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Peripheral chemoresponsiveness and exercise induced arterial hypoxemia in highly trained endurance athletes Cooper, Trevor Kenneth 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 0.82 L, FEV1 /FVC  =  =  4.69 ± 0.66 L, PVC  =  0.77 ± 0.08, FEFmax = 10.52 ± 1.57 L•sec’ and MVV ,  6.12 ±  =  194 ±  21 L.min’) were obtained on all subjects. Subjects exercised on a cycle ergometer to exhaustion to determine their maximal aerobic capacity (“O2max •kg mL.min ) , and ventilatory threshold (VO2TH 66.6 ± 4.7 1  =  =  , 1 5.08 ± 0.32 Lmin  , 1 3.29 ± 0.12 Lmin  ). Oxygen saturation of arterial hemoglobin (SaO2max) was 1 44.3 ± 4.2 mL.minl.kg monitored with an ear oximeter (Hewlett-Packard, 47201A), to determine whether subjects exhibited EIH (SaO2max Subjects with SaO2max Sa°2max  =  91%) during the maximal cycle ergometer test.  93% were placed in the normal saturation group (NOS,  93.4 ± 0.4 %) while subjects whose SaO2max  saturation group (LOS, 5 a°2max  =  91% were placed in the low  89.9 ± 0.9 %). Ventilatory responses to hypercapnic  (13% C0 ) and hyperoxic (100% 02) gas mixtures were determined at 2 , 21% 02, 66% N 2 rest, and during exercise on a cycle ergometer at approximately 25% VO2max, 50% Th. Hypercapnic peripheral chemoresponsiveness was lower in LOS 2 VO2max, V0 subjects than NOS subjects and increased in both groups from rest to 50 % VO max. 2 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 VO 2 during 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  xv  Acknowledgment 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 12  Statistical Analysis  14  Results 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 26  Hemoglobin Saturation  iv  Hyperoxic Chemoresponse  .  Pre-Stimulus Arterial Hemoglobin Saturation  27 30  Hyperoxic Peripheral Chemoresponse and Pre-Stimulus Arterial 32  Hemoglobin Saturation  33  Discussion  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 50  Exercise Induced Arterial Hypoxemia 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 53  Ventilatory Control Control Mechanisms  53  Central Control of Ventilation  54  Supra-Pontine Control  54  Central Chemoreception  55  Spinal Motor Neuron Interaction  55 55  Peripheral Control of Ventilation 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  max, peak power output, and SaO2max of subjects, group 2 VO 18  data and power output at VO , group data 2  18  Table 4  TH, 2 VO  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  max peak power output, and SaO2max individual subject 2 VO ,  ,  data  60  Table 9  Ti-j, individual data 2 TH, and power output at VO 2 VO  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  Table 28  Linear Regression, Hypercapnic Chemoresponse and Pre Hypercapnic Chemoresponse SaO2, LOS subjects  Table 29  79  80  Linear Regression, Hyperoxic Chemoresponse and Pre-Hyperoxic Chemoresponse SaO2, NOS subjects  81  Table 30  Linear Regression, Hyperoxic Chemoresponse and Pre-Hyperoxic  Table 31  Chemoresponse SaO2, LOS subjects 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  max, peak power output, and SaO2max, individual subject 2 VO  82  data  97  Table 34  max, peak power output, and SaO2max, group data 2 VO  99  Table 35  TH, and power output at /O 2 VO m, individual subject data 2  100  Table 36  TH, and power output at VO 2 VO TH, group data 2  102  vrn  LIST OF FIGURES Figure la  PCO2, P02, and Vj of single hypercapnic peripheral 21  chemoresponse Figure lb  PETCO2, ETO2, and Vj for a single hypercapnic peripheral 23  chemoresponse 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 27  chemoresponse Figure 4b  PETCO2, ETO2, and Vj for a single hyperoxic peripheral 29  chemoresponse 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 86  intensities, NOS subjects Figure 11  Hypercapnic peripheral chemoresponse at various exercise 87  intensities, LOS subjects Figure 12  Pre-C02 response SaO2 at various exercise intensities, NOS 88  subjects Figure 13  Pre-C02 response SaO2 at various exercise intensities, LOS 89  subjects Figure 14  Hyperoxic peripheral chemoresponse at various exercise 90  intensities, NOS subjects  ix  Figure 15  Hyperoxic peripheral chemoresponse at various exercise intensities, LOS subjects  Figure 16  91  Pre-02 response SaO2 at various exercise intensities, NOS 92  subjects Figure 17  Pre-O2 response SaO2 at various exercise intensities, LOS 93  subjects  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. Omnibus F ratio for RMANOVA trials x group interaction with x  F(x,y)int  numerator degrees of freedom, and y denominator degrees of freedom. Omnibus F ratio for linear polynomial contrast with 1 numerator degree  F(1,y)lin  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.  2 VCO  Rate of carbon dioxide elimination.  VE  Volume of air expired.  VE  Expired ventilation, or volume of air expired per minute.  2 VE/VCO  Ventilatory equivalent for carbon dioxide elimination.  2 VE/V0  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.  2 V0  Rate of oxygen uptake.  VO2max  Maximal rate of oxygen uptake.  x1u  2 VO  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 ) and maximal pulmonary blood volumes 1 33 L•min  (  ( 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 % VO max (11) while another group (20) did not 2 -  find evidence for such a hypoventilation accompanying a similar level of exercise induced arterial hypoxemia during exercise at essentially VO max. The difference 2 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 Pa 2 and ventilatory 0 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  1 or 60.0 1 •kg mL•min . 5.0 L•min  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 ) at a steadily increasing work rate (30 Watts•min’ ramp) from zero 1 revolutions•min load until they discontinued the test, or their pedaling frequency fell below 30 . During the test subjects breathed through a two-way, non-rebreathing 1 revolutions•minvalve (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 (V0 ). After the 2 ) and carbon dioxide elimination (VO 2 test was completed the VO 2 at the ventilatory threshold (VO TH) was determined 2 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 VO 2 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 V0 2 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 V0 2 intervals with the largest difference (Dmax) producing the 2 VO for that subject. Work rates at approximately 25% of VO2max, 50% of VO2max and 2 VO T H were determined from linear least squares regression analysis of VO 2 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 VO 2 (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 V0 , 2 , and VE on a breath-by-breath basis as well as an accurate record of end-tidal 02 2 VCO and C02 pressures (PETO2 and PETCO2) during the steady-state period preceding the chemoresponse tests. The V0 , VCO 2 , and VE data obtained and displayed in real time 2 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 twoway 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 Sa 2 was determined 0 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 VO .kg, and 1 max was less than 5.00 L•min’ or 60.0 mL•min 2 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 VO max 2  1 or 60.0 5.00 L•min  mL•min’ •kg 1 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 VO max values. 2 Interestingly, two subjects that did not satisfy the fitness selection criteria (VO max 2  =  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 TH data for subjects not qualifying for 2 VO2max, peak power, SaO2max and VO 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. Age, height, mass and body surface area of subjects, group data.  Table 1  AGE  HEIGHT  MASS  BSA  (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  GROUP  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 (L) (% Pred.)  FEV1 (L) (% Pred.)  FEV1/FVC  GROUP  FEFmax (L•sec’) (% Pred.)  LOS (n=7)  5.76 ± 0.78  4.51 ± 0.65  0.79 ± 0.09  11.25 ± 1.44  104± 12  98±7  6.60 ± 0.63  4.95 ± 0.65  107±4  97±6  NOS (n=5)  0.75 ± 0.07  MVV (L.min’) (% Pred.) *  197 ± 16  132± 14  109± 10  9.49 ± 1.18  188±27  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 VO max, or peak power 2 output (Table 3). Results from the VO2max test for all subjects are listed in Table 8. The •kg mL•min , mean VO2max of all subjects was 5.08 ± 0.32 L•min’ or 66.6 ± 4.7 1 indicating the high training status of the subjects. Values for VO max for subjects in both 2 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 VO max for subjects in each group 2 (LOS, 59.6 74.5; NOS, 62.6 69.9 1 .kg mL.min ) . As a result there was not a -  -  significant relationship between VO max and SaO2max in these subjects (r = 0.138, 2 F(1,10)reg  =  0.193, p  groups (LOS, r  =  =  0.669). This remained the case when subjects were separated into  0.392, F(1 1O)reg  =  0.909, p  17  =  0.384; NOS, r = 0.592, F(1,10)reg  =  1.62 1, p  =  0.293). These results are contrary to those reported previously by other authors  (39, 42). max peak power output, and SaO2max of subjects, group data. 2 VO  Table 3  ,  max 2 VO  VO2max  Peak Power  SaO2max  (L.minl)  .kgi) 1 (mL.min  (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  GROUP  *  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 VO TH of subjects in the LOS group was higher than in the NOS group 2 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 VO m than NOS 2 subjects  2 are listed in Table (tio = 3.346, p = 0.004). Individual subject values for VO  9. TH, group data. 2 TH, and power output at VO 2 VO  Table 4  TH 2 VO  2 VO  Power at VO TH 2  (L.min’)  .kg’) 1 (mL.min  (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 ±  Group  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 VO TH. Since this was thought to average around 75 2 % of VO max in highly trained endurance cyclists the absolute workloads of 25 % and 2 50 % of VO max and VO 2 TH were chosen for the lower exercise levels. This would have 2 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 VO TH of LOS subjects was higher than NOS subjects and as a result the 2 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 /power output relationship, are listed in Table 10. 2 V0  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.  8060-  I  I  I  I  I  180 140 120 100 100 90 80 70 > 60 50 40 ‘  -10  I  I  I  I  I  I  -5  0  5 Time (sec)  10  15  20  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 chemoresponse.  0  9-  50 40  0 -  0  0  00O00 I  —  I  0000  I  I  120 E  0  -  116 -000 114 ‘  112  0  0  00  0  I  —  0  0 I  0  0  0  0  0  I  I  1 60  140 120  0  -  100  0  80 -10  0,0  0  0•  0  0  I  I  I  -5  0  5 Time (sec)  ,0  0  0,0  0  0,  —  10  15  20  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.  23  Figure 2  Hypercapnic peripheral chemoresponse at various exercise intensities, group data.  2-  E E  1.5:  -  1—  C CM  0.5  -  C U 0-  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. 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  24  workloads in both groups (F(1,10)quad = 8.197, p  =  0.017). Individual subject, averaged,  hypercapnic chemoresponses are listed in Table 11.  Pre-C02 response SaO2 at various exercise intensities, group data.  Figure 3  100 99 98 97 96 95  -  -  -  -  -  94 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 Sa 2 during hypercapnic peripheral chemoresponse trials was 0 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,  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, r 2 0.115, p  =  2 =0.097, p 0.078; NOS, r  =  0.181).  26  =  HYPEROXIC CHEMORESPONSE The results of a typical hyperoxic peripheral chemoresponse trial can be seen in Figure 4a and Figure 4b.  PCO2, P02, and Vj of a single hyperoxic peripheral chemoresponse.  Figure 4a 60-  ir 800  ;  -  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  1 for a single hyperoxic peripheral PETCO2, ETO2, and V chemoresponse. -  E E  550 :popp00Co°°°,°  -  800  60O40O0200-  0 0-  0000000 I  —  140  0  0 I  I  I  -  120 100-  -  00  pOp  000 U  0  1  U-  60-10  -5  00 0 0 0  000  I  I  I  I  I  I  0  5  10 Time (see)  15  20  25  30  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  0.115), nor was there a significant interaction effect (F(3,30)int  1.224, p  =  =  2.152, 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.  30  25  20  15  10  5  -  -  -  -  -  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  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.  Pre-02 response SaO2 at various exercise intensities, group data.  Figure 6  100 99 C  98  -  -  -  ti) C  97 96 95  -  -  -  94Rest  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.  31  Hyperoxic Peripheral Chemoresponse and Pre-Stimulus Arterial Hemoglobin Saturation There was not a significant linear relationship between hyperoxic peripheral 2 chemoresponse and pre-stimulus SaO2 in either group of subjects (LOS, r 2 0.540; NOS, r  =  0.002, p  =  0.846).  32  =  0.015, p  =  DISCUSSION Exercise induced arterial hypoxemia occurs in 40 to 50 % of highly trained endurance athletes (39, 42) and has a detrimental effect on both VO max and exercise 2 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 2 VO m ax 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 2 VO m ax 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  max criteria, or 3) they qualified for the LOS group but that group was already full. 2 VO The incidence of exercise induced arterial hypoxemia in all subjects meeting the VO max 2 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 VO max criteria that did 2 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 VO max. 2 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 ) than 1 athletes in this study was higher at rest (mean ± SD, 0.54 ± 0.30 L•minl.mmHg .mmHg 4 L.min ) values reported for healthy untrained males (mean ± SD, 0.38 ± 0.14 1 (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 VO max, although 2 both groups were exercising at their VO , and the difference in hypercapnic peripheral 2 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, P a 1 1 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.  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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 .kg to highly trained endurance athletes mL.min ) max of approximately 40 1 2 (VO .kg which of these potentially limiting mLmin ) max of approximately 60 to 75 1 2 (VO 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 and highly trained endurance athletes (VE/V0 2  =  =  19.0 ± 0.4, V]/Vco 2  15.7 ± 0.2, VE/VCO 2  =  22.6 ± 0.7) 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 P0 2 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 CO 2 (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, , CO 2 2 flux to the 5. a sensor responding to pulmonary blood flow, mixed venous C0 lung, or some other unknown humoral substance, 6. an intrapulmonary chemoreceptor, also not yet identified, sensing mixed venous blood pH.  53  2 This feed-forward response would yield an exercise ventilation proportional to the CO 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 2 CO 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 t the maximal reduction in ventilation during administration of 100% 02 (i.e., ‘silencing 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 .mmHg in healthy untrained individuals (32) to as high L•min range from 0.38 ± 0.14 1 •mmHg’ in highly trained endurance athletes at rest (25). Thus, 1 as 2.15 ± 0.62 L•min 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  APPENDIX B TABLES Table 6  Age, height, mass, and body surface area, individual subject data. AGE  HEIGHT  MASS  BSA  (yrs)  (cm)  (kg)  (m2)  TM  28  177  65.7  1.81  PT  31  183  84.0  2.06  DB  27  190  76.3  2.03  GA  24  184  81.4  2.04  HT  24  174  69.8  1.84  BT  46  179  79.7  1.98  RR  28  184  78.6  2.01  SF  25  178  74.7  1.93  MF  33  184  79.9  2.03  DH  21  191  80.8  2.09  ME  20  189  80.8  2.08  JF  22  174  67.2  1.80  MEAN±SD  27±7  182± 6  76.6 ± 6.0  1.98 ±0.11  SUBJECT  58  Table 7  Pulmonary function, individual subject data. FVC (L) (% Pred.)  FEV1 (L) (% Pred.)  FEVi/FVC  FEFm (L•sec’) (% Pred.)  MVV (L•min) (% Pred.)  TM  5.21 98  3.72 84  0.71  9.40 114  183 105  PT  6.99 122  4.80 101  0.69  11.58 133  211 115  DB  6.31 98  5.39 101  0.85  12.07 138  203 102  GA  5.71 95  5.27 105  0.92  13.48 152  221 114  HT  6.20 120  4.25 98  0.69  9.70 116  183 102  BT  5.13 104  3.99 99  0.78  11.90 146  203 128  RR  6.39 107  4.62 94  0.72  8.10 93  184 97  SF  6.18 112  4.07 88  0.66  9.18 107  158 85  MF  5.91 102  4.91 102  0.83  9.25 107  192 105  DH  7.31 109  5.74 103  0.79  11.36 125  231 111  ME  7.20 107  5.40 98  0.75  9.55 105  177 86  IF  4.77 92  4.15 95  0.87  10.65 128  178 98  MEAN± SD  6.11±0.82 105±9  4.69±0.66 97±6  0.77±0.08  10.52±1.57 122±18  194±21 97±11  SUBJECT  59  Table 8  max, peak power output, and SaO2max, individual subject data. 2 VO max 2 VO  max 2 VO  Peak Power  SaO2max  ) 1 (L•min  .kg (mL•min ) 1  (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  SUBJECT  SaO2m is the lowest arterial hemoglobin saturation during maximal cycle ergometer test.  60  Table 9  TH and power output at VO 2 VO TH, individual data. 2 ,  ‘‘O2Th  2 VO  Power at VO TH 2  (L•min’)  1 .kg (mL•min ) 1  (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  SUBJECT  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  •mmHg LOS, low oxygen saturation; NOS, L•min ; Values are means ± SD Units are 4 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 1 •mmHg LOS, low oxygen saturation; NOS, Lmin ; 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  Rest  VLPO  LPO  MPO  TM  99.4± 1.4  98.1 ± 1.0  97.2±0.5  97.2±0.9  PT  97.0± 1.1  96.8±0.8  96.1 ±0.8  96.2± 1.0  DB  97.6±0.6  96.7 ± 0.9  95.4± 1.1  95.0 ± 0.7  GA  98.0±0.8  97.9±0.4  96.5 ± 0.4  96.2 ± 0.6  HT  97.0± 1.3  97.2±0.9  97.0 ± 0.6  96.3±0.7  BT  96.7 ± 2.1  97.2±0.8  95.8 ±0.9  94.3±1.4  RR  97.2± 1.3  98.2± 1.3  96.1 ± 1.3  96.1 ± 1.3  SF  96.9± 1.1  97.2± 1.0  96.1 ± 1.1  96.0 ± 0.5  MF  97.9± 1.7  98.1±0.9  97.5±1.2  95.4± 1.7  DH  97.9±0.9  96.5 ± 0.6  96.3 ± 0.9  97.5±0.5  ME  98.9± 1.9  97.8±0.5  96.2±0.8  96.6± 1.0  JF  98.3± 1.2  96.9± 1.2  94.9± 1.6  94.2± 1.0  MEAN±SD  97.7±0.8  97.4±0.6  96.3 ± 0.7  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 MULTI VARIATE 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 GROUPS  0.172  3  0.057  0.894  0.456  0.426  0.451  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)  SOURCE  SS  DF  MS  F  P  LEVELS  1.469  1  1.469  13.413  0.004  LEVELS X GROUPS  0.042  1  0.042  0.380  0.552  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 GROUPS  0.090  1  0.090  1.370  0.269  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 GROUPS  0.040  1  0.040  2.343  0.157  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 GROUPS  4.909  3  1.636  3.213  0.037  0.044  0.037  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 GROUPS  1.488  1  1.488  2.264  0.163  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 GROUPS  2.333  1  2.333  6.596  0.028  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 GROUPS  1.088  1  1.088  2.105  0.177  ERROR  5.169  10  0.517  74  Table 23  RMANOVA, Hyperoxic Chemoresponse.  UNIVARIATE AND MULTI VARIATE 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 GROUPS  66.757  3  22.252  1.224  0.318  0.317  0.318  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)  SOURCE  SS  DF  MS  F  P  LEVELS  83.122  1  83.122  2.968  0.116  LEVELS X GROUPS  11.933  1  11.933  0.426  0.529  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 GROUPS  28.392  1  28.392  1.887  0.200  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 GROUPS  26.432  1  26.432  2.297  0.161  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 GROUPS  0.619  3  0.206  0.456  0.715  0.669  0.715  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)  SOURCE  SS  DF  MS  F  P  LEVELS  23.989  1  23.989  36.276  0.000  LEVELS X GROUPS  0.552  1  0.552  0.835  0.382  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 GROUPS  0.011  1  0.011  0.019  0.892  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 GROUPS  0.056  1  0.056  0.439  0.523  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  2 R  ADJ. R 2  S.E.E.  20  0.3 12  0.097  0.047  0.835  REGRESSION COEFFICIENTS VARIABLE  COEFF.  STD ERROR  STD COEF  CONSTANT  97.479  0.546  0.000  .  RESP  -0.660  0.474  -0.312  1.000  T  P(2 TAIL)  178.460  0.000  -1.392  0.181  TOLERANCE  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  2 R  ADJ. R 2  S.E.E.  28  0.338  0.115  0.080  1.247  REGRESSION COEFFICIENTS VARIABLE  COEFF.  STD ERROR  STD COEF  CONSTANT  97.954  0.666  0.000  .  RESP  -1.596  0.870  -0.338  1.000  T  P(2 TAIL)  146.979  0.000  -1.834  0.078  TOLERANCE  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  2 R  ADJ. R 2  S.E.E.  20  0.217  0.047  0.000  0.938  REGRESSION COEFFICIENTS VARIABLE  COEFF.  STD ERROR  STD COEF  CONSTANT  96.454  0.635  0.000  RESP  0.032  0.034  0.217  T  P(2 TAIL)  151.785  0.000  0.944  0.358  TOLERANCE  .  1.000  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  2 R  ADJ. R 2  S.E.E.  28  0.121  0.015  0.000  1.212  REGRESSION COEFFICIENTS T  P(2 TAIL)  137.235  0.000  -0.621  0.540  TOLERANCE  VARIABLE  COEFF.  STh ERROR  STD COEF  CONSTANT  97.098  0.708  0.000  .  RESP  -0.023  0.038  -0.121  1.000  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  APPENDIX C FIGURES  Power output at various exercise intensities, group data.  Figure 7  350 300 250 200 C  150  -  -  -  -  -  1) 0  100  -  50 0LPO  VLPO  MPO  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.  83  Power output at various exercise intensities, NOS subjects.  Figure 8  350 p  RR  D  SF  p  MF  —N----  DH  w  ME  300 250  az C  200 150 100 50 0 Rest  VLPO  LPO  MPO  VLPO, very low power output; LPO, low power output; MPO, moderate power output.  84  Figure 9  Power output at various exercise intensities, LOS subjects.  350 p  TM  D  PT  p  DB  —NH--  GA  150  w  HT  100  L  BT  300 250 200 0 C  —0---— JF  50 0 Rest  VLPO  LPO  MPO  VLPO, very low power output; LPO, low power output; MPO, moderate power output.  85  Hypercapnic peripheral chemoresponse at various exercise intensities,  Figure 10  NOS subjects.  2.0  -  11.U  -  12  p  RR  D  SF  o  MF  —N-—DH  1)  rJ)  08  o c)  wME  0.4-  0.0-  I  Rest  VLPO  LPO  MPO  VLPO, very low power output; LPO, low power output; MPO, moderate power output.  86  Hypercapnic peripheral chemoresponse at various exercise intensities,  Figure 11  LOS subjects.  2.0  -  1.6-  p  TM  D  PT  oDB 12  I I  Rest  I•  VLPO  LPO  MPO  VLPO, very low power output; LPO, low power output; MPO, moderate power output.  87  Figure 12  Pre-C02 response SaO2 at various exercise intensities, NOS subjects.  100  -  p  RR  D  SF  0  MF  99 98 97—-—DH 96-  8  m  ME  9594 93  -  -  Rest  VLPO  LPO  MPO  VLPO, very low power output; LPO, low power output; MPO, moderate power output.  88  Pre-C02 response SaO2 at various exercise intensities, LOS subjects.  Figure 13  100  -  98  p  TM  o  PT  0  DB  —s--- GA  w  HT BT  96-  —0--— JF 95 94 93  -  -  I  Rest  VLPO  I  I  LPO  MPO  I  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  D  SF  30 25 20:  —is-—DH  10  ME  W  15  -  5-  I  I  Rest  VLPO  LPO  MPO  VLPO, very low power output; LPO, low power output; MPO, moderate power output.  90  Figure 15  Hyperoxic peripheral chemoresponse at various exercise intensities, LOS subjects.  35  -  30 25-  p  TM  D  PT  p  DB  —N--GA HT  w  20  BT —Q-—JF  is10  -  5-  I  Rest  VLPO  LPO  MPO  VLPO, very low power output; LPO, low power output; MPO, moderate power output.  91  Figure 16  Pre-02 response SaO2 at various exercise intensities, NOS subjects.  100 99 98  I  97 96 95 94 93  -  p  RR  D  SF  p  MF  —1SF—  DH  w  ME  -  -  -  -  -  -  I  Rest  VLPO  I  I  LPO  MPO  VLPO, very low power output; LPO, low power output; MPO, moderate power output.  92  Figure 17  Pre-02 response SaO2 at various exercise intensities, LOS subjects.  100 99  -  p  TM  D  PT  p  DB  -  —u-— GA w  HT BT  —0— JF  9594  -  93Rest  VLPO  LPO  MPO  VLPO, very low power output; LPO, low power output; MPO, moderate power output.  93  APPENDIX D EXCLUDED SUBJECT DATA  Table 31 Subject  Age, height, mass, and body surface area, individual subject data.  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  (yrs)  (cm)  (kg)  (m2)  UNFIT,NORMAL (n = 8)  30±6  182±7  79.7±9.7  2.01±0.16  UNFIT, EN (n = 2)  29±7  187±6  87.5 ±9.2  2.13 ±0.14  FIT,NORMAL (n = 11)  28±5  181±6  75.5±9.1  1.95±0.15  FIT, EIH (n = 3)  24±3  180± 2  70.1± 6.3  1.89±0.07  GROUP  Values are means ± SD. Groups are UNFIT, (VO max <5.00 L•min’ or 60.0 mL•min 2 ); FIT, (VO 4 l.kg max 2 91.0 %); EIH, (SaO2max  .kgi); NORMAL, (SaO2max> 1 5.00 L•min’ or 60.0 mL.min 91.0 %).  96  Table 33  max, peak power output, and lowest arterial hemoglobin 2 VO saturation during maximal cycle ergometer test, individual subject data. max 2 VO  max 2 VO  Peak Power  SaO2max  ) 1 (Lmin  4 .kg (mL.min ) 1  (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  Subject  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  max, peak power output, and lowest arterial hemoglobin 2 VO saturation during maximal cycle ergometer test, group data. max 2 VO  max 2 VO  Peak Power  SaO2max  (L.min’)  (mLmin’ .kg’)  (Watts)  (%)  UNFIT, NORMAL (n = 8)  4.34±0.34  54.7 ± 3.6  414±26  93.7± 1.3  UNFIT,EIH (n = 2)  4.69±0.19  53.8±3.5  440±7  90.4±0.1  FIT, NORMAL (n = 11)  4.83 ± 0.37  64.4 ± 4.8  452 ± 36  92.1 ± 1.0  FIT, EN (n = 3)  4.85 ± 0.28  66.8 ± 0.7  467 ± 14  89.8 ± 0.6  GROUP  Values are means ± SD. Groups are UNFIT, (VO 1 or 60.0 mL•min max <5.00 L•min 2 ); FIT, (VO 4 ‘.kg max 2 91.0 %); EIH, (SaO2max  1 or 60.0 1 .kg mL.min ) ; NORMAL, (SaO2max> 5.00 L•min 91.0 %).  99  Table 35  TH, and power output at VO 2 VO TH’ individual subject data. 2 Power at  TH 2 VO  2 VO  Subject  (L•min’)  (mL•min’ •kg ) 1  (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  TH and power output at VO 2 VO TH, group data. 2 ,  TH 2 VO  Th 2 V0  Power at VO 2  (L•min’)  •kg (mL•min ) 1  (Watts)  UNFIT, NORMAL (n = 8)  2.94 ± 0.30  37.2 ± 4.8  259±26  UNFIT, EN (n = 2)  3.03 ± 0.07  34.9 ± 4.5  265 ± 14  FIT, NORMAL (n = 11)  3.15 ±0.15  41.4±4.1  276±31  FIT, EIH (n = 3)  3.01 ± 0.46  42.8 ± 2.7  277±6  GROUP  Values are means ± SD. Groups are UNFIT, (VO2max <5.00 L•min’ or 60.0 mL•min ‘.kg’); FIT, (VO2max 91.0 %); EIH, (Sa°2max  •kg 1 mL.min ) ; NORMAL, (SaO2max> 5.00 L•min’ or 60.0 4 91.0 %).  102  

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