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Exercise-induced arterial hypoxemia in healthy young women; role of mechanical constraints to ventilation Dominelli, Paolo Biagio 2012

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1  Exercise-induced arterial hypoxemia in healthy young women; role of mechanical constraints to ventilation by  Paolo Biagio Dominelli B.H.K., The University of British Columbia, 2010  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE in The Faculty of Graduate Studies (Kinesiology)  THE UNIVERSITY OF BRITISH COLUMBIA (VANCOUVER) April, 2012  © Paolo Biagio Dominelli, 2012  ii  Abstract Many young adult male athletes with a high maximal O2 consumption (V ˙O2Max) show exercise-induced arterial hypoxemia (EIAH). In women, EIAH may occur at submaximal exercise intensities and at lower fitness levels, but this is controversial. Greater EIAH in women may be attributed to their increased mechanical constraints to ventilation owing to smaller airway diameters. Accordingly, the purpose of this study was to characterize EIAH, gas exchange and respiratory mechanics during exercise in young healthy women. Subjects (n=31, V ˙O2Max =481, range 28-62 mL/kg/min) completed a step-wise maximal test on a treadmill. A 3-stage constant load exercise test was also completed where the inspired gas was switched between room air and heliox (21% O2: 79% He). Arterial blood gases (PaO2, PaCO2, pH), corrected for esophageal temperature, and oxyhemoglobin saturation (SaO2) were measured at rest and during the last 30 s of each exercise stage. The work of breathing (WOB) was obtained using an esophageal balloon-tipped catheter. Expiratory flow limitation (EFL) was determined by superimposing tidal flow-volume loops on the maximum expiratory flow-volume curve. Twenty of the 31 women developed some degree of EIAH with a nadir PaO2 and SaO2 ranging from 58-103 mmHg and 87-98%; respectively. Subjects with EIAH were fitter (V ˙O2Max 51±1 vs. 42±2 mL/kg/min), had a greater V ˙EMax (91±3 vs. 77±4 L/min) and had an increased resistive WOB (30±2 vs. 19±1 cmH2O/breath); for the EIAH and non-EIAH groups respectively (P<0.05). Six untrained subjects (V ˙O2Max <50 mL/kg/min) developed EIAH and 18/20 of the EIAH group were hypoxemia at submaximal intensities. Six distinct patterns of hypoxemia were observed indicating multiple mechanisms are responsible for EIAH in women. Fourteen subjects developed EFL and 12/14 who showed flow limitation also displayed EIAH. Inspiring heliox gas decreased the WOB by ~32% and partially reversed any EIAH. In conclusion, the pulmonary system response to progressive treadmill exercise in healthy young women is variable and distinct patterns of EIAH exist. EIAH appears to start at submaximal intensities and untrained women can develop hypoxemia. Mechanical ventilatory constraints can lead to or exacerbate EIAH in women, while inspiring heliox gas can partially reverse EIAH.  iii  Preface This thesis contains original data collected and analyzed for partial fulfilment of the author’s Master of Science degree. All protocols were approved by the Clinical Research Ethics Board (Approval number: H10-03237) at the University of British Columbia.  iv  Table of Contents Abstract .............................................................................................................................. ii Preface............................................................................................................................... iii Table of Contents ............................................................................................................. iv List of Tables ................................................................................................................... vii List of Figures ................................................................................................................. viii List of Abbreviations ..................................................................................................... xiv Acknowledgements ....................................................................................................... xvii Introduction ........................................................................................................................1 Hypotheses .......................................................................................................................5 Methods...............................................................................................................................6 Subjects ............................................................................................................................6 Experimental Overview ...................................................................................................6 Measurements and Procedures.........................................................................................7 Spirometry and pulmonary diffusion..........................................................................7 Arterial catheterization and blood sampling...............................................................7 Pressure measurement and esophageal temperature thermistor placement ................8 Static recoil .................................................................................................................9 Ventilatory and metabolic parameters ........................................................................9 Functional residual capacity, maximal inspiratory pressure and forced vital capacities ..........................................................................................................................10 Maximal exercise test ...............................................................................................10 Constant load exercise bout ......................................................................................11 Repeated testing........................................................................................................12 Data collection and processing .................................................................................12 Data Analysis .................................................................................................................13 Maximal expiratory flow volume curve and operational lung volumes ...................13 Flow-volume and pressure-volume loops and expiratory flow limitation ...............13 Work of breathing.....................................................................................................13 Dynamic compliance ................................................................................................15  v Ventilatory capacity..................................................................................................15 Dysanapsis ................................................................................................................16 Calculations and corrections for environmental conditions .....................................16 Statistical analysis ....................................................................................................18 Results ...............................................................................................................................19 Descriptive Data ............................................................................................................19 Exercise Response For All Subjects ..............................................................................22 Blood gases ...............................................................................................................24 Respiratory mechanics..............................................................................................30 Exercise Response Split Into EIAH/NEIAH And EFL/NEFL ......................................35 EIAH vs. NEIAH ...........................................................................................................37 Blood gases for EIAH vs. NEAIH ...........................................................................40 Respiratory mechanics for EIAH and NEIAH groups .............................................45 EFL vs. NEFL ................................................................................................................51 Constant Load Heliox Trial ...........................................................................................53 Subjects With Repeated Testing ....................................................................................60 Repeated Subject 1- AC ...........................................................................................60 Repeated Subject #2- SW .........................................................................................63 Discussion..........................................................................................................................65 Major Finding ................................................................................................................65 Inter-subject variability, broad classifications and patterns of EIAH ......................65 Submaximal EIAH ...................................................................................................67 Untrained women .....................................................................................................70 Heliox breathing .......................................................................................................71 EIAH as a two-part problem.....................................................................................72 Insights into mechanisms of EIAH...........................................................................73 Comparisons to men .................................................................................................74 Methodlogical Considerations .......................................................................................75 Expiratory flow limitation ........................................................................................75 Work of breathing.....................................................................................................76  vi V ˙O2MAX vs. V ˙O2Peak ....................................................................................................77 Arterial blood gas sampling......................................................................................78 Dysanapsis/Airway size index ..................................................................................78 Constant load exercise bout ......................................................................................79 Menstrual cycle ........................................................................................................80 Core temperature ......................................................................................................80 Methodlogical Improvements ........................................................................................81 Full body plethysmography ......................................................................................81 Inert gas dilution for operational lung volumes .......................................................82 Blood sampling .........................................................................................................82 End-tidal forcing during constant load exercise .......................................................83 Unresolves Questions and Future Direction ..................................................................83 Arterial oxygen tension ............................................................................................83 Venous oxygen tension.............................................................................................84 Submaximal intensity. ..............................................................................................84 Blood flow and fatigue .............................................................................................85 Foot strike .................................................................................................................85 Oxygen content .........................................................................................................86 Heliox .......................................................................................................................86 Subclinical edema .....................................................................................................87 Older women ............................................................................................................88 Conclusion ........................................................................................................................89 References .........................................................................................................................90 Appendix A: Individual subject data .............................................................................97 Appendix B: Questionnaire...........................................................................................197  vii  List of Tables Table 1- Environmental conditions for testing ............................................................................... 6 Table 2- Descriptive variables for thirty-one subjects based on the appearance of any EIAH .... 20 Table 3- Descriptive variables for thirty-one subjects based on the appearance of any EFL ....... 21 Table 4- Metabolic and ventilatory data at maximal oxygen consumption for thirty-one subjects divided into groups based on the occurrence of any EIAH. ................................... 38 Table 5- Arterial blood data at maximal oxygen consumption for thirty-one subject divided into groups based on the occurrence of any EIAH. .............................................................. 39 Table 6- Respiratory mechanics data at maximal oxygen consumption for thirty-one subject divided into groups based on the occurrence of any EIAH. ................................................. 40 Table 7- Work of breathing constants for the EIAH and NEIAH groups .................................... 49  viii  List of Figures Figure 1- Maximal flow-volume curve with resting and maximal tidal flow-volume loops for a healthy woman during cycle exercise. ................................................................................. 3 Figure 2- Metabolic and ventilatory variables during maximal exercise test ............................... 23 Figure 3- Individual blood gas response to maximal exercise test. .............................................. 25 Figure 4- Relationships between blood gas variables at V ˙O2MAX. .................................................. 26 Figure 5- Grouped blood gas response during maximal exercise test. ......................................... 27 Figure 6- The relative contribution to changes in hemoglobin saturation and oxygen content during the maximal exercise test........................................................................................... 28 Figure 7- Acid-base, potassium and esophageal temperature changes during maximal exercise test. .......................................................................................................................... 29 Figure 8- Operational lung volumes during maximal exercise test. ............................................. 31 Figure 9- Respiratory mechanics during maximal exercise test. .................................................. 32 Figure 10- Work of breathing for all subjects at all time points for the maximal exercise test. ... 33 Figure 11- Minute ventilation, maximal ventilatory capacity, theoretical ventilation to offset EIAH and the associated arterial carbon dioxide tension during maximal exercise test. ..... 34 Figure 12- Maximal flow-volume curves and tidal flow volume loops with arterial oxygen tension for subjects split into four groups during maximal exercise test. ............................. 36 Figure 13- Dysanapsis index for subjects split into four mutually exclusive groups. .................. 37 Figure 14- Blood gas variables for the EIAH and NEIAH groups during maximal exercise test. ........................................................................................................................................ 42 Figure 15- Arterial oxyhemoglobin saturation for the EIAH and NEIAH groups during the maximal exercise test. ........................................................................................................... 43 Figure 16- Acid-base, potassium and esophageal temperature changes during maximal exercise test for EIAH and NEIAH groups........................................................................... 44 Figure 17- Respiratory mechanics for the EIAH and NEIAH groups during maximal exercise test. ........................................................................................................................................ 47  ix Figure 18- Minute ventilation, maximal ventilatory capacity, theoretical ventilation to offset EIAH and the associated arterial carbon dioxide tension during maximal exercise test for EIAH and NEIAH groups. .............................................................................................. 48 Figure 19- Patterns of hypoxemia for the EIAH group during the maximal exercise test. .......... 50 Figure 20- The work of breathing for the EFL and NEFL groups during the maximal exercise test. ........................................................................................................................................ 51 Figure 21- Minute ventilation, maximal ventilatory capacity, theoretical ventilation to offset EIAH and the associated arterial carbon dioxide tension during maximal exercise test for EFL and NEFL groups. ................................................................................................... 52 Figure 22- External breathing circuit resistance with air and heliox. ........................................... 54 Figure 23- Blood gas variables during the constant load exercise test for all subjects. ............... 55 Figure 24- Maximal expiratory flow volume curve and tidal flow volume loops while breathing air and heliox. ....................................................................................................... 56 Figure 25- Respiratory mechanics during the constant load exercise bout for all subjects. ......... 57 Figure 26- Work of breathing on air and heliox during the constant load exercise trial. ............. 58 Figure 27- Subjects who completed the constant load exercise bout and showed EIAH are split into EFL and NEFL groups with blood gas variables shown during the constant load exercise bout. ................................................................................................................ 59 Figure 28- Selected blood gas and ventilatory variables during the first and second testing days for subject AC. .............................................................................................................. 61 Figure 29- Maximal expiratory flow-volume curve for subject AC during the first and second testing days............................................................................................................................ 62 Figure 30- Maximal expiratory flow-volume curve and maximal tidal flow volume loop for subject SW during both testing days. .................................................................................... 63 Figure 31- Blood gas variables for SW during both testing days. ................................................ 64 Figure 32- Example, MEFV curve and descriptors. ..................................................................... 98 Figure 33- Example, arterial blood gases. .................................................................................... 99 Figure 34- Example, respiratory mechanics. .............................................................................. 100 Figure 35- AC (Day 1), MEFV curve and descriptors................................................................ 101  x Figure 36- AC (Day 1), arterial blood gases. .............................................................................. 102 Figure 37- AC (Day 1), respiratory mechanics. .......................................................................... 103 Figure 38- AC (Day 2), MEFV curve and descriptor. ................................................................ 104 Figure 39- AC (Day 2), arterial blood gases. .............................................................................. 105 Figure 40- AC (Day 2), respiratory mechanics. .......................................................................... 106 Figure 41- AH, MEFV curve and descriptors. ............................................................................ 107 Figure 42- AH, arterial blood gases. ........................................................................................... 108 Figure 43- AH, respiratory mechanics. ....................................................................................... 109 Figure 44- AM, MEFV curve and descriptors. ........................................................................... 110 Figure 45- AM, arterial blood gases. .......................................................................................... 111 Figure 46- AM, respiratory mechanics. ...................................................................................... 112 Figure 47- AS, MEFV curve and descriptors. ............................................................................ 113 Figure 48- AS, arterial blood gases............................................................................................. 114 Figure 49- AS, respiratory mechanics. ....................................................................................... 115 Figure 50- BS, MEFV curve and descriptors.............................................................................. 116 Figure 51- BS, arterial blood gases. ............................................................................................ 117 Figure 52- BS, respiratory mechanics. ........................................................................................ 118 Figure 53- CM, MEFV curve and descriptors. ........................................................................... 119 Figure 54- CM, arterial blood gases. .......................................................................................... 120 Figure 55- CM, respiratory mechanics. ...................................................................................... 121 Figure 56- CR, MEFV curve and descriptors. ............................................................................ 122 Figure 57- CR, arterial blood gases. ........................................................................................... 123 Figure 58- CR, respiratory mechanics. ....................................................................................... 124 Figure 59-EM, MEFV curve and descriptors. ............................................................................ 125  xi Figure 60- EM, arterial blood gases. ........................................................................................... 126 Figure 61- EM, respiratory mechanics........................................................................................ 127 Figure 62- GLY, MEFV curve and descriptors. ......................................................................... 128 Figure 63- GLY, arterial blood gases. ........................................................................................ 129 Figure 64-GLY, respiratory mechanics. ..................................................................................... 130 Figure 65- JB (Dec), MEFV curve and descriptors. ................................................................... 131 Figure 66- JB (Dec), arterial blood gases. .................................................................................. 132 Figure 67- JB (Dec), respiratory mechanics. .............................................................................. 133 Figure 68- JB, MEFV curve and descriptors. ............................................................................. 134 Figure 69- JB, arterial blood gases. ............................................................................................ 135 Figure 70- JB, respiratory mechanics. ........................................................................................ 136 Figure 71- JC, MEFV curve and descriptors. ............................................................................. 137 Figure 72- JC, arterial blood gases. ............................................................................................ 138 Figure 73- JC, respiratory mechanics. ........................................................................................ 139 Figure 74- JL, MEFV curve and descriptors. ............................................................................. 140 Figure 75- JL, arterial blood gases.............................................................................................. 141 Figure 76- JL, respiratory mechanics.......................................................................................... 142 Figure 77- JS (Dec), MEFV curve and descriptors..................................................................... 143 Figure 78- JS (Dec), arterial blood gases. ................................................................................... 144 Figure 79- JS (Dec), respiratory mechanics. ............................................................................... 145 Figure 80- JS (Nov), MEFV curve and descriptors. ................................................................... 146 Figure 81- JS (Nov), arterial blood gases. .................................................................................. 147 Figure 82- JS (Nov), respiratory mechanics. .............................................................................. 148 Figure 83- KM, MEFV curve and descriptors. ........................................................................... 149  xii Figure 84- KM, arterial blood gases. .......................................................................................... 150 Figure 85- KM, respiratory mechanics. ...................................................................................... 151 Figure 86- KS, MEFV curve and descriptors. ............................................................................ 152 Figure 87- KS, arterial blood gas. ............................................................................................... 153 Figure 88- KS, respiratory mechanics. ....................................................................................... 154 Figure 89-MB, MEFV curve and descriptors. ............................................................................ 155 Figure 90- MB, arterial blood gases. .......................................................................................... 156 Figure 91- MB, respiratory mechanics. ...................................................................................... 157 Figure 92- MF, MEFV curve and descriptors............................................................................. 158 Figure 93- MF, arterial blood gases. ........................................................................................... 159 Figure 94- MF, respiratory mechanics. ....................................................................................... 160 Figure 95- MG, MEFV curve and descriptors. ........................................................................... 161 Figure 96- MG, arterial blood gases. .......................................................................................... 162 Figure 97- MG, respiratory mechanics. ...................................................................................... 163 Figure 98- MM, MEFV curve and descriptors. .......................................................................... 164 Figure 99- MM, arterial blood gases........................................................................................... 165 Figure 100- MM, respiratory mechanics. ................................................................................... 166 Figure 101- NN, MEFV curve and descriptors. .......................................................................... 167 Figure 102- NN, arterial blood gases. ......................................................................................... 168 Figure 103- NN, respiratory mechanics. ..................................................................................... 169 Figure 104- NW, MEFV curve and descriptors. ......................................................................... 170 Figure 105- NW, arterial blood gases. ........................................................................................ 171 Figure 106- NW, respiratory mechanics. .................................................................................... 172 Figure 107- PH, MEFV curve and descriptors. .......................................................................... 173  xiii Figure 108- PH, arterial blood gases........................................................................................... 174 Figure 109- PH, respiratory mechanics. ..................................................................................... 175 Figure 110- RB, MEFV curve and descriptors. .......................................................................... 176 Figure 111- RB, arterial blood gases. ......................................................................................... 177 Figure 112- RB, respiratory mechanics. ..................................................................................... 178 Figure 113- SD, MEFV curve and descriptors. .......................................................................... 179 Figure 114- SD, arterial blood gases........................................................................................... 180 Figure 115- SD, respiratory mechanics. ..................................................................................... 181 Figure 116- SL, MEFV curve and descriptors. ........................................................................... 182 Figure 117- SL, arterial blood gases. .......................................................................................... 183 Figure 118- SL, respiratory mechanics. ...................................................................................... 184 Figure 119- SS- MEFV curve and descriptors............................................................................ 185 Figure 120- SS, arterial blood gases. .......................................................................................... 186 Figure 121- SS, respiratory mechanics. ...................................................................................... 187 Figure 122- SW (Jun), MEFV curve and descriptors. ................................................................ 188 Figure 123- SW (Jun), arterial blood gases. ............................................................................... 189 Figure 124- SW (Jun), respiratory mechanics. ........................................................................... 190 Figure 125- SW (Nov), MEFV curve and descriptors. ............................................................... 191 Figure 126- SW (Nov), arterial blood gases. .............................................................................. 192 Figure 127- SW (Nov), respiratory mechanics. .......................................................................... 193 Figure 128- VW, MEFV curve and descriptors. ......................................................................... 194 Figure 129- VW, arterial blood gases ......................................................................................... 195 Figure 130- VW, respiratory mechanics ..................................................................................... 196  xiv  List of Abbreviations Symbol  Definition  A  Alveolar  a  Arterial  A-aDO2  Alveolar to arterial oxygen difference  a-vDO2  Arterial to venous oxygen difference  ATPS  Atmospheric temperature pressure saturated  BMI  Body mass index  BSA  Body surface area  BTPS  Breathe temperature pressure saturated  CaO2  Oxygen content of arterial blood  CvO2  Oxygen content of venous blood  DLCO  Lung diffusion capacity for carbon monoxide  Eel  Expired elastic  Eres  Expired resistive  EFL  Expiratory flow limitation  EELV  End-expired lung volume  EILV  End-inspired lung volume  f  Breathing frequency  FRC  Functional residual volume  FV  Flow-volume  FEF75  Forced expiratory flow at 75% forced vital capacity  FEF50  Forced expiratory flow at 50% forced vital capacity  FEF25  Forced expiratory flow at 25% forced vital capacity  FEV1  Forced expiratory volume in 1 second  FiO2  Fraction of inspired oxygen  FiCO2  Fraction of inspired carbon dioxide  FVC  Forced vital capacity  gFVC  Graded forced vital capacity  Hct  Hematocrit  xv HR  Heart rate  Hb  Hemoglobin  Iel  Inspired elastic  Ires  Inspired resistive  IC  Inspiratory capacity  IFL  Inspiratory flow limitation  MFV  Maximal flow-volume  MEFV  Maximal expiratory flow-volume  MIP  Maximal inspiratory pressure  MVV  Maximal voluntary ventilation  ODC  Oxygen disassociation curve  P  Partial pressure  PB  Barometric pressure  Peso  Esophageal pressure  PH2O  Water vapour pressure  Pmt  Mouth pressure  Ptp  Transpulmonary pressure  Pst(50)  Static recoil pressure at 50% lung volume  PaO2  Partial pressure of oxygen in arterial blood  PaCO2  Partial pressure of carbon dioxide in arterial blood  PAO2  Partial pressure of oxygen in alveolar gas  PACO2  Partial pressure of carbon dioxide in alveolar gas  PA  Pulmonary artery  PAV  Proportional assist ventilator  PAP  Pulmonary artery pressure  PETCO2  Mixed end-tidal carbon dioxide tension  PEF  Peak expiratory flow  PV  Pressure-volume  Q ˙  Cardiac output  RER  Respiratory exchange ratio  xvi RV  Residual volume  SaO2  Arterial oxyhemoglobin saturation  STPD  Standard temperature pressure dry  TLC  Total lung capacity  Tam  Ambient temperature  Teso  Esophageal temperature  v  venous  V ˙A  Alveolar ventilation  V ˙E  Expired minute ventilation  V ˙ECAP  Theoretical maximal expired minute ventilation  V ˙ERES  Minute ventilation reserve  V ˙I  Inspired minute ventilation  V ˙O2  Oxygen consumption  V ˙O2Max  Maximal oxygen consumption  V ˙CO2  Carbon dioxide production  V ˙CO2Max  Maximal carbon dioxide production  VC  Vital capacity  VD  Physiological deadspace  VDV  Deadspace of breathing valve  VFL  Volume flow limited  VT  Tidal volume  WOB  Work of breathing  WOBEl  Elastic work of breathing  WOBRes  Resistive work of breathing  xvii  Acknowledgements I would like to acknowledge my supervisor, Dr William Sheel, and the members of my supervisory committee, Drs Glen Foster, Mike Koehle, and Don McKenzie, for their guidance and scholarly support throughout my studies. I am appreciative for their unique insights and continued support. I would also like to acknowledge Drs Giulio Dominelli, Mike Koehle, and William Henderson for volunteering their time and expertise in performing the difficult medical procedures. I also extend many thanks to members of the laboratory for assisting me with data collection. Finally, I wish to thank all the subjects who graciously volunteered for this study. I am grateful for their enthusiasm and dedication during the physically and mentally draining testing sessions.  1  Introduction When exercising at sea-level, healthy humans have long been thought to maintain arterial blood gases near resting levels throughout all intensities. Sporadic reports between the 1940’s and 1960’s however indicated that this belief may not be justified in all individuals (32, 46, 72). In the 1980’s Dempsey et al. (12) confirmed these earlier reports in a study involving highly trained male runners whose arterial oxygen tension (PaO2) fell considerably (>20 mmHg) during progressive running exercise. The fall in PaO2 was coined exercise-induced arterial hypoxemia (EIAH). Broadly, EIAH can be viewed as a failure of the respiratory system to precisely match the cardiovascular and metabolic systems output (13). This idea of physiological systems mismatching was termed the “Demand vs. Capacity” relationship (11) and relies on the fact that the respiratory system shows little to no positive adaptations in response to exercise training (73). Conversely, the cardiovascular and metabolic systems both show considerable increases in maximal output in response to endurance training (73). The demand vs. capacity concept is able to explain EIAH at maximal exercise, as the respiratory system is functioning at maximal capacity, while the cardiovascular and/or metabolic systems are not. Put another way, the respiratory system can become the limiting factor in exercise. However, EIAH also occurs during submaximal exercise intensities, when the respiratory system has the capacity to increase alveolar ventilation (V ˙A) and attempt to reverse the hypoxemia (12, 65). Therefore, while the demand vs. capacity theory can explain EIAH during intense exercise, it cannot describe why hypoxemia would be tolerated during submaximal exercise. To date, the mechanism(s) responsible submaximal hypoxemia in healthy humans remains a mystery. Throughout numerous studies, we are able to characterize EIAH in men with the following: i) EIAH occurs in some highly trained men, ii) EIAH is associated with a large gas exchange inefficiency as indicated by an alveolar to arterial oxygen gradient (A-aDO2) above 2025 mmHg, iii) mechanical ventilatory constraints can lead to, or exacerbate, EIAH in some highly trained men, iv) the underlying mechanism behind EIAH is attributed primarily to V ˙A/˙ Q mismatching and secondary to relative alveolar hypoventilation, however, diffusion limitations or intracardiac/intrathoracic shunts have not been conclusively excluded, v) EIAH can be reversed by inspiring slightly hyperoxic gas (FiO2 0.26), resulting in an increased V ˙O2Max and increased exercise performance/tolerance and vi) EIAH can occur at submaximal exercise intensities (13).  2 The primary goal of increasing V ˙A during exercise is to maintain arterial blood gases at resting levels despite increasing metabolic demand. The dynamic regulation of V ˙A and ultimately blood gases is complex and connects many physiological systems with multiple feedforward and feed-back loops, yet, the pulmonary mechanics responsible for respiration can be effectively reduced for ease of understanding and studying. Specifically, the respiratory system can be simplified into a series of air filled sacs that open to ducts and drain into a common vessel. As such, the respiratory system obeys the physical laws of flow through tubes and the maximal capacity of the respiratory system is dictated by these laws. As previously alluded to, the respiratory system is relatively fixed in its capacity to generate flow and volume. The primary measured variable that defines maximal ventilatory capacity is one’s maximal flowvolume (MFV) curve (Figure 1).  3  Expiratory flow  Figure 1- Maximal flow-volume curve with resting and maximal tidal flow-volume loops for a healthy woman during cycle exercise.  EFL  RV EILV  Inspiratory flow  Volume  EELV IFL  TLC  Legend: Solid line represents the maximal flow-volume curve, hashed line represents maximal exercise tidal flow-volume loops and the dotted line represents a resting flow-volume loop. Definition of abbreviations: EELV, end-expiratory lung volume; EFL, expiratory flow limitation; EILV, end-inspiratory lung volume; IFL, inspiratory flow limitation; RV, residual volume; TLC, total lung capacity. The MFV is said to be impenetrable, that is, all combinations of flow and volume must fall inside the outer boundary. In Figure 1, a MFV curve from a healthy woman along with a resting flow-volume (FV) loop and a maximal exercise FV loop is shown. At rest, there is considerable room to increase both inspiratory and expiratory flow and volume may increase via changes in end-inspiratory lung volume (EILV) and end-expiratory lung volume (EELV). However, at maximal exercise, the subject’s tidal FV loop intersects the MFV curve on both the inspiratory and expiratory aspect, which is referred to as inspiratory flow limitation (IFL) and expiratory flow limitation (EFL); respectively. When a subject is flow limited, they are unable  4 to increase flow at a given volume. When flow limitation occurs, a subject’s ventilation is mechanically constrained. Additionally, in Figure 1, EILV is approaching total lung capacity (TLC), therefore, any increases in tidal volume (VT), must come from decreasing EELV. However, by decreasing EELV, the subject would experience a greater degree of EFL. Experiencing flow limitation is not a benign condition; rather it is associated with negative physiological outcomes. For example, EFL can cause relative hyperinflation, forcing the respiratory musculature to contract at less than optimal lengths and hasten fatigue (42). Additionally, EFL has been shown to decrease stroke volume (80) and increase the elastic work of breathing (WOB)(27). The interaction between the MFV curve and tidal FV loops results in a dynamic balance between increasing ventilatory demand and a static ventilatory capacity. Previously, most research with regards to respiratory physiology used male subjects and there was not thought to be any sex-related differences, independent of gross size. However, this assumption is no longer justified as several sex-based differences with regards to the respiratory system have been identified and described. Specifically, even when matched for trunk height, women have smaller lungs (4) and smaller airways (50, 54, 76) compared to men. The smaller lungs and airways results in a reduced MFV curve for the average woman, when compared to a height matched man. Consequently, women often develop mechanical ventilatory constraints and have been shown to develop EFL more often and have a higher WOB when compared men (27, 52). Subsequently, at lower relative fitness levels, women show more mechanical constraints than men and some untrained woman can show EFL (15), a finding rarely reported in men. However, despite the above mentioned mechanical constraints, women appear to be more resistant to diaphragm fatigue then men (26). Given the aforementioned sex-differences in the respiratory system which result in greater mechanical ventilatory constraints, it was hypothesized that women may be especially prone to developing EIAH. The hypothesis was that women would develop severe flow limitation and would be mechanically unable to increase V ˙A to adequately meet metabolic demands. Put in other words, some women may not show a strong hyperventilatory response to intense exercise and would be relatively hypoventilating. Indeed, this was confirmed in a study by Harms et al (30) who found that 75% of women tested developed some degree of EIAH. Surprisingly, some untrained women (maximal oxygen consumption (V ˙O2Max) within 15% of predicted) developed EIAH, a finding which has not been reported in men. Similar to studies in  5 men, the degree of EIAH in women was found to be highly associated with the extent of the gas exchange inefficiency (30) and secondary to increasing mechanical ventilatory constraints (52). Similar to men, many of the women also began to display EIAH at submaximal exercise intensities. However, shortly thereafter, a similar study was conducted in which they found that women developed EIAH similar to men, in terms of severity and prevalence (33). That is, only trained women developed EIAH and the overall prevalence was ~24%. The methods and analysis were very similar between the two studies and cohorts were remarkably similar in anthropometrics, pulmonary function and fitness. Other studies have attempted to provide additional descriptive data on EIAH in women, but unfortunately, addressed a slight variation of the main questions (59, 85) or did not use optimal methodologies (24, 68, 88). Therefore, controversy still exists in the literature regarding EIAH in women and the necessary data to characterize this phenomenon is lacking. Specifically, a detailed assessment of mechanical ventilatory constraints, as it pertains to blood gas homeostasis, has not been done in women. As such, the purpose of this study is to more fully characterize EIAH and mechanical constraints in women. Importantly, this study assesses EIAH directly by measuring arterial blood gases and correcting them for core temperature and mechanical constraints will be aided by using an esophageal balloon catheter. Specifically, the purpose of this study is fivefold. First, to determine if EIAH occurs in women more often than is commonly reported in men. Second, to see if untrained women can develop EIAH. Third, to assess EIAH at all exercise intensities. Fourth, determine the role of mechanical ventilatory constraints in EIAH and women. Fifth, assess how relieving some mechanical ventialtory constraints with heliox gas will affect EIAH.  HYPOTHESES 1. Women will develop EIAH more often than is commonly reported in men. 2. Some untrained women will develop EIAH. 3. Women will develop EIAH at submaximal intensities. 4. Mechanical ventilatory constraints will be associated with the occurrence of EIAH in women. 5. Inspiring heliox gas will partially reverse EIAH in women who show mechanical ventilatory constraints.  6  Methods SUBJECTS Forty-two, young (19-42 years), healthy, non-smoking women were recruited for testing. There was a failure to cannulate the radial artery in nine subjects. One subject withdrew before arterial cannulation was finished and testing could not be completed in 1 subject. Subjects where cannulation failed or did not complete all testing have been excluded from all analysis. Therefore, the analyzed group was 31. The cohort included subjects from a variety of athletic disciplines including endurance trained (competitive runners, cyclists, triathletes’), mixed aerobic/anaerobic trained (rugby, soccer, rowing, roller-derby), primarily anaerobically/strength trained (hockey, baseball), active but not trained and non-obese sedentary subjects, with a large range (28-62 mL/kg/min) of V ˙O2Max values. The large range of V ˙O2Max values was desired to i) test our hypothesis regarding EIAH in untrained women ii) to better extend our findings at a population level. Subjects were free of any current or previously diagnosed cardiorespiratory illness and were excluded if they had any form of asthma or if they presently or formerly had a tumour or ulcer in their esophagus. Testing occurred at random points throughout the subject’s menstrual cycle and subjects were not excluded if they were taking oral contraceptives. Testing occurred at various times of days, with the environmental conditions remaining consistent between testing days (Table 1).  Table 1- Environmental conditions for testing Barometric pressure (mmHg) Humidity (%) Temperature (°C) Values are mean ± SD  Average 752 ± 8 37 ± 5 21 ± 1  Range 734-767 29-46 19-23  EXPERIMENTAL OVERVIEW  Upon arrival to the study area, subjects completed consent forms, physical activity and general medical questionnaires (See Appendix C) followed by spirometry and diffusion capacity measures. All protocols were approved by the Clinical Research Ethics Board (Approval number: H10-03237) at the University of British Columbia, which conforms to the Declaration  7 of Helsinki. An arterial catheter was placed in the radial artery near the subjects’ wrist. An esophageal balloon catheter and an esophageal temperature thermistor were then inserted and static recoil of the lungs and chest-wall were measured. Ten min of sitting resting metabolic and blood gas measures were obtained followed by assessment of functional residual capacity (FRC) in the standing position. Subjects’ then performed several maximal inspiratory pressure maneuvers followed by several forced vital capacity (FVC) and graded forced vital capacity (gFVC) maneuvers. A maximal test to exhaustion on a treadmill was then performed. After completion of the maximal exercise test, 24 subjects completed a secondary exercise bout whereby they ran at a sub-maximal intensity while breathing heliox gas to reduce mechanical ventilatory constraints (see Additional exercise bout below).  MEASUREMENTS AND PROCEDURES  Spirometry and pulmonary diffusion General pulmonary function measures (Spirolab II, Medical International Research) were performed according to ATS standards (4), including: FVC, forced expiratory volume in 1 second (FEV1), % of FVC first second; forced expiratory flow at 25-75 % of expiration and peak expiratory flow (PEF). Subjects also practiced performing the inspiratory capacity (IC) and gFVC maneuvers with visual feedback. Pulmonary diffusing capacity for carbon monoxide (Collins DSI) was measured according to ATS standards (4). All values were compared to standardized reference values (4)  Arterial catheterization and blood sampling Under sterile conditions, a physician inserted a 20-gauge arterial catheter (Radial Artery Catheter, Arrow International, Reading, PA) into the radial artery (approximately 3 cm proximal to the wrist) by percutaneous cannulation (Sledenger technique) after administering local anaesthesia (1% Xylocaine). The catheter was connected to a commercially available arterial blood sampling kit (VP1, Edwards Lifescience, Irvine CA) allowing for repeated blood samples and flushing of the sample line with 0.9% saline, the dead space between the catheter and sampling port was 3 mL. Subjects had a total of 100-250 mL of saline infused during all  8 flushing of the sample line. Before sampling, an excess of the dead space volume (~5 mL) was withdrawn into a non-heparinized syringe and discarded. Immediately thereafter, arterial blood samples (~3 mL) were collected in commercially available pre-heparinized syringes (Portex Pro-Vent, Smiths Medical, Keene NH) containing 23 I.U. per mL of dry lithium heparin. Preheparinized syringes were utilized to prevent clotting in the sampled blood. Additionally, care was taken to ensure adequate blood was sampled to prevent excessive heparin from compromising blood gas values. Blood samples had all air immediately evacuated and were repeatedly inverted manually to ensure the blood was fully mixed and there was homogeneity throughout the sample. Samples were analyzed within 2 min of sampling (most analyzed within 30 sec) with a calibrated blood gas analyzer (ABL Flex80 CO-OX, Radiometer, Copenhagen, Demark). Analyzed variables included: pH, PaO2, PaCO2, SaO2, Na+, K+, Cl-, Ca2+, [Hb], Hct, FO2Hb, FCOHb, FMetHb, FHHb and cHCO3. Total blood loss was estimated at 30-60 mL per subject, with none exceeding 100 mL. If PaO2 < 85 mmHg at rest, the sample was ran in duplicate or another sample was immediately obtained. All samples ran in duplicate were in close agreement.  Pressure measurement and esophageal temperature thermistor placement A topical anaesthetic (Xylocaine , 2% Lidocaine Hydrochloride) was applied to the subjects’ nares and nasal conchae before passing a balloon tipped latex catheter (no. 47–9005; Ackrad Laboratory, Cranford, NJ) through the nose. The balloon was positioned in the lower third of the esophagus to measure esophageal pressure and estimate pleural pressure. Subjects performed a brief Valsalva manoeuvre while the catheter was open to the atmosphere to empty the balloon, thereafter 1 mL of air was injected into the balloon using a glass syringe (56). The validity of the esophageal balloon position was assessed using a dynamic occlusion test before being secured in place with tape. The balloon catheter was connected to a piezoelectric pressure transducer (±100 cmH2O; Raytech Instruments, Vancouver, BC, Canada). Mouth pressure was measured through a port in the mouth piece and connected to the same piezoelectric pressure transducer. The pressure transducer was calibrated at baseline and before and after each test using a digital manometer (2021P, Digitron, Torquay UK). Transpulmonary pressure was taken as the difference between mouth and esophageal pressure. An esophageal temperature thermistor (Ret-1, Physitemp Instruments, Clinton, NJ) was placed in the esophagus to the same  9 depth as the esophageal balloon catheter and connected to a temperature sensor (Thermalert TH5, Physitemp Instruments, Clinton, NJ). Prior to placement, the thermistor and sensor was calibrated using in several water baths within a physiologically relevant temperature range (3542 °C).  Static recoil Static recoil at 50% FVC was determined using previously accepted methods (83). While standing, the subjects breathed through a mouth piece connected to a volume displacement spirometer (Ohio 822, Houston, Texas). The subjects were instructed to inhale to total lung capacity several times in order to gather an accurate volume history. The subjects then again inhale to total lung capacity and were asked to exhale passively; without the use of respiratory muscles. The expired tube was occluded during the expiration, for ~1 sec, and the subjects were told to relax during the occlusion. The occlusion occurred at 50% of FVC, as determined by the spirometer; volume was corrected to reflect inspiration under ATPS conditions and expiration of BTPS conditions. Static transpulmonary pressure was read during the middle of the cardiac oscillations (83).  Ventilatory and metabolic parameters Subjects breathed through a low-resistance, two-way non-rebreathing valve (model 2700B, Hans Rudolph, Kansas City, MO) attached to large bore tubing. Inspired and expired flow was measured by separate, independently calibrated pneumotachographs (model 3813, Hans Rudolph, Kansas City, MO). Average resistance of the breathing circuit was 0.68 cmH2O/L/sec and ranged from 0.57-0.89 cmH2O/L/sec over a physiological range of flows (0.58 L/sec). Ventilatory and mixed expired metabolic parameters were gathered using a customized metabolic cart consisting of expired and inspired pneumotachographs and calibrated O2 and CO2 analyzers (Model S-3-A/I and Model CD-3A, respectively, Applied Electrochemistry, Pittsburgh, PA). Expired gas was collected in a 5 L mixing chamber and sampled via port near the rear of the chamber. Inspired and expired ventilation was measured directly with the pneumotachograph, additionally, inspired ventilation was calculated using the Haldane conversion. Before expired gas was analysed, the sample was drawn through bi-permeable Nafion tubing contained within an air-tight de-humidification chamber containing Drierite  10 (Anhydrous Calcium Sulfate) ensuring the gas was analysed dry; the gas remained in the sample line throughout drying and was not directly exposed to drying salts or subject to further mixing. All volumes were corrected using the Gay-Lussac ideal gas laws and are expressed in STPD.  Functional residual capacity, maximal inspiratory pressure and forced vital capacities Functional residual capacity will differ depending on body position (i.e., standing vs. sitting) as the chest and abdominal wall’s compliance changes slightly. Therefore, FRC measurements were performed in the standing position as it best represents a running stance. After standing, the subjects’ were instructed to breath quietly for several min. Throughout the quiet breathing the subjects’ were prompted to perform several inspiratory capacity (IC) maneuvers. The exact instructions given were “at the end of a normal breath out, take a maximal breath all the way in till you fill up your lungs.” Next, subjects performed several maximal inspiratory pressure maneuvers (MIP) at FRC by inspiring through a mouth piece with a pin-hole opening. While standing, several FVC and gFVC were performed in order to construct the MEFV curve. FVCs were performed according to ATS standards (4). To perform gFVCs the subject were instructed to inspire maximally, but expire with a submaximal effort, but ensure all air is expired. Submaximal efforts ranged from 70-95% of maximum, as instructed by the experimenter. Both FVC and gFVC were performed immediately before and after the exercise bout. Post-exercise maneuvers account for any exercise related bronchodilation while the graded maneuvers are intended to minimize the effect of thoracic gas compression; both of which ensure EFL is not overestimated (25).  Maximal exercise test During the exercise test, all subjects’ wore a chest harness attached to a support structure around the treadmill (model TMX425C, Full Vision Inc, Newton, KA). The support structure was also used to keep the pneumotachographs, pressure transducer, pnuemotach heater, pneumotach amplifier and temperature sensor close to the subject and minimize any motion artefacts associated with running exercise. The test was a staged maximal test to exhaustion and consisted of between 3-9 stages. The starting workload was be determined during the selfselected warm-up and was between 3.5-5.5 mph at 0% grade. Every 2.5 min, the speed of the treadmill increased by 1 mph until a comfortable speed or 10 mph is reached. At this point the  11 grade of the treadmill was increased by 1% every 2.5 min until volitional fatigue. Heart rate and ratings of dyspnea and leg discomfort (according to Borg scale ((8)) were assessed every min. At approximately the 2 and 2.5 min mark of each stage the subjects were instructed to perform an IC maneuver. Immediately after the first IC maneuver a blood sample was drawn and analyzed. At maximal exercise, repeated blood samples were drawn without an associated IC maneuver. Several subjects had another blood sample taken immediately (<1 min) after exercise while sitting on a chair on the treadmill.  Constant load exercise bout After performing the maximal exercise test, 24 subjects sat and rested until their esophageal temperature and ventilation returned to resting or near resting levels (15-20 min). All subjects were to eligible to participate in the constant load exercise bout, however, some could not due to either: time constraints, mental/physical fatigue or self-reported poor tolerance of instrumentation (esohageal balloon). After the initial 15-20 min, subjects continued to rest for an additional 5 min while ventilatory and metabolic parameters were gathered. Near the end of the final 5 min of rest, a blood sample was drawn and analyzed. Subjects then performed a bout of constant load exercise, with the intensity being 1 or 2 stages less than their maximal. The constant load exercise bout consisted of three phases where different inspirates were used. For the 1st and 3rd phase, the subject breathed room air, during the 2nd phase the subject inspired heliox (20.93-21.17% O2: balance He%) gas. The subjects were aware they would breathe a compressed gas, but were blinded to the gas composition or the intended effects. After testing, subjects were queried on any difference in breathing sensations during stage 2, after which, they were informed of the gas concentration and the desired effect. The heliox gas was humidified in a re-humidification chamber to achieve ~50% humidity. Each stage lasted between 2.5 and 3 min. During the final 30 sec of each stage, an IC maneuver was performed and a blood sample was drawn. Immediately after the 3rd stage, the subject was switched back to breathing heliox gas and performed several FVC and gFVC maneuvers. The pneumotachographs were then recalibrated using heliox gas. The average resistance of the breathing circuit with heliox was 0.34 cmH2O/L/sec and ranged from 0.3-0.5 cmH2O/L/sec over a physiological range of flows (1.5-9.5 L/sec). Offline, data was segmented and ventilatory and metabolic were adjusted for the heliox gas containing a slightly different O2 concentration and different humidity.  12  Repeated testing Two subjects (AC and SW) were tested over multiple days in attempt to better understand underlying mechanisms behind their observed EIAH. Subject AC was tested a total of 4 times. The first two testing days occurred 4.5 months apart and were identical to the above outlined procedures. On the second testing day, a mildly hyperoxic hypercapnic inspirate (FiO2 0.22, FiCO2 0.035) was utilized rather than heliox for the constant load exercise bout. The mild hyperoxia was due to a gas supplier error. The hypercapnic gas was used to increase the drive to breath and determine if the subject mechanically could not breathe more (due to EFL) or they chose not to (chemosensitivity). During the third and fourth visit, the subject performed an identical maximal exercise test except without an arterial catheter or esophageal balloon catheter; therefore SaO2 was estimated via pulse oximetry and some respiratory mechanics were not assessed. For the third visit, the subject inspired a slightly hyperoxic gas (FiO2 0.26) for the entire test and on the fourth visit they inspired compressed room air; the subject was blinded to the condition. The hyperoxic gas was used for two reasons: 1) to eliminate the EIAH and to keep the SaO2 at resting levels, 2) test whether shunts were the primary mechanism behind the EIAH. Subject SW was tested twice, 5 months apart, with identical procedures as outlined above. During the first test, the subject had recently recovered from an injury and was “relatively” untrained. For the second testing day, the subject had increased their V ˙O2Max and considered themselves fully trained while competing in middle distance running. For subject SW, we aimed to assess the effect of increased aerobic training on EIAH.  Data collection and processing Raw data (flow, volume, pressure, ventilatory and mixed expired metabolic parameters) were recorded continuously at 200 Hz using a 16-channel analog-to-digital data acquisition system (PowerLab/16SP model ML 795, ADI, Colorado Springs, CO) and stored on a computer for subsequent analysis (LabChart v7.1.3, ADInstrument, Colorado Springs, CO). Blood gas values were extracted from the blood gas analyzer and stored on a computer for analysis and temperature correction.  13 DATA ANALYSIS  Maximal expiratory flow volume curve and operational lung volumes MEFV curves were defined as the highest flow at any given volume. This was determined by aligning pre and post exercise FVC and gFVC maneuvers to the highest volume, which represent the subjects’ forced vital capacity. With all maneuvers superimposed upon each other, the highest expiratory flow in 10 mL volume segments were taken as the outer boundary of the MEFV curve. End-expired lung volume was estimated by subtracting the IC volume from the subject’s FVC. End-inspired lung volume was determined by adding the tidal volume to endexpired lung volume. Volumes were corrected for any pneumotachograph drift using customized software (IC of DOOM, LabVIEW software V6.1; National Instruments, Austin, TX). Additionally, peak esophageal pressure during the IC maneuver was used to ensure the subject attained similar peak pressures.  Flow-volume and pressure-volume loops and expiratory flow limitation Composite average flow-volume and pressure-volume loops were generated using customized software (BIBO, LabVIEW software V6.1; National Instruments, Austin, TX). Between 8 and 15 breaths were used for the construction of the averaged loop and were taken immediately before the IC maneuver. The flow-volume loops were aligned on the MEFV curve according to end-expiratory lung volume. Expiratory flow limitation was determined by dividing the part of the tidal flow-volume loop that intersects with the MEFV curve by the tidal volume. Expiratory flow limitation was only considered if > 5% of the tidal volume intersected the MEFV curve (14).  Work of breathing The energetic work of breathing was estimated by construction of modified Campbell diagrams (71) and integration of transpulmonary pressure-volume (PV) loops. For modified Campbell diagrams, a tidal volume-esophageal pressure loop from the previous analysis was graphed and the zero flow points at end-inspiratory and end-expiratory lung volume were connected with a line representing the dynamic compliance of the lungs, the compliance of the  14 chest-wall was estimated using data from previously published work (19). The functional residual capacity was set as the intersection of the chest-wall and lung compliance lines. The area enclosed by the volume-pressure loop was split into its four constituent parts: inspiratory resistive work, expiratory resistive work, expiratory elastic work and inspiratory elastic work; with the latter two having an additional component added that falls outside the enclosed loop. The four components were summed and multiplied by breathing frequency, and expressed in J/min. The PV loops were constructed from similar breaths as outlined above, except transpulmonary pressure was utilized. This form of analysis is able to discern between inspiratory elastic work, inspiratory resistive work and total expiratory work. The distinction is accomplished by first connecting EELV and EILV with a straight line, representing the total system compliance. A right angle triangle was created by connecting an iso-pressure line from EELV to an iso-volume line from EILV. The area bound by the triangle represents the inspiratory elastic component and needs to include the portion falling outside the PV curve to include all appreciable work. Inspiratory elastic work is needed to overcome the lungs tendency to recoil inwards and is a function of the specific compliance at which the ventilation occurs at. The area bound by the total compliance line and the lower part of the PV curve from EELV to EILV represents the inspiratory resistive work. The three components were summed and multiplied by breathing frequency, and expressed in J/min. To facilitate comparisons between individuals and groups, each individual had a regression equations fitted to relationship between WOB and V ˙E. The equation used is similar to that described by Otis (60) and employed by others (27) and is described by 3 2 WOB  a  VE  b  VE  where WOB is the work of breathing in J/min, a is the constant for the resistive component, b is the component for the viscous component and V ˙E is expired minute ventilation. The resistive component of the WOB is to overcome the resistance to airflow and is linked to airway size and geometry. The viscous component of the WOB is to deform elastic and non-elastic lung tissue and is similar between most healthy individuals. To determine the mechanical efficiency of breathing, we utilized equations described by Otis et al (61). These equations determine the optimal f, which minimizes work, for a given V ˙A and deadspace. Frequencies above the nadir result in increased viscous and turbulent work (due to higher flows and deadspace ventilating), while f below result in significantly greater elastic  15 work (due to large tidal volume). Each subject’s optimal f for every V ˙A and the associated minimal work was compared to the measured f and estimated work. For every stage we obtained an absolute inefficiency in work described by the following equation  WIneff    W n  where WIneff is the average absolute inefficient work, ∆W is the absolute deviation of work from the minimal and n is the number of VA used. However, as V ˙A increase, the work increased exponentially, therefore, the inefficient work was also calculated relative to minimal work; as described by the following equations  W  WIneff (%)    ((W  ) *100)  Min  n  where WIneff(%) is the average relative inefficient work, ∆W is the absolute deviation of work from the minimal, WMin is the minimal work at the given V ˙A and n is the number of V ˙A used in the calculation  Dynamic compliance Dynamic compliance was determined by adapting the technique described by Mead and Whittenberger (55). This technique relies on the transpulmonary pressure-volume and flowvolume loops created from the previous analysis (see Flow-volume and pressure-volume loops above). Dynamic compliance was determined by dividing the transpulmonary pressure difference between the two zero flow points (end-inspiration and end-expiration) by the volume change and expressed in mL/cmH2O.  Ventilatory capacity The method used to estimate ventilatory capacity (V ˙ECap) is similar to that described by Johnson et al. (55) and Jensen et al. (40, 43). This method determines the theoretical ventilation if the subject breathed exclusively along their MEFV curve for a given tidal volume and endexpiratory lung volume. The flow-volume loop used were the same as determined from the previous analysis (see Flow-volume and pressure-volume loops above). The volume of the tidal breath was divided into volume equal segments; ranging from 30-40 mL. Each volume segment  16 is then divided by the corresponding maximal expiratory flow to give an estimated minimal expiratory time. All equal volume segments are summed to give a minimal expiratory time for the tidal breath. Inspiratory time will be determined using the inspiratory-to-total breathing cycle time ratio. Maximal breathing frequency is determined after the minimal tidal breath time is calculated. Measured tidal volume and calculated maximal breathing frequency are multiplied to give the V ˙ECap for each stage. Ventilatory reserve is the difference between ventilatory capacity and measured minute ventilation.  Dysanapsis The degree of dysanapsis was determined using the ratio originally proposed by Mead (75): a measurement sensitive to lung size versus a measurement sensitive to airway size. This estimate was used to assess differences in relative airway size by minimizing the confounding effect of absolute lung volume. Lung size was determined using the FVC, and airway size was estimated using the following equation;  AS   FEF50 FVC  Pst 50  where AS is airway size, FEF50 is forced expired flow at 50% forced vital capacity, FVC is forced vital capacity and Pst50 is static recoil of the lungs and chest-wall at 50% forced vital capacity.  Calculations and corrections for environmental conditions Water vapour pressure was calculated using the following formula;  PH 2 0  %Hu  (13.955  (0.6584  T )  (0.0419  T 2 )) where PH2O is the water vapour pressure, % Hu is the percent humidity and T is ambient temperature. Water vapour pressure was used to correct gas concentrations for different ambient environmental conditions. Physiological deadspace was calculated using the standard equation;  VD V T  PaCO2  P ET CO2  VDV PaCO2  where VD is physiological deadspace, VT is tidal volume, PaCO2 is temperature corrected arterial carbon dioxide tension, PETCO2 is mixed end-tidal carbon dioxide tension and VDV is the  17 breathing valve deadspace (105mL). Blood gases were corrected for any temperature and pH changes associated with exercise according to standard formulas (75). Alveolar PO2 was estimated using a modification of the alveolar gas equation;  PA O2  Fi O2  ( PB  PH 2 0 )   Pa CO2  (1  Fi O2 (1  RER )) RER  where PAO2 is ideal alveolar O2, FiO2 is the fraction of inspired oxygen (room air 20.93 or heliox oxygen content), PB is daily barometric pressure, PH2O is the saturated water vapour pressure at esophageal temperature, PaCO2 is temperature corrected arterial carbon dioxide tension and RER is respiratory exchange ratio. The A-aDO2 was derived by subtracting PaO2 from PAO2. Oxyhemoglobin saturation was measured directly by the blood gas analyzer and SaO2 was also calculated if pH, temperature and PaCO2 remained unchanged from ideal resting conditions (7.4, 37°C, 40 mmHg; respectively) (indicating what percent of the desaturation was due solely to changes in PaO2) and if PaO2 remained at resting levels, but with pH, temperature and PaCO2 at their respective levels. Arterial oxygen content was determined using the equations;  CaO2  (1.39  Hb   SaO2 )  0.003  PaO2 100  where CaO2 is arterial oxygen content, Hb is hemoglobin concentration (g/dL), SaO2 is oxyhemoglobin saturation and PaO2 is arterial oxygen tension. Arterial oxygen content was calculated using: directly measured values obtained by blood gas analysis, SaO2 and PaO2 at resting levels (indicating an ideal situation), SaO2 due to only PaO2 decrease and SaO2 due to temperature, pH and PaCO2 changes. The latter two intended to identify which aspect influenced CaO2 the most. Alveolar ventilation was calculated using the alveolar ventilation equation;  VCO2 VA  ( )K PaCO2 where V ˙A is alveolar ventilation, V ˙CO2 is carbon dioxide production, PaCO2 is arterial tension of carbon dioxide and K is a constant (0.863). For all subjects at maximal and near maximal intensities, we determined the theoretical V ˙A and V ˙E needed to maintain PaO2 at resting levels. This was accomplished by determining the PAO2 needed to return PaO2 to resting levels, using the concurrent A-aDO2 for every stage, as it is not possible to accurately estimate any changes A-aDO2 for a given increase in ventilation. After PAO2 was determined, the alveolar gas  18 equation was resolved to indicate what the PaCO2 would be for this increased ventilation. The estimated PaCO2 was then used in the alveolar ventilation equation (along with concurrent V ˙CO2) to predict the needed V ˙A. Measured dead-space space ventilation for each workload was used to predict V ˙E. Bicarbonate content was calculated using temperature corrected pH and PaCO2 values according to the following equations;  HCO31  0.23 Pa CO2  10( pH  pKp) where HCO3-1 is bicarbonate (mmol/L), PaCO2 is arterial tension of carbon dioxide, pH is the negative base of hydrogen ions in solution and pKp is negative log base of the acid dissociation constant calculated with the following equations;  pKp  6.125  log(1  10( pH 8.7) ) Statistical analysis Pearson product moment correlations were used to determine relationships between selected variables. All subjects were pooled together and compared at different percentages of their V ˙O2Max (Rest (~8%), 60, 80, 90, 100%) using a repeated measures analysis of variance. When significant F ratios were detected, Tukey’s post-hoc test was used. Subjects were also partitioned into groups based on the appearance of EIAH (EIAH and NEIAH group) and any EFL (EFL and NEFL). We utilized the common definition of EIAH, which is a 10 mmHg decrease in PaO2 during exercise, compared to rest (13). The EIAH group was compared to the NEIAH group at rest and at different percentages of their V ˙O2Max using unpaired t-tests with bonferroni corrections. Independently, EFL and NEFL groups were comparing using similar methods. For the heliox trial, only subjects who previously showed EIAH were included. Using a repeated measures analysis of variance, rest, air breathing and heliox time points were compared. When significant F ratios were detected, Tukey’s post-hoc test was used. The group that completed the constant load exercise test were subdivided based on the appearance of EFL. The EFL and NEFL groups for the heliox trail were at rest, air breathing and heliox breathing compared using unpaired t-tests with bonferroni corrections. Before any bonferroni corrections, alpha was set at 0.05.  19  Results DESCRIPTIVE DATA Anthropometric and resting pulmonary function values for the cohort as a whole are shown in Table 2. Pulmonary function was similar to predicted values, however, there was considerable variation, where values ranged from 80-120% of predicted. No subjects were excluded for pulmonary function <80% of predicted. Descriptive characteristics based upon the appearance EIAH (n=20, 65%) are shown in Table 2. The EIAH and NEIAH groups were similar with respect to all variables except diffusion capacity. Based on criteria used by others (30), 10 subjects showed mild EIAH (PaO2 decrease 10-15 mmHg from rest), 5 showed moderate EIAH (PaO2 decrease 15-20 mmHg from rest) and 5 showed severe EIAH (PaO2 decrease +20 mmHg from rest). Eighteen subjects showed EIAH at submaximal intensities, defined as intensities at least 1 exercise stage below the maximal. One subject (CM) displayed EIAH at submaximal intensities, but not at maximal intensity, while all other EIAH subjects maintained a PaO2 10 mmHg below rest at maximal exercise. Six subjects with a V ˙O2Max < 50 mL/kg/min showed EIAH, with three having a V ˙O2Max < 45 mL/kg/min. Table 3 displays descriptive characteristics for subjects split into groups based on the appearance of EFL. The NEFL groups had superior lung function, while the groups were similar anthropometrically (Table 3). The average severity of EFL was 39% of VT, ranging from 14-69%. Six subjects showed EFL at exercise intensities other than maximum.  20 Table 2- Descriptive variables for thirty-one subjects based on the appearance of any EIAH All  EIAH (n=20)  NEIAH (n=11)  Value  Range  Value  Range  Value  Range  Age (yrs)  26 ± 1  19-42  27 ± 2  19-42  25 ± 2  19-34  Height (cm)  168 ± 1  157-188  169 ±1  161-179  167 ± 3  157-188  Weight (kg)  62 ± 1  48-81  62 ± 1  51-72  65 ± 3  48-81  BMI (kg/m2)  22.4 ± 0.4  18-29.4  21.9 ± 0.5  18.0-25.7  23.3 ± 0.9  18.5-29.4  2  BSA (m )  1.72 ± 0.02 1.47-2.05 1.71 ± 0.02 1.50-1.88 1.74 ± 0.05 1.47-2.05  Hb (g/dL)  12.1 ± 0.1  10.1-13.4  12.7 ± 0.2  11.3-13.7  12.0 ± 0.3  10.1-13.2  Hct (%)  37 ± 1  31-42  37 ± 1  35-42  37 ± 1  31-41  FVC (L)  4.0 ± 0.1  2.9-4.8  4.0 ± 0.1  2.9-4.8  4.0 ± 0.1  3.7-4.7  104 ± 2  82-120  103 ± 2  82-118  105 ± 2  95-120  3.4 ± 0.1  2.7-4  3.4 ± 0.1  2.7-4.0  3.4 ± 0.1  3.0-3.9  101 ± 2  84-116  101 ± 2  84-116  100 ± 2  84-112  85 ± 1  69-95  86 ± 1  69-95  85 ± 2  73-93  102 ± 1  81-122  102 ± 2  81-122  100 ± 2  88-112  PEF (L/sec)  7.9 ± 0.2  4.5-10.1  8.1 ± 0.3  4.5-10.1  7.4 ± 0.3  6.2-8.9  FEF75 (L/sec)  6.6 ± 0.2  4.5-8.9  6.8 ± 0.3  4.5-8.9  6.3 ± 0.2  5.5-7.2  FEF50 (L/sec)  4.6 ± 0.2  2.9-7.5  4.7 ± 0.3  2.9-7.5  4.5 ± 0.2  3.1-5.3  FEF25 (L/sec)  2.4 ± 0.2  0.8-4.9  2.4 ± 0.2  0.8-4.9  2.2 ± 0.2  1.3-3.5  DLCO (mmHg/ml/min)  27.2 ± 0.9  20.3-37.3  28.2 ± 1.0  22.1-37.2  24.7 ± 1.5  20.6-32.8  % Pred  103 ± 4  81-144  109 ± 4  85-144  91 ± 5*  81-116  MIP (cmH2O)  97 ± 4  41-134  97 ± 5  62-134  98 ± 7  41-13  % Pred  123 ± 5  50-173  122 ± 7  69-173  123 ± 9  50-157  % Pred FEV1 (L) % Pred FEV1/FVC (%) % Pred  All values are mean ± SE. EIAH, exercise induced arterial hypoxemia; NEIAH, no exercise induced arterial hypoxemia; yrs, years; BMI, body mass index; BSA, body surface area; Hb, hemoglobin; Hct, hematocrit; FVC, forced vital capacity; Pred, predicted; FEV1, forced expired volume in 1 sec; PEF, peak expiratory flow; FEF75, forced expiratory flow at 75% FVC; FEF50, forced expiratory flow at 50% FVC; FEF25, forced expiratory flow at 25% FVC; DLCO, carbon monoxide diffusion capacity of the lung; MIP, maximal inspiratory pressure. * significantly different from EIAH group (P < 0.05).  21 Table 3- Descriptive variables for thirty-one subjects based on the appearance of any EFL EFL (n=14)  NEFL (n=17)  Value  Range  Value  Range  Age (yrs)  26 ± 2  19-38  26 ± 2  19-42  Height (cm)  168 ± 1  161-177  169 ± 2  157-188  Weight (kg)  64 ± 2  51-74  63 ± 2  48-81  22.8 ± 0.6 19.5-26.9  22.0 ± 0.7  18-29.4  BSA (m )  1.7 ± 0.03  1.7 ± 0.03  1.5-2.1  Hb (g/dL)  11.8 ± 0.2 10.1-12.8 12.3 ± 0.2* 11.1-13.7  BMI (kg/m2) 2  1.5-1.9  Hct (%)  36 ± 0.6  31-39  38 ± 0.5*  34-44  FVC (L)  4.0 ± 0.1  2.9-4.8  4.1 ± 0.1  3.5-4.7  101 ± 2  82-114  105 ± 2  95-120  3.3 ± 0.1  2.7-3.9  3.5 ± 0.1*  3.1-4  97 ± 2  84-112  104 ± 2*  84-116  84 ± 2  69-95  86 ± 1  73-95  101 ± 3  81-122  102 ± 2  88-112  PEF (L/sec)  7.8 ± 0.4  4.5-10.1  8.0 ± 0.2  6.6-9.8  FEF75 (L/sec)  6.4 ± 0.4  4.5-8.7  6.8 ± 0.2  5.5-8.9  FEF50 (L/sec)  4.6 ± 0.3  2.9-6.6  5.0 ± 0.2*  3.1-7.5  FEF25 (L/sec)  1.9 ± 0.2  0.8-4.5  2.7 ± 0.2*  1.3-4.9  26.8 ± 1.2  20.6-37.3  89-138  102 ± 5  81-144  62-134  95 ± 5  41-123  69-173  120 ± 7  50-160  % Pred FEV1 (L) % Pred FEV1/FVC (%) % Pred  DLCO (mmHg/ml/min) 27.8 ± 1.5 22.1-35.6 % Pred MIP (cmH2O) % Pred  106 ± 6 100 ± 6 126 ± 9  All values are mean ± SE. EFL, expiratory flow limited; NEFL, no expiratory flow limitation; yrs, years; BMI, body mass index; BSA, body surface area; Hb, hemoglobin; Hct, hematocrit; FVC, forced vital capacity; Pred, predicted; FEV1, forced expired volume in 1 sec; PEF, peak expiratory flow; FEF75, forced expiratory flow at 75% FVC; FEF50, forced expiratory flow at 50% FVC; FEF25, forced expiratory flow at 25% FVC; DLCO, carbon monoxide diffusion capacity of the lung; MIP, maximal inspiratory pressure. * significantly different from EFL group (P < 0.05).  22 EXERCISE RESPONSE FOR ALL SUBJECTS Figure 2 shows ventilatory and metabolic measures during incremental treadmill exercise test. The subjects, as a whole, demonstrated the expected response with respect to all variables.  23 Figure 2- Metabolic and ventilatory variables during maximal exercise test 2.5  60 VT f  50 40  1.5  30  1.0  f (bpm)  VT (L)  2.0  20 0.5 10 0.0  0  100  VE and VA (L/min)  VE VA  80 60 40 20 0  VO2 and VCO2 (L/min)  3.5 VO2  3.0  VCO2  2.5 2.0 1.5 1.0 0.5 0.0 1.2  RER  1.1 1.0 0.9 0.8 0.7 0  20  40  60  80  100  % VO2Max  Legend: For each variable, each time point is different from preceding point, except VT, where the 60, 80 and 100% V ˙O2Max are similar (P < 0.05). VT, tidal volume, f, breathing frequency; V ˙E, minute ventilation; V ˙A, alveolar ventilation; V ˙O2, oxygen consumption; V ˙CO2, carbon dioxide production; RER, respiratory exchange ratio. Error bars are ± SE, n=30.  24 Blood gases In Figure 3, the blood gas response for each subject is shown. The three subjects in Panel A with resting PaO2 values at or below 80 mmHg had an additional resting sample taken to ensure the values were not erroneous. The samples were in close agreement (1-2 mmHg) and the three subjects with low resting PaO2 had SaO2 > 98%. There was high variability amongst PaO2 and PaCO2 at all exercise intensities, while SaO2 and A-aDO2 became more variable at higher intensities. Figure 4 shows relationships between blood gas variables at V ˙O2Max for all subjects. The degree of PaO2 change was weakly related to PaCO2 levels and highly related to the degree of gas exchange inefficiency (Panel A and B). Higher fitness levels were associated with greater hypoxemia (Panel C) and greater gas exchange impairments (Panel D), however, there are notable outliers in both. The grouped blood gas response to progressive exercise is shown in Figure 5. On average, subjects met the criteria for EIAH between 60 and 80% of V ˙O2Max, indicating, that on average our subjects became hypoxemia at submaximal intensities (Panel A). Indeed, the lowest PaO2 was achieved at 80% of V ˙O2Max and then showed some increase toward resting values. The rise in PaO2 near maximal exercise was concurrent with a hyperventilatory response (Figure 5, Panel C) and a plateauing of A-aDO2 (Figure 5, Panel D. Oxyhemoglobin saturation fell progressively throughout exercise and ended below the cited threshold for decrements in V ˙O2Max (SaO2 > 95% and/or 3% decrease from rest) (29). The decrease in SaO2 was due to both PaO2 changes and shifting of the oxygen dissociation curve due to blood acidity, hyperthermia and PaCO2 changes (Figure 6,7). Despite SaO2 decreasing, the CaO2 rose throughout exercise, but not to the extent it could have if EIAH was not present (Figure 6, Panel B). The rise in CaO2 was due to a progressive increase in hemoglobin concentration (Figure 6, Panel C). Figure 7 demonstrates the extent of the exercise related acidity and hyperthermia. While arterial pH was relatively maintained until 90% V ˙O2Max, thereafter, it declined sharply (Figure 7, Panel A). Circulating plasma K+ rose progressively during exercise but was slightly below other reported values (30, 52) (Figure 7, Panel C). Esophgeal temperature increased exponentially as exercise progressed (Figure 7, Panel D). We obtained a blood sample immediately after exercise in some subjects (within 1 min of exercise cessation) and PaO2 and SaO2 had already returned to pre-exercise levels.  25 Figure 3- Individual blood gas response to maximal exercise test. 110  A  50 45  PaCO2 (mmHg)  PaO2 (mmHg)  100 90 80 70 60  40 35 30 25  50 0  0 0  50  B  10  20  30  40  50  60  70  0  VO2 (mL/kg/min)  C  100  10  20  30  40  50  60  70  50  60  70  VO2 (mL/kg/min)  D  98 96  SaO2 (%)  A-aDO2 (mmHg)  40  30  20  94 92 90 88  10  86 0  0 0  10  20  30  40  VO2 (mL/kg/min)  50  60  70  0  10  20  30  40  VO2 (mL/kg/min)  Legend: PaO2, arterial oxygen tension; PaCO2, arterial carbon dioxide tension; A-aDO2, alveolar to arterial oxygen difference; SaO2, oxyhemoglobin saturation. n=31  26 Figure 4- Relationships between blood gas variables at V ˙O2MAX. A  R = -0.94 P < 0.0001 y = -1.08x + 114.5  120  110  110  100  100  PaO2 (mmHg)  PaO2 (mmHg)  120  B R = -0.35 P < 0.05 y = -1.06x+124.9  90 80  90 80  70  70  60  60  0  0 0  30  35  40  45  0  10  PaCO2 (mmHg)  C 120  20  30  40  50  A-aDO2 (mmHg)  D  R = -0.60 P <0.001 y = -0.87x + 127  50  R = 0.56 P <0.001 y= 0.71x-7.59  110 100  A-aDO2 (mmHg)  PaO2 (mmHg)  40  90 80 70  30  20  10  60 0  0 0 25  30  35  40  45  50  VO2Max (mL/kg/min)  55  60  65  0 25  30  35  40  45  50  55  60  65  VO2Max (mL/kg/min)  Legend: PaO2, arterial oxygen tension; PaCO2, arterial carbon dioxide tension; A-aDO2, alveolar to arterial oxygen difference. n=31.  27 Figure 5- Grouped blood gas response during maximal exercise test. A  120 115  *  110  98  *  *  *  105  SaO2 (%)  PaO2 and PAO2 (mmHg)  B  100  100 95 90  *  *  85  *  80  PaO2  75  PAO2  * 96  * *  94  * 92  0  0 0  20  40  60  80  0  100  20  40  C  D  30  100  *  *  41  80  % VO2Max  % VO2Max 42  60  *  * 25  A-aDO2 (mmHg)  PaCO2 (mmHg)  40 39 38 37 36  *  20  15  10  5  35 0  0 0  20  40  60  % VO2Max  80  100  0  20  40  60  80  100  % VO2Max  Legend: The dotted line in Panel A represent the 10 mmHg decrement in PaO2 from rest. PAO2, alveolar oxygen tension; PaO2, arterial oxygen tension; SaO2, oxyhemoglobin saturation PaCO2, arterial carbon dioxide tension; A-aDO2, alveolar to arterial oxygen difference. * significantly different from rest, ψ, significantly different from maximal exercise (P<0.05). n=30.  28 Figure 6- The relative contribution to changes in hemoglobin saturation and oxygen content during the maximal exercise test. A  100  SaO2 (%)  98  96  94  92 0  B  Actual Ideal PaO2 Changes: Resting pH, Temp, PaCO2 pH, Temp, PaCO2 Changes: Resting PaO2  19.0  18.5  CaO2 (mL/dL)  18.0  17.5  17.0  16.5  16.0 0.0 14.0  Hb Hct  13.5  *  Hb (g/dL)  13.0 12.5  *  * *  *  44  *  42  * * 40  12.0 11.5  38  Hct (%)  C  11.0 36  10.5 10.0 0.0  34 0 0  20  40  60  80  100  % VO2Max  Legend: Ideal oxygen content is derived using resting saturation and with concurrent hemoglobin concentration. Resting pH, temperature and PaCO2 was defined as 7.40, 37°C and 40 mmHg; respectively. SaO2, oxyhemoglobin saturation; PaO2, arterial oxygen tension; PaCO2, arterial carbon dioxide tension; CaO2, arterial oxygen content; Hb, hemoglobin concentration; Hct, hematocrit. * significantly different from rest, ψ, significantly different from maximal exercise (P<0.05). n=30.  29 Figure 7- Acid-base, potassium and esophageal temperature changes during maximal exercise test. 7.40  B *  7.36  *  7.28  *  20  18  -  pH  7.32  24  22  HCO3 (mmol/L)  A  7.24  *  16  * 14  7.20 0  0.00 0  20  40  60  80  0  100  20  40  6.0  * 5.5  D  39.0  *  *  *  5.0  100  38.5  *  Teso (°C)  *  4.5  +  K (mmol/L)  80  % VO2Max  % VO2Max  C  60  4.0  38.0  * 37.5  * 37.0  3.5  36.5 0.0  0.0 0  20  40  60  80  0  100  20  40  60  80  100  % VO2Max  % VO2Max  ψ  Legend: Teso, esophageal temperature.* significantly different from rest, , significantly different from maximal exercise (P<0.05). n=30 except Panel C which is n=24.  30 Respiratory mechanics In two subjects, the esophageal balloon was suspected of being displaced near the end of exercise, therefore some groups only include 28 subjects. We suspect the balloon to have been displaced because the tidal ∆Peso had become unphysiologically low (<8 cmH2O for 2 L VT) and during extraction had moved significantly higher in the subjects(s) esophagus (<20cm from nares). Figure 8 shows the changes in operational lung volumes during the maximal exercise test. As expected, EILV rose consistently throughout exercise (Figure 8) and in some subjects approached TLC (>90% FVC). End-expiratory lung volume progressively decreased during exercise, but, increased back toward FRC at maximal intensities (Figure 8). Figure 9 (Panel A, B) displays both WOB and esophageal pressure swing exponential increase throughout exercise. When broken into constituent components, elastic WOB (WOBEl) was a greater contributor to total WOB then the resistive component; however, at maximal intensities the difference between the two was negligible (Figure 9, Panel C). Individual plots for WOB are shown in Figure 10, with little difference between EIAH and NEIAH subjects (Panel A, B, D). However, despite having similar ventilations, the WOB appears to be associated with a decreasing PaO2 in the EIAH group, indicating their exercise hyperpnea is relatively ineffective (Figure 10, Panel C). Figure 11 displays the relationship between V ˙E, V ˙ECAP and the theoretical ventilation needed to completely offset the hypoxemia and bring PaO2 back to resting levels along with the accompanying PaCO2 changes. Figure 11, Panel A demonstrated that the theoretical PaCO2 that would result from offsetting EIAH would be significantly lower than the actual PaCO2 and low in absolute values. Figure 11, Panel B shows that V ˙ECAP remains stable during exercise, yet V ˙E and the theoretical V ˙E necessary to offset EIAH continue to increase and approach V ˙ECAP.  31 Figure 8- Operational lung volumes during maximal exercise test. 100  *  Operation lung volume (% FVC)  90 80  *  *  *  70 60 50 40  *  *  *  60  80  *  30 20 10 0 0  20  40  100  120  % VO2Max  Legend: Open circles represent end-inspiratory lung volume while filled circles represent endexpiratory lung volume. FVC, forced vital capacity; V ˙O2Max, maximal oxygen consumption. * ψ significantly different from rest, , significantly different from maximal exercise (P<0.05). n=30  32 Figure 9- Respiratory mechanics during maximal exercise test. A  350  B  50  300 40  Peso (cmH2O)  WOB (J/min)  250 200 150  30  20  100 10 50 0  0 0  20  40  60  80  100  0  20  % VO2Max  100  * *  40  25 20 15 10  *  *  45  VT/FVC (%)  El & Res work (cmH2O/breath)  80  D  50 Resistive Elastic  30  60  % VO2Max  C  35  40  35 30 25 20  5  15  0  10 0 0  20  40  60  % VO2Max  80  100  0  20  40  60  80  100  % VO2Max  Legend: In Panel A,B,C all time points are statistically different from each other. WOB, work of breathing; ∆Peso esophageal pressure swings; El, elastic; Res, resistive; VT, tidal volume; FVC, forced vital capacity; V ˙O2Max, maximal oxygen consumption. * significantly different from rest, ψ , significantly different from maximal exercise (P<0.05). Panel A and C n=28, Panel B n=29, Panel D n=30.  33 Figure 10- Work of breathing for all subjects at all time points for the maximal exercise test. A  450  EIAH Guenette et al  400  400  350  350  300  300  WOB (J/min)  WOB (J/min)  B  450  250 200 150  250 200 150  100  100  50  50  0  0 0  20  40  60  80  100  120  140  0  20  40  VE (L/min)  60  80  100  120  140  100  120  140  VE (L/min)  NEIAH EIAH C  110  D  450 400  100 350  90  WOB (J/min)  PaO2 (mmHg)  R = 0.23, P > 0.05  80 70 R = 0.45, P <0.0001  60  300 250 200 150 100 50  50 0  0 0  100  200  300  WOB (J/min)  400  0  20  40  60  80  VE (L/min)  Legend: Regression in Panel A is from Guenette et al. J Physiol 2007 with 10 trained cyclists. WOB, work of breathing; V ˙E, minute ventilation; PaO2, arterial oxygen tension. n=31.  34 Figure 11- Minute ventilation, maximal ventilatory capacity, theoretical ventilation to offset EIAH and the associated arterial carbon dioxide tension during maximal exercise test. A  42 40 38  PaCO2 (mmHg)  36 34 32 30 28 26  Actual Predicted  24 0 0  20  40  60  80  100  % VO2Max  A *  200  *  *  *  Ventilation (L/min)  150  VE VECap  100  VE to eliminate EIAH  50  0 0  20  40  60  80  100  % VO2Max  Legend: Predicted PaCO2 is calculated using alveolar gas equation and the minute ventilation needed to eliminate the EIAH. PaCO2, arterial carbon dioxide tension; V ˙E, minute ventilation, V ˙ ˙O2Max, maximal oxygen consumption. * significantly different from V ˙ ECap, ventilatory capacity; V ψ ˙ECap, , significantly different from V ˙E, ϕ, different from PaCO2 predicted. (P<0.05). E and V  n=30  35 EXERCISE RESPONSE SPLIT INTO EIAH/NEIAH AND EFL/NEFL Figure 12 shows the MEFV curves and tidal FV loops for the subjects split independently into EIAH/NEIAH and EFL/NEFL groups. The EIAH group shows the most dramatic drop in PaO2 (Panel A) and does not display any EFL. The NEIAH group maintains and increases PaO2 and also does not show any EFL. The EFL group becomes flow limited during maximal intensities, but still increases PaO2. The NEFL group maintains considerable ventilatory reserve and shows little to no EIAH. The EFL and NEFL groups had similar V ˙O2Max values (P > 0.05). Subjects who show any EFL appear to show more dysanapsis than those who do not show any EFL (Figure 13), while the appearance of EIAH appears to be less related to dysanapsis (Figure 13).  36 Figure 12- Maximal flow-volume curves and tidal flow volume loops with arterial oxygen tension for subjects split into four groups during maximal exercise test. B- NEIAH VO2Max 42 mL/kg/min (n=10)  10  10  8  8  6  6  Flow (L/sec)  Flow (L/sec)  A- EIAH VO2Max 51 mL/kg/min (n=20)  4 2 0 -3  -2  -1  -4 -2  -4  -4  -6  -6  100  100  90  80 Rest  D- NEFL VO2Max 49 mL/kg/min (n=16)  6  6  Flow (L/sec)  8  4 2 0 -1  4 2 0  0  -4 -2  -4  -4  -6  -6  100  100 PaO2 (mmHg)  -2  90  80  70  Rest  0  VO 2Max  70  8  -2  -1  80  10  -3  -2  90  10  -4  -3  Rest  VO 2Max  C- EFL VO2Max 47 mL/kg/min (n=14)  Flow (L/sec)  0  -2  70  PaO2 (mmHg)  2  0  PaO2 (mmHg)  PaO2 (mmHg)  -4  4  VO 2Max  -3  -2  -1  0  90  80  70  Rest  VO 2Max  Legend: Groups split based on the appearance of and EIAH or any EFL. A, EIAH; B NEIAH; C, EFL; D, NEFL. EIAH, exercise induced arterial hypoxemia; NEIAH, no exercise induced arterial hypoxemia; EFL, expiratory flow limitation; NEFL, no expiratory flow limitation.  37 Figure 13- Dysanapsis index for subjects split into four mutually exclusive groups. 0.4  Dysanapsis Index  0.3  0.2  0.1  EIAH with EFL (n=8) EIAH with no EFL (n=5) NEIAH with EFL (n=3) NEIAH with no EFL (n=6)  0.0 0.0  3.0  3.5  4.0  4.5  FVC (L)  Legend: Line is the regression for all subjects pooled. EIAH, exercise induced arterial hypoxemia; NEIAH, no exercise induced arterial hypoxemia; EFL, expiratory flow limitation; NEFL, no expiratory flow limitation. FVC, forced vital capacity. Error bars are SE. EIAH VS. NEIAH Tables 4, 5 and 6 compare metabolic and ventilatory, blood gas and lung mechanics variables between the EIAH and NEIAH groups at V ˙O2Max. The EIAH group was significantly fitter and had larger ventilations (Table 4). The EIAH had lower PaO2, SaO2 and larger A-aDO2 and a higher core temperature (Table 5). The difference in SaO2 between groups was due to changes in PaO2 and not temperature, pH or PaCO2. Consequently, the EIAH groups CaO2 did not rise as much as the NEIAH group (Table 5). Operational lung volumes were similar between groups. The EIAH group had a greater WOBRes, leading to a greater total WOB. While the groups had similar V ˙ECap, the EIAH group used a greater proportion of it.  38 Table 4- Metabolic and ventilatory data at maximal oxygen consumption for thirty-one subjects divided into groups based on the occurrence of any EIAH. All  EIAH (n=20)  NEIAH (n=11)  Value  Range  Value  Range  Value  Range  3.0 ± 0.1  1.9-3.7  3.2 ± 0.1  2.4-3.7  2.7 ± 0.1*  1.9-3.3  (mL/kg/min)  48 ± 1  28-62  51 ± 1  38-62  42 ± 2*  28-52  V ˙CO2 (L/min)  3.3 ± 0.1  1.9-4.1  3.5 ± 0.1  2.7-4.1  2.9 ± 0.1*  1.9-3.6  RER  1.1 ± 0.01  0.89-1.23  1.1 ± 0.01  1-1.19  1.08 ± 0.01  0.89-1.23  V ˙E (L/min)  87 ± 2  58-115  91 ± 3  63-115  77 ±4*  58-96  V ˙A (L/min)  76 ± 2  54-93  80 ± 2  61-93  69 ± 2*  54-80  VT (L)  1.9 ± 0.1  1.4-2.6  1.9 ±0.1  1.5-2.6  1.8 ± 0.1  1.4-2.1  f (bpm)  55 ± 2  34-71  56 ± 2  40-71  52 ± 3  34-68  VD (L)  0.4 ± 0.03  0.08-1.1  0.3 ± 0.02  0.2-0.6  0.4 ± 0.08  0.08-1.1  VD/VT  0.18 ± 0.02  0.05-0.6  0.18 ± 0.01  0.09-0.27  0.2 ± 0.04  0.05-0.6  V ˙E/V ˙O2  29 ± 1  20-34  29 ± 1  25-32  29 ± 1  20-34  V ˙E/V ˙CO2  26 ± 1  21-32  26 ± 1  22-32  27 ± 1  21-31  Ti (s)  0.55 ± 0.02  0.38-0.9  Te (s) TTot (s)  V ˙O2 (L/min)  Ti/Ttot (%)  0.52 ± 0.02 0.38-0.71  0.58 ± 0.04 0.43-0.76  0.58 ± 0.02 0.44-0.88  0.57 ± 0.02  0.45-0.81  0.57 ± 0.03  0.44-0.70  1.13 ± 0.04 0.84-1.78  1.10 ± 0.04  0.84-1.49  1.15 ± 0.06  0.89-1.45  48 ± 1  41-56  50 ± 1*  47-54  49 ± 1  41-56  Values are mean ± SE. V ˙O2, oxygen consumption; V ˙CO2, carbon dioxide production; RER, respiratory exchange ratio;V ˙E, expired minute ventilation; V ˙A, alveolar ventilation; VT, tidal volume; f, breathing frequency; VD, physiological deadspace; Ti, inspiratory time; Te, expiratory time; TTot, total breathing time. * Significantly different from EIAH group, P <0.05.  39 Table 5- Arterial blood data at maximal oxygen consumption for thirty-one subject divided into groups based on the occurrence of any EIAH. All EIAH (n=20) NEIAH (n=11) Value  Range  Value  Range  Value  Range  PaO2 (mmHg)  85 ± 2  67-105  80 ± 2  67-89  95 ± 2*  77-105  ∆PaO2 rest (mmHg)  -8 ± 2  -23-+31  -14 ± 1  -23-(-4)  5 ± 3*  -6-+31  PAO2 (mmHg)  112 ± 1  103-119  111 ± 1  103-119  113 ±1  106-118  A-aDO2 (mmHg)  27 ± 2  11-45  31 ± 1  21-45  17 ± 1*  11-26  PaCO2 (mmHg)  38 ± 1  30-46  38 ± 1  30-46  37 ± 1.0  30-42  pH  7.24 ± 0.01 7.14-7.36 7.23 ± 0.01 7.14-7.31 7.25 ± 0.02 7.16-7.36 -  HCO3 (mmol/L)  16 ± 0.4  11-22  15 ± 0.3  11-17  16 ± 0.8  13-22  K+ (mmol/L)  5.7 ± 0.1  4.9-6.3  5.7 ± 0.1  4.9-6.2  5.7 ± 0.1  5.2-6.3  Teso (°C)  38.6 ± 0.1  37.2-40  38.9 ± 0.2  37.5-40.0 38.1 ± 0.2* 37.3-39.3  SaO2 (%)  94.3 ± 0.5  87.1-97.9  93.2 ± 0.5  87.1-96.0 96.3 ± 0.3* 94.6-97.9  PaO2 changes  96.1 ± 0.3  93.1-98.1  95.6 ± 0.3  93.1-96.8 97.1 ± 0.3* 95.2-98.1  pH,Teso,PaCO2  94.7 ± 0.2  91.4-97.0  94.5 ± 0.3  91.4-96.5  95.1 ± 0.4  93.0-97.0  13.4 ± 0.2  11.4-15.7  13.4 ± 0.2  12.2-15.7  13.3 ± 0.4  11.4-15.2  41 ± 1  35-48  41 ± 1  38-48  41 ± 1  35-47  17.8 ± 0.2  15.5-20.7  17.6 0.2  16-19.7  18.1 ± 0.5  15.5-20.7  PaO2 changes  18.1 ± 0.2  15.8-20.9  18.1 ± 0.2  16.4-20.7  18.2 ± 0.5  15.8-20.9  pH,Teso, PaCO2  17.9 ± 0.2  15.1-20.7  17.9 ± 0.2  16.4-20.7  17.8 ± 0.5  15.1-20.4  Ideal  18.5 ± 0.2  15.8-21.8 18.6 ± 0.3  17.0-21.8  18.3 ± 0.2  15.8-21.8  ∆CaO2 rest (mL/dL)  +1.0 ± 0.2  -0.8-2.5  +1.5 ± 0.3*  0.1-3.2  Hb (g/dL) Hct (%) CaO2 (ml/dL)  -0.8-3.2  +0.75 ± 0.2  Values are mean ± SE. PaO2, arterial oxygen tension; ∆ PaO2 rest, change in arterial oxygen tension from rest; PAO2, alveolar oxygen tension; A-aDO2, alveolar to arterial oxygen difference; PaCO2, arterial carbon dioxide production; Teso, esophageal temperature; SaO2, arterial oxyhemoglobin saturation; Hb, hemoglobin concentration; Hct, hematocrit; CaO2, arterial oxygen content; ∆CaO2 rest, change in arterial oxygen content from rest. * Significantly different from EIAH group, P <0.05.  40 Table 6- Respiratory mechanics data at maximal oxygen consumption for thirty-one subject divided into groups based on the occurrence of any EIAH. All EIAH (n=20) NEIAH (n=11) Value  Range  Value  Range  Value  Range  EELV (% FVC)  38 ± 2  21-63  36 ± 2  21-49  40 ± 3  23-63  EILV (% FVC)  87 ± 1  73-96  87 ± 2  73-96  88 ± 2  74-96  WOBc (J/min)  289 ± 17 124-507 324 ± 19 158-507 224 ± 24* 124-330  WOBpv (J/min)  223 ± 13 100-386 253 ± 14 151-386 170 ± 17* 100-247  WOBEl (cmH2O/br)  27 ± 2  14-50  29 ± 2  16-50  24 ± 3  14-37  51 ± 2  32-74  49 ± 2  32-74  55 ± 2  45-64  26 ± 2  14-49  30 ± 2  15-49  19 ± 1*  14-24  % tot  49 ± 2  26-68  51 ± 2  26-68  45 ± 2  36-55  ∆Peso (cmH2O)  45 ± 2  26-66  49 ± 2  33-66  39 ± 3*  23-50  Comp (mL/cmH2O)  72 ± 4  46-145  68 ± 3  46-95  80 ± 10  48-145  V ˙ECap (L/min)  167 ± 6  103-246  167 ± 9  103-246  168 ± 10  130-229  V ˙E/V ˙ECap (%)  54 ± 2  32-77  57 ± 2  36-77  48 ± 3*  32-66  59-283  153 ± 11  89-283  75 ± 3*  59-88  76 ± 6  17-149  93 ± 6  52-149  44 ± 4*  17-59  16 ± 3.5  0-58  19 ± 5  0-58  9±5  0-37  % tot WOBRes (cmH2O/br)  V ˙E offset EIAH (L/min) 125 ± 10 %V ˙ECap EFL (%)  Values are mean ± SE. EELV, end expiratory lung volume; FVC, forced vital capacity; EILV, end inspiratory lung volume; WOBc, work of breathing using Campbell diagrams; WOBpv, work of breathing using pressure-volume loops; WOBEl, elastic work of breathing; WOBRes, resistive work of breathing; ∆Peso, esophageal pressure swings per breath; Comp, compliance; V ˙ECap, maximal ventilatory capacity; V ˙E, minute ventilation; EIAH, exercise induced arterial hypoxemia; EFL, expiratory flow limitation. * Significantly different from EIAH group, P <0.05. Blood gases for EIAH vs. NEAIH Figure 14 shows the arterial blood gas variable during the maximal exercise test for the EIAH and NEIAH groups. The groups had similar PAO2 at all time points, while the EIAH group had significantly lower PaO2 from 80% V ˙O2Max onward, due to a greater A-aDO2 (Panel A,C). Both groups displayed a rise in PaO2 at maximal exercise, but the NEIAH groups was greater and resulted in a maximal exercise PaO2 > Resting levels. Similarly, the EIAH groups  41 had lower SaO2 from 80% V ˙O2Max onward, which was due to decreased PaO2 and not a rightward shifting of the oxygen disassociation curve ODC (Figure 14, Panel B; Figure 15). As such, the EIAH and NEIAH groups had similar changes in acid-base balance (Figure 16, Panel A,B) and had similar Teso except for maximal exercise.  42 Figure 14- Blood gas variables for the EIAH and NEIAH groups during maximal exercise test. A  120  B  100  115 98  105  *  100  *  95  *  90  *  SaO2 (%)  PaO2 and PAO2 (mmHg)  110  85  94  80 75  EIAH PAO2  70  NEIAH PAO2  92  0  0 0  20  40  60  80  100  % VO2Max  0  20  40  60  80  100  % VO2Max  EIAH NEIAH  C  42  D  40  *  40  30  A-aDO2 (mmHg)  PaCO2 (mmHg)  *  96  38  36  *  *  20  10  34 0  0 0  20  40  60  % VO2Max  80  100  0  20  40  60  80  100  % VO2Max  Legend: PAO2, alveolar oxygen tension; PaO2; SaO2, arterial oxyhemoglobin saturation; PaCO2, arterial carbon dioxide tension; AaDO2, alveolar to arterial oxygen difference, V ˙O2Max, maximal oxygen consumption. *, P < 0.01; ψ, P < 0.05. n=30.  43 Figure 15- Arterial oxyhemoglobin saturation for the EIAH and NEIAH groups during the maximal exercise test. A  100  SaO2 measured (%)  99 98  *  97  *  96 95 94 93 92 0  SaO2 due to PaO2 changes (%)  100  B  99 98  *  97  *  96 95 94 93  SaO2 due to temp, pH, CO 2 changes (%)  92 0  C  100 99 98 97 96 95 94 93  EIAH NEIAH  92 0 0  20  40  60  80  100  % VO2Max  Legend: Panel A is directly measured while Panel B and C represent calculated values. SaO2, arterial oxyhemoglobin saturation, V ˙O2Max, maximal oxygen consumption. *, significantly different from EIAH. P < 0.01. n=30.  44 Figure 16- Acid-base, potassium and esophageal temperature changes during maximal exercise test for EIAH and NEIAH groups. A  7.40  B  26 24  7.36  HCO3 (mmol/L)  22 20  -  pH  7.32  7.28  18 16  7.24  14 7.20 0.00  0 0  20  40  60  80  100  0  40  EIAH NEIAH  % VO2Max  C  7.0  20  80  100  % VO2Max  D  39.5  6.5  60  *  39.0  6.0  Teso (°C)  5.0  +  K (mmol/L)  38.5 5.5  38.0 37.5  4.5 4.0  37.0  3.5  36.5 0.0  0.0 0  20  40  60  % VO2Max  80  100  0  20  40  60  80  100  % VO2Max  Legend: Teso, esophageal temperature, V ˙O2Max, maximal oxygen consumption. * P <0.01. n=30 except Panel C which is n=24  45 Respiratory mechanics for EIAH and NEIAH groups Figure 17 show the WOB and its constituent components for the EIAH and NEIAH groups. The EIAH groups had a higher WOB at the same percent of V ˙O2Max (Panel A), this is attributed to the higher V ˙E (Panel B) as the two groups have similar WOB when compared at isovolumes (Figure 10). The higher WOB in the EIAH group was the result of a higher WOBRes, as the groups had similar WOBEl (Panel C). There was no difference in tidal esophageal pressure swings. The groups also had similar changes in operational lung volumes. Eleven of the 20 EIAH subjects showed some form of EFL, while only 3/10 of the NEIAH subjects showed any EFL. In Figure 18 Panel A, the EIAH group’s predicted PaCO2 is extremely low as they increased their V ˙E to completely offset the hypoxemia. The EIAH and NEIAH groups have similar V ˙ECap, yet if the EIAH group increased their V ˙E to offset the hypoxemia, they would be required to ventilate very near their V ˙ECap (Figure 18 Panel B). Table 7 shows each subject’s constants for the equation described in the methods above (See Work of Breathing). There was no difference between EIAH and NEIAH groups. There was no difference in the mechanical breathing efficiency between the EIAH and NEIAH groups with the subject average being 1.6% of ideal f. However, some subjects during maximal intensity were up to 19% and incurred substantial WOB due to excessively high f. Figure 19 displays the MEF curve, tidal FV loops and PaO2 for the EIAH group split into 6 distinct patterns of hypoxemia. Subjects in Panel A display a gradual decrease in PaO2 with the capacity to increase ventilation, a response that is typically seen in trained men. Subjects in Panel B demonstrate an immediate fall in PaO2 upon exercise onset, at ~90% V ˙O2Max, the group increases V ˙E and raises their PaO2 back towards resting levels and does not show any EFL. The “U shaped” response in PaO2 has not been reported in men. In Panel C, the subjects again show an immediate decrease in PaO2, however as exercise intensity increases, PaO2 remain stable despite an apparent ability to increase V ˙E. In Panel D, PaO2 is maintained until the onset of EFL (80% V ˙O2Max) at which point they sharply decrease and remain stable. Decreases in PaO2, due to EFL, have been reported in highly trained men, but is not seen in men with unremarkable fitness, which is in contrast to the women represented in Panel D. Panel E also shows an immediate drop in PaO2 upon exercise onset and a slight rebound near maximal intensities. However, unlike Panel B, subjects in Panel E are unable to substantially increase their PaO2 due to the onset of EFL. Finally, Panel F shows a nearly  46 identical response as Panel C (immediate PaO2 drop followed by a plateauing), except, at maximal exercise they display some EFL, which may have prevented any increase in PaO2.  47 Figure 17- Respiratory mechanics for the EIAH and NEIAH groups during maximal exercise test. A  350  *  B  100  *  300 80  *  VE (L/min)  WOB (J/min)  250 200 150  *  *  60  40  100 20 50 0  0 0  20  40  60  80  100  0  20  % VO2Max  40  60  80  100  80  100  % VO2Max  C  40  D *  50  30  *  20  40  Peso (cmH2O)  WOBEl (cmH2O/br)  WOBRes (cmH2O/br)  EIAH NEIAH  10 0 40 30 20  30  20  10  10 0  0 0  20  40  60  % VO2Max  80  100  0  20  40  60  % VO2Max  Legend: WOB, work of breathing; V ˙E, minute ventilation; WOBRes, resistive work of breathing; WOBEl, elastic work of breathing; ∆Peso, tidal esophageal swing. V ˙O2Max, maximal oxygen consumption. * P < 0.01, ψ P < 0.05. Panel A and C n=28, Panel B n=29, Panel D n=30.  48 Figure 18- Minute ventilation, maximal ventilatory capacity, theoretical ventilation to offset EIAH and the associated arterial carbon dioxide tension during maximal exercise test for EIAH and NEIAH groups. A  45  PaCO2 (mmHg)  40  35  30  25  Measured PaCO2  20  Predicted PaCO2 to offset EIAH  0 0  20  40  60  80  100  % VO2Max  B  200 175  Ventilation (L/min)  150 125  Measured VE (EIAH) VECap (EIAH) Predicted VE to offset EIAH  100  *  Measured VE (NEIAH)  *  VECap (NEIAH)  75  * 50 25 0 0  20  40  60  80  100  % VO2Max  Legend: In Panel B, the V ˙E to offset EIAH is 60, 78 and 92% of V ˙ECap at 60, 80 and 100% V ˙O2Max; respectively. PaCO2, arterial carbon dioxide tension; V ˙E, minute ventilation; V ˙ECap, ventilatory capacity; EIAH, exercise induced arterial hypoxemia; V ˙O2Max, maximal oxygen consumption. Φ, significantly different from predicted PaCO2; ψ, significantly different from V ˙E and V ˙E to offset EIAH; *, significantly different from NEIAH V ˙E. P < 0.01. n=30.  49  Table 7- Work of breathing constants for the EIAH and NEIAH groups Subject AC AH AM AS BS CM CR EM GLY JB JBarc JC JL JShep JS KM MB MF MG MM NN NW PH RB SD SL SS SW VW  Constant A Constant B 3.97E-06 3.18E-02 2.33E-04 1.11E-02 4.52E-13 2.40E-02 4.71E-05 2.90E-02 2.06E-12 3.34E-02 5.55E-13 2.86E-02 1.56E-12 3.19E-02 8.35E-13 3.78E-02 3.22E-12 3.48E-02 1.24E-13 3.42E-02 1.28E-12 3.02E-02 1.86E-05 1.80E-02 8.36E-13 1.79E-02 1.33E-12 2.13E-02 1.27E-04 2.76E-02 1.07E-12 3.80E-02 1.52E-04 1.63E-02 1.34E-12 2.92E-02 3.91E-04 5.97E-03 3.13E-05 2.83E-02 1.95E-13 3.15E-02 7.32E-13 2.65E-02 8.59E-13 3.48E-02 7.02E-05 2.30E-02 2.74E-05 3.51E-02 2.84E-12 2.10E-02 6.83E-13 2.27E-02 3.45E-06 2.31E-02 1.08E-04 3.87E-02  All mean 4.18E-05 2.71E-02 EIAH mean 2.37E-05 2.86E-02 NEIAH mean 7.63E-05 2.43E-02 Legend: Constant A and B are from the WOB equation described in the methods. EIAH, exercise induced arterial hypoxemia; NEAIH, no exercise induced arterial hypoxemia.  50 Figure 19- Patterns of hypoxemia for the EIAH group during the maximal exercise test.  Expired flow (L/sec)  8 6 4 2  6 4 2 0  -1  0  Volume (L)  100 90 80 70 Rest  60  80  90  70  Expired flow (L/sec)  2  60  80  90  -3  -2  -1  70 Rest  60  80  90  100  70 60  80  90  10  2  0  80  10  4  -1  90  Rest  6  100  8 6 4 2 0  -4  PaO2 (mmHg)  80  -2  Volume (L)  F-VO2Max 45 mL/kg/min (n=3)  -3  -2  -1  0  -4  Volume (L)  100  90  -3  100  E-VO2Max 52 mL/kg/min (n=4)  0  Volume (L)  100  2  -4  0 -4  4  100  8  0  6  0  80  10  4  -1  90  D-VO2Max 48 mL/kg/min (n=3)  6  -2  Volume (L)  Rest  8  -3  100  100  8  0 -4  PaO2 (mmHg)  -2  Expired flow (L/sec)  -3  PaO2 (mmHg)  PaO2 (mmHg)  -4  Expired flow (L/sec)  C-VO2Max 53 mL/kg/min (n=3) 10  8  0  PaO2 (mmHg)  B-VO2Max 55 mL/kg/min (n=4) 10  PaO2 (mmHg)  Expired flow (L/sec)  10  Expired flow (L/sec)  A-VO2Max 55 mL/kg/min (n=3)  90 80 70 Rest  60  80  90  100  -3  -2  -1  0  Volume (L)  100 90 80 70 Rest  60  80  90  100  Legend: The grey area represents a PaO2 within 10 mmHg of rest. Rest, 60, 80, 90 and 100 are percent of V ˙O2Max. PaO2, arterial oxygen tension, V ˙O2Max, maximal oxygen consumption.  51 EFL VS. NEFL Eleven of the 14 subjects in the EFL groups also demonstrated some EIAH, while 9/16 subjects in the NEFL group showed some degree of EIAH. The EFL/NEFL groups were similar with respect to V ˙O2 and V ˙E at maximal exercise. Furthermore, both groups showed had similar changes in PaO2, A-aDO2, SaO2 and acid-base balance. However, above 40 L/min, the EFL group had a significantly higher WOB (Figure 20). Figure 21 shows the relationship between V ˙ ˙E ECap, V  and the theoretical V ˙E required to offset any EIAH. The EFL and NEFL groups have  similar V ˙E and V ˙E to offset EIAH at all intensities, however, the EFL group has a significantly lower V ˙ECap at all intensities (Panel B). This results in the V ˙E to offset EIAH approaching and nearly meeting V ˙ECap in the EFL group. At V ˙O2Max, the V ˙E required to eliminate EIAH would be 87% of V ˙ECap in the EFL group and 68% of V ˙ECap in the NEFL group. Figure 20- The work of breathing for the EFL and NEFL groups during the maximal exercise test. 800 EFL NEFL  WOB (J/min)  600  400  200  0 0  20  40  60  80  100  120  140  160  VE (L/min)  Legend: At 40 L/min, the EFL group’s WOB is significantly greater than the NEFL group’s. WOB, work of breathing; V ˙E, minute ventilation. P < 0.05.  52 Figure 21- Minute ventilation, maximal ventilatory capacity, theoretical ventilation to offset EIAH and the associated arterial carbon dioxide tension during maximal exercise test for EFL and NEFL groups. A  45  PaCO2 (mmHg)  40  35  30  25  Measured PaCO2 (EFL) Predicted PaCO2 (EFL) Predicted PaCO2 (NEFL)  20  Measured PaCO2 (NEFL)  0 0  20  40  60  80  100  % VO2Max  B *  225 200  *  * *  *  Ventilation (L/min)  175 150 125  VE (EFL) VECap (EFL)  100  VE to eliminate EIAH (EFL) VE (NEFL)  75  VECap (NEFL) VE to eliminate EIAH (NEFL)  50 25 0 0  20  40  60  80  100  % VO2Max  Legend: PaCO2, arterial carbon dioxide tension; V ˙E, minute ventilation; V ˙ECap, ventilatory capacity; EFL, expiratory flow limited; NEFL, no expiratory flow limitation; EIAH, exercise induced arterial hypoxemia. V ˙O2Max, maximal oxygen consumption. *, significantly different from EFL V ˙ECap. P < 0.01. n=30.  53 CONSTANT LOAD HELIOX TRIAL Twenty-four of the 31 subjects were able to complete the constant load heliox trial. Eighteen of the 24 showed some degree of EIAH during the maximal exercise test and 11 showed some EFL. Figure 22 shows the resistance in the external breathing apparatus for room air and heliox gas. As expected, the heliox gas decreased resistance at all flows and the difference was more pronounced at higher flows where turbulent flow starts to predominate. Figure 23 shows arterial blood gas variables for all subjects pooled during the constant load heliox trial. Arterial oxygen tension and SaO2 had returned to pre-exercise levels in all subjects. Subjects displaying EIAH during the V ˙O2Max test presented a similar degree of hypoxemia during the constant load exercise bout. Inspiring heliox gas increased PaO2, primarily through an increase in PAO2 (Figure 23, Panel A,B). Breathing heliox resulted in SaO2 remaining similar to the first air breathing condition before falling again when switched back to room air (Panel C). Figure 24 shows the composite MEFV curve for room air and heliox. The heliox MEFV curve is identical to the air MEFV in terms of FVC (3.8 vs. 3.81 L for heliox and air; respectively) however, expiratory flows are greater at given volumes, resulting in an increased the V ˙ECap for the heliox MEFV. If subjects ventilated on air with rates observed during heliox breathing, they would be very close to developing EFL. During heliox breathing, subjects increased V ˙E, yet had a lower total WOB (Figure 25, Panel A,C) and lower tidal ∆Peso swings (Panel B). Furthermore, the decreased WOB appears to be primarily though decreases in WOBRes (Panel D). Figure 26 shows the regression line for air breathing WOB along with individual points for all the subjects during the heliox phase. The average V ˙E during heliox breathing was 77 L/min with a corresponding WOB of 110 J/min, which is a 32% reduction in WOB compared to air at a similar V ˙E. To facilitate better comparisons, the 18 subjects who showed EIAH during the maximal exercise test were partitioned in groups depending on the appearance of EFL during the maximal exercise test. Subjects who had EFL demonstrated greater improvement in PaO2 and SaO2 compared to the NEFL group (Figure 27, Panel A, B, C), but had little effect on CaO2.  54 Figure 22- External breathing circuit resistance with air and heliox. 8 Room Air Heliox  Resistance (cmH2O)  6  4  1.83 cmH2O 2  0 0  2  4  6  8  10  Flow (L/sec)  Legend: Resistance of the external breathing circuit measured by the measured pressure drop from mouth piece to pneumotachograph. At a flow of 5 L/sec the resistance was 1.83 cmH2O less when using heliox. Average resistance was 0.68 cmH2O/L/sec for air and 0.34 cmH2O/L/sec on heliox  55 Figure 23- Blood gas variables during the constant load exercise test for all subjects. A  0  *  110  -2  105  -4  PaO2 Rest (mmHg)  PaO2 & PAO2 (mmHg)  115  100 95 90  *  85  -6 -8  *  -10 -12 -14  80 PAO2 75  -16  PaO2  0  -18 Rest  100  B  Air 1  Heliox  Air 2  C  18.5  Rest  Air 1  Heliox  Air 2  Rest  Air 1  Heliox  Air 2  D  18.0  *  CaO2 (mL/dL)  SaO2 (%)  98  *  96  17.5  17.0  94 16.5 0  0.0 Rest  Air 1  Heliox  Air 2  Legend: PAO2, alveolar oxygen tension; PaO2, arterial oxygen tension; ∆PaO2,change in arterial oxygen tension from rest; SaO2, oxyhemoglobin saturation; CaO2, oxygen content of arterial blood. Ψ, significantly different from Air 1; *, significantly different from Air 2. P < 0.0125. n=24.  56 Figure 24- Maximal expiratory flow volume curve and tidal flow volume loops while breathing air and heliox. 12 10  Flow (L/sec)  8 6 4 2 0 -2 Air Heliox  -4 -4  -3  -2  -1  0  Volume (L)  Legend: The tidal flow-volume loops are composite averages for both air breathing conditions and the heliox stage. n=24.  57 Figure 25- Respiratory mechanics during the constant load exercise bout for all subjects. 85  A  40  B *  38  80  36  Peso (cmH2O)  VE (L/min)  75 70 65  *  30  26  55 0  0 Air 1  Heliox  Air 2  Air 1  C  Heliox  Air 2  *  180 160 140 120 100  WOBEl & WOBRes (cmH2O/breath)  D  200  WOB (J/min)  32  28  60  220  *  34  24  *  22 20  *  18 16  *  14 12 10 8  Resistive Elastic  0  0 Air 1  Heliox  Air 2  Air 1  Heliox  Air 2  Legend: V ˙E, minute ventilation; ∆Peso, tidal esophageal pressure swing; WOB, work of breathing; WOBEl, elastic work of breathing; WOBRes, resistive work of breathing. Ψ, significantly different from Air 1; *, significantly different from heliox; ϕ, significantly different from Air 2. P < 0.025. n=24,  58 Figure 26- Work of breathing on air and heliox during the constant load exercise trial. 600  500  WOB (J/min)  400  300  200  100  0 0  20  40  60  80  100  120  140  VE (L/min) Legend: Open square represent the average V ˙E and associated WOB during the heliox phase. At the average heliox V ˙E (77 L/min) the WOB is decreased by 60 J/min or 32% compared to air. Solid line represents the regression for air breathing. WOB, work of breathing; V ˙E, minute ventilation.  59 Figure 27- Subjects who completed the constant load exercise bout and showed EIAH are split into EFL and NEFL groups with blood gas variables shown during the constant load exercise bout. 115  A  0  B  110 -5  PaO2 Rest (mmHg)  PaO2 & PAO2 (mmHg)  105 100 95 90  *  85 80  *  -10  -15  -20  75 70 0  -25 Rest  Air 1  Heliox  Air 2  Rest  Air 1  Heliox  Air 2  Rest  Air 1  Heliox  Air 2  EFL NEFL 100  C  18.5  18.0  CaO2 (mL/dL)  98  SaO2 (%)  D  96  94  17.5  17.0  16.5 92 0  0.0 Rest  Air 1  Heliox  Air 2  Legend: PAO2, alveolar oxygen tension; PaO2, arterial oxygen tension; ∆PaO2,change in arterial oxygen tension from rest; SaO2, oxyhemoglobin saturation; CaO2, oxygen content of arterial blood. *, significantly different from NEFL group. Open circles (○) represent the flow limited group. Filled circles (●) represent the non-flow limited group. P < 0.0125. n=18.  60 SUBJECTS WITH REPEATED TESTING Two subjects had the maximal exercise test repeated in attempt to answer different questions. With both subjects we wanted to test the repeatability of EIAH over a relatively short time frame (4-5 months). For subject AC, we also sought to determine if V ˙O2Max would increase if EIAH was eliminated (via FiO2 0.26) and to test their chemosensitivity by using a FiCO2 of 0.035 during the constant load exercise bout. For subject SW, we wanted to determine the effect of endurance training on blood gas homeostasis. Their data will be presented individually and only their first visit has been included in any of the above results. Repeated Subject 1- AC On the first visit, the subject demonstrated significant EIAH in the first stage of exercise (Figure 28, Panel A). At maximal intensities, the subject had a severe gas exchange impairment (A-aDO2 > 35 mmHg), low SaO2 (91%) and lacked a significant hyperventilatory response (PaCO2 > 40 mmHg) (Figure 28, Panel B, C, D). The subject also showed EFL during the last two stages of exercise (Figure 29). During the constant load exercise bout, the heliox breathing increased V ˙E, PaO2 and temporarily prevented SaO2 from falling (Figure 28, Panel A,C,F). During the second testing day (4.5 months later), the subject showed similar changes in blood gases, showed EFL, had similar V ˙E and achieved a similar V ˙O2Max for the maximal test (Figure 28). During the subsequent constant load exercise bout, the subject inspired a slightly hyperoxic hypercapnic gas (FiO2 0.22, FiCO2 0.035) rather than heliox. The hypercapnic inspirate raised PaCO2 levels, but did not change V ˙E (Figure 28, Panel B, F). All respiratory mechanics variable were similar for the first two testing days (See appendix). During the third visit, maximal exercise test inspiring FiO2 0.26 without arterial catheterization and esophageal balloon, the subject maintained a SaO2 > 98%, exercised 45 sec longer and increased their V ˙O2Max by 5 mL/kg/min with no changes in weight (Figure 28). During the fourth visit, maximal exercise test inspiring compressed room air without arterial catheterization and esophageal balloon, the subject’s SaO2 fell to similar levels as the first and second visit and achieved a comparable V ˙O2Max.  61 Figure 28- Selected blood gas and ventilatory variables during the first and second testing days for subject AC. Day 1 gExT Day 2 gExT He (79%) CO2 (3.5%)  A  PaO2 (mmHg)  95 90 85 80  20  70  0 7.40 7.35  40  7.30  E  pH  45  35  7.25  30  7.20  25  7.15  100  C  100  F  Hyperoxic Air  80  VE (L/min)  98  SaO2 (%)  30  10  B  D  40  75  50  PaCO2 (mmHg)  50  A-aDO2 (mmHg)  100  96 94 92  60 40 20  90  0 Rest  4 mph  5 mph  6 mph  7 mph  Rest  C 1 6Cmph 2 C3  Rest  4 mph  5 mph  6 mph  7 mph  Rest  C 1 6Cmph 2 C3  Legend: For each panel, the two series represent the graded exercise test and the constant load exercise test (left to right; respectively). gExT, graded exercise test; He, Heliox; PaO2, oxygen tension in arterial blood; PaCO2, carbon dioxide tension in arterial blood; SaO2, arterial oxyhemoglobin saturation; A-aDO2, alveolar to arterial oxygen difference; V ˙E, expired minute ventilation.  62 Figure 29- Maximal expiratory flow-volume curve for subject AC during the first and second testing days. 12  A 28% EFL 7 mph (Air)  10 8 21% EFL 6 mph (Heliox)  Flow (L/sec)  6 4 2 0 Max exercise EELV approaching FRC  -2 -4  VO2max 38 mL/kg/min -6 12  Heliox MEFV MEFV Rest 4 mph 5 mph 6 mph 6 mph He or CO2  B  10  40% EFL at 7 mph (Air)  7 mph  8 31% EFL at 6 mph (Air)  Flow (L/sec)  6 4 2 0 Max exercise EELV above FRC  -2 -4  VO2max 40 mL/kg/min -6 -3  -2  -1  0  Volume (L)  Legend: Maximal expiratory flow-volume curves, tidal flow-volume from Days 1 and 2 of testing. Panel A represents data from Day1 while panel B represents data from Day 2; both include the graded exercise test and the altered inspirate stage of the constant load exercise test. The grey shaded area in panel A represents the increased ventilatory capacity resulting from heliox inspiration. The heliox gas was composed of 21% O2, balance He and the hypercapnic mixture was composed of 3.5% CO2, 21.7% O2, balance N2. EFL, expiratory flow limitation; EELV, end-expiratory lung volume; FRC functional residual capacity; MEFV, maximal expiratory flow-volume curve; V ˙O2MAX, maximal oxygen consumption.  63 Repeated Subject #2- SW The second subject who was tested twice is a competitive middle distance runner. During the first testing session (June) SW was “relatively” untrained (V ˙O2MAX 60 mL/kg/min), as she was recovering from an injury. The second testing day (Nov) was done when the subject was back to a full training schedule and achieved aV ˙O2MAX of 68 mL/kg/min, with only minor weight change (-1 kg) and an increase in absolute V ˙O2MAX (3.43 L/min vs. 3.82 L/min for the first and second testing day). Figure 30 shows the subjects MEFV curve along with a maximal exercise FV loop; with little difference between the testing days. Figure 31 displays selected blood gases from the both training days. Despite being fitter and completing another exercise stage of exercise, there was little changes in the blood gases. The slight decrease in SaO2seen in Figure 31 Panel C is due solely to rightward shifting of the ODC (decrease pH, increase Teso). The esophageal balloon catheter was displaced during the maximal exercise test for the second day, therefore, all associated data for that day is discarded as it is not known exactly when the balloon moved. The subject also demonstrated a similar response to heliox breathing during the constant load exercise test (See Appendix A).  Figure 30- Maximal expiratory flow-volume curve and maximal tidal flow volume loop for subject SW during both testing days. 10  Jun Nov  8  Flow (L/sec)  6 4 2 0 -2 -4 -6 -4  -3  -2  -1  0  Volume (L)  Legend: Thicker lines represent the maximal expiratory flow volume curve, thinner lines are maximal flow volume loops.  64  Figure 31- Blood gas variables for SW during both testing days. 105  A  35 30  A-aDO2 (mmHg)  PaO2 (mmHg)  100 95 90 85 80  20 15 10  0  0 2  4  6  8  2  10  Stage  4  C  40  6  8  10  8  10  Stage  June November  D  38  98  36 96  PaCO2  SaO2 (%)  25  5  75  100  B  34  94 32 92  30  0  0 2  4  6  Stage  8  10  2  4  6  Stage  Footnote: PaO2, arterial oxygen tension; A-aDO2, alveolar to arterial oxygen difference; SaO2, arterial oxyhemoglobin saturation; PaCO2, arterial carbon dioxide tension.  65  Discussion MAJOR FINDINGS The overarching purpose of this study was to characterize EIAH, gas exchange and respiratory mechanics during exercise in young healthy women. Secondly, we aimed to investigate the role of mechanical ventilatory constraints on EIAH in young healthy women. The major findings from this study are five-fold. First, in exercising women, there is a high degree of inter-subject variability in blood gas homeostasis and broad classifications of groups are not optimal when describing the mechanisms behind EIAH. Second, EIAH begins to develop at submaximal intensities in the majority of women (90%) in this study who display hypoxemia. Third, untrained women with unremarkable aerobic fitness levels can develop EIAH. Fourth, mechanical ventilatory constraints can lead to and/or exacerbate EIAH in women. Furthermore, mechanical ventilatory constraints could be an underlying mechanism behind EIAH in some untrained women. Fifth, relieving mechanical ventilatory constraints with heliox gas can partially reverse EIAH and heliox’s effects appear to be greater in those that develop EFL. To date, this study is the largest assessing temperature corrected blood gases in women, the largest study on respiratory mechanics in women and the only study to make detailed blood gas measurements and respiratory mechanics measures in exercising women.  Inter-subject variability, broad classifications and patterns of EIAH After examining Figure 2, one could determine that the subjects in the current study showed a homogenous and typical or “textbook” response to dynamic exercise. That is, V ˙O2, V ˙ CO2 and V ˙E all increase linearly with exercise intensity until a threshold is attained whereby the latter two increase exponentially. Moreover, increasing V ˙E is driven by increasing VT during low intensity exercise and increasing f during intense exercise. However, the primary goal of pulmonary ventilation during exercise is to maintain arterial blood gases within a narrow range despite increasing metabolic demand. Therefore, to most accurately understand dynamics of pulmonary ventilation, one should examine arterial blood gases during exercise. Figure 3 shows individual plots of arterial blood gases during the maximal exercise test and there is considerable variability with all variables. Specifically, at rest, PaO2 ranged from 75-~100 mmHg, yet all subjects maintained normal oxygenation (SaO2 > 97%) (Figure 3, Panel A). At (near) maximal  66 exercise, great variation in PaO2 was observed (range: 58-105 mmHg). Furthermore, at any given V ˙O2 there was ~20 mmHg range in A-aDO2 (Figure 3, Panel C). While SaO2 values are all ~98% at rest, upon exercise termination, there is an 11% range (87-98%), which, with all other factors being equal, would result in a 2 mL/dL difference in CaO2; enough to possibly elicit peripheral muscle fatigue (3, 70). However, there is a trend towards both worsening gas exchange and decreasing PaO2 as aerobic fitness increases (Figure 4, Panel C,D)(30), but notable exceptions exist (See EIAH in untrained women below).The high degree of variability is consistent with other reports in women (29, 30, 68, 85) but is not universal (33, 35). Commonly, when studying EIAH, subjects are grouped and analyzed together, a necessary step to make statistical comparison. Unfortunately, broad grouping results in the loss of intra-subjects patterns, which could aid in describing the mechanism(s) behind EIAH. Based upon Figure 5, one could determine that the average female becomes hypoxemic during submaximal exercise until (near) maximal intensities when the corresponding increase in V ˙E results in increasing PaO2. This generalization, albeit statistically correct, provides little or no information regarding why or how the subject(s) are developing EIAH. Splitting a cohort into EIAH and NEIAH groups can offer some insight into potential mechanisms. For example, in Figure 12 Panel A, B it could be concluded that mechanical ventilatory constraints play little role in EIAH development, as both groups appear to have considerable ventilatory reserve, and the likely mechanism would be intrinsic to the pulmonary system (e.g., V ˙A/˙ Q mismatch, pulmonary diffusion impairment, arterial-venous shunt). However, this broad classification could also conceal intra-subject patterns regarding EIAH mechanisms. Rather a more instructive approach would be to partition and analyze the subjects based on the pattern of hypoxemia displayed, as illustrated in Figure 19. In this figure, the 20 subjects who showed any EIAH were split into 6 groups based on the pattern of hypoxemia throughout the maximal exercise test. While this study did not aim to test for any specific mechanism, we can make educated inferences based on MEFV curve, tidal FV loop dynamics and changes in PaO2. The subjects in Figure 19, Panel A show a consistent decrease in PaO2 throughout exercise and do not appear to be mechanically constrained. The progressive drop in PaO2, due to a worsening A-aDO2, would suggest a progressive V ˙A/˙ Q mismatch or a diffusion limitation related to increasing Q ˙ and less time for blood gas equilibrium to occur. The subjects in Panel B have a similar V ˙O2MAX and MEFV curve as Panel A, but show a dramatically different response  67 with respect to PaO2. Immediately upon starting exercise PaO2 decreases suggesting that pulmonary edema is not likely the primary mechanism and an acute V ˙A/Q ˙ mismatch or an exercise induced shunt could be possible. However, near maximal exercise the subjects increase V ˙ E  substantially and PaO2 rises, giving a “U” shape to the pattern of EIAH. We suggest that this  group experiences submaximal EIAH, for an unknown reason, but has a strong drive to increase ventilation near maximal intensities. In Panel C, this group of subjects show an immediate decrease in PaO2, however, thereafter there is little change. Mechanically, these subjects could increase their ventilation, but they apparently “choose” not to. Since the subjects shown in Panel B and C initially have similar patterns and both have the capacity to increase V ˙E, it could be speculated that there is a difference in chemosensitivity between the groups that is only apparent during intense exercise. The mechanism responsible for EIAH in the subjects represented by Panel D is most noticeable; as the subjects are able to maintain PaO2 near resting levels until the onset of severe EFL. Thereafter, V ˙E is constrained and the subjects are unable to increase their ventilation to offset any EIAH. It should be emphasized that, the subjects in Panel D benefitted the most from inspiring heliox. Initially, the subjects in Panel E respond identically as Panel B with an initial drop in PaO2 with the onset of exercise. However, their rise in PaO2 is blunted by substantial EFL and they are unable to sufficiently reverse the hypoxemia. It could be suggested that the subjects in Panel B and E have a similarly strong drive to breath near the end of exercise, but the subjects in Panel E are confounded by EFL and therefore not able to increase their PaO2 to a similar degree as the subjects in Panel B. Finally, subjects in Panel F displays the sharp initial fall in PaO2, followed by the plateau, a similar response to subjects in Panel C. However, subjects in Panel F also shows EFL near the end of exercise, therefore, it would be difficult to discern whether their lack of PaO2 rebound is due to a mechanical constraint or blunted ventilatory drive. By analysing the pattern of EIAH, we can better appreciate the role, or lack thereof in some cases, of mechanical ventilatory constraints.  Submaximal EIAH The majority (18/20) of subjects in the current study who developed EIAH did so at submaximal intensities (Figure 3, Panel A). Additionally, the nadir PaO2 in many subjects occurred at an intensities other than maximal. Submaximal EIAH has been reported by others (12, 30, 52, 66, 67, 70, 79, 85), but only a select few papers describe it in detail (30, 66). To  68 date, any mechanism explaining submaximal EIAH remains elusive and there is little descriptive data. However, submaximal EIAH does appear to occur more often during treadmill exercise (33) and women appear to be especially prone (30, 68). Traditional theories regarding EIAH, demand vs. capacity, cannot begin to explain submaximal EIAH, as all relevant organ systems have considerable capacity to increase output in response to increases in exercise intensity. Therefore, we must first ask, why do some individuals tolerate submaximal EIAH? Again, the current study did not test for specific mechanisms and is not able to provide any direct evidence, yet, we can speculate on some potential causes given the descriptive data. Below we present 4 theories on why some subjects would tolerate submaximal EIAH. First, and the simplest explanation, the decrease in PaO2 may not be a sufficient physiological stress to elicit any response. Although PaO2 initially drops in many subjects, SaO2 remains near resting levels, therefore, CaO2 is largely maintained. This would suggest that submaximal EIAH has little or no effect on peripheral muscle fatigue. The main counterargument is the apparent randomness of who develops submaximal EIAH. Trained male subjects develop (submaximal) EIAH and resting chemosensitivity does not appear to be different between trained and untrained subjects (77). If submaximal EIAH has no consequences, why would unfit men not develop it or why do they prevent it by increasing V ˙E sufficiently? Women of all fitness levels appear to be able to develop EIAH, therefore, the same question exist, why do some tolerate submaximal EIAH and other do not? This discrepancy suggests that submaximal EIAH does negatively affect the humans response to exercise or preventing it hinders in some way. Second, submaximal EIAH may represent a lag between pulmonary systems response to exercise. The lag could have two different origins: a lag between exercise onset and hyperpnea or a lag in the response to rapid changes in metabolism. First, the exact cause of initial exercise hyperpnea is relatively unknown, but stretch receptors that respond to the muscular contraction are implicated as a contributing factor. In dogs, it has been shown that the central and peripheral chemoreceptors are intricately linked and the stimulus in one effects the output in the other (7). In other words, there appears to be a “gain” function between the two receptors. A possibility is that the muscle receptors could modulate the relative output of the central and peripheral chemoreceptors and affect the secondary drive to breath. That is, upon exercise onset, after the initial central command related increase in output, the central and peripheral chemoreceptors  69 become less sensitive to the oncoming changes in blood gases. When pH is measured intraarterially, decreases during exercise are not linear, rather an oscillating wave (5). The gain in the central and peripheral chemoreceptors may be decreased to eliminate reactions to cyclical changes and result in a more smooth output. Another distinct lag could arise from fast changes in metabolism without a coincidental increase in ventilation. Immediately upon starting exercise, RER drops from its higher pre-exercise anticipatory range. The fall in RER would reflect a fast switch from glucose metabolism to fat metabolism, resulting in a relative decrease in V ˙CO2. Decreased V ˙CO2 and PaCO2 returning to the lungs can both decrease ventilation (63, 64). Simultaneously, V ˙O2 is unchanged, therefore, the PvO2 immediately returning to the lungs could be low. The low PvO2 coupled with a decreased ventilatory drive from CO2 changes would result in an increased equilibrium time and possible lack of complete oxygenation at endcapillary. The lag theory could help explain why the hypoxemia appears to be fast onset and why it appears more in treadmill exercise over biking. Third, our data suggests that submaximal EIAH is not exclusively due to relative alveolar hypoventilation (PaCO2 < 38 mmHg). Rather, submaximal EIAH is also related to gas exchange impairments as evident by the simultaneous increases in the A-aDO2. However, we observed that while the gas exchange impairment occurs rapidly it also resolves equally as fast (See subject EM, MF and MB in appendix). We obtained post-exercise blood samples in some subjects (within 15-30 sec of exercise termination) and both PaO2 and the A-aDO2 had returned to pre-exercise levels. Furthermore, the degree of EIAH experienced during the maximal test was similar to the constant load test. This suggests that there is no carry-over effect of gasexchange impairment and the mechanism is only temporary. The lack of carry-over effect has been reported in a previous studies with female runners (79) and male cyclists (53). However, treadmill exercise is better able to elicit gas exchange impairments, when compared to cycling (33). A reasonable explanation is that the A-aDO2 could be related to some motion disturbance caused by running, more specifically, the foot-strike. Women, due to the greater WOB, have considerable tidal ∆Peso swings during exercise, which results in large changes in intrathoracic pressure. Similarly, during each foot-strike, there is a temporary change in Peso that could be similar or paradoxical to the intended pressure change. However, it is not known if the footstrikes affects all area of the lungs equally, or if the force is dispersed in proportion to chest-wall and muscular action. These large tidal changes in pressure coupled with temporary “spikes”  70 could result in small, temporary V ˙A/Q ˙ mismatches. Specifically, the pressure swings would cause small peripheral blood vessels and airways to be temporarily occluded in a heterogeneous fashion throughout the lung. The idea of a mechanically related V ˙A/Q ˙ mismatch was previously proposed by Johnson et al (42): “[EFL] may contribute to misdistribution of [V ˙A/˙ Q ] ratios during maximal exercise by causing nonuniformity in inspired V ˙E distribution secondary to dynamic compression of airways on expiration”.  The results of this thesis extend their idea to include blood vessels and propose that women could be especially prone to the mechanically induced V ˙A/Q ˙ due to their higher WOB. Alternately, the foot-strike would cause shear mechanical forces on the blood vessels which could result in a vasospasms. The vasospasms would result in similar transient changes in blood flow. Both hypotheses require appropriate testing. Fourth, tolerating submaximal EIAH may be a “strategy” to minimize respiratory effort and/or diaphragm and peripheral muscle fatigue. As seen in Figure 18 B, the V ˙E needed to offset EIAH can be considerable and would result in a substantial WOB and oxygen cost (1). Also, excessive WOB (and the ensuing fatigue of the respiratory musculature) can lead to systemic deficits in such as decreased blood flow to peripheral muscles (30). Individuals who tolerate submaximal EIAH may do so because reversing it would result in more severe consequences such as diaphragm fatigue, excessive oxygen cost of breathing and decreased leg blood flow. Finally, EIAH in men has been shown to lead to peripheral muscle fatigue (70), so presumably, submaximal EIAH would contribute to increasing fatigue. However, women appear to be more fatigue resistant compared to men in respiratory and locomotor musculature (26, 37). Therefore, women may tolerate the fatiguing effect of EIAH because they are inherently more fatigue resistant and the energetic cost to offset the hypoxemia would result in considerable energetic costs.  Untrained women Some of the subjects in the current study who showed EIAH and were healthy but relatively untrained. Specifically, we had 6 subjects with a V ˙O2MAX under 50 ml/kg/min and 3  71 with a V ˙O2MAX under 45 mL/kg/min who developed EIAH. All of the untrained women who developed EIAH also had EFL, three of which developed EFL at submaximal intensities. Furthermore, 2 of the untrained subjects were able to maintain blood gas homeostasis until the onset of EFL. We believe our data along with others (30) provides evidence that untrained women can develop EIAH and that mechanical ventilatory constraints are a contributing factor to EIAH. Untrained women have previously been demonstrated to show significant mechanical ventilatory constraints (15) which could increase EIAH. The respiratory system show little or no positive adaptations to exercise training, therefore, the smaller lungs and airways in women would result in a lower ventilatory capacity that cannot be altered.  Heliox breathing Heliox breathing appeared to have the desired effect during our constant load exercise bout where mechanical ventilatory constraints were minimized by; i) expanding the MEFV curve by reducing turbulent flow over the effort independent aspect; and ii) decreasing the mechanical WOB by reducing WOBRes. The increase in MEFV is seen in Figure 24, where gains in expiratory flow are more significant over the effort independent aspect. This is important for two reasons. First, in healthy subjects, EFL occurs over the middle part of the MEFV. In this section of the MEFV maximal flow is determined by intrinsic factors rather than effort (22, 38, 62). Secondly, it implies that turbulent flow is, at some aspect of the airway tree, predominant over the effort independent aspect during air breathing. The increased MEFV allowed many subjects to increase their V ˙E and partially offset some of the EIAH. Partial relief of EIAH has been demonstrated by others when utilizing heliox gas (12, 52). The other effect of heliox in the present study was reductions in the total WOB (Figure 28). Theoretically, heliox should only decrease WOBRes, however, we also found a slight decrease in WOBEl (Figure 25, D). It is possible that the decreased WOBEl can be attributed to small but systemic errors in the application of Campbell diagrams or pressure artefacts that alter the analysis of PV loops. Another possible explanation for the change in WOBEl is differences in operational lung volume during heliox breathing. While there was no statistical difference in EELV between stages, Figure 24 indicates that during heliox breathing it decreased slightly. The small change in EELV may be sufficient to change the aspect of the PV curve the subjects were breathing on, thus altering WOBEl. Overall, heliox appeared to decrease the WOB by ~30% compared to room air.  72 A 30% reduction in WOB would reduce the oxygen cost of hyperpnea (1), but, based on other research, it may not elicit changes in peripheral blood flow (28). Harms et al. (28) found that when the WOB was increased (50%) with a proportional assist ventilator (PAV) that leg blood flow was reduced by only 11% with considerable between-subject variation. However, as mentioned in Submaximal EIAH above, we speculate that high WOB and/or mechanical constraints may cause a gas exchange impairment, which heliox may partially alleviate. This theory is further confounded by heliox’s effect on gas exchange, which it has been shown to improve and worsen (10, 17).  EIAH as a two-part problem Often, EIAH is seen as a decrease in PaO2, which results in decreases in SaO2 and compromised oxygen delivery. However changes in the shape of the ODC from metabolic acidosis and hyperthermia can result in similar changes in SaO2. In the present study, about 50% of the reduction in SaO2 could be attributed to changes in the ODC, which is similar to other studies in women (30). Furthermore, the SaO2 from pH, Teso and PaCO2 changes alone ranged from 91-97%, indicating that some women were not affected by ODC changes while other were. Ideally, one would keep their lung cool and alkaline, while the metabolically active tissue became hot and acidic. This situation would promote loading of oxygen at the lungs and offloading at the muscle. However, temperature confounds this problem because as blood is heated, more oxygen can become dissolved and the PaO2 will increase; the opposite is true for cooling (75). Temperature related changes in PaO2 probably play little role during most situations because of the shape of the ODC. In the absence of EIAH, loading occurs on the upper flat part of the ODC, where large changes in PaO2 have little effect on SaO2, so hyperthermia related increases in PaO2would be irrelevant. However, the hyperthermia would shift the ODC and result in a lower SaO2, such is the case with most men. In women (or trained men) who develop severe EIAH, oxygen loading may start to occur on the steeper part of the ODC where small changes PaO2 can result in larger changes in SaO2. Effectively, the ODC shape change could be cancelled out by the increase in PaO2. Finally, women appear to have a different thermoregulatory response then men due to with a ~10% difference in fat-mass and surface area to body mass ratios (44). Women also appear to dissipate heat approximately 50% less than men during cold water submersion (82). Therefore, some of the discrepancies in EIAH observed  73 between men and women at intense exercise could be due to differences in regulating core temperature.  Insights into mechanisms of EIAH The four mechanisms thought to contribute to EIAH are: relative alveolar hypoventilation, intra-cardiac or intra-pulmonary shunting, diffusion limitation and V ˙A/Q ˙ mismatching. The present study is only able to provide direct evidence for relative alveolar hypoventilation, but we make insights for the others. A shunt, intracardiac or intrapulmonary, was not assessed in this study; therefore, we cannot conclusively determine its significance. However, we believe it is unlikely as the primary or exclusive mechanism. First, intracardiac shunts, in the form of patent foramen ovale (PFO) have been shown to have little effect on pulmonary gas exchange (47). Anecdotally, one of our subjects has a confirmed PFO, but, despite being the fittest subject tested (V ˙O2Max= 67 mL/kg/min) she displayed relatively mild EIAH (nadir PaO2 = 80 mmHg). Also, some subjects (n=4) completed a hyperoxic inspirate stage during the constant load exercise bout where SaO2 returned to resting levels in all subjects. If the EIAH was due solely to a shunt, little benefit should be observed during slightly hyperoxic breathing. Unfortunately, it is not possible to assess shunting during running exercise and resting measures may not translate effectively to exercise. Specifically, the shunts could open in response to high pulmonary pressures and flows that occur during intense exercise and shut immediately upon exercise cessation. All of our subjects had normal diffusion capacities at rest (Table 2). However, this does not indicate that diffusion was necessarily ideal during exercise. However, a diffusion limitation, other than extraordinary low PvO2, seem unlikely given EIAH began to develop immediately upon starting exercise. Diffusions limitations were often thought to be due to high Q ˙ , which result in rapid red blood cell transit time (12) or excessive pulmonary artery pressure (PAP) that result in some pulmonary edema (87), both of which would not develop immediately. In some subjects, we are able demonstrate that hypoventilation was a probable mechanism behind EIAH. In these subjects, the hypoxemia coincided with the occurrence of EFL (Figure 19, D). While alveolar hypoventilation was not the primary cause of EIAH in most subjects, few would have been able to fully eliminate EIAH due to mechanical ventilatory constraints (Figure 18, B). By elimination, the primary causes appears to be V ˙A/Q ˙ mismatching as postulated by others others  74 (13, 84). However, there is evidence suggesting no intrinsic sex-difference with respect to V ˙A/Q ˙ mismatching (59), therefore, we are left with the unanswered question regarding why women appear to develop EIAH more often than men, as mechanical constraints do not appear to explain all of the variance.  Comparisons to men The current study did not make any measures in men; therefore, we cannot make direct comparisons between the sexes. However, below we compare some of the results from this thesis with commonly reported findings in men. When examining the patterns of hypoxemia in the current study (Figure 19), some patterns have been previously been documented in men. Specifically, the slow progressive decline in PaO2 without any mechanical constraints (12) (Figure 19, Panel A) and mechanical constraints inducing a PaO2 drop (42) (Figure 19, Panel D) are common in men. However, the sharp initial decrease in PaO2 has also been reported in men (66, 70), albeit, to a lesser degree than women. To my knowledge, the “U” shape pattern of hypoxemia (Figure 19, Panel B) has not been reported in men, as such, potential mechanisms responsible for sex-difference in EIAH could be found within this group. To date, there have not been any reports of untrained men developing EIAH, which is in contrast to our study and others (30). A possible explanation for this sex-based discrepancy could be the increased mechanical ventilatory constraints reported in women(27, 52) . Reports of untrained men experiencing mechanical constraints are rare, as the male respiratory system is generally “overbuilt” (11). That is, at V ˙O2Max, the untrained male’s respiratory system is capable of increasing output, whereas the cardiac and/or metabolic systems generally are not. As one engages in aerobic training, the cardiac and metabolic systems increase capacity (73), unlike the respiratory system (4). After considerable aerobic training, some highly fit men can have their respiratory system become the limiting factor in exercise (12, 42). However, this situation only occurs in highly trained men with extraordinary fitness levels (V ˙O2Max > 65-70+ mL/kg/min). Conversely, on average, women’s respiratory has substantially less capacity; therefore, their respiratory system could become the limiting factor in exercise at a lower relative fitness level. All of our subjects had “normal” resting spirometry (>80% predicted), but, our untrained subjects who had EIAH had lower than predicted FVC, FEV1 and midrange expiratory flows (no  75 statistics were done due to low numbers). The lower FEV1 and midrange flows are indicative of a lower ventilatory capacity, furthermore, all of our untrained EIAH subjects developed EFL. The prevalence of EIAH in men has been estimated at 50% of highly trained (V ˙O2Max 65+ mL/kg/min) subjects and it is thought not to occur in in untrained men (13). In women, the prevalence appears to be higher. Our study and others (30, 68) has found the prevalence to be 65-75% of ALL subjects tested including those with a low aerobic capacity. Furthermore, in our study, only one subject with a V ˙O2Max > 50 mL/kg/min did not develop EIAH, indicating that almost all of our trained women developed EIAH to some degree. Therefore, when comparing trained men and women (V ˙O2Max > 50 and 60 mL/kg/min; respectively) the prevalence appears to be ~93% and 50% in women and men; respectively. Adequate statistical analysis between men and women with regards to EIAH prevalence would be difficult due to the difference in cohorts, as studies in men typically only involve trained subjects. To date, the present study and two others have assessed EIAH prevalence in healthy women using temperature corrected blood gases (30, 33). Our results are similar to those of Harms et al. (30) although the prevalence was slightly higher (76%) compared to the present study (65%). However, the discrepancy can be easily explained by their study’s higher fitness levels. Conversely, Hopkins et al. (33) found only 25% of women developed EIAH and only trained subjects could become hypoxemic during exercise. However, their contradictory findings could have arisen due to some problematic methodologies and results such as: arterial blood temperature correction, negative A-aDO2 during moderate exercise, “core” temperature < 37°C during moderate exercise and peaking under 38°C, high resting PaO2 (108-113 mmHg) and low resting PaCO2 (<30 mmHg) with the latter two indicative of hyperventilation during rest.  METHODLOGICAL CONSIDERATIONS  Expiratory flow limitation In the current study, EFL was assessed by superimposing tidal FV loops on the MEFV curves. This technique has been used extensively by others and shown to be reliable in both healthy and clinical populations (31, 41, 42, 58, 86). However, accuracy is dependent on three factors. First, the MEFV curve must be developed properly. The subjects must expire forcefully while thoracic gas compression and post-exercise bronchodilation are accounted for (25).  76 Subjects must also be screened for asthma of any form. Second, the IC maneuver needs to be performed properly, that is, the subject must have correct timing and inspire to TLC. Third, one must be confident that the tidal breaths used for analysis are a good representation and free of any unwanted noise artefacts. In the current study, we had subjects practice the IC maneuver at rest with visual feedback, performed gFVCs and compared the peak negative Peso at rest to exercise IC maneuvers. Therefore, we are confident our assessment of EFL is accurate and reliable.  Work of breathing Our WOB measurements must be acknowledged to be a best estimate, as there are several confounding factors, which presently cannot be accurately accounted for. First, during running, there is a considerable pressure change during the foot-strike. But, experimentally, we are unsure if the change in pressure is isolated to the esophagus (or gastric) or if it is transferred wholly or partially to the pleura space. Next, the foot-strike pressure change can be beneficial or harmful towards the intended pressure swing. For example, we can simplify the pleural pressure changes during respiration into a sine wave, with the decreasing amplitude and trough representing inspiration while increasing amplitude and crest representing expiration. If another wave (foot-strike) is added to the original, it can be in-phase and produce a constructive force OR out-of-phase and produce a destructive force on the total amplitude. If the foot-strike is destructive, it would require additional muscular effort to achieve similar amplitude. Altering and ultimately synchronizing breathing patterns in response to rhythmic exercise is referred to as entrainment. The contents of the thoracic cavity are largely tethered to the chest-wall and are held firmly in place; however, the abdominal contents are not tethered. During running, the abdominal contents represent a large mass that is constantly accelerating and decelerating in response to vertical displacement during running. During inspiration, the diaphragm moves downwards towards the abdominal cavity, if the abdominal contents are accelerating up during this inspiration, the diaphragm would have an additional opposing force to must work against. The force to overcome the abdominal contents momentum would not be reflected as a spike in gastric or esophageal pressure, but rather a temporary resistive force that decreases the overall net force created by the musculature contraction. To date, few studies have attempted to address the role of foot-strike artefacts on pulmonary mechanics. One study found the foot-strike had no  77 appreciable effect on volume changes, regardless of entrainment (6), however, they did not measure the pressure changes. The second factor is the role of musculature in stabilizing the distortion of the chest-wall and/or stabilizing the abdominal wall during breathing. During rest and low intensity exercise, the chest-wall moves in a “natural” pattern, that is, in planes of least resistance. However, during strenuous breathing associated with heavy exercise, the chest-wall is distorted by accessory respiratory muscles applying unequal force and by upper body movement (20, 23). Furthermore, the abdominal wall must remain ridged to stabilize abdominal contents during rapid contractions of the diaphragm. To accurately account for both the aforementioned factors, one must first determine the natural pattern of chest and abdominal wall movements. The natural movement pattern can only be truly assessed by placing a temporarily paralysed subject inside a drinker spirometer and ventilate them via external negative pressure (similar to an iron lung) while assessing the movement of both the abdominal and chest-wall (23). Next, during exercise the movements of the abdominal and chest-wall needs to be accurately tracked in three planes while simultaneously measuring volume changes. Currently, making the resting measures entirely possible, but, are invasive, highly technical and prone to measurement errors. Assessing the movements during exercise is possible using optoelectronic plethysmography, but this technique is limited to biking exercise where the upper body can remain motionless. Presumably, during running the motion of the arms and torso, would at a minimum distort the chest-wall somewhat and surely abdominal muscle must contract. Third, one must determine the contribution to total volume change between the thoracic and abdominal cavity. This is necessary because any individual compartment may have a volume change in the opposite direction of the total system. Depending on whether the volume change occurred in the thorax or abdomen will change the amount of elastic work required (23). This possible underestimation of WOB is not trivial, rather the WOB has been estimated to be up to 25% lower when using just modified Campbell diagrams compared when chest-wall distortion and abdominal stabilization are not accounted for (23). V ˙O2MAX vs. V ˙O2Peak Admittedly, not all subjects may have exercised to their true maximum; therefore, our values could be expressed as VO2Peak. With naïve subjects and invasive experimental protocols,  78 there is a tendency for subjects to terminate exercise before their maximum. Treadmill exercise is prone to this pitfall as subjects may be hesitant about falling when fully instrumented. Despite the potential psychological limitation, all subject met most, if not all the general accepted criteria for V ˙O2Max. All but two subjects attained an RER above 1.05 and all but one subject showed significant: acidification of arterial blood, decrease in bicarbonate levels, increase in esophageal temperature and a maximum HR within 10% of predicted maximum. Therefore, we are confident that our subject pool performed at or very near maximal work rates.  Arterial blood gas sampling When measuring ABG, there are three primary sources of error. First, since the gas tension of arterial blood is substantially different from the atmosphere, blood must be drawn anaerobically and all air bubbles must be immediately evacuated. In the current study, we utilized commercially available arterial blood specific syringes, which allow air to be evacuated through a one-way membrane in the cap. The one-way membrane allowed the sample to be immediately sealed and any air bubbles removed without a second exposure to the atmosphere. Secondly, oxygen consumption and carbon dioxide production will continue in the blood after sampling, therefore, arterial blood should be analysed immediately. Ice baths can slow down metabolic activity and preserve the sample; however, quick analysis is optimal. In the present study, samples were analysed within 2 min after collection and most often within 30 sec. Therefore, there is little risk that our samples had errors from delays in analysis. Finally, an appropriate amount of heparin must be introduced into the sample to prevent the blood from clotting, yet, the amount cannot be excessive (which can alter PaCO2). To control the amount of heparin introduced, we utilized pre-heparinized syringes and withdrew a similar blood volume every sample. Additionally, samples were repeatedly inverted before analysis to ensure homogeneity of heparin and blood throughout the sample.  Dysanapsis/Airway size index Our measure of airway size is not a true anatomical measure, but rather an overall index of relative airway size. The dysanapsis index has several caveats that should be considered. First, one cannot discern where along the airway tree possible differences exist. Second, all comparisons must be made at iso-lung volumes because the dysanapsis index is a relative  79 measure. Due to the effect of airway length (36) (mainly trachea and main bronchi) the dysanapsis index is negatively related to lung volume, therefore, the index is scaled to VC (or FVC). Technically, estimating dysanapsis requires simple measures; however, accurately performing several static recoil maneuvers requires adequate practice and is not intuitive to all subjects.  Constant load exercise bout For our constant load exercise bout, we utilized one experimental gas (heliox) which is used to manipulate mechanical constraints. Ideally, we would have also performed trials using a mildly hypoxic mixture (FiO2 0.17), mildly hyperoxic mixture (FiO2 0.26) and a hypercapnic mixture (FiCO2 0.04). Utilizing these additional gases mixtures would allow a more complete analysis of EIAH mechanism (chemosensitivity and shunts). However, most (if not all) of our subjects where mentally and physically fatigued after the two exercise bouts, especially in cases where arterial catheterization took an abnormal amount of time. Therefore, we felt that results may have been compromised if subjects were asked to perform another bout and may not have given optimal effort. The stages of exercise were 2-2.5 min in length, however, we found that subjects often did not reach a steady state situation until the second stage. We aimed to keep the exercise bout as brief as possible, but acknowledge the first stage could have been extended for optimal results. Furthermore, rather than a constant load exercise bout where we manipulated one stage, we could have had each subject complete other maximal tests only breathing the altered inspirate. Thus, we would have had a full range of intensities for every gas type, unfortunately, the same fatigue issue would exist. Having subjects return on different days would eliminate the fatigue, but would have proven difficult logistically and would require multiple arterial catheterizations. The desired property of heliox gas is its decreased density, which promotes laminar flow. The tendency toward laminar flow would be present in all circuits that the heliox flows, including the breathing circuit. Figure 22 indicates that resistance was 50% less when using air compared to heliox (0.68 vs. 0.34 cmH2O/L/sec). The decrease in circuit resistance would result in a smaller driving pressure needed for a given flow rate. Our goal for using heliox was to decrease mechanical constraints, be it in the breathing circuit or intrathoracic, and use each subject as their own control. However, this method then does not allow us to make accurate  80 assessments of differences in airway size or geometry between subjects. For example, a subject who achieves higher flows would see a greater reduction in external circuit resistance as the two regression lines in Figure 22 are not parallel. Likewise, an individual with abnormally small airways would also see a great benefit to inspiring heliox. Partitioning the reduction in WOB between external circuit resistance and airway resistance is not possible, as we can only determine the reduction in Pmt, not Peso. However, when the decrease in external resistance via heliox was applied to a Pmt-volume loop, the WOB would decrease by ~20%. Figure 26 suggest that the total WOB decreases by 32% using heliox (at a ventilation of 77 L/min). Therefore, it is possible that the significant amount of WOB changes via heliox arose from minimizing breathing circuit resistance. This problem could have been eliminated by added screens to the breathing circuit until the heliox resistance was similar to the air. However, this adds a degree of complexity that was not necessary given the goal was to minimize any mechanical constraint and not to make claims based on airway size.  Menstrual cycle We did not attempt to control for the menstrual cycle in the present study, which has been employed in similar studies (30). Variations in circulating hormones throughout the menstrual cycle could effect chemosensitivity and alter ventilation (81). However, recent work (49) has shown that this precaution may not be necessary or practical for exercise testing. In their study, women not taking oral contraceptive and regularly menstruating, provided daily urine sample throughout an entire cycle. Several conclusions were drawn from this study: 1) Most women could not accurately self-report cycle phase. 2) There was considerable inter and intra-subject variation in hormone levels. 3) Circulating hormone levels affect resting chemosensitivity, but had no effect during exercise (49). Therefore, we believe that attempting to control for the menstrual cycle would be time consuming, impractical, expensive and ultimately futile as our primary aim was to assess the response to exercise.  Core temperature When analyzing arterial blood samples during exercise, it is crucial that the gas tensions are corrected for core temperature. During strenuous exercise core temperature can vary from near resting levels (~37 °C) to as much as ~40 °C (Table 5). By default, blood gas analyzers  81 measure and express gas tension at 37 °C, however, if the subject’s core temperature was 40 °C, PaO2 would be underestimated by over 10 mmHg. The optimal core temperature to correct blood gases would be pulmonary artery (PA) temperature, as it reflects the conditions during pulmonary gas exchange. However, PA catheterization is highly invasive and has considerable risks associated; therefore it is rarely, if ever, used for core temperature measurements in healthy exercising subjects. Several sites are commonly used as a surrogate for PA temperature, including: esophageal, rectal, peripheral arterial temperature (radial) and intramuscular. The latter two sites are not ideal because they do not accurately represent the temperature at the lungs. Peripheral arterial temperature is often lower than core temperature and is highly influenced by surrounding tissue, which is often cooler. Furthermore, intra-arterial temperature measurement is influenced by the blood flow during sampling. Intramuscular temperature is significantly lower than core temperature during rest and rises extraordinarily during exercise (74), due to the close proximity of metabolically active tissue. Therefore, intramuscular temperature would be ideal for measuring gas-exchange at the working muscle and estimated the a-vDO2, where PvO2 requires correcting. However, the current study assessed pulmonary gas exchange, therefore, intramuscular temperature serves little purpose. For the current study, we chose esophageal temperature correction for several reasons. First, studies have indicated that esophageal temperature is closely related to PA temperature (~0.1 °C difference) (45, 69, 78). Secondly, when compared to other measuring sites, esophageal temperature is the most similar to PA temperature (45, 69). Finally, our esophageal thermistor was placed after the esophageal balloon catheter (which has depth markings), therefore, we are confident the thermistor tip was consistently placed in the distal esophagus in close proximity to the heart.  METHODLOGICAL IMPROVEMENTS  Full body plethysmography To determine each subject’s MFV curves, we had them perform several FVC and gFVC maneuvers and took the highest flow at any given volume. Using MFV curves is both simple, reliable and been utilized robustly in research, however, it makes no measure of pressure. Ideally, we should determine the critical pressures, for all volumes, whereby any increase in Ppl does not result in greater flow. To obtain these measures, a subject would need to be placed  82 inside a full body plethysmograph and perform several exhalations at different volume and different efforts. The plethysmograph allows for the simultaneous measurement of flow, volume and pressure. Measuring flow, volume and pressure simultaneously allows the determination of the pressure at which flow is limited, which is the most correct definition of EFL (39). The full body plethysmography technique has been used by other researchers to make detailed measured of mechanical constraints experienced during treadmill exercise (42). Unfortunately, inspiratory flow is not limited by the same gas compressive effect as expiratory flow, therefore, the only appropriate method to determine IFL, also requires a full body plethysmograph. To determine the inspiratory aspect of a MFV curve, one must make several respiratory efforts at multiple fixed lung volume (2). Accomplishing both of the above techniques requires considerable technical expertise and a sufficiently sensitive (small) full body plethysmograph.  Inert gas dilution for operational lung volumes An alternative method for determining operational lung volumes is to have a subject inspire inert gases during exercise. This is accomplished by breathing from a bag of known gas concentration and volume. At the end of expiration, the subject is switched from breathing room air to the bag containing the inert gas(es). Subsequently, the expired inert gas concentrations are measured for several breaths after the initial inspiration, until the inert gas(es) reach equilibrium. By knowing the initial concentrations, the bag volume and the equilibrium concentrations, one can calculate the EELV. However, inert gas dilution has several caveats and assumptions. First, while it is possible to obtain accurate timing for valve switching during low intensity exercise, this can prove difficult and often erroneous during intense exercise when f are high. Next, inert gas dilution assumes that the entire lung is equally ventilated and the gas diffuses evenly. This assumption holds true for most healthy people; however, given the high degree of gas exchange inefficiency observed in the current study, it may not be entirely accurate.  Blood sampling Obtaining arterial blood in discrete samples provides an overall trend of blood gas changes, but lacks temporal sensitivity. In essence, we are sampling blood gases at 0.0067 Hz (1 sample every 2.5 min), whereas our other measures are sampled at 200 Hz and expressed in 10  83 sec averages. Therefore, we are “missing” 15 possible time points in between blood samples and are connecting the two data points with a straight line. However, we could utilize in-dwelling blood gas electrodes which continuously measure blood gases intra-arterially and provide valuable temporal data. Gathering on-line blood gas values would be crucial in determining the mechanism behind the initial fall in PaO2 upon exercise onset. In several subjects, the first sample demonstrated significant hypoxemia (PaO2 decreased +10 mmHg compared to rest) and subsequently PaO2 remained relatively stable throughout testing. By collecting on-line blood gases we could determine the pattern of initial PaO2 drop. An especially tantalizing possibility would be to combine on-line arterial blood gases and venous blood gases measured at (near) the right atrium and proximal to the main working muscle (femoral). Thus allowing for high temporal measures of gas exchange at the level of the lungs and working muscle.  End-tidal forcing during constant load exercise In this study, subjects inspired pre-mixed gases with fixed concentrations for the constant load exercise bout. This method allowed administration of a similar “dose” of the altered inspirate. However, additional information regarding mechanism behind EIAH and EFL could have been obtained by using an end-tidal forcing system capable of high flows associated with exercise. For example, when administering the hyperoxic mixture, upon reaching steady state ventilation patterns, we could slowly raise the FiO2 breath-by-breath until a desired PAO2 was obtained. This process would allow us to determine precisely the amount of added O2 necessary to offset the hypoxemia. Similarly, by slowing replacing nitrogen with helium, we change the mechanical work of breathing in increments, rather than a single step.  UNRESOLVED QUESTIONS AND FUTURE DIRECTION  Arterial oxygen tension Is there a threshold for decreases in PaO2? This is still unknown, more precisely, how much does PaO2 have to decrease before V ˙O2Max and exercise performance is affected? Studies have assessed decreases in SaO2 (29), but we are unsure specific to PaO2. How does the change in PaO2 affect other organ systems? Is the problem in decreased oxygen delivery (CaO2) or does  84 tissue become increasingly hypoxic (PaO2 issue)? Is there a training effect to EIAH? Some studies have found that EIAH gets worse with training (57, 72), yet in our subject who we tested after significant fitness gains showed a similar degree of EIAH (Figure 31). Could EIAH be an innate structural and functional difference that remains relatively static in individuals? Or does an individual need to train to the point where their respiratory system becomes the limiting factor? For example, our subject that improved their aerobic fitness still has considerable capacity to increase ventilation, so their EIAH would be due to intrinsic properties. Some people may not be able to increase their aerobic capacities to a level where the pulmonary system becomes the limiting factor; such is probably the case in most men. Conversely, a subject who has relatively small lungs and airways would not have to train intensely before they began to be mechanically constrained. Finally, how does the PaO2 drop initially during submaximal EIAH? Is the decline linear? Curvilinear? A linear trend with oscillations? Furthermore, does the PvO2 drop in a similar fashion? Or does PvO2 drop first and then PaO2 lag behind?  Venous oxygen tension Mixed venous and femoral PvO2 can become exceedingly low (<15 mmHg) during various forms of exercise in men (9, 21, 34). But, does the PvO2 in women get as low or lower and does a sex-difference exist? Others have shown a sex-difference in muscle metabolism (18), therefore, it is conceivable that for a given workload and PaO2, the PvO2 could be different in women. The most obvious answer would be to make PvO2 measures at multiple sites (immediately proximal to working muscle and close the right atrium) in exercising women while assessing EIAH. The PvO2 in exercising women could be especially valuable when determining the mechanism behind submaximal EIAH in women.  Submaximal intensity. As outlines above, submaximal EIAH remains a mystery. Conceivable, subjects are mechanically able to eliminate it, but they don’t. We believe there are 4 key questions to be answered. 1) Does submaximal EIAH have a functional consequence, such as altered blood flow and/or fatigue? 2) Why do some subjects tolerate submaximal EIAH while others don’t? 3) Why do women appear to be especially prone to developing submaximal EIAH? 4) Why does running exercise elicit submaximal EIAH more often than cycling? A possible solution would be to have  85 a group of male and female subjects complete a cycle, treadmill and skiing maximal test. Skiing and running are both whole body exercises, while skiing eliminates much of the motion and footstrike artefacts. Furthermore, PaO2 could be titrated at submaximal intensities until fatigue or V ˙ O2MAX decrements are observed.  Blood flow and fatigue In men, changes in WOB has been shown to alter limb blood flow, presumably, by preferentially supplying the respiratory muscles (28). Women, compared to men, have a higher WOB at similar ventilations (27). Are based sex-difference in WOB enough to elicit changes in limb blood flow? To date, no studies have attempted to address this question. Presumable, one would have to match men and women for fitness levels and manipulate their WOB with a PAV. Specifically, at a given ventilation, increase the men’s WOB until it is similar to that of the women and vice versa. Similarly, does the onset of EIAH have any effect on limb blood flow? Localized hypoxia can cause vasodilation and increase blood flow, but is the decrement in PaO2 observed in EIAH sufficient? Recently, studies have assessed peripheral muscle fatigue as it related to EIAH (3, 70) using femoral nerve stimulation. Both studies were conducted in men and found that hypoxemia increased the amount of fatigue experienced. Does this relationship extent to women? Women appear to develop EIAH more often and more severely, but also appear to be more fatigue resistant in many muscles.  Foot strike The contents of the thoracic cavity are largely tethered to the chest-wall, whereas, abdominal contents are not. Presumably, there is some motion in the abdominal viscera during running. If abdominal contents are displaced vertically, while the diaphragm is contracting, an added strain could be added to the diaphragms work. This would not be reflected in a pressure change, but rather as a temporary resistance that needs to be overcome. Also, as outlined earlier, the foot-strike may play a role in creating temporary V ˙A/Q ˙ mismatches by creating more areas of the lungs where vessels are occluded. However, to the author’s knowledge, it is not known experimentally if the foot-strike artefact observed in the esophagus and stomach equally affects the pleural space. If it does not, any assumption regarding the footstrike could prove to be false.  86  Oxygen content In the current study, all but a few subjects increased their CaO2 throughout exercise, despite a decrease in SaO2 (Table 5). Several questions remain with regard to oxygen content and delivery. Is oxygen content manipulated by more than saturation and Hb? For example, changes in temperature, pH and CO2 will alter the shape of the oxygen dissociation curve for a given PaO2. Temperature and acid-base balance is highly individualized; therefore, some subjects may prone to alterations in content due to changes in ODC shape. Furthermore, could CaO2 be manipulated through difference in “environment” in different parts of the body? For example, during exercise, metabolic activity causes muscles to become more acidic and increase their temperature; which promotes offloading of oxygen at the muscle. What would happen if the muscle was to remain cooler and less acidic? Would this decrease offloading and increase CvO2 due to a lesser utilization at the muscle? Also, what would be the effect of increased temperature at the site of oxygen loading (lungs)? Could this hinder the exchange of oxygen and decrease the CaO2?  Heliox The desired property of heliox gas is decreased density, which increases the tendency towards laminar flow and minimizes turbulent flow. By keeping airflow laminar, the total WOB is decreased, due to less resistive work, and the tidal ∆Peso required per breath is decreased. Additionally, heliox breathing will increase expiratory flow along the MEFV curve without changing lung volume. Therefore, heliox can partially or fully relive mechanical constraints encountered during exercise. However, is this the only effect heliox breathing has during exercise? The author believes there are several other important factors that must be acknowledged with respect to heliox breathing. First, helium, as the inert backing gas, is more efficient at diffusing then nitrogen. Gases travel primary by bulk flow in the larger conducting airways, but, once into the smaller peripheral airways, gases travel largely by diffusion. Therefore, helium may allow for quicker and more efficient gas movement deep in the lung. The improvement in gas diffusion could lead to an improvement in the A-aDO2. Improving gas exchange with helium has been demonstrated in exercising horses (17), but refuted when using mechanically ventilated dogs as a model (10). Second, helium has a lower specific heat capacity  87 then nitrogen, therefore, it will transfer heat more effectively. During exercise, there is substantial heat loss in the airways due to evaporation and convection, especially during high flow associated with heavy exercise. Helium may increase heat loss and cool the airways more than nitrogen. Cooling of the airways can lead to an acute asthma attack, or a general inflammation of the airways. However, cooling of the airways could aid in central heat dissipation and could lower core temperature. A lower core temperature would be beneficial during exercise as temperature significantly shifts the ODC and hinders oxygen pick-up in the lungs. Finally, is the effect of heliox sufficient to elicit systemic changes in blood flow or peripheral muscle fatigue? By substantially reducing the WOB via a PAV, peripheral blood flow can increase (28). Also, altering CaO2 can change the severity of peripheral muscle fatigue and exercise performance (3). A solution to the above problems could be addressed by a PAV with heliox and a high density gas (SF6). The PAV would allow manipulation of the WOB and mechanical constraints while the effects of the gas density could be independently varied, thus independently altering mechanical constraints and gas density factors.  Subclinical edema The blood-gas barrier in alveoli is both thin, yet remarkable strong. In pathological conditions, such as congestive heart failure, rises in PAP can lead to pulmonary edema. Furthermore, rises PAP is implicated the causative factor behind high-altitude pulmonary edema, which can affect previously healthy human during ascent to altitude. During acute exercise, venous return to the heart increases and the heart beat faster and more forcefully, resulting in a greater Q ˙ which increases PAP. As such, it is possible that a potential mechanism behind EIAH is pulmonary edema causing a diffusion limitation. Others have attempted to detect pulmonary edema after exercise with mixed results (16, 48, 87). An explanation for the mixed results could be the lack of sensitivity in the instruments, the time delay between end of exercise and imaging and the inability to assess edema during exercise. Therefore, it is possible that there is a very small, subclinical, amount of edema during exercise that quickly resolves, but is sufficient to contribute to gas exchange inefficiencies.  88  Older women Previous studies on men have demonstrated that EIAH is more prevalent in older men compared to their younger counterparts (65). Healthy aging negatively effects pulmonary function in all individuals through a decrease in lung elasticity and stiffening of the chest-wall (19, 51, 83), both of which decrease ventilatory capacity (41). On average, women, irrespective of age, already have a decreased ventilatory capacity (52), therefore, it is possible that the effects of healthy aging could exacerbate EIAH. Due to the process of aging, some women who previously did not show any mechanical constraints or EIAH could begin to develop significant ventilatory constraints which lead to EIAH. Furthermore, our hypothesis of regarding mechanically induced V ˙A/Q ˙ mismatch could be exacerbated in older women due to decreased elasticity in their airways which results in an earlier equal pressure point and greater compression of airways (and blood vessels). To date, there has not been a study to assess EIAH in healthy older women.  89  Conclusion In young healthy women, there is considerable variability with respect to blood gas homeostasis during dynamic treadmill exercise. Some women experience significant and sudden gas exchange inefficiencies immediately upon starting to exercise, while others maintain their blood gases at (near) resting levels. Yet, the majority of women do develop some degree of EIAH, however, the pattern and/or mechanism(s) behind the hypoxemia is varied between subjects. Compared to trained men, trained women appear to develop EIAH more often and unlike untrained men, some untrained women can develop EIAH. In contrast to untrained men, untrained women develop mechanical ventilatory constraints during exercise, which could be a mechanism to explain EIAH in untrained women. Relieving EIAH by inspiring heliox gas will partially offset the decrease in PaO2, through increase ventilation, and the effect is greater in subjects who demonstrate EFL. In conclusion, the pulmonary systems response to dynamic exercise in women appears to be highly variable and unique to each subject. However, further investigation need to be completed to determine if the difference have systemic consequences such as decreased blood flow and/or increased fatigue to peripheral musculature that could negatively affect exercise tolerance or performance.  90  References 1. Aaron EA, Seow KC, Johnson BD, and Dempsey JA. Oxygen cost of exercise hyperpnea: implications for performance. J Appl Physiol 72: 1818-1825, 1992. 2. Agostoni E and Fenn WO. Velocity of muscle shortening as a limiting factor in respiratory air flow. J Appl Physiol 15: 349-353, 1960. 3. Amann M, Romer LM, Pegelow DF, Jacques AJ, Hess CJ, and Dempsey JA. Effects of arterial oxygen content on peripheral locomotor muscle fatigue. J Appl Physiol 101: 119-127, 2006. 4. ATS. Standardization of spirometry, 1994 update. American Thoracic Society. Am J Respir Crit Care Med 152: 1107-1136, 1995. 5. Band DM, Wolff CB, Ward J, Cochrane GM, and Prior J. Respiratory oscillations in arterial carbon dioxide tension as a control signal in exercise. Nature 1980 3: 84-85, 1980. 6. Banzett RB, Mead J, Reid MB, and Topulos GP. Locomotion in men has no appreciable mechanical effect on breathing. J Appl Physiol 72: 1922-1926, 1992. 7. Blain GM, Smith CA, Henderson KS, and Dempsey JA. Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2. J Physiol 588: 24552471. 8. Borg GA. Psychophysical Bases of Perceived Exertion. Med Sci Sports Exerc 14: 377381, 1982. 9. Calbet JAL, Holmberg H-C, Rosdahl H, van Hall G, Jensen-Urstad M, and Saltin B. Why do arms extract less oxygen than legs during exercise? AJP- Reg Integ Comp Physiol 289: R1448-R1458, 2005. 10. Christopherson SK and Hlastala MP. Pulmonary gas exchange during altered density gas breathing. J Appl Physiol 52: 221-225, 1982. 11.  Dempsey JA. Is the lung built for exercise? Med Sci Sports Exerc 18: 143-155, 1986.  12. Dempsey JA, Hanson PG, and Henderson KS. Exercise-induced arterial hypoxaemia in healthy human subjects at sea level. J Physiol 355: 161-175, 1984. 13. Dempsey JA and Wagner PD. Exercise-induced arterial hypoxemia. J Appl Physiol 87: 1997-2006, 1999. 14. Derchak PA, Stager JM, Tanner DA, and Chapman RF. Expiratory flow limitation confounds ventilatory response during exercise in athletes. Med Sci Sports Exerc 32: 1873-1879, 2000.  91 15. Dominelli PB, Guenette JA, Wilkie SS, Foster GE, and Sheel AW. Determinants of Expiratory Flow Limitation in Healthy Women during Exercise. Med Sci Sports Excerc 43: 1666-1674 2011. 16. Eldridge MW, Braun RK, Yoneda KY, and Walby WF. Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema. J Appl Physiol 100: 972-980, 2006. 17. Erickson BK, Seaman J, Kubo K, Hiraga A, Kai M, Yamaya Y, and Wagner PD. Mechanism of reduction in alveolar-arterial PO2 difference by helium breathing in the exercising horse. J Appl Physiol 76: 2794-2801, 1994. 18. Esbjarnsson-Liljedahl M, Sundberg CJ, Norman B, and Jansson E. Metabolic response in type I and type II muscle fibers during a 30-s cycle sprint in men and women. J J Appl Physiol 87: 1326-1332, 1999. 19. Estenne M, Yernault JC, and De Troyer A. Rib cage and diaphragm-abdomen compliance in humans: effects of age and posture. J J Appl Physiol 59: 1842-1848, 1985. 20. Goldman MD, Grimby G, and Mead J. Mechanical work of breathing derived from rib cage and abdominal V-P partitioning. J Appl Physiol 41: 752-763, 1976. 21. Gonzalez-Alonso J and Calbet JAL. Reductions in Systemic and Skeletal Muscle Blood Flow and Oxygen Delivery Limit Maximal Aerobic Capacity in Humans. Circulation 107: 824830, 2003. 22. Green M, Mead J, and Turner JM. Variability of maximum expiratory flow-volume curves. J Appl Physiol 37: 67-74, 1974. 23. Grimby G, Bunn J, and Mead J. Relative contribution of rib cage and abdomen to ventilation during exercise. J Appl Physiol 24: 159-166, 1968. 24. Guenette JA, Diep TT, Koehle MS, Foster GE, Richards JC, and Sheel AW. Acute hypoxic ventilatory response and exercise-induced arterial hypoxemia in men and women. Respir Physiol Neurobiol 143: 37-48, 2004. 25. Guenette JA, Dominelli PB, Reeve SS, Durkin CM, Eves ND, and Sheel AW. Effect of thoracic gas compression and bronchodilation on the assessment of expiratory flow limitation during exercise in healthy humans. Respir Physiol Neurobiol 170: 279-286, 2010. 26. Guenette JA, Romer LM, Querido JS, Chua R, Eves ND, Road JD, McKenzie DC, and Sheel AW. Sex differences in exercise-induced diaphragmatic fatigue in endurance-trained athletes. J Appl Physiol 109: 35-46. 27. Guenette JA, Witt JD, McKenzie DC, Road JD, and Sheel AW. Respiratory mechanics during exercise in endurance-trained men and women. J Physiol 581: 1309-1322, 2007.  92  28. Harms CA, Babcock MA, McClaran SR, Pegelow DF, Nickele GA, Nelson WB, and Dempsey JA. Respiratory muscle work compromises leg blood flow during maximal exercise. J Appl Physiol 82: 1573-1583, 1997. 29. Harms CA, McClaran SR, Nickele GA, Pegelow DF, Nelson WB, and Dempsey JA. Effect of exercise-induced arterial O2 desaturation on O2max in women. Medi Sci Sports Exerc 32: 1101-1108, 2000. 30. Harms CA, McClaran SR, Nickele GA, Pegelow DF, Nelson WB, and Dempsey JA. Exercise-induced arterial hypoxaemia in healthy young women. J Physiol 507: 619-628, 1998. 31. Henke KG, Sharratt M, Pegelow D, and Dempsey JA. Regulation of end-expiratory lung volume during exercise. J Appl Physiol 64: 135-146, 1988. 32. Holmgren A and Linderholm H. Oxygen and Carbon Dioxide Tensions of Arterial Blood during Heavy and Exhaustive Exercise. Acta Physiologica Scandinavica 44: 203-215, 1958. 33. Hopkins SR, Barker RC, Brutsaert TD, Gavin TP, Entin P, Olfert IM, Veisel S, and Wagner PD. Pulmonary gas exchange during exercise in women: effects of exercise type and work increment. J Appl Physiol 89: 721-730, 2000. 34. Hopkins SR, Gavin TP, Siafakas NM, Haseler LJ, Olfert IM, Wagner H, and Wagner PD. Effect of prolonged, heavy exercise on pulmonary gas exchange in athletes. J J Appl Physiol 85: 1523-1532, 1998. 35. Hopkins SR and Harms CA. Gender and Pulmonary Gas Exchange During Exercise. Exerc Sport Sci Rev 32: 50-56, 2004. 36. Hughes JM, Hoppin FG, Jr, and Mead J. Effect of lung inflation on bronchial length and diameter in excised lungs. J Appl Physiol l 32: 25-35, 1972. 37. Hunter SK and Enoka RM. Sex differences in the fatigability of arm muscles depends on absolute force during isometric contractions. J Appl Physiol 91: 2686-2694, 2001. 38.  Hyatt RE. Expiratory flow limitation. J Appl Physiol 55: 1-7, 1983.  39. Hyatt RE and Flath RE. Relationship of air flow to pressure during maximal respiratory effort in man. J Appl Physiol 21: 477-482, 1966. 40. Jensen JI, Lyager S, and Pedersen OF. The relationship between maximal ventilation, breathing pattern and mechanical limitation of ventilation. J Physiol 309: 521-532, 1980. 41. Johnson BD, Reddan WG, Seow KC, and Dempsey JA. Mechanical constraints on exercise hyperpnea in a fit aging population. Am Rev Respir Dis 143: 968-977, 1991.  93 42. Johnson BD, Saupe KW, and Dempsey JA. Mechanical constraints on exercise hyperpnea in endurance athletes. J Appl Physiol l 73: 874-886, 1992. 43. Johnson BD, Scanlon PD, and Beck KC. Regulation of ventilatory capacity during exercise in asthmatics. J Appl Physiol 79: 892-901, 1995. 44. Kaciuba-Uscilko H and Grucza R. Gender differences in thermoregulation. Curr Opin Clin Nutr Metab Care 4: 533-536, 2001. 45. Lefrant JY, Muller L, de La Coussaye JE, Benbabaali M, Lebris C, Zeitoun N, Mari C, Saïssi G, Ripart J, and Eledjam JJ. Temperature measurement in intensive care patients: comparison of urinary bladder, oesophageal, rectal, axillary, and inguinal methods versus pulmonary artery core method. Intens Care Med29: 414-418, 2003. 46. Lilienthal JL, Riley RL, Proemmel DD, and Franke RE. An experimental analysis in man of the oxygen pressure gradient from alveolar air to arterial blood during rest and exercise at sea level and at altitude. Am J Physiol- Legacy Content 147: 199-216, 1946. 47. Lovering AT, Stickland MK, Amann M, O'Brien MJ, Hokanson JS, and Eldridge MW. Effect of a patent foramen ovale on pulmonary gas exchange efficiency at rest and during exercise. J Appl Physiol 110: 1354-1361. 48. MacNutt M, Guenette J, Witt J, Yuan R, Mayo J, and McKenzie D. Intense hypoxic cycle exercise does not alter lung density in competitive male cyclists. Eur J Appl Physiol 99: 623-631, 2007. 49. MacNutt MJ, De Souza MJ, Tomczak SE, Homer JL, and Sheel AW. Resting and exercise ventilatory chemosensitivity across the menstrual cycle. J Appl Physiol 112: 737-747. 50. Martin TR, Castile RG, Fredberg JJ, Wohl ME, and Mead J. Airway size is related to sex but not lung size in normal adults. J Appl Physiol 63: 2042-2047, 1987. 51. McClaran SR, Babcock MA, Pegelow DF, Reddan WG, and Dempsey JA. Longitudinal effects of aging on lung function at rest and exercise in healthy active fit elderly adults. J J Appl Physiol 78: 1957-1968, 1995. 52. McClaran SR, Harms CA, Pegelow DF, and Dempsey JA. Smaller lungs in women affect exercise hyperpnea. J Appl Physiol 84: 1872-1881, 1998. 53. McKenzie DC, Lama IL, Potts JE, Sheel AW, and Coutts KD. The effect of repeat exercise on pulmonary diffusing capacity and EIH in trained athletes. Medi Sci Sports Exerc 31: 99-104, 1999. 54. Mead J. Dysanapsis in normal lungs assessed by the relationship between maximal flow, static recoil, and vital capacity. Am Rev Respir Dis 121: 339-342, 1980.  94 55. Mead J and Whittenberger JL. Physical Properties of Human Lungs Measured During Spontaneous Respiration. J Appl Physiol 5: 779-796, 1953. 56. Milic-Emili J, Mead J, Turner JM, and Glauser EM. Improved technique for estimating pleural pressure from esophageal balloons. J Appl Physiol 19: 207-211, 1964. 57. Miyachi M and Katayama K. Effects of maximal interval training on arterial oxygen desaturation and ventilation during heavy exercise. Jpn J Physiol 49: 401-407, 1999. 58. Mota S, Casan P, Drobnic F, Giner J, Ruiz O, Sanchis J, and Milic-Emili J. Expiratory flow limitation during exercise in competition cyclists. J Appl Physiol 86: 611-616, 1999. 59. Olfert IM, Balouch J, Kleinsasser A, Knapp A, Wagner H, Wagner PD, and Hopkins SR. Does gender affect human pulmonary gas exchange during exercise? J Physiol 557: 529-541, 2004. 60. Otis AB. The work of breathing. Washington, DC: American Physiological Society, 1964. 61. Otis AB, Fenn WO, and Rahn H. Mechanics of Breathing in Man. J Appl Physiol 2: 592607, 1950. 62. Pellegrino R, Brusasco V, Rodarte JR, and Babb TG. Expiratory flow limitation and regulation of end-expiratory lung volume during exercise. J Appl Physiol 74: 2552-2558, 1993. 63. Phillipson EA, Bowes G, Townsend ER, Duffin J, and Cooper JD. Carotid chemoreceptors in ventilatory responses to changes in venous CO2 load. J J Appl Physiol 51: 1398-1403, 1981. 64. Phillipson EA, Duffin J, and Cooper JD. Critical dependence of respiratory rhythmicity on metabolic CO2 load. J Appl Physiol 50: 45-54, 1981. 65. Prefaut C, Anselme F, Caillaud C, and Masse-Biron J. Exercise-induced hypoxemia in older athletes. J Appl Physiol 76: 120-126, 1994. 66. Rice AJ, Scroop GC, Gore CJ, Thornton AT, Chapman M, Greville HW, Holmes M, and Scicchitano R. Exercise-induced hypoxaemia in highly trained cyclists at 40% peak oxygen uptaje. Eur J Appl Physiol Occup Physiol 79: 353-359, 1999. 67. Rice AJ, Thornton AT, Gore CJ, Scroop GC, Greville HW, Wagner H, Wagner PD, and Hopkins SR. Pulmonary gas exchange during exercise in highly trained cyclists with arterial hypoxemia. J Appl Physiol 87: 1802-1812, 1999. 68. Richards JC, McKenzie DC, Warburton DER, Road JD, and Sheel AW. Prevalence of Exercise-Induced Arterial Hypoxemia in Healthy Women. Med Sci Sports Exerc 36: 1514-1521, 2004.  95 69. Robinson JL, Seal RF, Spady DW, and Joffres MR. Comparison of esophageal, rectal, axillary, bladder, tympanic, and pulmonary artery temperatures in children. J Pediat 133: 553556, 1998. 70. Romer LM, Haverkamp HC, Lovering AT, Pegelow DF, and Dempsey JA. Effect of exercise-induced arterial hypoxemia on quadriceps muscle fatigue in healthy humans. AMJRegul Integr Comp Physiol 290: R365-R375, 2006. 71. Roussos C and Campbell EJM. Respiratory muscle energetics. In: Handbook of physiology. Bethesda, MD, 1986, p. 481-509. 72. Rowell LB, Taylor HL, Wang Y, and Carlson WS. Saturation of arterial blood with oxygen during maximal exercise. J Appl Physiol 19: 284-286, 1964. 73. Saltin B, Blomqvist G, Mitchell JH, Johnson RL, Wildenthal K, Chapman CB, Frenkel E, Norton W, Siperstein M, Suki W, Vastagh G, and Prengler A. A Longitudinal Study of Adaptive Changes in Oxygen Transport and Body Composition. Circulation 38: VII-1-VII-78, 1968. 74. Scroop GC and Shipp NJ. Exercise-Induced Hypoxemia: Fact or Fallacy? Medi Sci Sports Exerc 42: 120-126 2010. 75.  Severinghaus JW. Blood gas calculator. J Appl Physiol 21: 1108-1116, 1966.  76. Sheel AW, Guenette JA, Yuan R, Holy L, Mayo JR, McWilliams AM, Lam S, and Coxson HO. Evidence for dysanapsis using computed tomographic imaging of the airways in older ex-smokers. J Appl Physiol 107: 1622-1628, 2009. 77. Sheel AW, Koehle MS, Guenette JA, Foster GE, Sporer BC, Diep TT, and McKenzie DC. Human ventilatory responsiveness to hypoxia is unrelated to maximal aerobic capacity. J Appl Physiol 100: 1204-1209, 2006. 78. Shiraki K, Konda N, and Sagawa S. Esophageal and tympanic temperature responses to core blood temperature changes during hyperthermia. J Appl Physiol 61: 98-102, 1986. 79. St. Croix CM, Harms CA, McClaran SR, Nickele GA, Pegelow DF, Nelson WB, and Dempsey JA. Effects of prior exercise on exercise-induced arterial hypoxemia in young women. J Appl Physiol 85: 1556-1563, 1998. 80. Stark-Leyva KN, Beck KC, and Johnson BD. Influence of expiratory loading and hyperinflation on cardiac output during exercise. J Appl Physiol 96: 1920-1927, 2004. 81. Tatsumi K, Pickett CK, Jacoby CR, Weil JV, and Moore LG. Role of endogenous female hormones in hypoxic chemosensitivity. J Appl Physiol 83: 1706-1710, 1997.  96 82. Tikuisis P, Jacobs I, Moroz D, Vallerand AL, and Martineau L. Comparison of thermoregulatory responses between men and women immersed in cold water. J Appl Physiol 89: 1403-1411, 2000. 83. Turner JM, Mead J, and Wohl ME. Elasticity of human lungs in relation to age. J Appl Physiol 25: 664-671, 1968. 84. Wagner PD, Gale GE, Moon RE, Torre-Bueno JR, Stolp BW, and Saltzman HA. Pulmonary gas exchange in humans exercising at sea level and simulated altitude. J Appl Physiol 61: 260-270, 1986. 85. Wetter TJ, St. Croix CM, Pegelow DF, Sonetti DA, and Dempsey JA. Effects of exhaustive endurance exercise on pulmonary gas exchange and airway function in women. J Appl Physiol 91: 847-858, 2001. 86. Younes M and Kivinen G. Respiratory mechanics and breathing pattern during and following maximal exercise. J Appl Physiol 57: 1773-1782, 1984. 87. Zavorsky GS. Evidence of pulmonary oedema triggered by exercise in healthy humans and detected with various imaging techniques. Acta Physiologica 189: 305-317, 2007. 88. Zavorsky GS, Saul L, Murias JM, and Ruiz P. Pulmonary gas exchange does not worsen during repeat exercise in women. Respir Physiol Neurobiol 153: 226-236, 2006.  97  Appendix A: Individual subject data This appendix contains the individual subject data. Each subject has three pages, beginning with their description and MEFV curve with tidal FV for the maximal exercise test and the constant load test. Immediately following is a page dedicated to arterial blood gas variables and a page of mechanics related data. Two subjects (AC and SW) who were tested twice have both included and marked as “Day 1” and “Day 2”. The first set is an example and is NOT data collected or used for the study, rather is serves as a legend for all others.  98 Figure 32- Example, MEFV curve and descriptors. Subject SMcC- Big mountain skier, GNAR Supplement Daily ***EXAMPLE*** Dysanapsis Age Height Weight BMI FVC FVC DLCO yr  cm  kg/m2  kg  L  %  34 185 85 24.8 6.84 110 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER  12  L/min  mL/kg/min  L/min  L/min  5.55  65  5.98  165  1.08  VO2max MEFV  10 8  Flow (L/sec)  6  mL/min/mmHg  32.31  MIP cmH2O  0.15  -150  VT  Fb  EFL  EELV  L  bpm  %  % FVC  3.2  52  0  32  Stage 9 mph 10 mph 10 mph 1% 10 mph 2% 10 mph 3% 10 mph 4% 10mph 5%  EFL (%) 0 0 0 0 0 0 0  ˙E/V V ˙ECap (%) 35 37 38 40 45 50 55  4 2 0 -2 -4 -6 12  Tidal FV loops, max or EFL loops are bolded  Constant at 10mph 3%, He Stage Air Heliox Air  10 8  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 38 30 37  Flow (L/sec)  6 4 2 0 -2 -4  Heliox Air  -6 -4  -3  -2  Volume (L)  -1  0  99  120  ***EXAMPLE*** 100  99  SaO2 (%)  110 105 100 95 90 10 mmHg  95  Actual Ideal PaO2 change only (Temp 37, pH 7.40, PaCO2 40)  93  from rest  Temp, pH, PaCO2 change (rest PaO2)  23.0  CaO2 (mL/dL)  20 18 16 14 12 10 8 6 4 2 0  VO2max test  Constant load test  40  21.5 21.0  17.0  7.45  16.8  7.35 36  22.0  20.5  7.40  38  22.5  7.50  7.30  34  7.25  32  7.20  42 40  16.6 16.4  38  16.2 16.0  36  15.8 15.6 Open on right axis  34  39.0  6.5  24  38.5  6.0  22  38.0 37.5 mph  37.0  last speed plus grade  inspired gas  K+ (mmol/L)  PaCO2 (mmHg)  96 94  42  Temp (C)  97  20  5.5 5.0  Filled on left axis  Rest 5  6  7  8  9 10 1% 2% 3% Rest Air 1 He Air 2  18 16  4.5  14  4.0  12  3.5  36.5  Hct (%)  85  98  10 Rest 5  6  7  8  9 10 1% 2% 3% Rest Air 1 He Air 2  HCO3 (mmol/L)  115  pH Hb (g/dL)  A-aDO2 (mmHg)  PaO2 and PAO2 (mmHg)  Figure 33- Example, arterial blood gases.  100 Figure 34- Example, respiratory mechanics.  Peso (cmH2O)  300 200 100  50 40 30 20 10 0  40 Elastic Resistive  20 10 0 100 EILV EELV  3.5  300  3.0 2.5  250  2.0 200  1.5  150  1.0  100  0.5  400  0.25  VD (mL)  0.20  60 40 20  300 0.15 200  0.10 0.05  100  180 160 140 120 100 80 60 40 20 0  0.00 35  VE/VO2 and VE/VCO2  (L/min)  0  VE VA VECap VE  PaO2 rest  30 25 20 15  Rest 5  6  7  8  9 10 1% 2% 3% Rest Air 1 He Air 2  Rest 5  6  7  8  9 10 1% 2% 3% Rest Air 1 He Air 2  VD/VT  30  350  VT (L)  0  Cdyn (mL/cmH2O)  WOB (J/min) El and Res WOB (cmH 2O/brth)  60  PV Loops Campbell  80  % FVC  70  ***EXAMPLE***  400  101 Figure 35- AC (Day 1), MEFV curve and descriptors. Subject AC(Jun)- Cycle/Run (Rec). 30-60min/3-4x/wk. DAY 1 Age Height Weight BMI FVC FVC DLCO yr  cm  kg/m2  kg  L  %  36 162 67.8 25.8 3.68 91 Peak exercise, 7.5 mph V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  2.60  38  2.98  73  12  1.16  VO2max  8 6  Flow (L/sec)  27.38  MIP cmH2O  0.11  -115  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.5  63  28  39  Stage 4.5 mph 5.5 mph 6.5 mph 7.5a mph 7.5b mph  10  Dysanapsis  mL/min/mmHg  EFL (%) 0 0 8 28 12  ˙E/V V ˙ECap (%) 35 44 56 62 52  4 2 0 -2 -4 -6 12  Stage Air Heliox Air  Constant at 6.5 mph, He  10 8  EFL (%) 9 50 51  ˙E/V V ˙ECap (%) 57 67 62  Flow (L/sec)  6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  102  100 110  SaO2 (%)  98 100 90  70  90  40  19  30 20 10  18 17 16 15  40  7.35  13.5  7.30  38  7.25  36  12.5  11.5  7.15  11.0  38.5  5.5  K+ (mmol/L)  6.0  37.5  38  12.0  39.0  38.0  40  13.0  7.20 34  42  36  24 22 20  5.0  18  4.5  16 14  4.0  37.0  6.5 mph  36.5 Rest  4.5  5.5  6.5  7.5a 7.5b  Rest Air 1 He Air 2  Hct (%)  14.0  6.5 mph  3.5 Rest  4.5  5.5  6.5  7.5a 7.5b  Rest Air 1 He Air 2  12 10  -  7.40  HCO3 (mmol/L)  42  pH Hb (g/dL)  PaCO2 (mmHg)  94 92  0  Temp (C)  96  80  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 36- AC (Day 1), arterial blood gases.  103  300  50  250  40  200 150 100  0 220 200 180 160 140 120 100 80 60  2.0  500  0.30  20 15 10 5 0 100  1.5 1.0 0.5 0.0 0.28  400  60 40  0.26 0.24  300  0.22 0.20  200  20 0  0.18 0.16  100  120 100 80 60 40 20  6.5 mph  0 Rest  4.5  5.5  6.5  7.5a 7.5b  Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  50  140  45 40 35 30 25  6.5 mph  20 Rest  4.5  5.5  6.5  7.5a 7.5b  Rest Air 1 He Air 2  VD/VT  VD (mL)  % FVC  10  0  80  (L/min)  20  25  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  50  30  VT (L)  Peso (cmH2O)  WOB (J/min)  Figure 37- AC (Day 1), respiratory mechanics.  104 Figure 38- AC (Day 2), MEFV curve and descriptor. Subject AC (NOV)-. Run (Rec). 30-45min/2-3x/wk. DAY 2 Age Height Weight BMI FVC FVC yr  cm  kg/m2  kg  L  %  36 163 69 26.0 3.61 90 Peak exercise, 7 mph V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  2.85  41  3.19  83  10  1.11  24.71  0.11  -106  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.5  65  38  40  Stage 4 mph 5 mph 6 mph 7 mph a 7 mph b  6  MIP cmH2O  VO2max  8  Flow (L/sec)  Dysanapsis  DLCO  mL/min/mmHg  EFL (%) 0 0 38 46 45  ˙E/V V ˙ECap (%) 35 49 62 64 64  4  2  0  -2  -4  -6 10  Constant at 6 mph, CO2  Stage Air CO2 Air  8  EFL (%) 33 47 52  ˙E/V V ˙ECap (%) 47 62 62  Flow (L/sec)  6  4  2  0  -2  -4  -6 -4  -3  -2  Volume (L)  -1  0  105  120  100 99  110  SaO2 (%)  PaO2 & PAO2 (mmHg)  Figure 39- AC (Day 2), arterial blood gases.  100 90 80  98 97 96 95 94  70  93  CaO2 (mL/dL)  30 20 10  46 44 42 40 38 36 34 32 30 28  17.5 17.0 16.5  7.40  13.5  7.35  13.0  42  7.30  40 12.5  39 38  7.25  12.0  7.20  11.5  Hct (%)  41  37 36  6.0  38.0  K+ (mmol/L)  37.8  Temp (C)  18.0  16.0  pH Hb (g/dL)  PaCO2 (mmHg)  0  18.5  37.6 37.4 37.2  5.5  20  5.0  18  4.5 16  4.0 3.5  37.0  6 mph  36.8 Rest  4  5  6  7a  7b  Rest Air 1 CO2 Air 2  6 mph  3.0 Rest  4  5  6  7a  7b  Rest Air 1 CO2 Air 2  14  HCO3 (mmol/L)  A-aDO2 (mmHg)  19.0 40  106  60  250  50  Peso (cmH2O)  300  200 150 100  40 30 20  50  10  0  0 2.0  25 20 15 10 5 0  160  1.8  140  1.6  120  1.4  100  1.2  80  1.0  VT (L)  30  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  Figure 40- AC (Day 2), respiratory mechanics.  0.8  60  0.6  40  100  0.20 250  40  0.10  150  20  100  0.05  0  50  0.00  45  140 120  (L/min)  200  100 80 60 40 20  6 mph  0 Rest  4  5  6  7a  7b  Rest Air 1 CO2 Air 2  40 35 30 25  6 mph  20 Rest  4  5  6  7a  7b  Rest Air 1 CO2 Air 2  VD/VT  VD (mL)  0.15  60  VE/VO2 and VE/VCO2  % FVC  80  107 Figure 41- AH, MEFV curve and descriptors. Subject AH- Run/Hike/Swim/Bike. 30-40min. 3-4x/wk. Age Height Weight BMI FVC FVC Yr  cm  kg/m2  kg  L  %  22 166 58.2 21.1 3.96 100 Peak exercise, 8.5 mph, 2% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.00  51.5  3.27  87  12  1.06  VO2max  10 8  Dysanapsis  DLCO mL/min/mmHg  25.32  MIP cmH2O  0.18  -120  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.8  57  0  49  Stage 5 mph 6 mph 7 mph 8 mph  EFL (%) 0 0 0 0  ˙E/V V ˙ECap (%) 19 25 33 41  Stage Air Heliox  EFL (%) 0 0  ˙E/V V ˙ECap (%) 35 30  Flow (L/sec)  6 4 2 0 -2 -4 -6 12  Constant at 10mph, He  10 8  Flow (L/sec)  6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  108  120  100 99  SaO2 (%)  110 100  96  80  94  25  18.0  20  17.5  15 10 5  17.0 16.5 16.0 15.5  7.35  12.8  7.30 7.25 7.20  40 39  12.6 12.4  38  12.2  37  12.0 11.8  7.15  36  11.6  7.10  35  6.5  38.6 38.4 38.2 38.0 37.8 37.6 37.4 37.2 37.0 36.8  K+ (mmol/L)  6.0 5.5 5.0 4.5 4.0  7 mph Rest  5  6  7  8  Rest Air 1  He  Hct (%)  13.0  7 mph  3.5 Rest  5  6  7  Rest Air 1  He  26 24 22 20 18 16 14 12 10 8  -  7.40  HCO3 (mmol/L)  44 42 40 38 36 34 32 30 28  pH Hb (g/dL)  PaCO2 (mmHg)  97  95  0  Temp (C)  98  90  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 42- AH, arterial blood gases.  109  50  250  40  200 150 100  30 20  50  10  0  0 160  30 20 10  2.0  140 1.5 120 100  1.0  80 0.5 60  0  40  0.0  100  400  0.25 0.20  60 40 20  300 0.15 200  0.10 0.05  100  0  0.00 40  200 150 100 50  7 mph  0 Rest  5  6  7  8  Rest Air 1  He  VE/VO2 and VE/VCO2  250  35 30 25 20  7 mph  15 Rest  5  6  7  8  Rest Air 1  He  VD/VT  VD (mL)  % FVC  80  (L/min)  VT (L)  Peso (cmH2O)  300  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  Figure 43- AH, respiratory mechanics.  110  Figure 44- AM, MEFV curve and descriptors.  Subject AM- Run/Bike/Swim/Ski (Touring). 1.5hrs/4x/wk Age Height Weight BMI FVC FVC yr  cm  kg/m2  kg  L  %  19 162 60.2 22.9 3.95 104 Peak exercise, 8.5 mph, 2% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  2.88  48  3.14  96  8  1.09  VO2max  4  MIP cmH2O  0.3  -94  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.7  68  37  36  Stage 4.5 mph 5.5 mph 6.5 mph 7.5 mph 8.5 mph 8.5 mph 2%  6  Flow (L/sec)  Dysanapsis  DLCO mL/min/mmHg  EFL (%) 0 0 0 0 0 37  ˙E/V V ˙ECap (%) 22 27 33 41 62 67  2  0  -2  -4  -6 -4  -3  -2  Volume (L)  -1  0  111  100  110  99  105  98  SaO2 (%)  115  100 95 90  95 94 93  25  16.0  20 15 10 5  15.5 15.0 14.5 14.0  44  7.35  42  7.30  40 7.25  38 36  7.20  34  7.15  12.0  35 11.5  K+ (mmol/L)  37.5 37.0 36.5 Rest 4.5 5.5 6.5 7.5 8.5 2%a 2%b  11.0  33 32 31  39.0  38.0  34  10.5  39.5  38.5  36  Hct (%)  7.40  10.0  30  6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0  26 24 22 20 18 16 14 12 Rest 4.5 5.5 6.5 7.5 8.5 2%a 2%b  HCO3 (mmol/L)  46  pH Hb (g/dL)  PaCO2 (mmHg)  96  80  0  Temp (C)  97  85  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 45- AM, arterial blood gases.  112 Figure 46- AM, respiratory mechanics. 40  250  Peso (cmH2O)  200 150 100  0  20 10 0 2.0  25 20 15 10 5  140 1.5  120 100  1.0  80  0.5  60  0  0.0  100  500  80  400  0.30 0.28  60 40  0.26 0.24  300  0.22 0.20  200  0.18  20 100  0.16  0 35  160 140 120 100 80 60 40 20 0  VE/VO2 and VE/VCO2  (L/min)  VT (L)  Cdyn (mL/cmH2O)  30  VD (mL)  % FVC  El and Res WOB (cmH 2O/brth)  50  30  30 25 20 15  Rest 4.5 5.5 6.5 7.5 8.5 2%a 2%b  Rest 4.5 5.5 6.5 7.5 8.5 2%a 2%b  VD/VT  WOB (J/min)  300  113 Figure 47- AS, MEFV curve and descriptors. Subject AS- Running/Cycling/Hockey/Swim (Rec). ~1hr/5-6x week Age Height Weight BMI FVC FVC DLCO yr  cm  kg/m2  kg  L  %  29 170 67.7 23.4 4.03 104 Peak exercise, 8 mph. 1% V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  48  3.72  95  3.24  1.16  Dysanapsis  MIP  mL/min/mmHg  cmH2O  -110 VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.69  65  19  38  VO2max  Stage 5 mph 6 mph 7 mph 8 mph 8 mph 1%  Flow (L/sec)  10  EFL (%) 0 0 0 0 19  ˙E/V V ˙ECap (%) 20 29 36 50 40  5  0  -5  14  Constant at 7 mph, He  Stage Air Heliox Air  12 10  EFL (%) 0 0 24  ˙E/V V ˙ECap (%) 35 32 49  Flow (L/sec)  8 6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  114  100  110  98  SaO2 (%)  120  100 90 80  90 50  17.5  40  17.0  30 20 10  16.5 16.0 15.5 15.0 13.0  40 39  12.5  40  7.35  38  7.30  36  7.25  34  38 12.0 37 11.5  32  7.20  30  7.15  K+ (mmol/L)  38.5 38.0 37.5 37.0  7 mph  36.5 Rest  5  6  7  8a  8b  1%  Rest Air 1 He Air 2  36  11.0  39.0  Hct (%)  7.40  35  100 90 80 70 60 50 40 30 20 10 0  24 22 20 18 16  7 mph Rest  5  6  7  8a  8b  1%  Rest Air 1 He Air 2  14 12  -  7.45  42  HCO3 (mmol/L)  44  pH Hb (g/dL)  PaCO2 (mmHg)  94 92  0  Temp (C)  96  70  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 48- AS, arterial blood gases.  115 Figure 49- AS, respiratory mechanics. 400  60  Peso (cmH2O)  WOB (J/min)  50 300 200 100  40 30 20  40  250  2.5  200  2.0  150  1.5  100  1.0  0  50  0.5  100  350  0.20  30 20 10  300  60 40  0.15  250 200  0.10  150 0.05  100  20  50  0  0.00  200 150 100 50  7 mph  0 Rest  5  6  7  8a  8b  1%  Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  35 30 25 20  7 mph  15 Rest  5  6  7  8a  8b  1%  Rest Air 1 He Air 2  VD/VT  VD (mL)  % FVC  80  (L/min)  VT (L)  0  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  10 0  116 Figure 50- BS, MEFV curve and descriptors. Subject BS- Run (Rec). 1-2hrs/3x/wk Age Height Weight BMI yr  cm  kg  FVC  DLCO  L  %  mL/min/mmHg  kg/m  22 173 60 20.0 4.53 108 Peak exercise 8 mph, 1% V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  2.73  46  2.75  88  10  1.00  VO2max  8  6  Flow (L/sec)  Dysanapsis  FVC  2  MIP cmH2O  0.18  -91  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.2  48  50  21  Stage 5 mph 6 mph 7 mph 8 mph 8 mph 1%  EFL (%) 0 0 0 0 50  ˙E/V V ˙ECap (%) 20 29 38 51 69  4  2  0  -2  -4  -6 -4  -3  -2  Volume (L)  -1  0  117  120  100 99  110  SaO2 (%)  PaO2 & PAO2 (mmHg)  Figure 51- BS, arterial blood gases.  100  98 97 96  90  95  CaO2 (mL/dL)  20 10  17.0 16.5 16.0  7.45  13.5  40  34  7.40  13.0  39  33  7.35  32 7.30  31  38  12.5  37 12.0  36  30  7.25  11.5  35  29  7.20  11.0  34  6.0  38.0  20  37.0 36.5  5.5  18  5.0  16  4.5  14  4.0  12  -  37.5  K+ (mmol/L)  Temp (C)  Hct (%)  15.5  35  pH Hb (g/dL)  PaCO2 (mmHg)  0  17.5  3.5  36.0 Rest  5  6  7  8  1%  HCO3 (mmol/L)  A-aDO2 (mmHg)  18.0 30  10 Rest  5  6  7  8  1%  118 Figure 52- BS, respiratory mechanics. 50  100  40 30 20 10  0  0  50  200  40 30 20 10  2.5  180  2.0  160 140  1.5  120  1.0  100 80  0.5  60  0 100  0.0  400  0.25 0.20  60 40 20  300 0.15 200  0.10 0.05  100  0  0.00  VE/VO2 and VE/VCO2  40 150 100 50  35 30 25 20  0 Rest  5  6  7  8  1%  Rest  5  6  7  8  1%  VD/VT  VD (mL)  % FVC  80  (L/min)  VT (L)  Peso (cmH2O)  200  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  300  119 Figure 53- CM, MEFV curve and descriptors. Subject CM- Varsity track (10km+), Nordic Skiing. Run/Bike/Swim 1+hr/daily Dysanapsis Age Height Weight BMI FVC FVC DLCO yr  cm  kg/m2  kg  L  %  20 169 60.4 21.1 3.9 96 Peak exercise, 8 mph, 3% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.41  56.5  3.67  97  12  1.07  VO2max  8 6  Flow (L/sec)  cmH2O  28.04  -86  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.58  71.2  0  49  Stage 5 mph 6 mph 7 mph 8 mph 8 mph 1% 8 mph 2% 8 mph 3% 8 mph 3%  10  4  MIP  mL/min/mmHg  EFL (%) 0 0 0 0 0 0 0 0  ˙E/V V ˙ECap (%) 34 40 43 49 48 58 58 51  2 0 -2 -4 -6 12  Constant at 8 mph, He  Stage Air Heliox Air  10 8  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 49 37 59  Flow (L/sec)  6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  120  100 110  99  SaO2 (%)  100 90 80  96  30  20.0  25  19.5  20 15 10 5  19.0 18.5 18.0 17.5 17.0  14.0  7.35 38  pH Hb (g/dL)  7.40  40  7.30  36  40  K+ (mmol/L)  39 38 37  44  13.5 42 13.0 40  12.5  7.25  34  46  12.0  38  6.0  24  5.5  22  5.0  20  4.5 18  4.0  16  3.5  8 mph  36 Rest 5  6  7  8  1% 2% 3% Rest Air 1 He Air 2  Hct (%)  42  14.5  8 mph  3.0 Rest 5  6  7  8  1% 2% 3%  Rest Air 1 He Air 2  14  -  7.45  HCO3 (mmol/L)  0  PaCO2 (mmHg)  97  94  44  Temp (C)  98  95  70  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 54- CM, arterial blood gases.  121 Figure 55- CM, respiratory mechanics. 60  Peso (cmH2O)  50  300 200 100  30 20  0  0  20 10  1.8  120  1.6 1.4  100  1.2  80  1.0 0.8  60  0.6  100  400  0.22  80  350  0.20  VD (mL)  0  60 40  0.18  300  0.16  250  0.14  200  0.12  20  150  0.10  0  100  0.08  40  150 100 50  8 mph  0 Rest 5  6  7  8 1% 2% 3%a3%b Rest Air 1 He Air 2  35 30 25 20  8 mph Rest 5  6  7  8 1% 2% 3%a3%b Rest Air 1 He Air 2  VD/VT  30  140  VT (L)  2.0  Cdyn (mL/cmH2O)  40  200  (L/min)  40  10  VE/VO2 and VE/VCO2  % FVC  El and Res WOB (cmH 2O/brth)  WOB (J/min)  400  122 Figure 56- CR, MEFV curve and descriptors. Subject CR- Run/Yoga (Rec). 60 min/4-6x/wk Age Height Weight BMI FVC yr  cm  kg/m2  kg  DLCO  %  mL/min/mmHg  22 158 58 23.2 3.66 104 Peak exercise, 7.5 mph V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  2.69  46  2.99  90  10  1.11  VO2max  8  6  Flow (L/sec)  Dysanapsis  FVC  L  21.47  MIP cmH2O  0.24  -123  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.6  66  0  47  Stage 4.5 mph 5.5 mph 6.5 mph 7.5 mph  EFL (%) 0 0 0 0  ˙E/V V ˙ECap (%) 21 34 49 50  Stage Air Heliox Air  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 33 25 38  4  2  0  -2  -4  -6 10  Constant at 10mph, He  8  Flow (L/sec)  6  4  2  0  -2  -4  -6 -3  -2  Volume (L)  -1  0  123  120  100  115  99  110  SaO2 (%)  105 100 95  95  CaO2 (mL/dL)  15 10 5 0  21 20 19 18 17  7.45  15.0 44  14.5  38  7.35 34  14.0 42  13.5 13.0  40  7.30  32  Hct (%)  36  pH Hb (g/dL)  7.40  12.5 7.25  12.0  38  39.0  5.5  22  38.5  5.0  K+ (mmol/L)  30  38.0 37.5  20  4.5 18 4.0  -  A-aDO2 (mmHg)  22  40  PaCO2 (mmHg)  97 96  90 20  Temp (C)  98  16  3.5  37.0  5.5 mph  36.5 Rest  4.5  5.5  6.5  7.5  Rest Air 1 He Air 2  HCO3 (mmol/L)  PaO2 & PAO2 (mmHg)  Figure 57- CR, arterial blood gases.  5.5 mph  3.0 Rest  4.5  5.5  6.5  7.5  Rest Air 1 He Air 2  14  124 Figure 58- CR, respiratory mechanics. 50  Peso (cmH2O)  200 100  20 10  2.5  100  2.0  80  1.5  60  1.0  0  40  0.5  100  400  0.25  300  0.20  200  0.15  100  0.10  0  0.05  30 20 10  60 40 20  180 160 140 120 100 80 60 40 20 0  5.5 mph Rest  4.5  5.5  6.5  7.5  Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  0  35 30 25 20  5.5 mph Rest  4.5  5.5  6.5  7.5  Rest Air 1 He Air 2  VT (L)  0  VD (mL)  % FVC  30  120  80  (L/min)  40  VD/VT  0  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  300  125 Figure 59-EM, MEFV curve and descriptors. Subject EM- Wrestling/Canoeing/Rollerderby. 1-2hrs/daily Age Height Weight BMI FVC FVC yr  cm  kg/m2  kg  L  %  28 163 60 22.6 3.76 104 Peak exercise, 8 mph, 2% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  2.99  50  3.15  81  12  1.1  MIP cmH2O  35.58  -124  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.66  57  57  36  VO2max  Stage 5 mph 6 mph 7 mph 8 mph 8 mph 2%  10 8 6  Flow (L/sec)  Dysanapsis  DLCO  mL/min/mmHg  EFL (%) 0 0 0 69 58  ˙E/V V ˙ECap (%) 32 49 71 79 68  4 2 0 -2 -4 -6 12  Constant at 7mph, He  Stage Air Heliox Air  10 8  EFL (%) 0 0 71  ˙E/V V ˙ECap (%) 68 36 76  Flow (L/sec)  6 4 2 0 -2 -4 -6 -3  -2  Volume (L)  -1  0  126  100 110 98  SaO2 (%)  PaO2 & PAO2 (mmHg)  Figure 60- EM, arterial blood gases.  100 90  96 94  80  92  70  90  30  CaO2 (mL/dL)  20 10  16  7.40  13.5  38  7.35  13.0  7.30  36  7.25 34  7.20  42 40  12.5 38 12.0 36  32  7.15  11.5  30  7.10  11.0  34  5.5  22  5.0  20  K+ (mmol/L)  38.0 37.8 37.6 37.4 37.2  4.5  18  4.0 16  3.5  14  3.0  37.0  7 mph  36.8 Rest 5  6  7  8 2%a 2%b Post Rest Air 1 He Air 2  Hct (%)  40  38.2  Temp (C)  17  15  pH Hb (g/dL)  PaCO2 (mmHg)  0  18  7 mph  2.5 Rest 5  6  7  8 2%a 2%b Post  Rest Air 1 He Air 2  12  HCO3 (mmol/L)  A-aDO2 (mmHg)  19  127  60  250  50  150 100  40 30 20  50  10  0  0 200  30 20 10  2.5  180  2.0  160 140  1.5  120  1.0  100 80  0.5  60  0 100  0.0  400  0.25  300  0.20  VD (mL)  % FVC  80 60 40  0.15  200  0.10  20  100 0.05 35  7 mph Rest 5  6  7  8 2%a 2%b Post Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  (L/min)  0 200 160 180 140 120 100 80 60 40 20 0  VT (L)  200  30 25 20  7 mph  15 Rest 5  6  7  8 2%a 2%b Post  Rest Air 1 He Air 2  VD/VT  Peso (cmH2O)  300  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  Figure 61- EM, respiratory mechanics.  128 Figure 62- GLY, MEFV curve and descriptors. Subject GLY- Soccer/Run/Cycle. 1hr/3-5x/wk Age Height Weight BMI FVC yr  cm  kg/m2  kg  DLCO  %  mL/min/mmHg  23 174 68 22.5 3.97 94 Peak exercise, 8.5 mph, 4% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.75  53  4.01  106  1.4  VO2max  MIP cmH2O  0.24  -103  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.1  59  14  23  Stage 4.5 mph 5.5 mph 6.5 mph 7.5 mph 8.5 mph 8.5 mph 2% 8.5 mph 4%  10  Flow (L/sec)  Dysanapsis  FVC  L  EFL (%) 0 0 0 0 0 0 14  ˙E/V V ˙ECap (%) 11 19 23 24 34 42 58  5  0  -5  Constant at 8 mph, He  Stage Air Heliox Air  12 10  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 28 30 38  Flow (L/sec)  8 6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  129  100  130 120  SaO2 (%)  PaO2 & PAO2 (mmHg)  Figure 63- GLY, arterial blood gases.  110 100 90  98 96 94  80 70  92  30  CaO2 (mL/dL)  20 10  17.5 17.0 16.5 16.0  7.40 7.35 7.30 7.25 7.20  41  13.4 13.2  40  13.0 12.8  39  12.6 12.4  7.15  12.2  7.10  12.0  38 37  6.5  40  24 6.0  39  K+ (mmol/L)  Temp (C)  Hct (%)  50 48 46 44 42 40 38 36 34  pH Hb (g/dL)  PaCO2 (mmHg)  0  18.0  38 37  22 5.5 20 5.0 18 4.5 16 4.0  8 mph  36 Rest 4.5 5.5 6.5 7.5 8.5 2% 4%  Re A1 O2 A2 He  8 mph  3.5 Rest 4.5 5.5 6.5 7.5 8.5 2% 4%  Re A1 O2 A2 He  14  HCO3 (mmol/L)  A-aDO2 (mmHg)  18.5  130 Figure 64-GLY, respiratory mechanics. 400  70  Peso (cmH2O)  WOB (J/min)  60 300 200 100  50 40 30 20  30 20 10 0  120  2.0  100 1.5 80 1.0  60  0.5  600  0.30  80  500  0.25  400  0.20  300  0.15  20  200  0.10  0  100  0.05  300  40  VD (mL)  40  100  60 40  200  (L/min)  2.5  150 100 50  8 mph  0 Rest 4.5 5.5 6.5 7.5 8.5 2% 4%  Re A1 O2 A2 He  35 30 25 20  8 mph  15 Rest 4.5 5.5 6.5 7.5 8.5 2% 4%  Re A1 O2 A2 He  ResIns (cmH2O/L/sec)  140  VD/VT  40  Cdyn (mL/cmH2O)  0  VE/VO2 and VE/VCO2  % FVC  El and Res WOB (cmH 2O/brth)  10 0  131 Figure 65- JB (Dec), MEFV curve and descriptors. Subject JB (Dec)- Rugby. 1.5-2.5hrs/4x/wk. Age Height Weight BMI FVC yr  cm  kg/m2  kg  21 157 72.4 29.4 Peak exercise, 7 mph V ˙O2 V ˙O2 V ˙CO2 V ˙E L/min  mL/kg/min  L/min  L/min  3.25  46  3.32  77  8  Dysanapsis  FVC  DLCO  L  %  mL/min/mmHg  cmH2O  4  114  26.02  -103  RER 1.03  MIP  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.7  38  0  50  VO2max  6  Flow (L/sec)  4  2  0  -2  -4  -6 -4  -3  -2  Volume (L)  -1  0  132  99 110  SaO2 (%)  98 100 90  96 95  70  94  40  18.5  30 20 10  18.0 17.5 17.0 16.5  7.45  41  7.40 7.35  40  7.30  39  7.25  38  41.0  13.4  pH Hb (g/dL)  42  13.2  40.5  13.0  40.0  12.8  39.5  12.6  39.0  12.4 12.2  38.5  12.0  38.0  37.8 24  K+ (mmol/L)  37.6 37.4 37.2 37.0  22 20  36.8 36.6  0 Rest  4  5  6  7  18 Rest  4  5  6  7  HCO3 (mmol/L)  26  38.0  Temp (C)  Hct (%)  0  PaCO2 (mmHg)  97  80  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 66- JB (Dec), arterial blood gases.  133 Figure 67- JB (Dec), respiratory mechanics. 60 50  Peso (cmH2O)  200 150 100  0  40  160  2.0  140  1.8  20 10  1.6  120  1.4  100  1.2  80  1.0  60  0.8  0  40  100  200  0.6 0.14 0.12  150  60 40  0.10 0.08  100  0.06 0.04  50  20  0.02  0  0  0.00  30  VE/VO2 and VE/VCO2  140 120 100 80 60 40 20 0 Rest  4  5  6  7  VT (L)  30  VD (mL)  % FVC  20  0  80  (L/min)  30  10  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  50  40  28 26 24 22 20 18 16 Rest  4  5  6  7  VD/VT  WOB (J/min)  250  134 Figure 68- JB, MEFV curve and descriptors. Subject JB- Varsity softball. Running/Gym, 1.5hrs/4x week Age Height Weight BMI FVC FVC Yr  cm  kg/m2  kg  L  %  23 177 64 20.4 4.14 95 Peak exercise, 8.5 mph, 2% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  2.98  46.6  2.96  84  14  1.01  VO2max  10  Flow (L/sec)  8  MIP cmH2O  0.22  -107  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.76  56  0  44  Stage 4.5 mph 5.5 mph 6.5 mph 7.5 mph 8.5 mph 8.5 mph 2%  12  Dysanapsis  DLCO  mL/min/mmHg  EFL (%) 0 0 0 0 0 0  ˙E/V V ˙ECap (%) 19 26 31 39 42 45  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 37 27 42  6 4 2 0 -2 -4 -6 14  Constant at 7.5 mph, He  Stage Air Heliox Air  12 10  Flow (L/sec)  8 6 4 2 0 -2 -4 -6 -3  -2  Volume (L)  -1  0  135  115  100  110 105  SaO2 (%)  100 95 90 80  92  CaO2 (mL/dL)  15 10 5  17.5 17.0 16.5 16.0 15.5 15.0  7.40  13.0  40  38  7.35  12.5  39  36  7.30  34  7.25  32  7.20  pH Hb (g/dL)  40  38  12.0  37 11.5  36  7.15  28  7.10  10.5  34  39.0  6.5  24  38.5  6.0  22  K+ (mmol/L)  30  11.0  38.0 37.5 37.0  20  5.5  18  5.0  16  4.5  14  4.0  7.5 mph  36.5 Rest 4.5  5.5  6.5  7.5  8.5  2%  Rest Air 1 He Air 2  35  7.5 mph  3.5 Rest 4.5  5.5  6.5  7.5  8.5  2%  Rest Air 1 He Air 2  12 10  Hct (%)  A-aDO2 (mmHg)  18.0  0  PaCO2 (mmHg)  96 94  85  20  Temp (C)  98  HCO3 (mmol/L)  PaO2 & PAO2 (mmHg)  Figure 69- JB, arterial blood gases.  136 Figure 70- JB, respiratory mechanics. 50  Peso (cmH2O)  200 100  30 20 10 0  100  1400  0.7  80  1200  0.6  1000  0.5  800  0.4  30 20  VD (mL)  10  60 40  2.0 1.5 1.0 0.5  600  0.3  20  400  0.2  0  200  0.1  150 100 50  7.5 mph  0 Rest 4.5  5.5  6.5  7.5  8.5  2%  Rest Air 1 He Air 2  VT (L)  Cdyn (mL/cmH2O)  2.5  0  220 200 180 160 140 120 100 80 60  50 40 30 20  7.5 mph Rest 4.5  5.5  6.5  7.5  8.5  2%  Rest Air 1 He Air 2  VD/VT  0  300 200  (L/min)  40  VE/VO2 and VE/VCO2  % FVC  El and Res WOB (cmH 2O/brth)  WOB (J/min)  300  137 Figure 71- JC, MEFV curve and descriptors. Subject JC- Run/Basketball. 90min/3-5x/wk Age Height Weight BMI FVC yr  cm  kg/m2  kg  DLCO  %  mL/min/mmHg  23 173 72 24.1 4.23 101 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.69  51  3.83  109  14  1.04  VO2max  10 8  MIP cmH2O  -103 VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.2  60  42  47  Stage 4.5 mph 5.5 mph 6.5 mph 7.5 mph 7.5 mph 2% 7.5 mph 4%  12  Flow (L/sec)  Dysanapsis  FVC  L  EFL (%) 0 0 0 0 0 0  ˙E/V V ˙ECap (%) 18 21 28 34 43 51  6 4 2 0 -2 -4 -6  14  Constant at 7.5 mph 4%, He  Stage Air Heliox  12  EFL (%) 0 0  ˙E/V V ˙ECap (%) 40 30  10  Flow (L/sec)  8 6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  138  120  99 98  SaO2 (%)  110 100 90 80  95 94 92  40  18.0  30 20 10  17.5 17.0 16.5 16.0 15.5  7.35  12.5  39  38 7.30  36 34  pH Hb (g/dL)  40  38 37  12.0 36  7.25  11.5  7.20  11.0  35  32 30  6.5  39.5  6.0  K+ (mmol/L)  40.0  39.0 38.5 38.0  34  7.5 mph 4% 22  5.5  20  5.0  18  4.5 16  4.0  37.5  7.5 mph 4%  37.0 Rest 4.5 5.5 6.5 7.5 2% 4% 6%  Rest Air 1  He  Hct (%)  13.0  3.5  14 Rest 4.5 5.5 6.5 7.5 2% 4% 6%  Rest Air 1  He  -  7.40  HCO3 (mmol/L)  42  PaCO2 (mmHg)  96  70  0  Temp (C)  97  93  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 72- JC, arterial blood gases.  139 Figure 73- JC, respiratory mechanics. 70 60  Peso (cmH2O)  400 300 200 100  40 30 20  200  50  180  30 20 10  2.0  160 140  1.5  120 100  1.0  80 60  0  600  80  500  VD (mL)  100  60 40  0.3  0  100  300  45  100 50  7.5 mph 4%  0 Rest 4.5 5.5 6.5 7.5 2% 4% 6%  Rest Air 1  He  0.4  300 200  150  0.5  400  20  200  0.5  0.2 0.1  7.5 mph 4%  40 35 30 25 20 Rest 4.5 5.5 6.5 7.5 2% 4% 6%  Rest Air 1  He  VD/VT  40  2.5  VT (L)  60  Cdyn (mL/cmH2O)  10  250  (L/min)  50  0  VE/VO2 and VE/VCO2  % FVC  El and Res WOB (cmH 2O/brth)  WOB (J/min)  500  140 Figure 74- JL, MEFV curve and descriptors. Subject JL- Weight training/light cardio. 1hr/1-3x/wk. Age Height Weight BMI FVC FVC yr  cm  kg/m2  kg  L  %  21 164 59 21.9 3.77 98 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  2.37 10  mL/kg/min  L/min  L/min  40  2.72  80  1.16  VO2max  22.78  6  MIP cmH2O  0.37  -41  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.8  53  0  30  Stage 4.5 mph 5.5 mph 6.5 mph 7.5 mph 7.5 mph 1%  8  Flow (L/sec)  Dysanapsis  DLCO mL/min/mmHg  EFL (%) 0 0 0 0 0  ˙E/V V ˙ECap (%) 13 26 40 47 56  4  2  0  -2  -4  -6 10  Stage Air Heliox Air  Constant at 7 mph, He  8  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 31 33 45  Flow (L/sec)  6  4  2  0  -2  -4  -6 -3  -2  Volume (L)  -1  0  141  120  SaO2 (%)  110 100 90 80  20.0  25  19.5  20 15 10 5  19.0 18.5 18.0 17.5  7.35 7.30 7.25 7.20  K+ (mmol/L)  37.6 37.4 37.2 37.0 36.8  7 mph  36.6 Rest  4.5  5.5  6.5  7.5  1%  Rest Air 1 He Air 2  15.0  44  14.5  43 42  14.0  41 13.5  40  13.0  39  12.5  38  7.0  26  6.5  24  6.0  22  5.5  20  5.0  18  4.5  16  4.0  7 mph  3.5 Rest  4.5  5.5  6.5  7.5  1%  Rest Air 1 He Air 2  14 12  HCO3 (mmol/L)  7.40  50 48 46 44 42 40 38 36 34 32  Hct (%)  17.0  pH Hb (g/dL)  PaCO2 (mmHg)  0  Temp (C)  98.0 97.5 97.0 96.5 96.0 95.5 95.0 94.5 94.0  30  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 75- JL, arterial blood gases.  142 Figure 76- JL, respiratory mechanics. 30 25  120  Peso (cmH2O)  100 80 60 40  10  0 200  Cdyn (mL/cmH2O)  14 12 10 8 6 4 2  2.0  180 1.5  160 140  1.0  120 0.5  100 80  100  400  80  350  0.22  300  0.20  250  0.18  VD (mL)  0  60 40  0.0 0.24  0.16  200  0.14  20  150  0.12  0  100  0.10  200  40  150 100 50  7 mph  0 Rest  4.5  5.5  6.5  7.5  1%  Rest Air 1 He Air 2  VT (L)  0  VE/VO2 and VE/VCO2  El and Res WOB (cmH 2O/brth) % FVC  15  5  20  (L/min)  20  35 30 25 20  7 mph Rest  4.5  5.5  6.5  7.5  1%  Rest Air 1 He Air 2  VD/VT  WOB (J/min)  140  143 Figure 77- JS (Dec), MEFV curve and descriptors. Subject JS(DEC)- Rowing (Varsity). 1-2hrs/2xdaily. Age Height Weight BMI FVC FVC yr  cm  kg/m2  kg  L  %  19 177 63.8 20.4 4.36 98 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  3.50 10  mL/kg/min  L/min  L/min  55  3.85  101  1.10  VO2max  26.45  6  4  MIP cmH2O  0.13  -62  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.8  65  44  49  Stage 4 mph 5 mph 6 mph 7 mph 8 mph 8 mph 2%  8  Flow (L/sec)  Dysanapsis  DLCO mL/min/mmHg  EFL (%) 0 0 0 0 11 44  ˙E/V V ˙ECap (%) 27 33 36 42 60 61  2  0  -2  -4  -6 10  Constant at 8 mph, He  Stage Air Heliox Air  8  Flow (L/sec)  6  EFL (%) 0 0 76  ˙E/V V ˙ECap (%) 51 46 76  4  2  0  -2  -4  -6 -4  -3  -2  Volume (L)  -1  0  144  120  100 99  110  SaO2 (%)  100 90  96 95 94 18.5  30  CaO2 (mL/dL)  A-aDO2 (mmHg)  97  80 35 25 20 15 10  18.0 17.5 17.0  5 0  16.5 7.45  46  13.0  44 40  7.35  38 36  7.30  34 7.25  32  41  12.8  7.40  42  pH Hb (g/dL)  PaCO2 (mmHg)  98  40  12.6 39 12.4  Hct (%)  PaO2 & PAO2 (mmHg)  Figure 78- JS (Dec), arterial blood gases.  38  12.2 12.0  37 24  37.6  K+ (mmol/L)  Temp (C)  37.8 37.4 37.2 37.0  22 20 18  36.8  8 mph  36.6 Rest 4  5  6  7  8  2% 3% Rest Air 1 He Air 2  8 mph  0 Rest 4  5  6  7  8  2% 3%  Rest Air 1 He Air 2  16  HCO3 (mmol/L)  38.0  145 Figure 79- JS (Dec), respiratory mechanics. 35 30  Peso (cmH2O)  200 150 100 50  25 20 15 10 5  250  25 20 15 10 5  200  1.5 100  350  80  300  VD (mL)  100  0  100  180 160 140 120 100 80 60 40 20 0  32 30 28 26 24 22 20 18 16  5  6  7  8  2% 3% Rest Air 1 He Air 2  0.20 0.18 0.16 0.14 0.12  200 150  Rest 4  0.5  250  20  8 mph  1.0  50 0  40  2.0  150  0  60  2.5  VT (L)  30  0.10 0.08 0.06  8 mph Rest 4  5  6  7  8  2% 3%  Rest Air 1 He Air 2  VD/VT  0  Cdyn (mL/cmH2O)  0  VE/VO2 and VE/VCO2  (L/min)  % FVC  El and Res WOB (cmH 2O/brth)  WOB (J/min)  250  146 Figure 80- JS (Nov), MEFV curve and descriptors. Subject JS (NOV)- Run(Marathon)/Bike/Soccer/Skiing. 1hr+/daily Age Height Weight BMI FVC FVC DLCO yr  cm  kg/m2  kg  L  %  38 165 54.5 20.0 3.9 113 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.14  58  3.32  87  10  1.06  VO2max  6  Flow (L/sec)  24.45  MIP cmH2O  0.12  -75  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.0  51  39  41  Stage 5.5 mph 6.5 mph 7.5 mph 8.5 mph 9.5 mph  8  Dysanapsis  mL/min/mmHg  EFL (%) 0 0 0 0 39  ˙E/V V ˙ECap (%) 28 31 39 46 60  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 36 32 38  4  2  0  -2  -4  12  Constant at 7 mph, He  Stage Air Heliox Air  10 8  Flow (L/sec)  6 4 2 0 -2 -4 -4  -3  -2  Volume (L)  -1  0  147  100 110  99  SaO2 (%)  100 90  95  CaO2 (mL/dL)  30 20 10  19.0 18.5 18.0 17.5 17.0 13.8  7.40 7.35  32  pH Hb (g/dL)  7.45  34  7.30  13.0  40  12.8  39  38.5  5.5  K+ (mmol/L)  6.0  37.5 37.0  41  13.2  39.0  38.0  42  13.4  12.6  7.25  30  43  13.6  38 24 22  5.0  20  4.5  18  4.0  16  3.5  7 mph  36.5 Rest 5.5  6.5  7.5  8.5  9.5 9.5 1% Rest Air 1 He Air 2  Hct (%)  7.50 36  -  A-aDO2 (mmHg)  19.5  0  PaCO2 (mmHg)  97 96  80 40  Temp (C)  98  HCO3 (mmol/L)  PaO2 & PAO2 (mmHg)  Figure 81- JS (Nov), arterial blood gases.  7 mph  3.0 Rest 5.5  6.5  7.5  8.5  9.5 9.5 1% Rest Air 1 He Air 2  14  148 Figure 82- JS (Nov), respiratory mechanics. 50  10 0  40  250  30 20 10  2.0 1.8  200  1.6 1.4  150  1.2 1.0  100  0  50  100  250  0.8 0.6 0.25 0.20  200  VD (mL)  % FVC  20  0  80 60 40  0.15 150 0.10 100  20  0.05  50  180 160 140 120 100 80 60 40 20 0  7 mph Rest 5.5  6.5  7.5  8.5  9.5 9.5 1% Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  0  (L/min)  30  VT (L)  100  40  0.00  35 30 25 20  7 mph  15 Rest 5.5  6.5  7.5  8.5  9.5 9.5 1% Rest Air 1 He Air 2  VD/VT  Peso (cmH2O)  200  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  300  149 Figure 83- KM, MEFV curve and descriptors. Subject KM- Run/Wight-train/Pilates. 1-1.5hrs/6x/wk. Age Height Weight BMI FVC FVC yr  cm  kg/m2  kg  L  %  26 161 50.5 19.5 2.92 82 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  2.41  48  2.86  63  6  1.19  VO2max  22.28  MIP cmH2O  0.35  -66  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.8  40  38  28  Stage 4.5 mph 5.5 mph 6.5 mph 7.5 mph 8.5 mph  4  Flow (L/sec)  Dysanapsis  DLCO mL/min/mmHg  EFL (%) 0 0 0 0 38  ˙E/V V ˙ECap (%) 26 32 43 49 62  2  0  -2  -4 6  Stage Air Heliox Air  Constant at 6.5 mph, He  Flow (L/sec)  4  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 35 35 38  2  0  -2  -4 -3  -2  -1  Volume (L)  0  150  115  100  110  99  SaO2 (%)  105 100 95 90  97 96  80  94  30  18.0  25  17.5  20 15 10 5  17.0 16.5 16.0 15.5  7.45  13.5  40  42  7.40  13.0  39  40  7.35  38  7.30  36  pH Hb (g/dL)  44  38  12.5  37 12.0  36  7.25  11.5  35  7.20  11.0  34  34  K+ (mmol/L)  38.5 38.0 37.5 37.0  6.5 mph  36.5 Rest  4.5  5.5  6.5  7.5  8.5  Rest Air 1 He Air 2  6.0  24  5.5  22  5.0  20  4.5  18  4.0 3.5  6.5 mph  3.0 Rest  4.5  5.5  6.5  7.5  8.5  Rest Air 1 He Air 2  16  HCO3 (mmol/L)  6.5  39.0  Temp (C)  Hct (%)  0  PaCO2 (mmHg)  98  95  85  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 84- KM, arterial blood gases.  151  40  150  30  50 0  0 180  2.0  160  1.8  20 15 10 5  1.6  140  1.4  120  1.2  100  1.0  80  0.8  0  60  100  200  0.6 0.14 0.12  150  VD (mL)  % FVC  10  25  80 60 40  0.10 0.08  100  0.06 0.04  50  20  0.02  0  0  160 140 120 100 80 60 40 20 0  35  6.5 mph Rest  4.5  5.5  6.5  7.5  8.5  Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  (L/min)  20  VT (L)  100  0.00  30 25 20  6.5 mph  15 Rest  4.5  5.5  6.5  7.5  8.5  Rest Air 1 He Air 2  VD/VT  Peso (cmH2O)  200  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  Figure 85- KM, respiratory mechanics.  152 Figure 86- KS, MEFV curve and descriptors. Subject KS- Hockey/Gymnastics. 10-15hrs/wk. 5-6x Age Height Weight BMI FVC FVC yr  cm  2  kg  kg/m  L  %  21 168 67 23.7 4.26 107 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.65  54  4.05  94  VO2max 8  6  Flow (L/sec)  4  2  0  -2  -4  -6  1.11  Dysanapsis  DLCO mL/min/mmHg  31.74  MIP cmH2O  0.15  -124  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.4  45  18  32  Stage 4 mph 6 mph 8 mph 9 mph  EFL (%) 0 0 55 18  ˙E/V V ˙ECap (%) 20 34 54 54  153  110  100  SaO2 (%)  105 100 95 90  80  92  25  18.5  20  18.0  15 10 5  17.5 17.0 16.5 16.0  42  7.45  13.0  7.40  41  7.35 40  7.30  42 40  12.5 38 12.0 36  39  7.25  11.5  38  7.20  11.0  34  6.5  24  40.0  K+ (mmol/L)  39.5 39.0 38.5 38.0 37.5  22  6.0  20 5.5  18  5.0  16 14  4.5  37.0  12  4.0  36.5 Rest  4  6  8  9  1%  Hct (%)  13.5  10 Rest  4  6  8  9  1%  -  7.50  HCO3 (mmol/L)  43  pH Hb (g/dL)  PaCO2 (mmHg)  96 94  0  Temp (C)  98  85  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 87- KS, arterial blood gas.  154  0  100 90 80 70 60 50 40 30 20 10 0  40  350  4.0  300  3.5  Peso (cmH2O)  300 200 100  Cdyn (mL/cmH2O)  30 20 10  3.0  250  2.5 200  2.0  150  1.5  0  100  1.0  100  400  0.25 0.20  VD (mL)  % FVC  80 60 40 20  300 0.15 200  0.10 0.05  100  0.00 30  180 160 140 120 100 80 60 40 20 0  VE/VO2 and VE/VCO2  (L/min)  0  Rest  4  6  8  9  1%  28 26 24 22 20 18 16 Rest  4  6  8  9  1%  VD/VT  El and Res WOB (cmH 2O/brth)  WOB (J/min)  400  VT (L)  Figure 88- KS, respiratory mechanics.  155 Figure 89-MB, MEFV curve and descriptors. Subject MB- Triathalon training. 8-16hrs/wk (daily). Competes internationally (Ironman) Dysanapsis Age Height Weight BMI FVC FVC DLCO MIP yr  cm  kg/m2  kg  L  %  42 169.5 52 18.1 3.99 112 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.21  62  3.3  87  12  1.13  VO2max  10 8  mL/min/mmHg  cmH2O  25.57  -113  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.2  46  0  31  Stage 5.5 mph 6.5 mph 7.5 mph 8.5 mph  EFL (%) 0 0 0 0  ˙E/V V ˙ECap (%) 24 36 45 52  Flow (L/sec)  6 4 2 0 -2 -4 -6 12  Constant at 7 mph, He  Stage Air Heliox Air  10 8  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 36 30 43  Flow (L/sec)  6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  156  130  100  120  98  SaO2 (%)  110 100 90 80  94 92 90  60  88  50  19.0  40  18.5  30 20 10  18.0 17.5 17.0 16.5  40  13.8  43  13.6  42  34  pH  7.3  36  Hb (g/dL)  7.4 38  13.4  41  13.2 40  13.0  7.2 32 7.1  30  12.8  39  12.6  38  39.0  K+ (mmol/L)  Temp (C)  38.5 38.0 37.5 37.0  7 mph  36.5 Rest (a) 5.5  6.5  7.5  8.5 Rest (b) Rest Air 1 He Air 2  7 mph  0 Rest (a) 5.5  6.5  7.5  8.5 Rest (b) Rest Air 1 He Air 2  26 24 22 20 18 16 14 12 10 8  Hct (%)  16.0 7.5  HCO3 (mmol/L)  0 42  PaCO2 (mmHg)  96  70  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 90- MB, arterial blood gases.  157  50  250  40  200 150 100  20  50  10  0  0  40  0  240 220 200 180 160 140 120 100 80  100  400  30 20 10  2.5 2.0 1.5 1.0 0.5 0.0 0.20 0.18  VD (mL)  300  60 40  0.16 0.14  200  0.12 0.10  100  20 0  0.08 0.06  0  (L/min)  150 100 50  7 mph  0 Rest (a) 5.5  6.5  7.5  8.5 Rest (b) Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  40 200  35 30 25 20  7 mph  15 Rest (a) 5.5  6.5  7.5  8.5 Rest (b) Rest Air 1 He Air 2  VD/VT  80  % FVC  30  VT (L)  Peso (cmH2O)  300  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  Figure 91- MB, respiratory mechanics.  158 Figure 92- MF, MEFV curve and descriptors. Subject MF- Run (Varsity). 2hr/2x/wk. Multivitamen, Iron Supplements Age Height Weight BMI FVC FVC DLCO yr  cm  kg/m2  kg  L  %  19 179 71.3 22.3 4.46 98 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.54  50  3.91  89  14  1.11  VO2max  10 8  Flow (L/sec)  26.64  MIP cmH2O  0.18  -74  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.4  44  0  36  EFL (%) 0 0 0 0 0  ˙E/V V ˙ECap (%) 18 25 30 32 36  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 26 24 28  Stage 5.5 mph 6.5 mph 7.5 mph 8.5 mph 8.5 mph 1%  12  Dysanapsis  mL/min/mmHg  6 4 2 0 -2 -4 -6 14  Constant at 8 mph, He  Stage Air Heliox Air  12 10  Flow (L/sec)  8 6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  159  100 110  SaO2 (%)  99  100 90 80  96 95 93  35  20.0  30  19.5  25 20 15 10 Sample taken as subject stopped  5  19.0 18.5 18.0 17.5 17.0  44  14.0  44  7.4  42  43  38 36  7.2  42 13.0  41 40  Hct (%)  7.3  Hb (g/dL)  13.5 40  pH  12.5  34  39  39.5  K+ (mmol/L)  39.0 38.5 38.0 37.5 37.0  8 mph  36.5 Rest 5.5  6.5  7.5  8.5  1% Stop Rest Air 1 He Air 2  12.0  38  100 90 80 70 60 50 40 30 20 10 0  24 22 20 18  -  7.1  32  HCO3 (mmol/L)  PaCO2 (mmHg)  97  70  0  Temp (C)  98  94  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 93- MF, arterial blood gases.  16 14  8 mph Rest 5.5  6.5  7.5  8.5  1% Stop  Rest Air 1 He Air 2  12  160 Figure 94- MF, respiratory mechanics.  150 100  40 30 20 10  0  0  Cdyn (mL/cmH2O)  50  30 20 10  2.5  120  2.0 100 1.5 80  1.0  60  0.5  350  0.25  80  300  VD (mL)  0 100  60 40  0.15 200 150  0  100  300  35  250 200 150 100 50  8 mph  0 Rest 5.5  6.5  7.5  8.5  1%  2%  Rest Air 1 He Air 2  0.20  250  20  VT (L)  Peso (cmH2O)  200  VE/VO2 and VE/VCO2  % FVC  El and Res WOB (cmH 2O/brth)  WOB (J/min)  250  (L/min)  50  Sample taken as subject stopped  0.10 0.05  30 25 20  8 mph  15 Rest 5.5  6.5  7.5  8.5  1%  2%  Rest Air 1 He Air 2  VD/VT  300  161 Figure 95- MG, MEFV curve and descriptors. Subject MG- Run (Rec) ~30min. 2-3x/wk Age Height Weight BMI FVC yr  cm  kg/m2  kg  DLCO  %  mL/min/mmHg  28 161 48 18.5 3.67 105 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  1.87  39  1.90  58  10  Dysanapsis  FVC  L  1.02  VO2max  20.61  0.27  -86  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.68  41  0  36  Stage 4 mph 5 mph 6 mph  8  MIP cmH2O  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 11 23 33  Flow (L/sec)  6  4  2  0  -2  -4  -6 -3  -2  Volume (L)  -1  0  162  120 110  SaO2 (%)  PaO2 & PAO2(mmHg)  Figure 96- MG, arterial blood gases.  100 90 80 70 60  98.5 98.0 97.5 97.0 96.5 96.0 95.5 95.0 94.5  CaO2 (mL/dL)  20 10  16.5 16.0  7.38  34  7.36  33 7.34  32 31  7.32  30  7.30  K+ (mmol/L)  37.4 37.3  40  12.5  39  12.0  38  11.5  37  11.0  36  6.0  22  5.5  20  5.0 18 4.5 16  4.0  37.2  3.5  37.1 Rest  4  5  6  Hct (%)  35  13.0  -  7.40  37.5  Temp (C)  17.0  15.5  36  pH Hb (g/dL)  PaCO2 (mmHg)  0  17.5  HCO3 (mmol/L)  A-aDO2 (mmHg)  18.0 30  14 Rest  4  5  6  163 Figure 97- MG, respiratory mechanics. 40  120  Peso (cmH2O)  WOB (J/min)  140 100 80 60 40  30 20 10 0  20  200  2.0  180  1.8  160  1.6  140  1.4  120  1.2  10 5  60  100  0  260 240 220 200 180 160 140 120 100  250  45  VD (mL)  % FVC  60 40  VE/VO2 and VE/VCO2  20  (L/min)  200 150 100 50  0.8  80  0  80  1.0  100  0.6 0.24 0.22 0.20 0.18 0.16 0.14 0.12 0.10  40 35 30 25 20  0 Rest  4  5  6  Rest  4  5  6  VD/VT  15  VT (L)  0  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  20  164 Figure 98- MM, MEFV curve and descriptors. Subject MM- Road/Mt Bike, Yoga. 1-6hr/daily (10-12hrs/wk) Age Height Weight BMI FVC FVC DLCO yr  cm  kg/m2  kg  L  %  31 173 72 24.1 4.74 120 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  3.23 16  mL/kg/min  L/min  L/min  45  3.52  73  Dysanapsis  mL/min/mmHg  32.11  1.09  VO2max  14 12 10  MIP cmH2O  0.22  -95  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.4  61  0  63  Stage 4.5 mph 5.5 mph 6.5 mph 7.5 mph 8.5 mph  EFL (%) 0 0 0 0 0  ˙E/V V ˙ECap (%) 20 21 29 31 32  Stage Air Heliox  EFL (%) 0 0  ˙E/V V ˙ECap (%) 31 24  Flow (L/sec)  8 6 4 2 0 -2 -4 -6  Constant at 7 mph, He 15  Flow (L/sec)  10  5  0  -5 -5  -4  -3  -2  Volume (L)  -1  0  165  98  SaO2 (%)  110 100 90  94 30  18.0  25  17.5  20 15 10 5  17.0 16.5 16.0 15.5 13.0  40  7.38 7.34 7.32  40  7.30 38  38 12.0 37 11.5  7.28 7.26  36  39  12.5  pH Hb (g/dL)  7.36  42  38.4  36  11.0  35  5.5  24 23  38.0 37.8 37.6 37.4  5.0 22 4.5  21  -  K+ (mmol/L)  38.2  20 4.0 19  37.2  7 mph  37.0 Rest  4.5  5.5  6.5  7.5  8.5  Rest Air 1  He  Hct (%)  44  HCO3 (mmol/L)  7.40  PaCO2 (mmHg)  96 95  0  Temp (C)  97  80  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 &PAO2(mmHg)  Figure 99- MM, arterial blood gases.  7 mph  3.5 Rest  4.5  5.5  6.5  7.5  8.5  Rest Air 1  He  18  166 Figure 100- MM, respiratory mechanics. 250  100 50  20 10  0  0  20  200  2.0  180  1.8  160  1.6  140  1.4  120  1.2  15 10 5 0  1.0  100  0.8  80  0.6  60  100  0.30 400  60 40  0.25 0.20  300  0.15 200  20  0.10 100  320  34  (L/min)  200 150 100 50  7 mph  0 Rest  4.5  5.5  6.5  7.5  8.5  Rest Air 1  He  VE/VO2 and VE/VCO2  0  0.05  32 30 28 26 24 22  7 mph  20 Rest  4.5  5.5  6.5  7.5  8.5  Rest Air 1  He  VD/VT  VD (mL)  80  % FVC  30  VT (L)  Peso (cmH2O)  150  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  40 200  167 Figure 101- NN, MEFV curve and descriptors. Subject NN- Big Run/Bike (Rec). 45mi/3-4x/wk. Age Height Weight BMI FVC FVC yr  cm  kg/m2  kg  L  %  32 165 65 23.9 3.54 99 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  2.93  45  3.38  75  10  1.15  VO2max  6  MIP cmH2O  37.33  -76  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.6  56  0  45  Stage 4.5 mph 5.5 mph 6.5 mph 7.5 mph  8  Flow (L/sec)  Dysanapsis  DLCO mL/min/mmHg  EFL (%) 0 0 0 0  ˙E/V V ˙ECap (%) 20 26 32 38  4  2  0  -2  -4  -6 10  Stage Air Heliox Air  Constant at 6.5 mph, He  8  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 33 32 44  Flow (L/sec)  6  4  2  0  -2  -4  -6 -3  -2  Volume (L)  -1  0  168  110  100 98  SaO2 (%)  100 90 80 70  92 90 86  40  20.0  30 20 10  19.5 19.0 18.5 18.0 17.5 17.0 15.0  45  7.4  K+ (mmol/L)  37.5 37.0  6.5 mph  36.5 Rest  4.5  5.5  6.5  7.5a 7.5b  Rest Air 1 He Air 2  41  13.0  39.0  38.0  42 13.5  7.1  38.5  43 14.0  40  100 90 80 70 60 50 40 30 20 10 0  24 22 20 18 16  6.5 mph Rest  4.5  5.5  6.5  7.5a 7.5b  Rest Air 1 He Air 2  14  -  7.2  Hb (g/dL)  7.3  Hct (%)  44  14.5  HCO3 (mmol/L)  48 46 44 42 40 38 36 34 32  pH  PaCO2 (mmHg)  94  60  0  Temp (C)  96  88  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 102- NN, arterial blood gases.  169 Figure 103- NN, respiratory mechanics. 40  100 50  10  0  0  30  160  0  40  2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4  100  400  0.20  300  0.15  200  0.10  100  0.05  0  0.00  25 20 15 10 5  VD (mL)  80  % FVC  20  60 40 20 0  140 120 100 80 60  (L/min)  150 100 50  6.5 mph  0 Rest  4.5  5.5  6.5  7.5a 7.5b  Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  35 200  30 25 20  6.5 mph  15 Rest  4.5  5.5  6.5  7.5a 7.5b  Rest Air 1 He Air 2  VT (L)  150  30  VD/VT  Peso (cmH2O)  200  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  250  170 Figure 104- NW, MEFV curve and descriptors. Subject NW- Biking/Cyling/Climbing. 1hr/3-5x week Age Height Weight BMI FVC FVC yr  cm  kg/m2  kg  L  %  31 168 60 21.3 4.41 118 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.43  57  3.59  99  16  1.05  VO2max  26.52  12 10 8 6  MIP cmH2O  0.19  -118  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.1  55  0  48  Stage 4 mph 5 mph 6 mph 7 mph 8 mph 8 mph 2% 8 mph 4% 8 mph 5%  14  Flow (L/sec)  Dysanapsis  DLCO mL/min/mmHg  EFL (%) 0 0 0 0 0 0 0 0  ˙E/V V ˙ECap (%) 19 25 30 36 45 48 50 48  4 2 0 -2 -4 -6 16  Constant at 8mph 2%, He  14 12  Stage Air Heliox  EFL (%) 0 0  ˙E/V V ˙ECap (%) 48 38  10  Flow (L/sec)  8 6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  171  100  SaO2 (%)  110 100 90  98 96  80  94  70  92  40  19.0  30  18.5  CaO2 (mL/dL)  A-aDO2 (mmHg)  PaO2 & PAO2 (mmHg)  Figure 105- NW, arterial blood gases.  20 10  18.0 17.5 17.0  0 14.2 14.0 13.8 13.6 13.4 13.2 13.0 12.8 12.6  43  40.0  6.0  24  39.5  5.5  36 7.25 34  K+ (mmol/L)  Temp (C)  7.20  39.0 38.5 38.0  41 40 39 38  22 20  5.0  18  4.5  16 14  4.0  37.5  8.5 2%  37.0 Rest 4  5  6  7  8 2% 4% 5% 6% Rest Air 1  He  Hct (%)  7.30  8.5 2%  3.5 Rest 4  5  6  7  8 2% 4% 5% 6%  Rest Air 1  He  12 10  -  38  42  HCO3 (mmol/L)  7.35  pH Hb (g/dL)  PaCO2 (mmHg)  7.40 40  172 Figure 106- NW, respiratory mechanics. 50  Peso (cmH2O)  200 100  30 20 10 0 2.5  0  240 220 200 180 160 140 120 100 80  100  600  0.30  80  500  30 20  VD (mL)  10  60 40  100  200  40  8.5 2% Rest 4  5  6  7  8 2% 4% 5% 6% Rest Air 1  He  0.5  0.25 0.20  0  0  1.0  300 200  50  1.5  400  20  100  2.0  VT (L)  Cdyn (mL/cmH2O)  40  150  (L/min)  40  0.15 0.10  35 30 25 20  8.5 2%  15 Rest 4  5  6  7  8 2% 4% 5% 6%  Rest Air 1  He  VD/VT  0  VE/VO2 and VE/VCO2  % FVC  El and Res WOB (cmH 2O/brth)  WOB (J/min)  300  173 Figure 107- PH, MEFV curve and descriptors. Subject PH- Run/Cyle Recreational. 30-90min/3-5x week Age Height Weight BMI FVC FVC yr  cm  kg/m2  kg  L  %  22 173 71 23.7 4.79 114 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.12  44  3.34  87  12 10 8  Flow (L/sec)  6  MIP cmH2O  -75  1.11  VO2max  Dysanapsis  DLCO mL/min/mmHg  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.71  59  42  42  Stage 4.5 mph 6 mph 7.5 mph 8.5 mph 8.5 mph 2%  EFL (%) 0 0 33 34 42  ˙E/V V ˙ECap (%) 35 47 60 63 70  Stage Air Heliox Air  EFL (%) 35 0 63  ˙E/V V ˙ECap (%) 68 50 72  4 2 0 -2 -4 -6 12  Constant at 7.5 mph 2%, He  10 8  Flow (L/sec)  6 4 2 0 -2 -4 -6 -5  -4  -3  -2  Volume (L)  -1  0  174  115  100  110  98  105  SaO2 (%)  PaO2 & PAO2 (mmHg)  Figure 108- PH, arterial blood gases.  100 95 90 85  94 92  80 25  20  20  CaO2 (mL/dL)  A-aDO2 (mmHg)  96  15 10 5 0  19 18 17 16  42  7.45  40  7.40  38  7.35  36  7.30  34  7.25  32  7.20  15  38.5  6.0  37.0  36  24 22  5.5  20  -  5.0  18  4.5  16  4.0  36.5  7.5 mph 2%  36.0 Rest 4.5  6  7.5  8.5  2%  4%  Rest Air 1 He Air 2  Hct (%)  38  6.5  37.5  40  13  39.0  38.0  42  HCO3 (mmol/L)  Hb (g/dL)  pH  14  12  K+ (mmol/L)  Temp (C)  PaCO2 (mmHg)  44  7.5 mph 2%  3.5 Rest 4.5  6  7.5  8.5  2%  4%  Rest Air 1 He Air 2  14  175 Figure 109- PH, respiratory mechanics. 70 60  Peso (cmH2O)  WOB (J/min)  300 200 100  50 40 30 20 0  20 10 0 100  2.0 1.5 1.0 0.5 0.25 0.20  300  VD (mL)  % FVC  2.5  350  80 60 40 20  250  0.15  200 0.10  150 100  0  50  160 140 120 100 80 60 40 20 0  40  7.5 mph 2% Rest 4.5  6  7.5  8.5  2%  4%  Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  (L/min)  260 240 220 200 180 160 140 120 100 80  VT (L)  30  0.05  35 30 25 20  7.5 mph 2%  15 Rest 4.5  6  7.5  8.5  2%  4%  Rest Air 1 He Air 2  VD/VT  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  10 0  176 Figure 110- RB, MEFV curve and descriptors. Subject RB- Rugby. 3hrs/5x/wk Age Height Weight BMI yr  cm  FVC  DLCO  L  %  mL/min/mmHg  19 161 60.2 23.2 4.17 111 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  3.39 12  mL/kg/min  L/min  L/min  56  3.90  98  1.15  VO2max  10 8 6  Flow (L/sec)  Dysanapsis  FVC  kg/m2  kg  26.84  MIP cmH2O  0.19  -105  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.8  65  0  39  Stage 3.5 mph 4.5 mph 5.5 mph 6.5 mph 7.5 mph 8.5 mph 8.5 mph 1%  EFL (%) 0 0 0 0 0 0 0  ˙E/V V ˙ECap (%) 20 25 30 32 39 48 52  4 2 0 -2 -4 -6 12  Stage Air Heliox Air  Constant at 8.5 mph, He  10  EFL (%) 0 0 46  ˙E/V V ˙ECap (%) 46 40 64  8  Flow (L/sec)  6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  177  100 110  98  100  SaO2 (%)  90 80  92  88 22  CaO2 (mL/dL)  30 20 10  20 19 18  40  16.0  50  7.40  15.5  48  7.35  38  pH Hb (g/dL)  42  7.45  15.0  46  36  7.30  34  7.25  32  7.20  13.5  42  30  7.15  13.0  40  14.5 44  14.0  6.0  39.0  24  K+ (mmol/L)  Temp (C)  5.5 38.5 38.0 37.5 37.0  22  5.0  20  4.5  18  4.0  16  3.5  7.5 mph Rest 3.5 4.5 5.5 6.5 7.5 8.5 1% 2% Rest Air 1 He Air 2  Hct (%)  0  21  7.5 mph  3.0 Rest 3.5 4.5 5.5 6.5 7.5 8.5 1% 2%  Rest Air 1 He Air 2  14 12  -  A-aDO2 (mmHg)  94  90  70 40  PaCO2 (mmHg)  96  HCO3 (mmol/L)  PaO2 & PAO2 (mmHg)  Figure 111- RB, arterial blood gases.  178 Figure 112- RB, respiratory mechanics. 60  Peso (cmH2O)  300 200 100  40 30 20  0  50  2.0  0  200 180 160 140 120 100 80 60 40  100  350  0.20  80  300  40 30 20 10  1.6 1.4 1.2 1.0 0.8 0.6  40  250 200  0.10  150 0.05  20  100  0  50  150 100 50  7.5 mph Rest 3.5 4.5 5.5 6.5 7.5 8.5 1% 2% Rest Air 1 He Air 2  0.00  34 32 30 28 26 24 22 20 18  7.5 mph Rest 3.5 4.5 5.5 6.5 7.5 8.5 1% 2%  Rest Air 1 He Air 2  VD/VT  VD (mL)  0.15  60  0  1.8  VT (L)  Cdyn (mL/cmH2O)  0  200  (L/min)  50  10  VE/VO2 and VE/VCO2  % FVC  El and Res WOB (cmH 2O/brth)  WOB (J/min)  400  179 Figure 113- SD, MEFV curve and descriptors. Subject SD- Competitive Rope Skipping, Run/Cycle (Rec). 1-2hr/4-6x wk Dysanapsis Age Height Weight BMI FVC FVC DLCO yr  cm  kg/m2  kg  L  %  26 163 62 23.3 3.46 95 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  2.90  47  3.20  86  14  1.1  VO2max  10 8  Flow (L/sec)  29.09  6  cmH2O  0.16  -134  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.6  62  17  39  Stage 4.5 mph 5.5 mph 6.5 mph 7.5 mph 8.5 mph 8.5 mph 2%  12  MIP  mL/min/mmHg  EFL (%) 0 0 0 0 39 17  ˙E/V V ˙ECap (%) 34 33 45 52 53 40  4 2 0 -2 -4 -6 14  Stage Air Heliox Air Hyperoxic  Constant at 8 mph, He, 26% O2  12 10  EFL (%) 0 0 0 0  ˙E/V V ˙ECap (%) 39 39 53 49  Flow (L/sec)  8 6 4 2 0 -2 -4 -6 -3  -2  Volume (L)  -1  0  180  100  140  99  130  SaO2 (%)  120 110 100 90  CaO2 (mL/dL)  30 20 10  19 18 17  42  7.35  41  7.30  40 7.25  39 38  7.20  37  7.15  14.0  44  13.5  42  13.0  40  12.5  38  12.0  36  Hct (%)  7.40  pH Hb (g/dL)  16  43  6.0  K+ (mmol/L)  22 5.5  20  5.0  18  4.5  -  A-aDO2 (mmHg)  20  0  PaCO2 (mmHg)  96  94  40  Temp (C)  97  95  80  38.2 38.0 37.8 37.6 37.4 37.2 37.0 36.8 36.6  98  16  4.0  8 mph Rest 4.5 5.5 6.5 7.5 8.5 2%a 2%b RestAir 1 He Air 2 O2  3.5  HCO3 (mmol/L)  PaO2 & PAO2 (mmHg)  Figure 114- SD, arterial blood gases.  14  8 mph Rest 4.5 5.5 6.5 7.5 8.5 2%a 2%b RestAir 1 He Air 2 O2  12  181 Figure 115- SD, respiratory mechanics. 60  400  Peso (cmH2O)  200 100  40 30 20  0  40  160  2.0  140  1.8  120  1.6  100  1.4  80  1.2  30 20 10  0.8  40  0  20  100  400  80  350  60  300  40  1.0  60  0.6 0.30 0.25 0.20  250 200  20  0.15  150 0  0.10  (L/min)  150 100 50 0  8 mph Rest 4.5 5.5 6.5 7.5 8.5 2%a 2%b Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  200  34 32 30 28 26 24 22  8 mph  20 Rest 4.5 5.5 6.5 7.5 8.5 2%a 2%b  Rest Air 1 He Air 2  VD/VT  Cdyn (mL/cmH2O)  0  VT (L)  10  VD (mL)  % FVC  El and Res WOB (cmH 2O/brth)  WOB (J/min)  50 300  182 Figure 116- SL, MEFV curve and descriptors. Subject SL- Cardio/Weights. 1hr/2-3x/wk Age Height Weight BMI FVC yr  cm  kg/m2  kg  DLCO  %  mL/min/mmHg  27 166 74.1 26.9 3.78 101 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  2.96 12  mL/kg/min  L/min  L/min  40  3.2  78  Dysanapsis  FVC  L  1.15  VO2max  25.52  8  0.11  -109  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.1  44  31  36  Stage 4.5 mph 5.5 mph 6.5 mph  10  MIP cmH2O  EFL (%) 0 0 31  ˙E/V V ˙ECap (%) 28 47 56  Flow (L/sec)  6 4 2 0 -2 -4 -6 14  Constant at 5.5 mph, He  Stage Air Heliox Air  12 10  EFL (%) 0 0 53  ˙E/V V ˙ECap (%) 43 37 61  Flow (L/sec)  8 6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  183  120 115 110 105 100 95 90 85 80  100 99  SaO2 (%)  PaO2 & PAO2 (mmHg)  Figure 117- SL, arterial blood gases.  98 97 96 95 94 21  20  CaO2 (mL/dL)  15 10 5 0  18  16  7.35  15  7.30 34  44 14  42  7.25  32  40  13 7.20  30  38 5.5  38.0 37.5  22  5.0  20  4.5 18 4.0  -  K+ (mmol/L)  39.0 38.5  16  3.5  5.5 mph  37.0 Rest  4.5  5.5  6.5  Rest Air 1 He Air 2  Hct (%)  36  48 46  Hb (g/dL)  38  7.40  pH  PaCO2 (mmHg)  19  17  40  Temp (C)  20  HCO3 (mmol/L)  A-aDO2 (mmHg)  25  5.5 mph  3.0 Rest  4.5  5.5  6.5  Rest Air 1 He Air 2  14  184 Figure 118- SL, respiratory mechanics.  Peso (cmH2O)  40  150 100 50  30 20 10 0  40 30 20 10  350  3.0  300  2.5  250  2.0  200 1.5  150 100  1.0  0  50  0.5  100  400  0.20 0.18  60 40 20  0.16  300  0.14 0.12  200  0.10 0.08  100  0.06  0  150 100 50  5.5 mph  0 Rest  4.5  5.5  6.5  Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  40 200  35 30 25 20  5.5 mph  15 Rest  4.5  5.5  6.5  Rest Air 1 He Air 2  VD/VT  VD (mL)  % FVC  80  (L/min)  VT (L)  0  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  200  185 Figure 119- SS- MEFV curve and descriptors. Subject SS- Running. 30-60min 5x/wk Age Height Weight BMI FVC yr  cm  kg/m2  kg  DLCO  %  mL/min/mmHg  32 169 56 19.6 3.84 102 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  2.93 12  mL/kg/min  L/min  L/min  52  3.12  89  1.1  VO2max  26.03  8 6  MIP cmH2O  0.28  -93  VT  Fb  EFL  EELV  L  bpm  %  % FVC  1.73  59 Stage 4 mph 5 mph 6 mph 7 mph 8 mph 9 mph 9 mph 1% 9 mph 2%  10  Flow (L/sec)  Dysanapsis  FVC  L  0  29  EFL (%) 0 0 0 0 0 0 0 0  ˙E/V V ˙ECap (%) 15 21 18 23 33 43 41 54  4 2 0 -2 -4 -6 12  Constant at 8.5n mph, He  Stage Air Heliox Air  10 8  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 30 24 39  Flow (L/sec)  6 4 2 0 -2 -4 -6 -3  -2  Volume (L)  -1  0  186  100 110  99  SaO2 (%)  PaO2 & PAO2 (mmHg)  Figure 120- SS, arterial blood gases.  100 90  98 97 96 95  80  94  CaO2 (mL/dL)  20 10  18.0 17.5 17.0  40  14.0  7.50 7.45  38  7.40 36  7.35 7.30  34  43 42  13.5  pH Hb (g/dL)  41 13.0 40 12.5  39  7.25 7.20  32  12.0  38  6.0  40  30  39  K+ (mmol/L)  Temp (C)  5.5  38 37  5.0  25  4.5 20  4.0 3.5  8.5 mph  36 Rest 4  5  6  7  8  9 1% 2% 3% Rest Air 1 He Air 2  8.5 mph  3.0 Rest 4  5  6  7  8  9 1% 2% 3% Rest Air 1 He Air 2  15  -  PaCO2 (mmHg)  18.5  Hct (%)  0  19.0  HCO3 (mmol/L)  A-aDO2 (mmHg)  19.5 30  187 Figure 121- SS, respiratory mechanics. 40  100 50  20 10  0  0  20  200  2.0  180  1.8  160  1.6  140  1.4  120  1.2  100  1.0  80  0.8  60  0.6  400  0.25  15 10 5 0 100 80  0.20  300  VD (mL)  % FVC  30  60 40  0.15 200 0.10 100  20 0  0.05  0  0.00  (L/min)  150 100 50  8.5 mph  0 Rest 4  5  6  7  8  9 1% 2% 3% Rest Air 1 He Air 2  VE/VO2 and VE/VCO2  300 200  VT (L)  150  40 35 30 25 20  8.5 mph  15 Rest 4  5  6  7  8  9 1% 2% 3% Rest Air 1 He Air 2  VD/VT  Peso (cmH2O)  200  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  250  188 Figure 122- SW (Jun), MEFV curve and descriptors. Subject SW (JUN)- Run/Swim/Bike/Weights. 1.5hrs 6x/wk. DAY 1 Age Height Weight BMI FVC FVC DLCO yr  cm  kg/m2  kg  L  %  26 174 57.8 19.1 4.63 112 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  3.43  mL/kg/min  L/min  L/min  59  3.72  112  1.08  VO2max  29.24  MIP cmH2O  0.25  -90  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.5  53  0  32  Stage 5.5 mph 6.5 mph 7.5 mph 8.5 mph 9.5 mph 9.5 mph 2% 9.5 mph 4% 9.5 mph 5%  10  Flow (L/sec)  Dysanapsis  mL/min/mmHg  EFL (%) 0 0 0 0 0 0 0 0  ˙E/V V ˙ECap (%) 20 24 28 37 40 45 50 57  5  0  -5  14  Stage Air Heliox Air  Constant at 10mph, He  12 10  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 47 33 52  Flow (L/sec)  8 6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  189  100 110 100 90 80  92 18.5  30  CaO2 (mL/dL)  25 20 15 10 5  17.5 17.0 16.5 16.0  7.50  14.0  41  38  7.45  13.5  40  7.40  36  7.35 34  7.30  pH Hb (g/dL)  40  13.0  38  12.0  32  7.25  11.5  37  30  7.20  11.0  36 26  6  K+ (mmol/L)  39.5 39.0 38.5 38.0  24 22  5  20 18  4  16  37.5  14 3  37.0 Rest5.5 6.5 7.5 8.5 9.5 2% 4%5%a5%b Rest Air 1 He Air 2  12 Rest5.5 6.5 7.5 8.5 9.5 2% 4%5%a5%b Rest Air 1 He Air 2  -  40.0  Temp (C)  39  12.5  Hct (%)  0  18.0  HCO3 (mmol/L)  A-aDO2 (mmHg)  96 94  35  PaCO2 (mmHg)  98  SaO2 (%)  PaO2 & PAO2 (mmHg)  Figure 123- SW (Jun), arterial blood gases.  190 Figure 124- SW (Jun), respiratory mechanics. 50  Peso (cmH2O)  300 200 100 0  30 20 10  3.0  30 20 10  2.5 250 2.0 200 1.5  150  1.0  100  0.5  50  100  600  80  500  0.22  400  0.20  300  0.18  VD (mL)  0  60 40  0.24  0.16  200  0.14  20  100  0.12  0  0  0.10  250  40  150 100 50  35 30 25 20  0 Rest5.5 6.5 7.5 8.5 9.5 2% 4%5%a5%b Rest Air 1 He Air 2  VT (L)  40  300  Rest5.5 6.5 7.5 8.5 9.5 2% 4%5%a5%b Rest Air 1 He Air 2  VD/VT  Cdyn (mL/cmH2O)  50  200  (L/min)  40  0  VE/VO2 and VE/VCO2  % FVC  El and Res WOB (cmH 2O/brth)  WOB (J/min)  400  191 Figure 125- SW (Nov), MEFV curve and descriptors. Subject SW NOV- Run (Varsity, 5000m),Swim,Bike,Weight. 1.5hrs 6-7x/wk. DAY 2 Dysanapsis Age Height Weight BMI FVC FVC DLCO yr  cm  kg/m2  kg  L  %  26 174 56.8 18.8 4.57 110 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  mL/kg/min  L/min  L/min  3.82  67  4.16  114  12  1.09  mL/min/mmHg  27.69  0.25  -72  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.58  51  VO2max  0  Stage 6 mph 7 mph 8 mph 9 mph 9 mph 1% 9 mph 2% 9 mph 3% 9 mph 4% 9 mph 5%  10 8 6  Flow (L/sec)  MIP cmH2O  31  EFL (%) 0 0 0 0 0 0 0 0 0  ˙E/V V ˙ECap (%) 24 28 30 38 35 44 49 50 55  4 2 0 -2 -4 -6 16  Stage Air Heliox Air  Constant at 10mph, He  14 12  EFL (%) 0 0 0  10  Flow (L/sec)  8 6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  ˙E/V V ˙ECap (%) 40 35 49  192  120  100  110  98  SaO2 (%)  PaO2 & PAO2 (mmHg)  Figure 126- SW (Nov), arterial blood gases.  100 90  96 94  80 92  CaO2 (mL/dL)  30 20 10  18.0 17.5 17.0  7.4  34  7.3  32  7.2  30  7.1  44  13.5  42  13.0 40 12.5 38  12.0 11.5  36  6.0  40.0  K+ (mmol/L)  39.5 39.0 38.5 38.0 37.5  24  5.5  22  5.0  20  4.5  18 16  4.0  14  3.5  9 mph 3%  37.0 Rest 6  7  8  9 1% 2%3% 4% 5% 6% Rest A1 He1He2 A2  Hct (%)  36  14.0  9 mph 3%  3.0 Rest 6  7  8  9 1% 2%3% 4% 5% 6% Rest A1 He1He2 A2  12 10  -  7.5  pH  38  Hb (g/dL)  PaCO2 (mmHg)  18.5  16.5  0  Temp (C)  19.0  HCO3 (mmol/L)  A-aDO2 (mmHg)  40  193 Figure 127- SW (Nov), respiratory mechanics.  25  200  Peso (cmH2O)  200 150 100 50  20 15 10 5 0 100  3.0  180  2.5  160 140  2.0  120  1.5  100 80  1.0  60  0.5  400  0.25 0.20  60 40 20  300 0.15 200  0.10 0.05  100  0  0.00  VE/VO2 and VE/VCO2  45 200 150 100 50  40 35 30 25 20 15  0 Rest 6  7  8  9 1% 2%3% 4% 5% 6%Rest A1 He1He2 A2  Rest 6  7  8  9 1% 2%3% 4% 5% 6% Rest A1 He1He2 A2  VD/VT  VD (mL)  % FVC  80  (L/min)  VT (L)  0  100 90 80 70 60 50 40 30 20 10 0  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  WOB (J/min)  250  194 Figure 128- VW, MEFV curve and descriptors. Subject VW- Yoga, Softball. 2hrs 3x/wk. Age Height Weight BMI FVC yr  cm  kg/m2  kg  DLCO  %  mL/min/mmHg  29 168 69.1 24.5 3.94 104 Peak exercise, 10 mph, 5% grade V ˙O2 V ˙O2 V ˙CO2 V ˙E RER L/min  2.47 12  mL/kg/min  L/min  L/min  35.7  3.00  75  Dysanapsis  FVC  L  1.23  VO2max  10 8  MIP cmH2O  0.18  -112  VT  Fb  EFL  EELV  L  bpm  %  % FVC  2.0  44  0  31  Stage 4 mph 5 mph 6 mph 7 mph  EFL (%) 0 0 0 29  ˙E/V V ˙ECap (%) 23 33 47 57  Stage Air Heliox Air  EFL (%) 0 0 0  ˙E/V V ˙ECap (%) 35 33 48  Flow (L/sec)  6 4 2 0 -2 -4 -6 12  Constant at 5.5 mph, He  10 8  Flow (L/sec)  6 4 2 0 -2 -4 -6 -4  -3  -2  Volume (L)  -1  0  195  120  100 99  110  SaO2 (%)  100 90  96  94 20  20  CaO2 (mL/dL)  15 10 5 0  19 18 17 16  7.40  14.5 44  7.38 7.34 7.32 7.30  pH Hb (g/dL)  7.36  14.0  7.28  42 13.5 40 13.0 38 12.5 36  7.26  12.0 6.0  39.0  22  K+ (mmol/L)  5.5  Temp (C)  Hct (%)  50 48 46 44 42 40 38 36 34 32  38.5 38.0 37.5  5.0  20  4.5  18  4.0 16  3.5  5.5 mph  37.0 Rest  4  5  6  7a  7b  Rest Air 1 He Air 2  5.5 mph  3.0 Rest  4  5  6  7a  7b  Rest Air 1 He Air 2  14  -  A-aDO2 (mmHg)  97  95  80 25  PaCO2 (mmHg)  98  HCO3 (mmol/L)  PaO2 & PAO2 (mmHg)  Figure 129- VW, arterial blood gases  196 Figure 130- VW, respiratory mechanics 60 50  Peso (cmH2O)  200 150 100  30 20 10  0  0  40  250  2.5  200  2.0  150  1.5  100  1.0  Cdyn (mL/cmH2O)  El and Res WOB (cmH 2O/brth)  50  40  30 20 10 0  VT (L)  WOB (J/min)  250  0.5  50  100  0.25 500  VD (mL)  60 40  0.15  300 200  0.10  20  100  0.05  0  0  0.00  180 160 140 120 100 80 60 40 20 0 Rest  4  5  6  7a  7b  Rest Air 1 He Air 2  35 30 25 20 Rest  4  5  6  7a  7b  Rest Air 1 He Air 2  VD/VT  0.20  400  VE/VO2 and VE/VCO2  (L/min)  % FVC  80  197  Appendix B: Questionnaire  Mechanical constraints in exercise induced arterial hypoxemia in young healthy women Subject Identifier: Medical History 1. Are you currently taking any medications (excluding oral contraceptives)? Please List: ____________________________________________________ 2. Do you currently smoke? YES/NO 3. Are you a past smoker? YES/NO 4. When was the last time you had a cold? ___________________ 5. Do you have asthma, other lung problems or significant illness? Please List: _____________________________________________________________________  6. Have you had recent nasopharyngeal surgery? YES/NO 7. Do you have an ulcer or tumour in your oesophagus? YES/NO 8. Are you sensitive to local anaesthetics or if you have allergies to latex? YES/NO 9. Do you have a history of bruising easily or having blood clotting problems? YES/NO 10. Are you currently taking any anti-inflammatory medication? YES/NO Physical Activity History Type of Physical Activity: _______________________________________________ Average Duration: _____________________________________________________ Average Frequency: ___________________________________________________  

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