 Pulmonary function, individual subject data. FVC FEV1 FEVi/FVC FEFm MVV SUBJECT (L) (L) (L•sec’) (L•min) (% Pred.) (% Pred.) (% Pred.) (% Pred.) TM 5.21 3.72 0.71 9.40 183 98 84 114 105 PT 6.99 4.80 0.69 11.58 211 122 101 133 115 DB 6.31 5.39 0.85 12.07 203 98 101 138 102 GA 5.71 5.27 0.92 13.48 221 95 105 152 114 HT 6.20 4.25 0.69 9.70 183 120 98 116 102 BT 5.13 3.99 0.78 11.90 203 104 99 146 128 RR 6.39 4.62 0.72 8.10 184 107 94 93 97 SF 6.18 4.07 0.66 9.18 158 112 88 107 85 MF 5.91 4.91 0.83 9.25 192 102 102 107 105 DH 7.31 5.74 0.79 11.36 231 109 103 125 111 ME 7.20 5.40 0.75 9.55 177 107 98 105 86 IF 4.77 4.15 0.87 10.65 178 92 95 128 98 MEAN± 6.11±0.82 4.69±0.66 0.77±0.08 10.52±1.57 194±21 SD 105±9 97±6 122±18 97±11 59 Table 8 VO2max, peak power output, and SaO2max, individual subject data. VO2max VO2max Peak Power SaO2max SUBJECT (L•min1) (mL•min1.kg) (Watts) (%) TM 4.92 74.9 470 90.0 PT 5.25 62.5 490 90.4 DB 5.21 68.3 479 90.0 GA 4.85 59.6 430 91.0 HT 5.14 73.6 470 89.6 BT 4.88 61.5 465 90.2 RR 5.15 65.5 435 93.4 SF 4.88 65.3 435 93.3 MF 5.00 62.6 455 93.2 DH 5.65 69.9 450 94.2 ME 5.54 68.6 490 93.1 IF 4.50 67.0 400 88.0 MEAN ± SD 5.08 ± 0.32 66.6 ± 4.7 456±27 91.4 ± 2.0 SaO2m is the lowest arterial hemoglobin saturation during maximal cycle ergometer test. 60 Table 9 VO2TH , and power output at VO2TH, individual data. ‘‘O2Th VO2 Power at VO2TH SUBJECT (L•min’) (mL•min1.kg1) (Watts) TM 3.22 49.9 300 PT 3.34 43.8 330 DB 3.36 45.6 310 GA 3.11 41.2 275 HT 3.48 53.0 335 BT 3.10 40.2 280 RR 3.41 43.4 265 SF 3.27 43.8 256 MF 3.15 39.4 258 DH 3.40 42.1 246 ME 3.34 41.3 270 JF 3.24 48.2 270 MEAN±SD 3.29± 0.12 44.3 ±4.2 283 ±29 61 Table 10 Workloads during chemoresponse tests, individual subject data. Exercise Level GROUP VLPO LPO MPO TM 70 190 260 PT 80 220 280 DB 60 180 310 GA 70 180 260 HT 90 220 300 BT 60 200 270 RR 60 200 230 SF 80 200 230 MF 70 190 220 DH 80 190 230 ME 95 215 250 JF 60 170 225 MEAN±SD 73± 12 196± 16 255±30 Values are means ± SD. Units are Watts; LOS, low oxygen saturation; NOS, normal oxygen saturation. VLPO, very low power output; LPO, low power output; MPO, moderate power output. 62 Table 11 Hypercapnic peripheral chemoresponse, individual subject data. Exercise Level SUBJECT Rest VLPO LPO MPO TM 0.24±0.19 0.86±0.33 0.74±0.19 0.76±0.31 PT 0.41 ± 0.08 0.66 ± 0.20 1.06 ± 0.26 0.99 ± 0.23 DB 0.60±0.27 0.93±0.37 1.14±0.38 0.54±0.11 GA 0.49 ± 0.26 0.73 ± 0.15 0.87 ± 0.38 0.80 ± 0.20 HT 0.22±0.10 0.44±0.27 0.64±0.18 0.77±0.29 BT 1.13 ± 0.29 0.65 ± 0.21 0.67 ± 0.25 0.86 ± 0.31 RR 0.60 ± 0.22 1.43 ± 0.53 1.75 ± 0.38 1.64 ± 0.38 SF 0.68±0.17 0.87±0.16 0.69±0.26 0.98±0.32 MF 0.99±0.47 1.45±0.61 1.13±0.23 1.20±0.33 DH 0.54 ± 0.30 1.05 ± 0.49 1.57 ± 0.45 1.59 ± 0.79 ME 0.37±0.31 1.16±0.66 1.24±0.33 0.72±0.50 JF 0.16±0.20 0.53±0.19 1.00±0.40 1.17±0.32 mean ± SD 0.54 ± 0.30 0.90 ± 0.33 1.04 ± 0.36 1.00 ± 0.34 Values are means ± SD Units are L•min4•m Hg;LOS, low oxygen saturation; NOS, normal oxygen saturation. VLPO, very low power output; LPO, low power output; MPO, moderate power output. 63 Table 12 Hypercapnic peripheral chemoresponse, group data. Exercise Level GROUP Rest VLPO LPO MPO LOS (n=7) 0.46 ± 0.33 0.69 ± 0.17 0.87 ± 0.20 0.84 ± 0.20 NO5 (n=5) 0.64 ± 0.23 1.19 ± 0.25 1.28 ± 0.41 1.23 ± 0.39 Values are means ± SD. Units are Lmin1•m Hg;LOS, low oxygen saturation; NOS, normal oxygen saturation. VLPO, very low power output; LPO, low power output; MPO, moderate power output. 64 Table 13 Pre-hypercapnic peripheral chemoresponse SaO2, individual subject data. Exercise Level SUBJECT Rest VLPO LPO MPO TM 98.8±1.0 97.9±0.5 97.1±0.7 95.9±0.6 PT 98.0±0.0 97.8±1.1 99.3±0.7 95.9±1.6 DB 97.7 ± 1.3 97.7 ± 0.7 96.0 ± 0.7 95.0 ± 0.6 GA 99.0±0.8 96.7±0.1 97.0±0.9 94.7± 1.0 HT 97.0 ± 0.6 96.0 ± 0.6 96.6 ± 0.7 95.6 ± 0.9 BT 96.6±0.8 97.7±0.7 96.6±0.5 96.0±0.8 RR 99.1±0.9 97.4±0.9 97.2±0.8 96.3±1.7 SF 96.7 ± 1.0 97.3 ± 0.9 96.2 ± 1.9 96.2 ± 0.9 MF 96.5±0.5 97.0±0.8 96.0±0.8 96.3± 1.4 DH 98.4 ± 0.9 97.3 ± 0.5 96.2 ± 0.7 96.4 ± 1.0 ME 96.8±0.8 96.5±0.5 95.4± 1.0 96.1±0.6 JF 96.9± 1.3 97.6± 1.3 96.0± 1.6 93.6± 1.6 MEAN ± SD 97.6 ± 1.0 97.2 ± 0.6 96.6 ± 1.0 95.7 ± 0.8 Values are means ± SD. Units are %. VLPO, very low power output; LPO, low power output; MPO, moderate power output. saturation. VLPO, very low power output; LPO, low power output; MPO, moderate power output. 65 Table 14 Pre-hypercapnic peripheral chemoresponse SaO2, group data. Exercise Level GROUP Rest VLPO LPO MPO LOS (n=7) 97.7 ± 0.9 97.4 ± 0.7 96.9 ± 1.1 95.2 ± 0.9 NOS (n=5) 97.5 ± 1.2 97.1 ± 0.4 96.2 ± 0.7 96.3 ± 0.1 Values are means ± SD. Units are %; LOS, low oxygen saturation; NOS, normal oxygen saturation. VLPO, very low power output; LPO, low power output; MPO, moderate power output. 66 Table 15 Hyperoxic peripheral chemoresponse, group data. Exercise Level GROUP Rest VLPO LPO MPO LOS (n=7) 18.6 ± 8.8 19.1 ± 6.8 16.2 ± 4.0 17.1 ± 5.2 NOS (n=5) 22.1 ± 7.5 15.9 ± 6.5 16.2 ± 5.5 17.7 ± 5.5 Values are means ± SD. Units are %; LOS, low oxygen saturation; NOS, normal oxygen saturation. VLPO, very low power output; LPO, low power output; MPO, moderate power output. 67 Table 16 Hyperoxic peripheral chemoresponse, individual subject data. Exercise Level SUBJECT Rest VLPO LPO MPO TM 11.0 16.4 11.5 17.5 PT 28.8 25.2 19.4 26.0 DB 12.4 9.2 11.4 16.3 GA 9.2 11.3 13.5 10.7 HT 16.7 24.7 20.6 12.5 BT 31.5 24.0 17.4 15.2 RR 21.8 8.2 12.0 7.3 SF 25.0 25.5 19.0 17.2 MF 9.8 13.3 8.8 17.2 DH 29.9 18.7 21.7 21.7 ME 24.0 14.0 19.3 19.3 JF 20.3 23.0 19.6 21.2 MEAN ± SD 20.0 ± 8.1 17.8 ± 6.6 16.2 ± 4.4 16.8 ± 5.1 Units are %. VLPO, very low power output; LPO, low power output; MPO, moderate power output. 68 Table 17 Pre-hyperoxic peripheral chemoresponse SaO2, group data. Exercise Level GROUP Rest VLPO LPO MPO LOS (n=7) 97.7±0.9 97.3±0.5 96.1 ±0.8 95.6± 1.1 NOS (n=5) 97.8 ± 0.8 97.6 ± 0.7 96.4 ± 0.6 96.3 ± 0.8 Values are means ± SD. Units are %; LOS, low oxygen saturation; NOS, normal oxygen saturation. VLPO, very low power output; LPO, low power output; MPO, moderate power output. 69 Table 18 Pre-hyperoxic peripheral chemoresponse SaO2, individual subject data. Exercise Level SUBJECT TM PT DB GA HT BT RR SF MF DH ME JF MEAN±SD Rest 99.4± 1.4 97.0± 1.1 97.6±0.6 98.0±0.8 97.0± 1.3 96.7 ± 2.1 97.2± 1.3 96.9± 1.1 97.9± 1.7 97.9±0.9 98.9± 1.9 98.3± 1.2 97.7±0.8 VLPO 98.1 ± 1.0 96.8±0.8 96.7 ± 0.9 97.9±0.4 97.2±0.9 97.2±0.8 98.2± 1.3 97.2± 1.0 98.1±0.9 96.5 ± 0.6 97.8±0.5 96.9± 1.2 97.4±0.6 LPO 97.2±0.5 96.1 ±0.8 95.4± 1.1 96.5 ± 0.4 97.0 ± 0.6 95.8 ±0.9 96.1 ± 1.3 96.1 ± 1.1 97.5±1.2 96.3 ± 0.9 96.2±0.8 94.9± 1.6 96.3 ± 0.7 MPO 97.2±0.9 96.2± 1.0 95.0 ± 0.7 96.2 ± 0.6 96.3±0.7 94.3±1.4 96.1 ± 1.3 96.0 ± 0.5 95.4± 1.7 97.5±0.5 96.6± 1.0 94.2± 1.0 95.9± 1.0 Values are means ± SD. Units are %. VLPO, very low power output; LPO, low power output; MPO, moderate power output. saturation. VLPO, very low power output; LPO, low power output; MPO, moderate power output. 70 Table 19 RMANOVA, Hypercapnic Chemoresponse. UNIVARIATE AND MULTIVARIATE REPEATED MEASURES ANALYSIS BETWEEN SUBJECTS SOURCE SS DF MS F P GROUP 1.563 1 1.563 13.652 0.004 ERROR 1.145 10 0.115 WITHIN SUBJECTS SOURCE SS DF MS F P G-G H-F LEVELS 2.012 3 0.67 1 10.446 0.000 0.001 0.000 LEVELS X 0.172 3 0.057 0.894 0.456 0.426 0.451 GROUPS ERROR 1.926 30 0.064 GREENHOUSE-GEISSER EPSILON: 0.6811 HUYNH-FELDT EPSILON: 0.9433 71 Table 20 Polynomial Contrasts, Hypercapnic Chemoresponse. SINGLE DEGREE OF FREEDOM POLYNOMIAL CONTRASTS POLYNOMIAL TEST OF ORDER 1 (LINEAR) SS DF MS F 1.469 1 1.469 13.413 P 0.004 SOURCE LEVELS LEVELS X 0.042 1 0.042 0.380 0.552 GROUPS ERROR 1.095 10 0.110 POLYNOMIAL TEST OF ORDER 2 (QUADRATIC) SOURCE SS DF MS F P LEVELS 0.540 1 0.540 8.197 0.017 LEVELS X 0.090 1 0.090 1.370 0.269 GROUPS ERROR 0.658 10 0.066 POLYNOMIAL TEST OF ORDER 3 (CUBIC) SOURCE SS DF MS F P LEVELS 0.003 1 0.003 0.189 0.673 LEVELS X 0.040 1 0.040 2.343 0.157 GROUPS ERROR 0.173 10 0.017 72 Table 21 RMANOVA, Pre-Hypercapnic Chemoresponse SaO2. UNIVARIATE AND MULTIVARIATE REPEATED MEASURES ANALYSIS BETWEEN SUBJECTS SOURCE SS DF MS F P GROUP 0.024 1 0.024 0.019 0.894 ERROR 13.092 10 1.309 WITHIN SUBJECTS SOURCE SS DF MS F P G-G H-F LEVELS 23.103 3 7.701 15.120 0.000 0.000 0.000 LEVELS X 4.909 3 1.636 3.213 0.037 0.044 0.037 GROUPS ERROR 15.280 30 0.509 GREENHOUSE-GEISSER EPSILON: 0.8860 HUYNH-FELDT EPSILON: 1.0000 73 Table 22 Polynomial Contrasts, Pre-Hypercapnic Chemoresponse SaO2, SINGLE DEGREE OF FREEDOM POLYNOMIAL CONTRASTS POLYNOMIAL TEST OF ORDER 1 (LINEAR) SOURCE SS DF MS F P LEVELS 22.548 1 22.548 34.299 0.000 LEVELS X 1.488 1 1.488 2.264 0.163 GROUPS ERROR 6.574 10 0.657 POLYNOMIAL TEST OF ORDER 2 (QUADRATIC) SOURCE SS DF MS F P LEVELS 0.550 1 0.550 1.555 0.241 LEVELS X 2.333 1 2.333 6.596 0.028 GROUPS ERROR 3.537 10 0.354 POLYNOMIAL TEST OF ORDER 3 (CUBIC) SOURCE SS DF MS F P LEVELS 0.005 1 0.005 0.010 0.922 LEVELS X 1.088 1 1.088 2.105 0.177 GROUPS ERROR 5.169 10 0.517 74 Table 23 RMANOVA, Hyperoxic Chemoresponse. UNIVARIATE AND MULTIVARIATE REPEATED MEASURES ANALYSIS BETWEEN SUBJECTS SOURCE SS DF MS F P GROUP 0.026 1 0.026 0.000 0.988 ERROR 1081.887 10 108.189 WITHIN SUBJECTS SOURCE SS DF MS F P G-G H-F LEVELS 117.389 3 39.130 2.152 0.115 0.130 0.115 LEVELS X 66.757 3 22.252 1.224 0.318 0.317 0.318 GROUPS ERROR 545.572 30 18.186 GREENHOUSE-GEISSER EPSILON: 0.8019 HUYNH-FELDT EPSILON: 1.0000 75 Table 24 Polynomial Contrasts, Hyperoxic Chemoresponse. SINGLE DEGREE OF FREEDOM POLYNOMIAL CONTRASTS POLYNOMIAL TEST OF ORDER 1 (LINEAR) SS DF MS FSOURCE P LEVELS 83.122 1 83.122 2.968 0.116 LEVELS X 11.933 1 11.933 0.426 0.529 GROUPS ERROR 280.023 10 28.002 POLYNOMIAL TEST OF ORDER 2 (QUADRATIC) SOURCE SS DF MS F P LEVELS 34.114 1 34.114 2.267 0.163 LEVELS X 28.392 1 28.392 1.887 0.200 GROUPS ERROR 150.498 10 15.050 POLYNOMIAL TEST OF ORDER 3 (CUBIC) SOURCE SS DF MS F P LEVELS 0.153 1 0.153 0.013 0.911 LEVELS X 26.432 1 26.432 2.297 0.161 GROUPS ERROR 115.051 10 11.505 76 Table 25 RMANOVA, Pre-Hyperoxic Chemoresponse SaO2. UNIVARIATE AND MULTIVARIATE REPEATED MEASURES ANALYSIS BETWEEN SUBJECTS SOURCE SS DF MS F P GROUP 1.332 1 1.332 0.966 0.349 ERROR 13.791 10 1.379 WITHIN SUBJECTS SOURCE SS DF MS F P G-G H-F LEVELS 25.502 3 8.501 18.769 0.000 0.000 0.000 LEVELS X 0.619 3 0.206 0.456 0.715 0.669 0.715 GROUPS ERROR 13.588 30 0.453 GREENHOUSE-GEISSER EPSILON: 0.7780 HUYNH-FELDT EPSILON: 1.0000 77 Table 26 Polynomial Contrasts, Pre-Hyperoxic Chemoresponse SaO2. SINGLE DEGREE OF FREEDOM POLYNOMIAL CONTRASTS POLYNOMIAL TEST OF ORDER 1 (LINEAR) SS DF MS F 23.989 1 23.989 36.276 P 0.000 SOURCE LEVELS LEVELS X 0.552 1 0.552 0.835 0.382 GROUPS ERROR 6.613 10 0.661 POLYNOMIAL TEST OF ORDER 2 (QUADRATIC) SOURCE SS DF MS F P LEVELS 0.001 1 0.001 0.002 0.967 LEVELS X 0.011 1 0.011 0.019 0.892 GROUPS ERROR 5.696 10 0.570 POLYNOMIAL TEST OF ORDER 3 (CUBIC) SOURCE SS DF MS F P LEVELS 1.512 1 1.512 11.828 0.006 LEVELS X 0.056 1 0.056 0.439 0.523 GROUPS ERROR 1.278 10 0.128 78 Table 27 Linear Regression, Hypercapnic Chemoresponse and Pre-Hypercapnic Chemoresponse SaO2, NOS subjects. DEPENDANT VARIABLE IS SATURATION N R R2 ADJ. R2 S.E.E. 20 0.3 12 0.097 0.047 0.835 REGRESSION COEFFICIENTS VARIABLE COEFF. STD STD TOLERANCE T P(2 TAIL) ERROR COEF CONSTANT 97.479 0.546 0.000 . 178.460 0.000 RESP -0.660 0.474 -0.312 1.000 -1.392 0.181 ANALYSIS OF VARIANCE SOURCE SS DF MS F P REGRESSION 1.351 1 1.351 1.937 0.181 RESIDUAL 12.554 18 0.697 79 Table 28 Linear Regression, Hypercapnic Chemoresponse and Pre-Hypercapnic Chemoresponse SaO2, LOS subjects. DEPENDANT VARIABLE IS SATURATION N R R2 ADJ. R2 S.E.E. 28 0.338 0.115 0.080 1.247 REGRESSION COEFFICIENTS VARIABLE COEFF. STD STD TOLERANCE T P(2 TAIL) ERROR COEF CONSTANT 97.954 0.666 0.000 . 146.979 0.000 RESP -1.596 0.870 -0.338 1.000 -1.834 0.078 ANALYSIS OF VARIANCE SOURCE SS DF MS F P REGRESSION 5.227 1 5.227 3.364 0.078 RESIDUAL 40.400 26 1.554 80 Table 29 Linear Regression, Hyperoxic Chemoresponse and Pre-Hyperoxic Chemoresponse SaO2, NOS subjects. DEPENDANT VARIABLE IS SATURATION N R R2 ADJ. R2 S.E.E. 20 0.217 0.047 0.000 0.938 REGRESSION COEFFICIENTS VARIABLE COEFF. STD STD TOLERANCE T P(2 TAIL) ERROR COEF CONSTANT 96.454 0.635 0.000 . 151.785 0.000 RESP 0.032 0.034 0.217 1.000 0.944 0.358 ANALYSIS OF VARIANCE SOURCE SS DF MS F P REGRESSION 0.784 1 0.784 0.890 0.358 RESIDUAL 15.848 18 0.880 81 Table 30 Linear Regression, Hyperoxic Chemoresponse and Pre-Hyperoxic Chemoresponse SaO2, LOS subjects. DEPENDANT VARIABLE IS SATURATION N R R2 ADJ. R2 S.E.E. 28 0.121 0.015 0.000 1.212 REGRESSION COEFFICIENTS VARIABLE COEFF. STh STD TOLERANCE T P(2 TAIL) ERROR COEF CONSTANT 97.098 0.708 0.000 . 137.235 0.000 RESP -0.023 0.038 -0.121 1.000 -0.621 0.540 ANALYSIS OF VARIANCE SOURCE SS DF MS F P REGRESSION 0.566 1 0.566 0.385 0.540 RESIDUAL 38.195 26 1.469 82 C 1) 0 APPENDIX C FIGURES Figure 7 Power output at various exercise intensities, group data. 350 - 300 - _ 250 - 200 - 150 - 100 - 50 0- Values are means ± SD. Open circles, LOS, low oxygen saturation; Open squares, NOS, normal oxygen saturation. VLPO, very low power output; LPO, low power output; MPO, moderate power output. VLPO LPO MPO 83 Figure 8 Power output at various exercise intensities, NOS subjects. 350 300 250 200 a z 150 C 100 50 0 VLPO, very low power output; LPO, low power output; MPO, moderate power output. p RR D SF p MF —N---- DH w ME Rest VLPO LPO MPO 84 Figure 9 Power output at various exercise intensities, LOS subjects. 350 300 250 200 0 150 C 100 50 0 p TM D PT p DB —NH-- GA w HT L BT —0---— JF VLPO, very low power output; LPO, low power output; MPO, moderate power output. Rest VLPO LPO MPO 85 Figure 10 Hypercapnic peripheral chemoresponse at various exercise intensities, NOS subjects. 2.0 - p RR 1- 1.U D SF - o MF 12 - —N-—DH 1) rJ) 08 ____ wME o 0.4- c) 0.0- I VLPO, very low power output; LPO, low power output; MPO, moderate power output. Rest VLPO LPO MPO 86 Figure 11 Hypercapnic peripheral chemoresponse at various exercise intensities, LOS subjects. 2.0 - p TM 1.6- D PT oDB 12 I I• I Rest VLPO MPO VLPO, very low power output; LPO, low power output; MPO, moderate power output. LPO 87 Figure 12 Pre-C02 response SaO2 at various exercise intensities, NOS subjects. 100 - p RR 99 D SF 98 0 MF 97- —-—DH 96- 8 m ME 95- 94 - 93 - VLPO, very low power output; LPO, low power output; MPO, moderate power output. Rest VLPO LPO MPO 88 Figure 13 Pre-C02 response SaO2 at various exercise intensities, LOS subjects. 100 - p TM o PT 98 0 DB —s--- GA w HT 96- BT —0--— JF 95 - 94 - 93 I I I I Rest VLPO LPO MPO VLPO, very low power output; LPO, low power output; MPO, moderate power output. 89 Figure 14 Hyperoxic peripheral chemoresponse at various exercise intensities, NOS subjects. 35 - p RR 30 D SF 25 ___ 20: —is-—DH 15 W ME 10 - 5- I I Rest MPO VLPO, very low power output; LPO, low power output; MPO, moderate power output. VLPO LPO 90 Figure 15 Hyperoxic peripheral chemoresponse at various exercise intensities, LOS subjects. 35 - p TM 30 D PT p DB 25- —N--GA w HT 20 BT is- —Q-—JF 10 - 5- I VLPO, very low power output; LPO, low power output; MPO, moderate power output. Rest VLPO LPO MPO 91 Figure 16 Pre-02 response SaO2 at various exercise intensities, NOS subjects. 100 - 99 - 95 - 94 - p RR D SF p MF —1SF— DH w ME 93 I I I Rest VLPO LPO MPO VLPO, very low power output; LPO, low power output; MPO, moderate power output. 98 - 97 - 96 -I 92 Pre-02 response SaO2 at various exercise intensities, LOS subjects. p TM D PT p DB —u-— GA w HT BT —0— JF Figure 17 100 - 99 - 95- 94 - 93- VLPO, very low power output; LPO, low power output; MPO, moderate power output. Rest VLPO LPO MPO 93 APPENDIX D Table 31 EXCLUDED SUBJECT DATA Age, height, mass, and body surface area, individual subject data. Subject Age Height Mass BSA (yrs) (cm) (kg) (m2) AC 42 173 68.0 1.81 AS 21 180 73.4 1.93 BG 35 181 77.8 1.98 CA 27 181 77.2 1.97 CJ 26 172 61.0 1.72 DL 32 191 94.6 2.25 FH 35 176 68.3 1.83 FM 25 181 77.6 1.98 JG 34 191 94.0 2.23 TV 23 181 78.6 1.99 KR 25 187 88.2 2.14 MF-W 22 181 65.0 1.84 MF-J 23 178 68.1 1.85 MS 24 183 81.0 2.03 MT 25 180 70.2 1.89 MW 28 172 65.8 1.78 NG 28 180 77.6 1.97 PK 26 185 84.5 2.09 RH 25 186 80.7 2.06 RM 29 183 78.9 2.01 TC 27 185 85.3 2.10 94 TG 26 187 81.2 2.06 TR 37 193 92.0 2.23 TS 29 172 64.9 1.76 mean±SD 28±5 182±6 77.2±9.5 1.98±0.15 Values are means ± SD. 95 Table 32 Age, height, mass, and body surface area, group data. Age Height Mass BSA GROUP (yrs) (cm) (kg) (m2) UNFIT,NORMAL 30±6 182±7 79.7±9.7 2.01±0.16 (n = 8) UNFIT, EN 29±7 187±6 87.5 ±9.2 2.13 ±0.14 (n = 2) FIT,NORMAL 28±5 181±6 75.5±9.1 1.95±0.15 (n = 11) FIT, EIH 24±3 180± 2 70.1± 6.3 1.89±0.07 (n = 3) Values are means ± SD. Groups are UNFIT, (VO2max <5.00 L•min’ or 60.0 mL•min l.kg4);FIT, (VO2max 5.00 L•min’ or 60.0 mL.min1.kgi); NORMAL, (SaO2max> 91.0 %); EIH, (SaO2max 91.0 %). 96 Table 33 VO2max, peak power output, and lowest arterial hemoglobin saturation during maximal cycle ergometer test, individual subject data. Subject VO2max VO2max Peak Power SaO2max (Lmin1) (mL.min4.kg1) (Watts) (%) AC 3.89 57.2 381 92.4 AS 4.72 64.3 500 93.0 BG 4.14 53.2 389 95.5 CA 5.15 66.7 450 90.0 CJ 4.25 69.7 410 91.5 DL 4.68 49.5 418 95.0 FH 4.38 64.1 415 91.3 FM 4.34 55.9 404 93.8 JG 4.82 51.3 445 90.4 JV 5.23 66.6 500 91.7 KR 4.44 50.3 430 93.2 MF-W 4.81 66.2 475 89.1 MF-J 4.60 67.6 475 90.3 MS 4.55 56.2 435 90.3 MT 4.68 66.6 475 92.3 MW 3.83 58.2 396 94.9 NG 4.67 60.2 412 91.1 PK 4.58 54.2 450 93.2 RH 4.86 60.2 445 92.8 RM 4.89 62.0 450 91.5 TC 5.01 58.7 465 91.8 TG 4.80 59.1 445 91.9 97 TR 5.59 60.8 488 91.9 TS 4.86 74.9 410 94.4 mean ± SD 4.66 ± 0.40 60.6 ± 6.5 440±34 92.2 ± 1.7 Values are means ± SD. 98 Table 34 VO2max, peak power output, and lowest arterial hemoglobin saturation during maximal cycle ergometer test, group data. GROUP VO2max (L.min’) 4.34±0.34 VO2max (mLmin’ .kg’) 54.7 ± 3.6 Peak Power (Watts) 414±26 SaO2max (%) 93.7± 1.3UNFIT, NORMAL (n = 8) UNFIT,EIH 4.69±0.19 53.8±3.5 440±7 90.4±0.1 (n = 2) FIT, NORMAL 4.83 ± 0.37 64.4 ± 4.8 452 ± 36 92.1 ± 1.0 (n = 11) FIT, EN 4.85 ± 0.28 66.8 ± 0.7 467 ± 14 89.8 ± 0.6 (n = 3) Values are means ± SD. Groups are UNFIT, (VO2max <5.00 L•min1 or 60.0 mL•min ‘.kg4); FIT, (VO2max 5.00 L•min1 or 60.0 mL.min1.kg);NORMAL, (SaO2max> 91.0 %); EIH, (SaO2max 91.0 %). 99 Table 35 VO2TH, and power output at VO2TH’ individual subject data. VO2TH VO2 Power at Subject (L•min’) (mL•min’•kg1) (Watts) AC 2.98 43.8 260 AS 3.20 43.6 310 BG 2.26 29.0 200 CA 3.50 45.3 280 CJ 2.73 44.8 250 DL 3.23 34.1 250 FH 2.74 40.1 238 FM 3.03 39.0 275 JG 2.98 31.7 255 JV 3.50 44.5 325 KR 3.10 35.2 270 MF-W 2.60 40.0 270 MF-J 2.93 43.1 280 MS 3.08 38.0 275 MT 2.84 34.7 280 MW 2.81 42.7 280 NG 3.00 39.3 234 PK 2.96 35.0 265 RH 3.35 41.4 280 RM 2.90 36.8 245 TC 3.30 38.7 290 TG 3.12 38.4 275 TR 3.84 41.8 310 100 TS 3.20 49.3 275 mean ± SD 3.05 ± 0.33 39.6 ± 4.8 270±27 Values are means ± SD. 101 Table 36 VO2TH , and power output at VO2TH, group data. VO2TH V02Th Power at VO2 GROUP (L•min’) (mL•min1•kg) (Watts) UNFIT, NORMAL 2.94 ± 0.30 37.2 ± 4.8 259±26 (n = 8) UNFIT, EN 3.03 ± 0.07 34.9 ± 4.5 265 ± 14 (n = 2) FIT, NORMAL 3.15 ±0.15 41.4±4.1 276±31 (n = 11) FIT, EIH 3.01 ± 0.46 42.8 ± 2.7 277±6 (n = 3) Values are means ± SD. Groups are UNFIT, (VO2max <5.00 L•min’ or 60.0 mL•min ‘.kg’); FIT, (VO2max 5.00 L•min’ or 60.0 mL.min1•kg4);NORMAL, (SaO2max> 91.0 %); EIH, (Sa°2max 91.0 %). 102

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