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An investigation of extravascular lung water during exercise in those individuals susceptible to immersion.. Carter, Eric Alexander 2011

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© Eric Alexander Carter, 2011 AN INVESTIGATION OF EXTRAVASCULAR LUNG WATER DURING EXERCISE IN THOSE INDIVIDUALS SUSCEPTIBLE TO IMMERSION PULMONARY EDEMA OR HIGH ALTITUDE PULMONARY EDEMA by   Eric Alexander Carter  B.S., The University of Vermont, 2009  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) August, 2011 ii  ABSTRACT Introduction: High altitude pulmonary edema (HAPE) is caused by hypoxic vasoconstriction, leading to increased pulmonary artery pressure (PPA). Increased PPA results in extravasation of fluid from the pulmonary capillaries to the interstitial space and inhibition of gas exchange. Immersion pulmonary edema (IPE) is likely the result of increased hydrostatic pressure due to water immersion combined with cold and physical exertion, further elevating PPA. During maximal exercise, some humans develop pulmonary edema independent of hypoxia or immersion; this is a possible cause of exercise-induced arterial hypoxemia (EIAH). Purpose: The purpose of this study was to 1) investigate the common mechanisms that are responsible for the development of HAPE, IPE, and EIAH; and 2) investigate the factors that determine an individual’s susceptibility to HAPE/IPE. Hypotheses: We hypothesize that 1) individuals susceptible to HAPE/IPE will develop increased extravascular lung water (EVLW) following exercise; and 2) these changes will not occur in HAPE/IPE-resistant controls. Methods: This study included 9 healthy fit participants who previously experienced HAPE or IPE.  Participants performed a 45-minute maximal exercise task on a cycle ergometer. A matched control group of 9 participants with experience at altitude or immersion and no history of HAPE/IPE also performed the task. Diffusion capacity of CO (DLco) was measured before and after exercise. Computed tomography was used to confirm EVLW following exercise. Results: Both groups showed a significant reduction in lung density post-exercise (p=0.013). Participants susceptible to HAPE/IPE had a significantly lower density compared to resistant participants (p=0.037). DLco decreased significantly after exercise (p<0.001), without difference in the change between groups (p=0.77). Discussion: Because of the post-exercise increase in volume, the decrease in lung density should be considered to represent no change in EVLW. The decrease in DLco was iii  consistent with results found in other studies. Lower lung density in HAPE/IPE-susceptible participants could be the result of damage caused by HAPE/IPE, increased vascular reactivity, or decreased lymphatics. Conclusion: Susceptibility to HAPE/IPE does not increase risk of developing EVLW during maximal exercise. Participants susceptible to HAPE/IPE displayed a significantly lower lung density that necessitates further research. iv  PREFACE Ethical review for all techniques has been carried out by the University of British Columbia Clinical Research Ethics Board for Experiments Involving Human Subjects (UBC CREB). The study CREB approval certificate is #H09-03125. v  TABLE OF CONTENTS  Abstract ........................................................................................................................................... ii Preface............................................................................................................................................ iv Table of Contents .............................................................................................................................v List of Tables ................................................................................................................................ vii List of Figures ................................................................................................................................ ix List of Abbreviations .......................................................................................................................x Acknowledgements ...................................................................................................................... xiii Dedication .................................................................................................................................... xiv 1. Introduction ..................................................................................................................................1 1.1 Background and Justification ............................................................................................ 1 1.2 Hypothesis .................................................................................................................... 3 2. Methods........................................................................................................................................5 2.1 Subjects ............................................................................................................................. 5 2.2 Protocol ............................................................................................................................. 5 2.3 Pulmonary Function and VO2max ...................................................................................... 6 2.4 Maximal Exercise Task..................................................................................................... 7 2.5 Computed Tomography .................................................................................................... 8 2.6 Diffusion Capacity of Carbon Monoxide ......................................................................... 9 2.7 Statistical Analysis .......................................................................................................... 10 3. Results ........................................................................................................................................12 3.1 Descriptive Data.............................................................................................................. 12 3.2 VO2max...................................................................................................................... 12 3.3 Maximal Exercise Task................................................................................................... 13 3.4 Computed Tomography .................................................................................................. 14 3.5 DLco ................................................................................................................................ 19 4. Discussion ..................................................................................................................................30 4.1 Key Findings ................................................................................................................... 30 4.2 Extravascular Lung Water .............................................................................................. 30 4.3 Pulmonary Edema Susceptible Lungs ............................................................................ 34 4.4 CT Lung Reconstruction ................................................................................................. 37 4.5 Limitations ...................................................................................................................... 38 vi  4.6 Future Directions ............................................................................................................ 39 5. Conclusion .................................................................................................................................40 References ......................................................................................................................................41 Appendix A:  Literature Review - Pulmonary Gas Exchange .......................................................50 A1. Physiology ...................................................................................................................... 50 A2. Pulmonary Stressors ....................................................................................................... 53 A3. High Altitude Pulmonary Edema ................................................................................... 59 A4. Immersion Pulmonary Edema ........................................................................................ 62 A5. Exercise induced Arterial Hypoxemia ........................................................................... 66 A6. Methods of Evaluating EVLW ...................................................................................... 70 Appendix B: Individual Data .........................................................................................................80  vii  LIST OF TABLES Table 3.1. Anthropometric and spirometric characteristics of 18 subjects. ...................................12 Table 3.2. Maximal oxygen consumption (VO2max), maximal oxygen consumption per kilogram (VO2max), peak power, maximum heart rate (MHR) and minimum arterial oxygen saturation (SPO2). ..............................................................................................................13 Table 3.3. Maximum heart rate (MHR), minimum arterial oxygen saturation (SPO2) during the third interval, mean interval power (INT Power), mean percent maximal power (INT Intensity). ...................................................................................................................14 Table 3.4. CT Lung data pre- and post- exercise. ..........................................................................15 Table 3.5. Pulmonary diffusion capacity of carbon monoxide breathing 21% oxygen (DL-21%) pre- and post- exercise, diffusion capacity corrected for alveolar volume (DL-21%/VA) pre- and post-exercise, and alveolar volume measured breathing 21% oxygen (VA-21%). ..........................................................................................................................20 Table 3.6. Diffusion capacity of the alveolar membrane (DM) and capillary blood volume (VC) components pre- and post-exercise. Values also presented corrected for alveolar volume (DM/VA and VC/VA). ............................................................................................21 Table 3.7. Mean change in diffusion capacity for carbon monoxide (Δ DL-21%), change in membrane diffusion (Δ DM) and change in capillary volume (Δ VC) calculated for groups of subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. ............................................................................................................................................26 Table A1. Extravascular lung water as measured using different subject populations and exercise types. Maximal oxygen consumption (VO2max), duration of exercise protocol, intensity of exercise protocol, type of measure, gender of participants, pre and post protocol result, and significance of change in EVLW. ...................................................68 Table A2. Changes in pulmonary diffusion capacity as measured in different populations performing different types of exercise. Maximal oxygen consumption (VO2max), duration of exercise protocol, type of exercise, gender of participants, and significant change in pulmonary diffusion capacity (DLco), membrane diffusion (DM), and capillary blood volume (VC). ..................................................................................................78 Table B1. Individual anthropometric and spirometric characteristics of 18 subjects. ...................80 Table B2. Maximal oxygen consumption (VO2max), peak power, maximum heart rate (MHR) and minimum arterial oxygen saturation (SPO2). ..............................................................81 Table B3. Maximum heart rate (MHR), minimum arterial oxygen saturation (SPO2), during third interval, mean interval power (INT Power), mean percent maximal power (INT Intensity). ..............................................................................................................................82 Table B4. Individual CT reconstruction algorithms and slice thicknesses for lung density pre- and post- exercise. ......................................................................................................83 Table B5. Individual CT reconstruction algorithms and slice thicknesses for lung mass pre- and post- exercise. ..................................................................................................................84 viii  Table B6. Individual CT reconstruction algorithms and slice thicknesses for lung volume pre- and post- exercise. .....................................................................................................85 Table B7. Pulmonary diffusion capacity of carbon monoxide breathing 21% oxygen (DL-21%), alveolar volume measured breathing 21% oxygen (VA), diffusion capacity of the alveolar membrane (DM) and capillary blood volume (VC) in each participant, pre and post exercise. .....................................................................................................................88 ix  LIST OF FIGURES Figure 3.2. CT lung mass pre- and post-exercise in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. ‡Significant difference between groups. .............................16 Figure 3.3. CT lung volume pre- and post-exercise in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. *Significantly different from pre-exercise mean (p < 0.05). .......................................................................................................................................17 Figure 3.4. Receiver operating characteristic graph for the ability to predict pulmonary edema susceptibility with CT lung density. Corresponding density is labeled at points on the curve. Upper and lower limits of the 95% confidence interval are indicated in light grey lines................................................................................................................................18 Figure 3.5. Mean lung density for each slice (aortic arch, trachea carina, top of T10) at each time point for resistant (PEr) and susceptible (PEs) subjects. ...............................................19 Figure 3.6. Diffusion capacity of carbon monoxide breathing 21% oxygen (a) and diffusion capacity of carbon monoxide breathing 21% oxygen corrected for alveolar volume (b) pre- and post-exercise in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. ..........................................................................................................................23 Figure 3.7. Membrane diffusion capacity (a) and membrane diffusion capacity (b) pre- and post-exercise corrected for alveolar volume in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. ..............................................................................................24 Figure 3.8. Capillary blood volume (a) and capillary blood volume corrected for alveolar volume (b) pre- and post-exercise in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. ............................................................................................................25 Figure 3.9. Mean change in diffusion capacity for carbon monoxide (Δ DL-21%) (a), change in membrane diffusion (Δ DM) (b), and change in capillary volume (Δ VC) (c) calculated for groups of subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. ............................................................................................................................................28 Figure 3.10. The relationship between the change in diffusion capacity for carbon monoxide (Δ DL-21%) and the mean interval power per kilogram of bodyweight. ......................28 Figure B1. CT lung density pre and post exercise. B35 spatial frequency reconstruction algorithm, 1mm slice thickness. .............................................................................86 Figure B2. CT lung mass pre and post exercise. B35 spatial frequency reconstruction algorithm, 1mm slice thickness......................................................................................................86 Figure B3. CT lung volume pre and post exercise. B35 spatial frequency reconstruction algorithm, 1mm slice thickness. .............................................................................87 Figure B4. Pulmonary diffusion capacity of carbon monoxide breathing 21% oxygen (DL-21%) in each participant, pre and post exercise. ....................................................................89 Figure B5. Pulmonary membrane diffusion capacity of carbon monoxide breathing 21% oxygen (DM) in each participant, pre and post exercise. .......................................................89 Figure B6. Pulmonary capillary blood volume (VC) in each participant, pre and post exercise. .........................................................................................................................................90 x  LIST OF ABBREVIATIONS HAPE High Altitude Pulmonary Edema EVLW Extravascular Lung Water IPE Immersion Pulmonary Edema EIAH Exercise Induced Arterial Hypoxemia A-a DO2 Alveolar-Arterial Oxygen Difference SaO2 Arterial Oxygen Saturation CT Computed Tomography SCUBA Self Contained Underwater Breathing Apparatus EPL Environmental Physiology Laboratory FVC Functional Vital Capacity FEV1.0 Forced Expiratory Volume in One Second VO2max Peak Oxygen Consumption RER Respiratory Exchange Ratio VE Minute Ventilation VCO2 Volume of CO2 SPO2 Pulse Oxygen Saturation VGH Vancouver General Hospital DLco Diffusion Capacity of CO DM Membrane Diffusion Capacity VC Pulmonary Capillary Blood Volume Hb Hemoglobin PEs Susceptible to Pulmonary Edema PEr Resistant to Pulmonary Edema ANOVA Analysis of Variance SPSS Statistical Package for the Social Sciences VA Alveolar Volume BAL Bronchoalveolar Lavage  ARDS Acute Respiratory Distress Syndrome PPA Pulmonary Artery Pressure MRI Magnetic Resonance Imaging ATS American Thoracic Society ERS European Respiratory Society PO2 Partial Pressure of Oxygen PAO2 Partial Pressure of Alveolar Oxygen PaO2 Partial Pressure of Arterial Oxygen Q Cardiac Output PLA Left Atrial Pressure CVP Central Venous Pressure PAWP Pulmonary Artery Wedge Pressure MSW Meters of Sea Water FRC Functional Residual Capacity VDC Voluntary Diaphragmatic Contractions kVp Peak Kilovoltage mA Miliamperes HU Hounsfield Units R Roentgens N0 Initial Number of Photons N Number of Transmitted Photons X Voxel Thickness µ Attenuation Coefficient  xiii  ACKNOWLEDGEMENTS Equipment and financial, logistical, and analytical support provided by: B.C. Sports Medicine Research Foundation Canadian Academy of Sport and Exercise Medicine Canadian Foundation for Innovation UBC Hospital – Department of Radiology UBC Thoracic Imaging Group UBC Air Pollution Exposure Laboratory This project could not have been completed without the generous help of my lab partners, the advice and guidance of my supervisor, and the support of my friends and family. In particular I would like to thank: Dr. MS Koehle Dr. DC McKenzie Dr. J Mayo Dr. H Coxson Dr. J Rupert Martin MacInnis Luisa Giles Sarah Koch Normand Richard Sally Lin Janille Durity-Wingson Xiaolin Ren  Dedication  xiv  DEDICATION   To my parents. 1  1. INTRODUCTION 1.1 Background and Justification Mountaineering, diving, and competitive swimming are all common recreational and commercial activities in North America. With these activities comes the risk of developing pulmonary edema, a life-threatening condition where fluid accumulates in the lung preventing the diffusion of oxygen into the capillaries.  At elevations above 2,500 metres, it is generally established that high altitude pulmonary edema (HAPE) is the result of acute hypoxia, which causes non-uniform vasoconstriction throughout the pulmonary bed. The unprotected arterioles and capillaries receive excess blood flow and pressure. Excess pressure results in capillary stress failure and eventual fluid leak out of the capillary into the alveolus. Extravascular lung water (EVLW) interferes with gas exchange at the level of the alveolus, causing hypoxemia (and resultant dyspnea) that is characteristic of HAPE [1]. Hypoxemia is worsened by exertion. Exertion increases capillary pressures, especially in hyperperfused areas of the lung [2]. A critical factor in HAPE is the rate of ascent. HAPE is most common in cases where the patient did not properly follow acclimatization guidelines [2].  Long distance swimmers [3], triathletes [4], and competitive breath hold divers [5] are susceptible to a comparable condition known as immersion pulmonary edema (IPE) [6]. Specifically, cold and increased inspiratory load due to immersion are believed to cause an increase in pulmonary artery pressure (PPA) and non-uniform vasoconstriction in the pulmonary capillaries. Immersion also increases hydrostatic pressure resulting in central pooling of blood and increased PPA [7]. These factors result in capillary stress failure leading to increases in EVLW [8-10]. Physical exertion, which raises PPA, is a significant risk factor for IPE [11]. 2  Recent research has indicated that some humans develop pulmonary edema during maximal exercise [12-14]. This exercise-induced pulmonary edema was hypothesized to be a contributing factor in a condition called exercise induced arterial hypoxemia (EIAH). EIAH is characterized by a widening of the alveolar-arterial O2 difference (A-a DO2) and a reduction in arterial O2 saturation (SaO2). It is estimated that EIAH occurs in 52% of highly trained athletes, and it is known that EIAH impairs exercise performance [15]. Koskolou et al. found a significant decrease in maximal exercise capacity in highly trained cyclists when EIAH was induced (% SaO2 = 87 ± 1%) [16]. Furthermore, the detrimental effects of EIAH on performance can be reversed with hyperoxia [17]. The transient increase in EVLW demonstrated in these studies could be the cause of impaired gas exchange and hypoxemia in EIAH [18].  The proposed mechanism of this transient pulmonary edema with exercise is believed to be increased capillary leakage caused by an elevated PPA, the very same mechanism proposed in both IPE and HAPE [19, 20]. As the presumed mechanism for the development of pulmonary edema in all three situations is similar, we hypothesize that there is a common underlying mechanism among these three conditions and that individuals with a susceptibility to either HAPE or IPE will be prone to increased EVLW during intense exercise in normoxia. Previous studies investigating EIAH and EVLW used only healthy subjects who had no history of pulmonary edema. It is possible that the inconsistent results from these studies suggest only a small subgroup of humans develop EVLW during sea-level exercise. The “susceptible” subgroup may also be likely to develop HAPE or IPE when exposed to their respective stressors. This study is the first to use subjects who have previously experienced HAPE or IPE as candidates for susceptibility to EVLW during exercise. 3  While HAPE and IPE are relatively rare, they are both potentially fatal and can occur in austere environments, away from effective medical care.  In fact, although HAPE is much less common than acute mountain sickness, it kills far more visitors to altitude [6]. An analysis by Lobenhoffer et al. of 166 cases of HAPE revealed an 11.4% mortality rate. Of those who did not receive oxygen or undertake immediate descent, the mortality rate was 49% [21].  At present there is no clinical or laboratory test to determine susceptibility to either IPE or HAPE.   If it can be shown that those individuals at risk of IPE and/or HAPE demonstrate a buildup of EVLW after exercise in normoxia, we can develop an a priori test for these conditions. Furthermore, by defining a common underlying pathophysiology, we can enhance our understanding of the mechanisms of these conditions leading to the development of treatments or preventative strategies.  1.2 Hypothesis Following a 45-minute bout of intense cycling, individuals susceptible to either HAPE or IPE will develop increased EVLW. We hypothesize that these changes will not occur in HAPE/IPE resistant control participants. Changes in EVLW will be characterized by: 1. Significantly reduced pulmonary diffusion capacity following exercise. 2. A significant decrease in pulse oxygen saturation during the exercise bout as compared to control participants. 3. A significant increase in lung density following exercise. A difference of 0.02 g*ml -1 is considered a meaningful change in lung density. In previous studies using computed tomography (CT), a standard deviation of 0.013 g*ml -1 was found [22, 23] corresponding to an effect size of f = 0.769. Using a power of 0.8 and an alpha set at a = 4  0.05, eight participants were needed for each group; however, a sample size of 18 was selected due to the likelihood of participants withdrawing from the study.  5  2. METHODS 2.1 Subjects Nine healthy fit male and female participants who had previously been diagnosed with HAPE or IPE were recruited for the experimental or pulmonary edema susceptible (PEs) group. A HAPE diagnosis was made with a chest x-ray showing pulmonary edema, or hemoptysis and dyspnea preventing further gain in altitude and resolving on descent. An IPE diagnosis was made with a chest x-ray showing pulmonary edema, or hemoptysis and dyspnea that required the participant exit the water. The study physician reviewed each case to confirm the diagnosis and determine eligibility. Nine healthy fit males and females were recruited to serve as the age-, sex-, weight-, and height-matched control or pulmonary edema resistant (PEr) group. To be eligible for the PEr group, participants must have previously travelled above 3000 metres, competed in at least two Ironman distance triathlons with a swim time under 75 minutes or have a valid self-contained underwater breathing apparatus (SCUBA) certification with a minimum of 10 cold water dives (<10 deg Centigrade) without experiencing any symptoms of pulmonary edema. All participants were non-smokers with no history of lung disease, abnormal lung function, asthma, heart disease or hypertension. Participants were recruited through posted advertisements, Dr. Koehle’s sport medicine practice, and existing contacts within the local mountaineering, skiing, search and rescue, swimming, and diving communities.  Participants were familiarized with the test protocol, and were required to sign an informed consent form prior to their inclusion in the experiment.  2.2 Protocol  This experiment utilized a parallel design with subjects from each group performing two tests, pre- and post-exercise. Participants completed two test days. During a familiarization day, 6  pulmonary function was measured and participants were screened for fitness level. The intervention day included a 45-minute maximal exercise task as well as pre- and post- spirometric and radiologic measures.  2.3 Pulmonary Function and VO2max  Participants reported to the Environmental Physiology Laboratory (EPL) to provide informed consent and to be familiarized with the metabolic cart, cycle ergometer, and spirometer. Participants were instructed to avoid exhaustive exercise for 24 hours, caffeine for 12 hours, and food or drink for 2 hours prior to the visit. Height and weight were measured with bare feet and wearing cycling clothing. A portable Spirobank spirometer (MIR, Roma, Italy) was used to confirm normal lung function according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines [24]. Subjects were instructed to wear a nose clip, and breathe room air through a disposable mouthpiece. Once breathing comfortably, subjects were told to exhale, followed by a full inhalation and then a rapid, complete expiration. Parameters measured included forced vital capacity (FVC) and forced expired volume in 1 second (FEV1.0).  Participants then performed an incremental cycle test to exhaustion using a Velotron Dynafit Pro cycle ergometer (Racermate Inc, WA, USA) and a metabolic cart (TrueOne® 2400, ParvoMedics, UT, USA).  Work rate started at 0 Watts (W), and increased by 0.5 W/sec until volitional exhaustion.  To ensure that maximal oxygen consumption was attained, at least 3 of the following criteria were met:  1) A plateau in VO2. 2) Attainment of at least 90% of age-predicted maximal heart rate (210 bpm – [0.65 x age]). 7  3) Respiratory exchange ratio (RER) > 1.1. 4) Inability to maintain a cadence of 60 rpm despite maximal effort and verbal encouragement. During the test, heart rate (HR) was recorded continuously using a short-range telemetry system and periodically (every 15 s) using a Polar portable heart rate monitor (Polar Oy, Kempele, Finland).  Participants inspired through a heated pneumotach (Hans Rudolph, USA) using a mouth piece equipped with a two-way non-rebreathing valve (2700 Series, Hans Rudolph, USA). Expired air passed into a mixing chamber where gas samples were analyzed for oxygen and carbon dioxide concentrations.  Minute ventilation (VE), VO2 and carbon dioxide output (VCO2) were averaged over 15 seconds and reported. Peak oxygen consumption was determined as an estimate of aerobic fitness by averaging the three highest consecutive 15-second values. Gas analyzers were calibrated with gases of a known concentration prior to each experiment. Peak power and time to completion of test were recorded for each participant. Pulse oxygen saturation (SPO2) was monitored using a Nonin 9600 pulse oximeter attached to the ear lobe (Nonin Medical Inc., MN, USA). After the test, participants performed a self-selected cool-down. 2.4 Maximal Exercise Task The intervention visit took place in the Radiology Department at Vancouver General Hospital (VGH). Participants were instructed to avoid exhaustive exercise for 24 hours, caffeine for 12 hours, and food or drink for 2 hours prior to the visit. The maximal exercise task consisted of a stationary-cycle test on a Velotron Dynafit Pro cycle ergometer (Racermate Inc, Seattle WA) with a protocol similar to one used in other studies to induce EIAH [25]. The task began with a 10-minute warm-up at 30% of peak power output achieved in the VO2max test, followed by three 5-minute “high-intensity” bouts of exercise separated by 10 minutes of recovery at 30% peak 8  power. The exercise bouts were performed at an intensity between 80 and 90% (self selected) of the recorded peak power output achieved during the VO2max. During the last two minutes of each interval, resistance was increased toward the peak power output attained at VO2max to ensure a maximal effort. Heart rate and SPO2 were monitored continuously during the exercise task. Following the exercise task, subjects were immediately transferred to a wheelchair where they rested until their HR reached a recovery plateau within a range of 5 bpm and remained at that rate for at least five minutes. 2.5 Computed Tomography Prior to, and following HR stabilization after the maximal exercise task, participants completed a chest CT scan to evaluate lung density (g*ml -1). Three slices of the lung were scanned at the level of the aortic arch, the tracheal carina, and the superior end plate of T10 with the subject breathing at functional residual capacity and pausing at the end of an inspiration. Scans were completed using a single turn 360 degree helical acquisition on a Sensation 16, 16 detector row “rotate-rotate” CT scanner (Siemens AG, Germany). The detector array uses 16 0.75 mm detector tracks which can give ten images 1 mm thick, five images 2 mm thick or two images 5mm thick. Due to technical difficulties, three subjects were scanned using a Sensation 64, 64 detector row “rotate-rotate” CT scanner (Siemens AG, Germany). The detector can give thirteen images 1 mm thick, seven images 2 mm thick, or three images 5 mm thick.  The scanner generates a potential difference of 120 kVp, a current of 80 mA, and a 0.5 second rotation time, with a field of view of 380 mm.  Tube current modulation is automatically applied in the x and y planes with an average dose length product per acquisition of 34 ± 1.4 mGy/cm. The scan yielded an effective dose of .95 mSev. The radiation dose from this scan is minimized as only 3 9  slices of the lung are imaged; equivalent to approximately one half of the yearly background radiation exposure in Vancouver, B.C. [22, 23].   Images were reconstructed using either a low (B35), intermediate (B45), or high (B60 with edge- enhancement) spatial frequency reconstruction algorithm. Once the images were reconstructed, the radiologist screened them for relevant abnormalities that would prevent inclusion in the analysis. Upon approval, images were transferred to a computer for density analysis. Custom software (EmphylxJ) was used to analyze the x-ray attenuation values of the lung following segmentation of the lung parenchyma. Lung tissue was segmented from the chest wall and mediastinum, and the voxel dimensions were summed in order to calculate CT lung volume. Once the mean CT attenuation of the lung (in Hounsfield units (HU)) is known, it can be converted to a density measure in g*ml -1 using equation one presented below. 1)                                     Density = (HU + 1000)/1000 2.6 Diffusion Capacity of Carbon Monoxide Pulmonary diffusion capacity was measured according to the ATS/ERS guidelines [26] using standard diffusion measuring equipment (W.E. Collins Inc, MA, USA). The protocol was consistent with previous studies performed within our group [13, 27, 28]. The pre-exercise diffusion capacity measurement was performed immediately before the exercise task. Participants remained seated for approximately 30 minutes prior to this measurement to mitigate any potential prior exercise effect on diffusion capacity. Measurements were again performed post-exercise after HR stabilized and after the CT scan was completed. Pulmonary diffusion capacity was measured using the single breath carbon monoxide diffusion capacity method 10  (DLco). The rate of disappearance of carbon monoxide (CO) (ml*min -1 *mmHg -1) was assessed after the participant inhaled a test gas of 21% O2, 10% helium (He), and 0.3% CO with a balance of nitrogen (N2). After a full inhalation, the participants held their breath for approximately 10 seconds after which they were instructed to exhale rapidly. This procedure was repeated until two trials were performed with values within 3 ml*min -1 *mmHg -1. Participants then underwent a five-minute washout period breathing a gas mixture containing 90% O2 and 10% N2. Diffusion capacity of CO measurements were then repeated using a second, high O2, gas mixture (10% He, 0.3% CO, Balance O2).  The expired gas was compared by the spirometer to determine the proportion of the carbon monoxide that has diffused into the blood. The measurement of DLco with high O2 gas mixture allowed for the partitioning of DLco into its two components, membrane diffusion (DM) and capillary blood volume (VC), according to the method developed by Roughton et al. [29, 30] and previously used by our research group [6, 13, 27, 28]. This partition will provide differentiation between a change in diffusion capacity due to variation in the permeability of the membrane (which would be expected with an increase in EVLW) and variation in capillary blood volume (usually caused by a confounding exercise effect). The gases were pre-mixed from a commercial supplier to minimize the chance of error. Hemoglobin (Hb), the concentration of which would affect measurements of DM and VC due to its affinity for oxygen, was measured with a HemoCue analyzer, using a single drop of capillary blood from the fingertip (HemoCue AB, Ängelholm, Sweden). 2.7 Statistical Analysis In this study, n = 18 with nine subjects in the experimental (PEs) group and nine subjects in the control (PEr) group. The primary outcome variable analyzed was lung density as measured by CT.  Two-by-two Analysis of Variances (ANOVA) tests were used to compare lung density, 11  mass, and volume between groups (PEr and PEs) pre- and post-exercise. Changes in DLco, DM, and VC were analyzed using two-by-two ANOVA tests between groups (PEr and PEs) pre- and post-exercise. All continuous variables were expressed as a mean of the group (± standard deviation). All data analyses were performed using the software program, Statistical Package for the Social Sciences (SPSS 17.0). Alpha was set at α = 0.05. A difference with p < 0.05 was considered statistically significant.  12  3. RESULTS 3.1 Descriptive Data Anthropometric data for all participants are presented in Table 3.1. Individual data are presented in Table B1 (Appendix). Independent samples t-tests were used to compare anthropometric and spirometric characteristics between groups to confirm a homogeneous sample. No differences were found between groups in any of the descriptive variables. Table 3.1. Anthropometric and spirometric characteristics of 18 subjects. Group Statistic Age (years) Height (cm) Weight (kg) FVC (L) FEV1.0 (L) PEs Mean 38 172 70.8 5.52 4.09  SD 13 9 13.3 1.64 1.32 PEr Mean 37 175 77.4 5.12 3.92  SD 15 9 11.3 0.99 0.69 SD, Standard deviation; PEs, Pulmonary edema susceptible; PEr, Pulmonary edema resistant. 3.2 VO2max  Table 3.2 shows the results for the VO2max test. All subjects had a resting pre-test SPO2 of 99- 100%. Individual data are found in Table B2. An independent samples t-test was used to compare fitness levels between groups, and no significant difference was found.  13  Table 3.2. Maximal oxygen consumption (VO2max), maximal oxygen consumption per kilogram (VO2max), peak power, maximum heart rate (MHR) and minimum arterial oxygen saturation (SPO2). Group Statistic VO2max (L*min) VO2max (mL*min*kg) Peak Power (watts) MHR (bpm) Min SPO2  (%) PEs Mean 3.46 48.36 314.67 184.22 92.78  SD 1.00 10.27 64.74 6.55 8.38 PEr Mean 4.05 51.89 334.00 177 90.67  SD 1.20 12.57 76.785 11.16 11.69 SD, Standard deviation; PEs, Pulmonary edema susceptible; PEr, Pulmonary edema resistant. 3.3 Maximal Exercise Task Table 3.3 shows the result of the 45-minute stationary cycle ergometry task. Heart rate values during the maximal exercise task were comparable to the maximal HR attained during the VO2max test. All subjects had a resting pre-test SPO2 of 99-100%. Individual data can be found in Table B3. Maximal exercise task variables were compared between groups with independent samples t-tests to confirm that both groups performed equal workloads. Oxygen saturation did significantly decrease in all subjects during exercise (t (1, 16) = 4.176, p < 0.001). The difference in SPO2 between groups was not significant (p = 0.261), but there appeared to be a trend towards lower SPO2 values in PEs participants compared to PEr participants.  14  Table 3.3. Maximum heart rate (MHR), minimum arterial oxygen saturation (SPO2) during the third interval, mean interval power (INT Power), mean percent maximal power (INT Intensity). Group Statistic MHR (bpm) Min SPO2 (%) INT Power (watts) INT Intensity (%) PEs Mean 188 91 233 73  SD 8 6 59 6 PEr* Mean 181 95 230* 71*  SD 11 4 58 6 *Power data for participant 002 was not measured, n = 8. SD, Standard deviation; PEs, Pulmonary edema susceptible; PEr, Pulmonary edema resistant. 3.4 Computed Tomography 3.4.1 Mean Lung Values Table 3.4 shows results for lung density, mass, and volume measured with CT pre- and post- exercise using the B35 spatial frequency reconstruction algorithm with 1-mm slice thickness, a standard densitometry research setting. Participants were scanned immediately before and approximately 11 minutes (± 1) after cessation of exercise. A review of previous studies evaluating EVLW after exercise (Table A1) suggests that a time to scan between 0 and 120 min does not affect the presence of EVLW on imaging. Individual results are located in Tables B4, B5, and B6. Pre- and post-exercise density, mass, and volume data are displayed in Figures 3.1, 3.2, and 3.3. Individual changes pre- and post-exercise are displayed in Figures B1, B2, and B3.  15  Table 3.4. CT Lung data pre- and post- exercise.  Group Statistic Density (g*mL -1) Mass (g) Volume (mL)   Pre Post Pre Post Pre Post PEs Mean .192‡ .179*‡ 127.9‡ 125.9‡ 666.6 701.6*  SD .035 .023 88.5 100.0 24.2 21.3 PEr Mean .220‡ .212*‡ 149.0‡ 147.9‡ 681.9 700.2*  SD .003 .030 19.2 21.3 95.7 88.4 *Significantly different from pre-exercise mean (p < 0.05). ‡Significant difference between groups. SD, Standard deviation; PEs, Pulmonary edema susceptible; PEr, Pulmonary edema resistant. A two-by-two repeated measures ANOVA was used to assess the impact of pulmonary edema susceptibility (PEr, PEs) on the participant’s CT lung density, mass and volume before and after the maximal exercise task. There was no significant interaction effect between pulmonary edema susceptibility and time for any of the CT variables. There was a significant main effect for time with both groups showing a reduction in density post-exercise (F (1, 16) = 7.869, p = 0.01). This corresponds to the significant increase in volume and the lack of change in mass following exercise (F (1, 16) = 9.649, p = 0.006; F (1, 16) = 0.5725, p = 0.460, respectively). The main effect of pulmonary edema susceptibility on density was significant (F (1, 16) = 5.20, p = 0.04), suggesting lower lung density in PEs subjects. There was no significant interaction effect for density, mass, or volume (F (1, 16) = 0.5038, p = 0.488; F (1, 16) = 0.0549, p = 0.818; F (1, 16) = 0.9574, p = 0.342; respectively). The main effect of pulmonary edema susceptibility on mass approached significance (F (1, 16) = 3.788, p = 0.069), suggesting a difference between groups at both time points that was unrelated to the exercise task.  16  De ns ity (g *m l-1 ) Pre Pos t 0.0 0.1 0.2 0.3 PEr PEs *‡ ‡   Figure 3.1. CT lung density pre- and post-exercise in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. *Significantly different from pre-exercise mean (p < 0.05). ‡Significant difference between groups. M as s ( g) Pre Po st 0 50 100 150 200 PEr PEs‡‡  Figure 3.2. CT lung mass pre- and post-exercise in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. ‡Significant difference between groups. 17  Vo lum e ( ml ) Pre Pos t 0 300 600 900 PEr - 1mm PEs - 1mm*  Figure 3.3. CT lung volume pre- and post-exercise in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. *Significantly different from pre-exercise mean (p < 0.05).  3.4.2 Receiver Operating Characteristic A receiver operating characteristic graph, using lung density as a continuous rating scale to predict susceptibility to pulmonary edema, is plotted in Fig. 3.4. At a density of 0.2367 g*ml -1, the sensitivity for pulmonary edema susceptibility was 88%, and the specificity was 39%. A density greater than 0.2367 g*mL -1 has a negative predictive value of 76% for HAPE and IPE susceptibility. The area under this curve was 0.757. 18   Figure 3.4. Receiver operating characteristic graph for the ability to predict pulmonary edema susceptibility with CT lung density. Corresponding density is labeled at points on the curve. Upper and lower limits of the 95% confidence interval are indicated in light grey lines. 3.4.3 Regional Density Distribution Density was determined in each subject at three positions along the lung. Each of the three slices was 10-mm thick. Slices were taken at the level of the aortic arch, the tracheal carina, and the top of the T10 vertebrae. In each group (PEs and PEr), CT density at each slice location (arch, carina, T10) did not differ pre- and post- exercise (PEr: F (2, 24) = 1.072, p = 0.358; PEs: F (2, 24) = 1.438 p = 0.257; Figure 3.5) .1782 g/ml .1925 g/ml .2076 g/ml .2367 g/ml .2503 g/ml .1562 g/ml 19  PEr Den sity (g *m l-1 ) Pre Pos t 0.0 0.1 0.2 0.3 PEs Pre Pos t 0.0 0.1 0.2 0.3 Aortic Arch Tracheal Carina Top of T10  Figure 3.5. Mean lung density for each slice (aortic arch, trachea carina, top of T10) at each time point for resistant (PEr) and susceptible (PEs) subjects. 3.5 DLco Diffusion capacity of CO was measured prior to the exercise task and again after the second CT scan, approximately 23 minutes (± 4) following cessation of exercise. Table 3.5 gives alveolar volume (VA) and DLco using 21% O2 for each group. DLco was then partitioned into the DM and VC components, which are listed in Table 3.6. A two-by-two repeated-measures ANOVA was used to assess the impact of pulmonary edema susceptibility (PEr, PEs) on each variable (DLco, DLco/VA, DM, DM/VA, VC, and VC/VA) before and after the maximal exercise task (Pre-DL-21% and Post-DL-21%). Tables 3.5 and 3.6 also include the respective values corrected for VA. Diffusion capacity for CO, DM, and VC, corrected for VA, are shown graphically in Figures 3.6, 3.7, and 3.8, respectively. The change in diffusion capacity (Δ DLco), change in membrane diffusion (Δ DM), and change in capillary volume (Δ VC) values are listed in Table 3.7 and plotted in Figure 3.9. Individual data can be found in Table B7. Individual changes in DLco pre- and post-exercise are displayed in Figure B4. 20  Table 3.5. Pulmonary diffusion capacity of carbon monoxide breathing 21% oxygen (DL-21%) pre- and post- exercise, diffusion capacity corrected for alveolar volume (DL-21%/VA) pre- and post-exercise, and alveolar volume measured breathing 21% oxygen (VA-21%). Group Statistic DL-21% (mL*min -1 *mmHg -1) DL-21%/VA (mL*min -1 *mmHg -1 *L -1) VA-21% (L)   Pre Post Pre Post  PEs Mean 32.92 29.43* 4.65 4.27* 6.89  SD 8.88 9.30 0.79 0.86 1.71 PEr Mean 33.72 30.05* 5.30 4.65* 6.42  SD 8.31 8.82 0.85 0.71 1.44 Total Mean 32.82 29.74* 4.97 4.46* 6.66  SD 8.39 8.80 0.87 0.79 1.55 *Significantly different from pre-exercise (p < 0.05). SD, Standard deviation; PEs, Pulmonary edema susceptible; PEr, Pulmonary edema resistant. There was no significant interaction effect on DLco between pulmonary edema susceptibility and time, (F (1, 16) = 1.16, p = 0.30). There was a significant main effect for time, with both groups showing a reduction in DL-21% in the post-exercise test (F (1, 16) = 31.49, p < 0.001). The main effect of susceptibility was not significant (F (1, 16) = 0.085, p = 0.77), suggesting no difference caused by susceptibility to pulmonary edema. When pulmonary diffusion capacity was corrected for alveolar volume (DL-21%/VA), there was no significant interaction effect between pulmonary edema susceptibility and time (F (1, 16) = 2.31, p = 0.15). There was a significant main effect for time (F (1, 16) = 33.37, p < 0.001), with both groups showing a reduction in DL-21%/VA in the post-test. The main effect of susceptibility was not significant (F (1, 16) = 1.88, p = 0.19), suggesting no difference caused by susceptibility to pulmonary edema. 21  Table 3.6. Diffusion capacity of the alveolar membrane (DM) and capillary blood volume (VC) components pre- and post-exercise. Values also presented corrected for alveolar volume (DM/VA and VC/VA). Group Statistic DM (mL*min -1 *mmHg -1) DM/VA (mL*min -1 *mmHg -1 *L -1) VC (mL) VC/VA (mL*L -1)   Pre Post Pre Post Pre Post Pre Post PEs Mean 42.45 41.96* 6.14 6.07* 92.99 66.64* 13.89 9.77*  SD 12.21 13.21 0.69 1.04 34.09 21.09 5.36 2.52 PEr Mean 45.10 41.23* 7.01 6.28* 87.26 78.09* 13.98 12.47*  SD 12.41 15.11 0.99 1.16 25.14 37.08 4.30 6.13 Total Mean 43.77 41.59* 6.57 6.18*† 90.13 72.36* 13.94 11.12*  SD 12.02 13.78 0.95 1.07 29.21 29.85 4.71 4.76 *Significantly different from pre-exercise (p < 0.05). †Significant interaction effect found (p < 0.05). SD, Standard deviation; PEs, Pulmonary edema susceptible; PEr, Pulmonary edema resistant. There was no significant interaction effect on DM between susceptibility group and time (F (1, 16) = 3.13, p = 0.10). There was a significant main effect for time (F (1, 16) = 5.20, p = 0.04), with both groups showing a reduction in DM in the post-exercise test. The main effect of susceptibility was not significant (F (1, 16) = 0.02, p = 0.88), suggesting no difference caused by susceptibility to pulmonary edema. When alveolar membrane diffusion capacity was corrected for alveolar volume (DM/VA), there was a significant interaction effect between susceptibility group and time, (F (1, 16) = 4.66, p = 0.04). There was a significant main effect for time, (F (1, 16) = 6.76, p = 0.02), with both groups showing a reduction in DM/VA in the post-test. The main effect of susceptibility was not significant (F (1, 16) = 1.54, p = 0.23), suggesting no difference caused by susceptibility to pulmonary edema alone. 22  There was no significant interaction effect on VC between susceptibility group and time (F (1, 16) = 1.97, p = 0.18). There was a significant main effect for time (F (1, 16) = 8.43, p = 0.01), with both groups showing a reduction in VC in the post-test. The main effect of susceptibility was not significant (F (1, 16) = 0.05, p = 0.83), suggesting no difference caused by susceptibility to pulmonary edema. When pulmonary capillary volume was corrected for alveolar volume (VC/VA), there was no significant interaction effect between susceptibility group and time (F (1, 16) = 1.71, p = 0.21). There was a significant main effect for time (F (1, 16) = 7.93, p = 0.01) with both groups showing a reduction in VC/VA in the post-test. The main effect of susceptibility was not significant (F (1, 16) = .48, p = 0.50), suggesting no difference caused by susceptibility to pulmonary edema.  23  (a) D L -2 1% (m l *m in -1 *m m Hg -1 ) Pre Pos t 0 10 20 30 40 50 PEr PEs  (b) D L -2 1% /V A (m l *m in -1 *m m Hg -1 *L -1 ) Pre Pos t 0 2 4 6 8 PEr PEs  Figure 3.6. Diffusion capacity of carbon monoxide breathing 21% oxygen (a) and diffusion capacity of carbon monoxide breathing 21% oxygen corrected for alveolar volume (b) pre- and post-exercise in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema.  24  (a) D M (m l *m in -1 *m m Hg -1 ) Pre Pos t 0 20 40 60 PEr PEs  (b) D M /V A (m l *m in -1 *m m Hg -1 *L -1 ) Pre Pos t 0 2 4 6 8 10 PEr PEs  Figure 3.7. Membrane diffusion capacity (a) and membrane diffusion capacity (b) pre- and post- exercise corrected for alveolar volume in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. 25  (a) V C (m l) Pre Pos t 0 50 100 150 PEr PEs  (b) V C /V A (m l *L -1 ) Pre Pos t 0 5 10 15 20 PEr PEs  Figure 3.8. Capillary blood volume (a) and capillary blood volume corrected for alveolar volume (b) pre- and post-exercise in subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. Independent samples t-tests were performed to assess the difference between groups for Δ DLco, Δ DM, and Δ VC (Figure 3.9). There was no significant difference for pulmonary edema susceptible and resistant subjects in Δ DLco (t (16) = 1.51, p = 0.169), Δ DM, (t (16) = 2.26, p = 0.053), or Δ VC (t (16) = 1.99, p = 0.081). 26  Table 3.7. Mean change in diffusion capacity for carbon monoxide (Δ DL-21%), change in membrane diffusion (Δ DM) and change in capillary volume (Δ VC) calculated for groups of subjects susceptible (PEs) and resistant (PEr) to pulmonary edema. Group Statistic Δ DL-21% (mL*min -1 *mmHg -1) Δ DM (mL*min -1 *mmHg -1) Δ VC (mL) PEs Mean -8.40 -1.54 -25.69  SD 5.66 8.04 16.30 PEr Mean -11.64 -10.33 -10.91  SD 9.03 11.49 25.93  SD, Standard deviation; PEs, Pulmonary edema susceptible; PEr, Pulmonary edema resistant. 27  (a)  D L- 21 % (m l * m in -1 *m m H g- 1 ) PE r PE s -20 -15 -10 -5 0  (b)  D M (m l * m in -1 *m m H g- 1 ) PE r PE s -25 -20 -15 -10 -5 0  28  (c)  V C (m l) PE r PE s -50 -40 -30 -20 -10 0  Figure 3.9. Mean change in diffusion capacity for carbon monoxide (Δ DL-21%) (a), change in membrane diffusion (Δ DM) (b), and change in capillary volume (Δ VC) (c) calculated for groups of subjects susceptible (PEs) and resistant (PEr) to pulmonary edema.  DL-21% (ml*min -1 *mmHg -1) M ea n In te rv al  P ow er (W /k g) -30 -20 -10 0 10 1 2 3 4 5 R2 = 0.3070   Figure 3.10. The relationship between the change in diffusion capacity for carbon monoxide (Δ DL-21%) and the mean interval power per kilogram of bodyweight. The relationship between mean interval power per kilogram bodyweight and Δ DLco was investigated using Pearson product-moment correlation coefficient (Figure 3.10). Preliminary 29  analyses were performed to ensure no violation of the assumptions of normality. There was a strong, positive correlation between the two variables (r = 0.55, n = 17, p = 0.021) with lower mean power per kilogram associated with greater decreases in DLco but Δ DLco was not significantly correlated with minimum SPO2 (p = 0.276).   30  4. DISCUSSION 4.1 Key Findings Following exhaustive cycle exercise in HAPE/IPE susceptible and resistant subjects, we observed no change in EVLW, as measured by CT or DLco, in either group. Membrane diffusion and pulmonary capillary volume decreased and lung volume increased post-exercise, but no difference was found between groups for any of these variables. A significant between-groups difference existed for density, unrelated to the maximal exercise task. Participants in the PEs group had a lower lung density than those in the PEr group.  4.2 Extravascular Lung Water 4.2.1 Introduction Exercise-induced arterial hypoxemia is a common phenomenon; healthy humans, exercising at high intensity, experience a widening of the A-a DO2 and a resulting decrease in SPO2. It has been hypothesized that pulmonary edema may be one of several possible causes of EIAH, but this point remains controversial with a significant amount of conflicting evidence [31, 32] . Pulmonary edema has been shown in healthy humans exercising maximally at sea level; these patients were likely hypoxemic as well [14]. It is possible that EIAH occurs through the same mechanism as HAPE and IPE, and therefore, those susceptible to HAPE and IPE may be more likely to develop EIAH caused by pulmonary edema. Podolsky et al. measured V/Q mismatch in HAPE susceptible individuals and found a significant difference compared to the resistant group. The authors concluded this difference was the result of a transient increase in EVLW [33]. The current study is the first to examine the development of EVLW in participants who are susceptible to HAPE or IPE compared to a cohort that has demonstrated resistance to pulmonary 31  edema in the same environments. This study showed no increase in EVLW after exercise in either group. 4.2.2 Pulmonary Diffusion Capacity Pulmonary diffusion capacity has previously been shown to decrease after exercise (See Table A2). This study confirms the decrease in DLco following exercise in subjects susceptible and resistant to pulmonary edema. Diffusion capacity of CO was partitioned into its components: DM and VC. The results of the partition, significant decreases in both components, were also consistent with previous studies [27]. This suggests a significant limitation in pulmonary diffusion capacity as a result of decreases in both membrane diffusion capacity and capillary blood volume. Lower power output during the exercise task was correlated with a greater decrease in DLco but not with DM and VC.  This was unrelated to subject group and seems to suggest that less fit individuals show a greater decrease in DLco than those able to output higher power, similar to trends shown by Sheel et al. [27]. It is possible that a diffusion limitation, which manifests during exercise, negatively affects power output. The change in DLco was not significantly correlated with minimum SPO2 during exercise, but this diffusion limitation could be an early sign of impending EIAH. 4.2.3 Oxygen Saturation In both HAPE and IPE, gas exchange impairment caused by fluid buildup can be clearly seen in a patient’s decreased SPO2 at rest and during exercise. Arterial oxygen saturations below 50% have been reported in HAPE patients at 4,500 meters [34]. Similarly, saturations below 70% have been seen in IPE patients at sea level [11]. EIAH is characterized by a widening of the A- aDO2 (reflected in a depressed SPO2, generally 88 – 93%) due to some combination of the effects 32  of intrapulmonary shunt, mismatch of ventilation and perfusion within the lung (V/Q mismatch), increased red blood cell transit time, or pulmonary edema [18]. In this study, SPO2 at rest in all subjects was 99-100%. Following exercise, SPO2 decreased significantly but did not differ statistically between groups. The mean SPO2 for the PEs group did appear to be trending lower suggesting some sort of pulmonary gas impairment. While DM did not differ significantly between groups, this trend could be explained by something other than a diffusion limitation. Eldridge et al. proposed a mechanism in which small intrapulmonary arteriovenous shunts act as “pop-off valves” in response to increasing pulmonary pressures [35]. If these shunts were more common in PEs participants, widening of the A-aDO2 would be likely, resulting in decreased SPO2. Conversely, if PEs participants had fewer shunts, higher pressures in the pulmonary capillary network could cause capillary stress failure and increased EVLW, resulting in decreased SPO2. Further research is necessary surrounding the existence, onset, and hemodynamic effect of intrapulmonary shunts in patients susceptible to HAPE and IPE. 4.2.4 Lung CT Density, Mass, and Volume The results of previous studies that use imaging (CT and Magnetic Resonance Imaging (MRI)) to measure exercise-induced lung water have been conflicting. There are a variety of potential reasons for the variation in results. Beginning with exercise intensity and duration, bouts have ranged from 5 to 120 minutes at a variety of intensities (See Table A1). Generally the shorter, higher intensity exercises show no change while medium and longer duration studies find a significant difference. The current study used a medium duration, with subjects maintaining a maximal sustainable power output of approximately 231 ± 57 watts. Extended delays between cessation of exercise and scanning may also have reduced the chance of identifying a change in EVLW. Of the studies reviewed, average time to scan was approximately one hour. According to 33  Schaffartik et al., interstitial edema can clear as quickly as 20 minutes in upright subjects [36]. This study had an average time-to-scan of 11 ± 1 minutes, allowing adequate time for central blood volume to stabilize, while minimizing extravascular fluid reabsorption into the lung.  This study found no difference in the change in lung density between groups. Contrary to previous studies, both groups showed decreased lung density after exercise. Decreased density could be the result of a transient decrease in central blood volume. Several studies have shown decreases in central blood volume and VC following exercise [27, 37, 38], the timing of which would have a significant effect on lung density. In this study, VC was significantly reduced, which could explain why lung density did not increase. Further research is needed to determine a more precise time course for the immediate increase and eventual decrease in VC. In the current study, if a drop in VC were the cause of the decrease in density post-exercise, we would expect a corresponding decrease in mass. As there was no decrease in mass, a decrease in VC as the primary cause of decreased density can be ruled out.  Had EVLW been present, volume would be expected to decrease as a result of decreased compliance and increased elasticity caused by fluid stiffening the lung [39], but in this study lung volume increased in both groups after exercise. Several explanations are possible for the observed increase in lung volume. If dilation of the large bronchi were to occur due to exercise, tethering of the large and small airways could increase the size of small bronchioles as well, resulting in increased volume on the scan. It is also possible that the increased volume is a learning effect. Participants were given a relatively brief inhalation time prior to CT image acquisition. Several participants described being surprised at the short amount of time given and described compensating for this during the second scan by inspiring more rapidly. This 34  explanation is supported by measures of VA using helium-dilution, which did not change following exercise. Participants were coached to make sure that they inspired the same volume for every scan but no other methods were employed to ensure breath size repeatability. This omission underlines the need for some sort of control in future studies to ensure equal inspiratory volume. A pneumotach measurement or chest restriction using a band would be effective, but a more realistic option would be more extensive familiarization with the auditory cues provided in the CT suite. Finally, volume differences may have resulted from differences in scan areas. The human lung can be represented with the shape of a bell. If slices were imaged slightly lower during the post-exercise acquisition, volume would be artificially increased. This explanation is unlikely due to the systemic nature of the increase in lung volume throughout all subjects. Position errors during scanning would be expected to occur randomly during both scans. Results from CT scan variables (lung density, mass, and volume) indicate that susceptibility to HAPE or IPE does not increase chances of developing EVLW during sea level exercise. 4.3 Pulmonary Edema Susceptible Lungs The CT scan estimates of lung water indicate that participants did not develop increased EVLW after exercise, but there was a significant between-group difference in density. There was no between group difference in volume at either time point, but the PEs participants had decreased lung density as compared to PEr subjects. This finding is despite all other spirometric and anthropometric measures not differing between groups, suggesting an inherent disparity in lung density between PEs and PEr participants. Decreased lung density implies less fluid in the slice, less tissue in the slice, or less dense tissue.  35  While no conclusions can be made regarding the reason for this difference in density, several possible explanations exist. Lower density could be the result of long-term lung damage due to previous HAPE or IPE insults. Potential evidence for a chronic change in lung morphology following HAPE comes from studies involving bronchoscopy of HAPE patients. Broncheoalveolar lavage (BAL) fluid taken from patients with acute HAPE contains significant concentrations of high-molecular-weight protein. The presence of these proteins suggests that the integrity of the alveolar epithelium has been compromised resulting in a “permeability” leak [40]. Follow-up lavage fluid also included inflammatory markers [41], indicating a reaction to lung injury. Schoene et al. also noted increased acid proteases in the fluid following HAPE [40]. When these degrading substances are released into the lung, likely by alveolar macrophages, they can break down lung tissue [42]. Over time, especially with multiple incidents of HAPE or IPE, one might expect this protease activity to accumulate, causing chronic degradation of lung tissue that could lower lung density in the susceptible subjects. Another potential mechanism for the decreased lung density in the PEs group comes from studies of acute respiratory distress syndrome (ARDS). Studies investigating long-term damage from ventilator induced pulmonary edema in patients with ARDS have shown increased lung scarring. In these patients, fibrous sacs of air called bullae form in the alveolar and parenchymal tissue. These sacs are then unable to participate in gas exchange [43, 44]. While the mechanism for lung injury is different in ARDS (ventilator induced vs. high altitude or water immersion), it is possible that the PEs participants in this study have similar scarring and bullae as a result of their previous incidents of pulmonary edema. In the current study, although the entire lungs were not 36  scanned, there was no overt evidence of bulllae or visible scarring in the PEs group when the slices were evaluated. If the PEs participant’s lungs contain fewer blood vessels or the same number of vessels with increased reactivity and decreased recruitment, less fluid would be present in the pulmonary circulation resulting in decreased density measured with CT. Research done by Ghorishi et al. examining the pulmonary system of lambs provides a possible explanation for differences in vasculature between PEs and PEr participants. The pulmonary vasculature of fetal lambs is highly sensitive to shear stress within vessels. At birth, these shear stress amplifying characteristics generally fade; however, in some lambs, the fetal characteristics are actually retained. The increased shear stress response could then influence vascular properties including wall thickness and composition [45]. Humans display a similar fetal phenotype, and if PEs individuals were to retain this accentuated shear-stress response after birth, increased remodeling could cause development of smooth muscle and increased pulmonary vasoconstriction or decreased capillary density. The result of pulmonary vascular remodeling would be decreased blood volume within the lung at any given time and increased flow within existing vessels that would in turn increase PPA and potentially cause pulmonary capillary stress failure. This hypothesis is supported by data in previously identified HAPE susceptible subjects, which show PPA is elevated even during rest at sea level [46].  If PEs participants do have fewer vessels or less recruitment, a lower pulmonary blood volume should have been reflected in spirometric VC measurements. No difference in VC was found, suggesting that density differences may be the result of fluid or tissue differences elsewhere in the lungs, for example, in the pulmonary lymphatic system.  37  The pulmonary lymphatic system is responsible for absorption of excess fluid within the lung. When fluid is extravasated from the capillaries into the interstitial and alveolar space, lymphatic capillaries usually reabsorb it. When extravasation of fluid overtakes the reabsorption capacity of the lymph, fluid buildup occurs. This buildup of excess fluid will eventually manifest as clinical pulmonary edema [47]. If PEs individuals have fewer pulmonary lymphatic vessels than those in the PEr group, pulmonary edema would be more likely when exposed to adverse environments such as high altitude or immersion. Fewer lymphatics would require less connective tissue and carry less fluid resulting in lower density. No studies comparing pulmonary lymphatic structure or flow between HAPE susceptible and HAPE resistant participants have been carried out. Further research examining possible differences is needed. 4.4 CT Lung Reconstruction Computed tomography scans were reconstructed on a computer using B35, B45, and B60 spatial frequency algorithms. CT scans assign voxels density values based on their individual Hounsfield unit value. Air is assigned a value of -1000 HU and bone 1000 HU, with fluid and tissue in between. In lung CT scans, narrowing the range of Hounsfield units can increase resolution. For example, letting -500 represent black and -200 represent white increases resolution when examining details of lung tissue [48]. Image thicknesses of 1mm, 2mm and 5mm were analyzed. Reducing the size of a voxel increases spatial resolution by decreasing the averaging that is required [44], but it also results in increased noise. Statistical tests described in the Results chapter were performed on the results of all algorithms and slice thicknesses. Additionally, all were compared using a one-way ANOVA, and no significant differences were found (See Table B4). During image analysis, it was discovered that the 5 mm slice thickness reconstructions from scans using the Sensation 16 scanner had a gap thickness of 2.2 mm rather 38  than 5 mm, yielding an effective thickness of 2.2 mm per slice. This error resulted in underestimation of mass and volume but had no effect on density.  For this reason, 5 mm image thickness values were not reported. 4.5 Limitations Several limitations are evident within this study. One of the common mechanisms associated with HAPE and IPE is increased PPA, which causes capillary stress failure. During this experiment, PPA was not measured and therefore cannot be ruled out as a mechanism for the difference in lung density between groups. A second limitation was the availability of volunteers eligible to participate in the study. Due to the relatively low number of people with confirmable cases of HAPE or IPE, it was necessary to create one experimental group rather than two. Because of this, the study assumes that HAPE and IPE are pathophysiologically equivalent phenomena, which has yet to be definitively proven. While this is certainly possible, it cannot be confirmed with this experiment. It is also difficult to confirm cases of HAPE or IPE. Sixteen individuals were identified with possible HAPE or IPE incidents but seven were excluded due to unreliable evidence to support their diagnosis. Finally, several errors occurred during CT scan acquisition. During one testing session, the Sensation 16 scanner used during the study stopped functioning, and scans were completed using a Sensation 64 scanner. This resulted in overestimations of volume and mass for three subjects. A correction factor was applied; however, there is still a slight margin of error that cannot be accounted for due to the bell shape of the lung. Density remained unaffected in all subjects. 39  4.6 Future Directions Future studies investigating EVLW and pulmonary edema susceptibility should be focused on confirming and then finding the cause of the density difference between groups. If this difference is the result of differences in the pulmonary lymphatic system, it would be beneficial to employ an imaging technique that can reliably quantify these vessels. It would also be useful to investigate factors such as hypoxia and fluid accumulation that may be acting to trigger lymph flow. Repeating the exercise protocol with a larger sample while measuring PPA would provide more information on differences in vasculature between groups. If differences were found in PPA, another logical step would be to determine if PEs participants were more or less likely to develop intrapulmonary shunts, which might be acting as “pop-off” valves under high pressure. It is possible that individuals susceptible to pulmonary edema might experience the opening of these shunts at higher PPA exposing their pulmonary capillaries to increased stress. Future studies of EVLW should use the Sensation 64 CT scanner, which produces a lower dose of radiation per scan, and during our trials, proved to be more reliable. Finally, separating the HAPE and IPE groups would help define differences in susceptibility within our PEs group. 40  5. CONCLUSION This study demonstrated no change in EVLW after exercise.  Decreases in DLco, DM and VC were demonstrated to be consistent with other studies investigating pulmonary diffusion capacity after maximal exercise. This was the first study of EVLW during sea level exercise to include participants who had previously experienced pulmonary edema due to high altitude or immersion. Pulmonary edema susceptible participants did not show any greater changes in lung density, SPO2, or DLco compared to PEr participants, suggesting that humans with previous HAPE or IPE incidents are not at any greater risk of developing EVLW during maximal exercise at normoxia. A novel finding was that mean lung density was significantly lower in PEs participants at both the pre- and post-exercise time points, suggesting an inherent difference in lung structure possibly as a result of previous pulmonary edema, pulmonary hypertension, or fewer lymphatics. Further investigation is necessary to confirm the existence and nature of this difference. 41  REFERENCES 1. Hultgren, M., H.N., High-altitude pulmonary edema: current concepts. Annual review of medicine, 1996. 47(1): p. 267-284. 2. 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Hypoxemia is an abnormally low PaO2 and can be caused by hypoventilation, shunt, diffusion limitation, or ventilation-perfusion inequality. A diffusion limitation could be caused by exercise, thickening of the blood-gas barrier, or a low inspired PO2. This decreases the difference between PAO2 and PaO2, reducing the diffusion gradient which is necessary for gas exchange. Concentration of O2 in any airspace of the lung is determined by the rate of ventilation (VA) to blood flow (Q). In an ideal lung, VA and Q are matched (VA/Q = 1). By decreasing VA/Q (decreasing ventilation) PAO2 decreases with PaO2 and arterial blood will be the same as mixed venous blood. By increasing VA/Q (decreasing perfusion) PAO2 equilibrates with inspired air while PaO2 decreases [49]. Diffusion Oxygen must move across the alveolar wall to enter the blood stream. This is a passive process called diffusion which uses no energy. The oxygen molecules are only able to move across the wall when going from an area of higher partial pressure to an area of lower partial pressure. This action is described by Fick’s law of diffusion. According to Fick’s law, a gas’ rate of transfer 51  through a tissue is proportional to the tissue area and the difference in the gas partial pressure on either side. The rate of transfer of the gas is also inversely proportional to the thickness of the tissue. Because the area of the blood gas barrier is so large (up to 100 meters2) as well as being very thin, conditions for diffusion are ideal [49]. This presents a problem however because the thin barrier provides very little protection from stressors outlined in the next section. Pulmonary Capillary Stress Failure Unlike the capillaries of the systemic circulation, [50] the pulmonary capillaries are unsupported by surrounding tissues and are therefore vulnerable to stress failure caused by high pressure. Using rabbit lungs, West et al. identified three principle forces which act on the capillary wall [51].  1) Increased wall stress due to circumferential tension on the capillary wall is caused by an increase in capillary transmural pressure. With a capillary transmural pressure gradient of just 22.5 mmHg, disruption of the endothelial and epithelial cells can occur with the basement membrane serving as the only remaining barrier [51]. 2) Surface tension at the alveolar lining layer due to surfactant supports the capillary. Increasing lung volume will increase surface tension and compress the endothelial and epithelial layers.   3) Longitudinal tension in the tissue element of the alveolar wall increases wall stress with lung inflation. These three factors make up the total wall stress which, due to the extreme thinness of the capillary wall, can approach the wall stress found in the aorta. This stress is transmitted through two single epithelial and endothelial layers of cells separated by two (or potentially even one) 52  very thin basement membranes. It is believed that much of the strength of the thin capillary wall comes from the basement membranes. In cases of stress failure, it is possible to see disruptions in the endothelial and epithelial layers while the basement membrane remains intact. This suggests its apparent greater strength. One study found that the relationship between transmural pressure and diameter of a renal tubule was the same with or without the epithelium suggesting the strength of the basement membrane [52]. When stress failure of the endothelium and epithelium occurs, increased capillary wall permeability is the result and leakage of protein occurs. Studies by West et al. suggest that moderate raises in capillary hydrostatic pressure results in leakage of low-protein fluid, while greater raises of hydrostatic pressure results in high-protein fluid leakage due to increased membrane permeability [51]. Pulmonary Pressures The mean PPA in humans is 15 mmHg. The systolic pressure is usually approximately 25 mmHg. These low pressures allow the walls of the vessels within the pulmonary circulation to be very thin [49]. During maximal exercise breathing room air, Wagner et al. estimated that the PPA rose to 35 – 40 mmHg [53]. This is believed to be the range at which interstitial edema can begin to form [28]. Mean PPA has been recorded at much higher values. Hultgren et al. gave an example of a 15 year old boy diagnosed with HAPE at an altitude of 3,782 meters with a mean PPA of 110 mmHg [1]. As discussed earlier, at any given moment, not all the pulmonary capillaries are open. To achieve this, West suggests that 37 mmHg would be necessary [54]. According to Starling’s law of capillary exchange, vessels subjected to this pressure would experience development of interstitial edema [55, 56]. 53  Left atrial pressure (PLA) is generally around 5 mmHg [49]. Mild elevations in PLA (18 to 25 mmHg) can cause interstitial edema [57, 58]. As PLA increases (>25 mmHg), the lung epithelium is disturbed and fluid can flood the alveoli as well [47].  A2. Pulmonary Stressors Hypoxia Exposure to hypoxia causes the pulmonary circulation to respond uniquely when compared to systemic circulation. The response is characterized by increases in PPA and pulmonary vascular resistance as a result of constriction of the small pulmonary vessels [59]. This hypoxic vasoconstriction is an important mechanism which decreases perfusion to poorly ventilated lung units and increases perfusion to better ventilated ones in order to decrease VA/Q mismatch. When exposed to hypoxia, the small intraparenchymal pulmonary arteries (150-1,600 µm), decreased in diameter up to 25% in a canine model. These vessels were found to contribute significantly to pulmonary vascular resistance [60]. Using small vein micropuncture in cats, it was found that hypoxic vasoconstriction occurs mainly in the small pulmonary arteries (30-50 µm) [61]. This work was confirmed by Kato et al. who employed a technique of rapidly freezing hypoxic cat lungs and found pulmonary vasoconstriction to occur in the small muscular pulmonary arteries [62].  In rats, the hypoxic response becomes evident approximately 17 minutes following exposure to hypoxic perfusate and reaches a maximum between 45 and 140 minutes [63].  Repeat exposure to hypoxia has been shown to result in attenuation of this vascular hypoxic response. It is unknown if this is the mechanism for acclimatization to high altitude [64]. The mechanism through which the hypoxic vasoconstrictive response occurs is not completely understood. It is possible that the response is initiated by the release of a vasoactive mediator 54  from within the lung also known as the mediator hypothesis. Unfortunately, no single agents that have been studied satisfy all the criteria to be considered a mediator; though Endothelian and Endothelial derived relaxing factor (nitric oxide) may be involved.  It is also possible that hypoxia acts directly on pulmonary vascular smooth muscle to cause vasoconstriction without a mediator [59].  Inhibition of the hypoxic response has been successful using calcium channel blockers. Nifedipine is an effective pulmonary vasodilator which is successful in lowering PPA and pulmonary vascular resistance while maintaining systemic vascular resistance and Q [59, 65].  Nifedipine is used as a preventative agent for individuals susceptible to HAPE. Hydration Hydration levels can influence PPA through increases in plasma volume which would be reflected in increases of VC. Jimenez et al. measured plasma volume using injected Evans blue dye after subjects had ingested a solution containing 128 g glycerol diluted with water to make a total volume of 256 ml. At regular time intervals, subjects drank a mean volume of 465 ml of water containing 1.2 g*l -1 NaCl. The total ingested volume was 21.4 ml*kg -1. Plasma volume was found to increase significantly (7.5%) [66]. Shifts in the vascular fluid compartment have been found to be caused by changes in hydration level [67-69]. Hydration status should be carefully considered when investigating increases in VC as a mechanism for increased EVLW. Hydration may also be an issue for athletes in austere environments trying to find the balance between proper hydration for exercise and hypohydration, which could put them at risk for HAPE or IPE. Body position The distribution of blood flow within the human lung is determined primarily by gravity and can have significant effects on PPA. In the upright human lung, perfusion decreases from the base to 55  the apex where it reaches very low levels. Because venous pressure is less than alveolar pressure in the upper lung, blood flow is determined by the gradient between arterial and alveolar pressure. In the dependent lung zones, flow is determined by the arterial-venous pressure difference [49]. When posture is changed to sitting, redistribution of perfusion is such that flow to the base of the lung remains the same while flow increases at the apex to a nearly uniform distribution. Marshall et al. found a significant increase in PPA between sitting (upright) and standing positions. While sitting, PPA was 7.4 ± 0.8 mmHg and increased to 11.2 ± 0.7 mmHg when standing. It is also recognized that when changing from sitting to supine position, the DLco increases significantly [28, 70]. This increase is likely because of the increase in perfusion which allows a greater surface area to be available for diffusion. These data demonstrate that PPA is not an appropriate estimation of pulmonary perfusion. It also demonstrates that when in the supine position, VA/Q mismatch is decreased [28]. The effect of body position on EVLW development may not significantly affect humans during upright cycling but could have a profound effect on the development of IPE. Swimmers and divers, primarily in the prone position, are exposing larger percentages of their lungs to increased perfusion, possibly increasing likelihood of IPE. Further research is necessary to determine if individuals susceptible to IPE have an exaggerated response to changes in body position. Cold Cold elicits a number of physiological responses in the human body. The greatest effect of cold on the development of IPE is peripheral vasoconstriction. Blood is redistributed from the peripheral to thoracic vessels causing an increase in preload and afterload. Keatinge et al. studied the cardiopulmonary response of an ice cold shower on humans. Subjects were sprayed with 0 - 2.5° C water for 2 minutes at 6 L/min. All subjects experienced a significant increase in the rate 56  and depth of breathing and PaCO2 decreased. There was also a significant increase in blood pressure and HR. Cardiac output was measured in two subjects and was found to increase significantly (7.9 and 6.5 to 12.4 and 13.0 L/min) [71]. Subjects who have previously experienced IPE show an increased vasoconstrictive response to cold when compared to control subjects. The vasoconstrictive response results in increased preload and afterload [72]. Peripheral vasoconstriction may cause a redistribution of blood increasing PPA. Wester et al. found an increase in HR and Q when subjects were immersed in cold water compared to warm water. Central venous pressure (CVP) and PPA increased significantly when immersed in cold water compared to warm water [8]. When water temperature is 1° - 2°C below body temperature it may be considered warm for diving but still results in a decreased core temperature and central pooling of blood [73]. Many swimmers and divers report unzipping their wetsuit to reduce constriction following feelings of dyspnea. While it may provide temporary relief, this reaction may exacerbate IPE by eliminating the insulative effects of the wetsuit [74]. Decreasing body temperature has also been shown to be related to increased pulmonary vascular resistance [75]. Increases in Q and central blood volume caused by cold induced vasoconstriction make it likely a major factor in IPE. Further research is warranted to investigate the cold response in individuals with repeat episodes of IPE.   Immersion Increased hydrostatic pressure due to immersion causes a redistribution of blood from the periphery to the core associated with an increase in intrathoracic blood volume of 700 mL. This shift can result in PPA increasing up to 12 mmHg [76]. Begin et al. found a 20 to 40% increase in Q with no increase in HR on immersion to the neck, confirming Arborelius’ findings. Q 57  increases reached these levels within 30 minutes of seated immersion [77].  At rest, immersion in warm water has been shown to significantly increase Q, PPA, pulmonary artery wedge pressure (PAWP), and CVP. Increases in HR and mean arterial pressure (MAP) also occurred. During cold-water immersed exercise trials, PPA was reported as high as 37 mmHg [8]. Dujic et al. studied divers during a single open sea dive to 30 msw and found an increase in PPA from 25 ± 3 to 33 ± 2 mmHg [78] which is well above the PPA which Wagner et al. suggested could lead to pulmonary capillary stress failure [53]. The likely cause of increased PPA is the increased intrathoracic blood volume and Q contributing to increased preload and afterload on the heart. As the depth of the dive increases, so does hydrostatic pressure. Immersion causes a sudden and temporary rise in cardiac output [79] as well as a negation of the effects of gravity on blood flow, which enhances venous return, increasing preload. Immersion can also increase sympathetic activity causing peripheral vasoconstriction and an increase in afterload [80]. Immersion can cause a decrease in the functional residual capacity of the lung. Begin et al. reported a 33-40% decrease, similar to the 46% decrease reported by Agostoni [77, 81]. It is believed to be caused primarily by a decrease in expiratory reserve volume. Immersion has been found to decrease DLco in the lung following SCUBA dives. Koehle et al. measured DLco in divers following a 60-minute dive to 4.5 msw in a swimming pool and found a significant reduction in DLco at 30 and 90 minutes post dive. This has been suggested to be caused by an increase in extravascular lung water, which impairs DLco [6]. A study by Prediletto et al. on breath-hold divers found mixed results when measuring DLco following a series of four dives from between 10 and 30 msw. They found a significant increase in DLco two minutes following the dives that subsequently decreased towards baseline. In four divers, DLco continued to 58  decrease >10% below baseline. It was concluded that extravascular lung water may impair DLco following breath-hold diving [82]. The increase in PPA during water immersion, likely the result of increased CO and central blood volume, appears to be sufficient a stimulus to cause development of sub-clinical EVLW and decrease DLco. Exercise Physical exertion is unavoidable in many of the situations that mountaineers, swimmers, and divers face. Exercise induces increases in oxygen consumption, ventilation, heart rate and stroke volume which result in increased Q. When Q increases, peripheral vascular resistance must decrease to avoid a large increase in systemic blood pressure. Despite this change in resistance, blood pressure does increase with the majority of the increase in systolic and mean blood pressure. Pulmonary artery pressure is elevated minimally (approx. 10 mmHg) due to a low resistance to flow [83]. With the onset of metabolic acidosis, it is possible that changes in respiratory patterns could also cause an increase in PPA [84]. A redistribution of blood flow is seen which involves vasoconstriction in organs such as the brain, gut, and kidneys. This blood is directed to exercising muscles that can go from receiving 15% of Q at rest to 80% of Q during maximal exercise [83]. Using a double indicator-dilution technique, supine exercise at 150 kg/m caused an increase in EVLW from 126 ± 15 ml sitting to 229 ± 22 ml. Cardiac output was found to increase in relation to increasing EVLW. Diffusion capacity increased from 22.6 ± 1.6 to 32.9 ± 1.9 ml*min -1 *torr -1. Exercise also caused a significant increase in pulmonary capillary blood volume [70]. While exercise causes redistribution of blood towards working muscles and the resultant increase in PPA is low, it is still sufficient to exacerbate stress on capillaries making exertion a major risk factor when in environments where HAPE or IPE are likely. 59  A3. High Altitude Pulmonary Edema High altitude pulmonary edema is a severe type of altitude illness in which the interstitial space and alveoli of the lungs fill with fluid, impairing gas exchange.  Signs and Symptoms Onset of HAPE is generally 2-3 days after arrival [85]. Symptoms may include dyspnea, weakness, cough, chest congestion, nausea, vomiting and headache which may worsen at night. Signs include tachypnea, tachycardia, pulmonary rales, and cyanosis [1]. Investigation will reveal low oxygen saturation and decreases in PaO2 and PaCO2 which are characteristic of arterial hypoxemia. In cases where oxygen delivery to the brain is severely impaired, confusion and coma may result. If left untreated, the outcome is death. Confusion and delirium may be compounded by symptoms of high altitude cerebral edema [86]. Pulmonary hypertension is constantly present. Pulmonary artery wedge pressure can be normal or slightly decreased and Q is generally low [1].  At elevations above 2,500 metres, it is generally established that HAPE is the result of acute hypoxia that causes nonuniform pulmonary vasoconstriction throughout the pulmonary bed. The unprotected arterioles and capillaries receive excess blood flow and pressure. This excess pressure results in capillary stress failure and eventual leakage out of the capillary into the alveolus.  This EVLW interferes with gas exchange at the level of the alveolus, causing the hypoxemia (and resultant shortness of breath) that is characteristic of HAPE [1].  Prevalence A critical factor in HAPE is the rate of ascent; HAPE is most common in cases where the subject did not properly acclimatize [2]. Of those who have a prior history of HAPE, some have demonstrated an abnormal elevation of PPA during acute hypoxia [87]. Children are more 60  susceptible to HAPE than adults. Hultgren et al. found that between age 13 and 20, the incidence of HAPE is 17% while in ages 21 and older the incidence is only 3% [88]. The risk of developing HAPE after a rapid ascent to 3,600 metres is about 0.5% in adults [86]. Occurrence of HAPE is rare below 2,500 metres [89]. Sub-clinical HAPE occurs 6 to 10 times more commonly than clinical HAPE [90, 91]. It is possible for susceptible individuals to ascend to high altitude without developing HAPE with a slow rate of ascent. Similarly, HAPE has been shown to occur in individuals with a successful history at high altitude [34]. Although no conclusive evidence exists, it is likely that HAPE susceptibility is represented on a continuum and that no individual could be completely resistant depending on rate of ascent, exertion, and final altitude [2].   Diagnosis At the 1991 International Hypoxia Symposium, a proposal for the diagnosis of HAPE required that two of the following criteria be met following a recent gain in altitude: dyspnea at rest, cough, weakness or decreased exercise performance, chest tightness, plus two of the following signs: rales or wheezing in at least one lung field, central cyanosis, tachycardia, or tachypenia [92]. When obtained, a chest radiograph will display three general abnormalities including vascular congestion without an infiltrate, patchy infiltrates, either localized or distributed throughout both lung fields and/or homogenous diffuse infiltrates, usually bilateral [93]. Infiltrates may show up for several days after symptoms abate. Weakness and fatigue accompanying symptoms may continue up to two weeks [86]. Pathophysiology Mortality is primarily dependent on access to medical care, specifically the ability to use supplemental oxygen and descend quickly. For this reason, mountaineers who are in remote 61  locations have the highest mortality rates. In one study of 166 cases of HAPE, the mortality rate was 11.4% however, in those patients who descended or were given oxygen, only four died (6%) [21]. Bronchoalveolar lavage fluid from climbers at 4400 m with HAPE contained significant amounts of high-molecular-weight proteins, erythrocytes, and leukocytes as well as increased leukotriene B4 indicating a “large pore leak” in capillary-alveolar interface. Also of note was the lack of neutrophil accumulation which accompanies other lung injury [40].  On autopsy, lungs show diffuse pulmonary edema with foamy fluid filling the airways. A small percentage of cases had pulmonary emboli or cerebral edema present. In 24 cases, histological studies were carried out and it was found that 46% of small pulmonary arteries and capillaries contained thrombi, 75% had infiltration with leukocytes, and 58% had alveolar hemorrhages [1]. Treatment The easiest and most effective treatment for HAPE is descent to a lower altitude. A descent of 600 to 900 meters is often sufficient to provide relief from symptoms [86] and other methods of treatment should only be considered as supplementary, not substitutions [1]. Oxygen administration is also an effective means to decrease the effect of HAPE. Portable hyperbaric bags such as the Gamow bag are useful if immediate descent is not possible. Their small size and no need of electricity makes them useful in remote situations. A study by Kasic et al. showed that a Gamow bag will give greater improvements in signs and symptoms of HAPE when compared with oxygen administration [94]. Nifedipine has shown to be effective at decreasing PPA and increasing SaO2 [95, 96]. Nifedipine also has potential to prevent HAPE. When taken upon ascent and continued, nidefipine prevented HAPE in 9 of 10 patients while a placebo prevented HAPE in 7 of 11 patients, all of whom had previously experienced HAPE [97]. Sildenafil is hypothesized to decrease PPA in HAPE patients and has been shown effective in 62  reducing pulmonary hypertension through its vasodilator effects [98]. Snyder et al. showed an attenuation of the increase in PPA during hypoxia exposure when patients were given 100 mg sildenafil [99]. Some patients have been given furosemide in order to reduce fluid volume however this has been shown to cause a potentially severe fall in systemic blood pressure which can delay recovery [100]. Maggiorini et al. has used both tadalafil and dexamethasone as a prophylactic in a study investigating HAPE prevention in 29 HAPE susceptible patients traveling to altitude. Dexamethasone, a steroid used to prevent acute mountain sickness, has been shown to induce vasodilatation. None of the ten participants who took dexamethasone before travelling to 4559 m in 24 hours developed HAPE.  Dexamethasone is believed to reverse endothelial dysfunction and stimulate the production of cyclic guanosine monophosphate as well enhancing nitric oxide availability in the pulmonary vessels. Only one of eight participants who were given tadalafil developed HAPE. Tadalafil is effective at restoring nitric oxide in subjects with decreased bioavailability [101]. While prophylactic drugs have a place in the prevention of HAPE, the most effective strategy is a slow rate of ascent. A4. Immersion Pulmonary Edema Immersion Pulmonary Edema (IPE) is a rare but potentially life threatening condition where patients immersed in water develop pulmonary edema. First reported in otherwise healthy SCUBA divers by Wilmshurst et al. in 1984, an increasing number of cases have been published in long distance swimmers and breath-hold divers [72, 102]. Onset of symptoms is rapid [4, 11], and the reasons patients develop IPE are not well understood.  Signs and Symptoms Symptoms include dyspnea, respiratory distress, cough, hemoptysis, chest tightness, expectoration of froth, weakness, and tachypenia. The most severe symptoms include loss of 63  consciousness, seizures, and cardiopulmonary arrest. Signs include cyanosis and rales upon chest auscultation [4, 11]. Diagnosis Chest radiograph is most commonly performed and used to confirm immersion pulmonary edema. Chest auscultation and CT are also successfully used. While radiographic measures may provide an easy method of diagnosis at the hospital, the use of ultrasound is emerging as a reliable field measure. A technique called ultrasound lung comets has already been used to identify individuals suffering from high altitude pulmonary edema [103]. Ultrasound machines are ultra-portable, ranging in size from a laptop to a large cellular phone. This could allow their use on a dive or rescue boat immediately after an incident occurs, eliminating the confound of an investigation that takes place significantly after the participant leaves the water.  Ultrasound evaluation also allows the ability to rule out other differential diagnoses such as pneumothorax. Pulse oximetry provides a quick indication of the presence of pulmonary edema which has been shown to range from 76 % to 94 % [4]. Pathophysiology To allow gas exchange through passive diffusion, the pulmonary blood-gas barrier must be extremely thin however it must be strong enough to withstand high stress when capillary pressure increases. Acute pulmonary edema may be caused by either an increase in pulmonary capillary permeability (noncardiogenic) or when pulmonary capillary pressure becomes greater than plasma oncotic pressure (cardiogenic). Pulmonary capillary stress failure occurs when increased PPA disrupts the blood-gas barrier membrane allowing fluid to leak into the interstitial and alveolar space [79]. Sudden increases in preload and afterload can cause blood displacement into the lungs which reduces FRC and, when combined with the increase in pulmonary closing 64  volume and decreased lung compliance caused by immersion, results in ventilation-perfusion mismatch, hypoxemia, and pulmonary capillary vasoconstriction. Non-uniform capillary vasoconstriction results in exposure of unprotected vessels to high pressures, facilitating stress failure. Because gravity has an effect on regional distribution of blood flow in the lung, dependent areas are more highly perfused and therefore more likely to accumulate fluid.  This vascular explanation for immersion pulmonary edema would explain why three subjects swimming in the lateral decubitus position would develop edema only in the dependent lung [80] while hypoxic vasoconstriction explains the patchy presentation of EVLW on radiograph and CT. It is possible that the garment swimmers and divers choose may affect PPA. In moderate water temperatures, many people choose to use a wetsuit. These suits are perceptibly tight and a diver who gains weight over the course of time but continues to use the same suit may compound increased hydrostatic pressure. Tight wetsuits are also attributed to the feelings of dyspnea during the onset of IPE though when unzipped, patients report little or no relief. It is also possible that these individuals are exposed to some degree of hypoxia before the onset of pulmonary edema. Certainly breath hold divers become hypoxic during a dive, even if just for a few seconds. It is also conceivable that long distance swimmers, especially in rough, choppy, open water could have breathing irregularities that result in slight hypoxia. Hypoxia could induce uneven pulmonary capillary vasoconstriction similar to the mechanism proposed in high altitude pulmonary edema. 65  Terminology Early case reports describe breath hold divers who lost consciousness underwater and surfaced without equalizing. These fatalities were attributed to “thoracic squeeze”. While their deaths could be explained as barotrauma, their loss of consciousness and expectoration of bloody froth underwater was unexplained. It is now believed that these patients initially suffered from IPE which caused them to lose consciousness after which they suffered fatal thoracic squeeze. The term swimming induced pulmonary edema (SIPE) was coined to describe pulmonary edema in triathletes and military trainees. The term SIPE implies that patients must be exerting themselves by swimming in order to develop pulmonary edema however, while exertion is a risk factor, pulmonary edema is also possible in divers who attain great depths in cold water while moving very little. Cold-induced pulmonary edema has also been used to describe IPE but recent cases in relatively warm water have also made this term misleading [104, 105].  For these reasons, the term immersion pulmonary edema is preferable to describe the development of pulmonary edema in an individual immersed in water regardless of activity type. Other Factors Excessive hydration before immersion can increase preload and pulmonary venous pressure [74]. Only a small number of patients [104] reported water overload. Acetylsalicylic acid (asprin) is taken frequently by breath hold divers in order to increase performance. While acetylsalicylic acid is not known to cause spontaneous hemorrhage, pulmonary edema may be aggravated by its anti-platelet effect [106].  Voluntary diaphragmatic contractions (VDC) are a maneuver used by breath-hold divers to increase their time underwater. The diver makes a forceful inspiratory effort against an obstructed airway which tricks mechanoreceptors into the illusion of breathing. Voluntary diaphragmatic contractions result in negative intrapulmonary pressures which increase 66  venous return, pulmonary blood volume, and pulmonary capillary hydrostatic pressure [107]. Each of these factors are reported in a small number of cases and should not be considered major contributing factors to the development of IPE but should not be discounted as they each may provide an additive effect in increasing PPA  or aggravation of pulmonary edema. Treatment Primary treatment of IPE involves immediate removal of the patient from water immersion. Other factors to consider depending on the conditions include cessation of physical activity, treatment of hypothermia, and administration of oxygen. Diuretics may reduce plasma volume and decrease PPA [11].  A5. Exercise induced Arterial Hypoxemia Recent research has indicated that some humans develop pulmonary edema during maximal exercise [12-14, 108]. This pulmonary edema has been hypothesized to be the cause of a phenomenon called exercise induced arterial hypoxemia (EIAH).  EIAH is characterized by a widening of the alveolar-to-arterial PO2 difference (A-a DO2) and a reduction in arterial O2 saturation. It is estimated that EIAH occurs in 52% of highly trained athletes [15] and has been shown to impair exercise performance. For example, Koskolou et al. found a significant decrease in maximal exercise capacity in highly trained cyclists when EIAH was induced (% SaO2 = 87 ± 1%) [16]. Furthermore, the detrimental effects of EIAH on performance can be reversed with hyperoxia [17]. The transient increase in EVLW demonstrated in these studies could be the cause of impaired gas exchange and hypoxemia in EIAH [18]. Table A1 summarizes all the studies examining lung density before and after exercise looking for an increase in EVLW. The proposed mechanism of this transient pulmonary edema with exercise is believed to be increased 67  capillary leakage caused by an elevated pulmonary arterial pressure, the very same mechanism proposed in both IPE and HAPE [19, 20]. 68  Table A1. Extravascular lung water as measured using different subject populations and exercise types. Maximal oxygen consumption (VO2max), duration of exercise protocol, intensity of exercise protocol, type of measure, gender of participants, pre and post protocol result, and significance of change in EVLW. Study VO2max Duration Intensity Measure Gender Pre Post Time to scan Result Unit (l*min -1) (min) (watts) (type) (m/f) (g*ml -1) (g*ml -1) (min) (p < 0.05) McKechnie et al.(1979) [14] Trained 90 km Race CXR M N/A N/A N/A yes Caillaud et al. (1995) [108] 4.8 ± 0.12 120 Race CT M 0.21 ± 0.009 0.25 ± 0.01 95 ± 25 yes McKenzie et al. (1998) [109] 4.5 ± 0.2 5 435 ± 19.9 MR M 0.23 ± 0.02 0.22 ± 0.01 N/A no Anholm et al. (1999) [110] Trained 70-90 km Race CXR N/A 0.8 ± 1.2** 1.8 ± 1.6 immediate yes Manier et al. (1999) [111] 66.4 ± 4.7‡ 120 75% max CT M 0.373 ± 0.044 0.352 ± 0.027 < 30 no McKenzie et al. (2005) [13] 4.8 ± 0.14 45 300 ± 8.8 MR M 0.22 ± 0.008 0.24 ± 0.018 90 yes Snyder et al. (2006) [112] 38 ± 8‡ Ramp To max CT M/F N/A -103 ± 20†† N/A yes† Zavorsky et al. (2006) [25] 3.12 ± 0.42 15 236 ± 27 CXR F 1.3 ±1.6** 1.9 ± 2.0** 33.2 ± 6.1 yes 69  Study VO2max Duration Intensity Measure Gender Pre Post Time to scan Result Unit (l*min -1) (min) (watts) (type) (m/f) (g*ml -1) (g*ml -1) (min) (p < 0.05) Hodges et al. (2007) [113] 65 ± 7.5‡ 60 race MR M 0.177 ± 0.019,  0.178 ± 0.021* 0.173 ± 0.019, 0.176 ± 0.019* 50 no Guenette et al. (2007) [22] 3.3 ± 0.4 5 x 3 km 335 ± 33* CT F 0.138 ± 0.014 0.137 ± 0.011 44 no MacNutt et al. (2007) [23] 4.65 ± 0.32 5 x 3 km 451 ± 29* CT M 0.18 ± 0.04 0.18 ± 0.04 76 no Present Study (2011) 3.75 ± 1.12 15 231 ± 57 CT M/F 0.2057 ± 0.034 0.1956 ± 0.031 11 ± 1 no *Indicates test was performed under hypoxic (15% O2) conditions. **Units are overall edema score. †Decrease in lung water volume. ††Units are EVLW in mL. ‡Units are ml*min* -1kg-1.70  A6. Methods of Evaluating EVLW Radiologic X-Ray Production X-rays are produced within a sealed glass vacuum that contains two electrodes. A high potential difference between electrodes allows electrons produced at the cathode to be accelerated towards the anode. When the electron is suddenly decelerated by the anode, an energy conversion occurs. The quantity of x-rays produced is dependent on the number of electrons that flow from cathode to anode. The current (in milliamperes) applied to the cathode equals the number of electrons flowing per second to the anode target.  The voltage applied to the cathode provides the potential difference that accelerates the electrons. Most of the energy in the electrons is converted into heat; less than 1% become x-rays. The heat generation of an x-ray tube is a product of peak kilovoltage (kVp), current (mA) and exposure time (sec). This is expressed as a heat unit or joule. When electrons are accelerated towards the target anode of an x-ray tube, they lose energy which produces x-rays. Two different interactions between electrons and the target anode cause x-ray production.  General radiation is the result of electrons passing near the nucleus of an atom of the target anode (usually tungsten). A photon of radiation is emitted when the electron is attracted toward the nucleus which causes it to deflect and decelerate, losing energy. An electron may be decelerated repeatedly, losing a small amount of energy with each interaction before coming to rest. It is also possible for the electron to collide directly with the nucleus. In this case, all the energy of the electron is emitted as one photon. The energy of a photon (and quality of the x-ray 71  beam) is related to the energy (keV) of the electron, which is the result of the potential difference (kVp) applied across the x-ray tube. In other words a photon could have an energy as high (though not always) as the keV of the electron produced by the potential difference kVp across the x-ray tube. Characteristic radiation is the result of an electron that ejects an electron from the inner orbit of the target tungsten atom. This results in an excess positive charge on the atom which must expel energy. This energy can be expelled by producing radiation. The x-rays produced are characteristic of the atom that has been ionized. If the potential is below 70 kVp, characteristic radiation is nonexistent (greater than 70 kV is needed to ionize the atom). Between 80 and 150 kVp, 10% to 28% overall radiation is due to characteristic radiation. Beyond 150 kVp, characteristic radiation begins to decrease, becoming negligible above 300 kVp.  Intensity of the x-ray beam is dependent on the number of photons in the beam times the energy within each proton. Intensity is measured in roentgens per minute (R/min). Intensity can be affected by the tube kilovoltage, current, target material, and filtration of the beam.  When x-ray photons interact with matter they can either be absorbed or scattered. When a photon is scattered, it is deflected in a random direction and is no longer useful. If a photon is absorbed, it no longer exists and is removed from the x-ray beam. Scattering is represented as black on an x-ray film and contributes to the noise of the x-ray, which may partially or totally obscure an image. Attenuation If intensity of an x-ray beam is the product of quality and quantity, attenuation is the loss of intensity of the beam as it cross matter caused by absorption or scattering of photons. Four 72  factors affect the attenuation of x-rays. An increase in radiation energy results in decreased attenuation but increasing the density, atomic number, or electrons per gram of the tissue will result in increased attenuation. Energy can affect the contrast seen on the x-ray film. If two tissues have significantly different attenuation coefficients, a low energy x-ray beam will display lots of contrast while a higher energy beam will reduce contrast and hopefully make the image more useful. Attenuation and density have a linear relationship because an increase in density means an increase in the electrons present to absorb x-rays. The linear attenuation coefficient is the expected amount of attenuation per thickness of tissue. The linear attenuation coefficient is specific to monochromatic radiation. It depends on the energy of the x-ray beam as well as the type of tissue. Tissues of different densities will attenuate more or less energy. The mass attenuation coefficient is independent of the density of the absorber and is the same even if the physical state of the material differs. Patient exposure is measured in roentgens (R) or coulombs per kilogram (C*Kg -1). The unit of absorbed dose is the rad or gray (Gy). One Gy equals 100 rads.  Computed Tomography Computed Tomography (CT) was first demonstrated by G.N. Hounsfield in April 1972. Using a computer to reconstruct multiple projections of an object, CT allows differentiation between various soft tissues which make up the internal structure of a patient. 73  Using a rotate-rotate scanner, the patient is held stationary while a gantry holding an x-ray tube opposite a detector array rotates. The x-ray beam is collimated (accurately made parallel) into a fan beam in order to image the entire patient in each scan. Sometimes up to 700 detectors are necessary to image the entire object. As the gantry rotates, successive projections are made, sometimes up to 1000 in less than 1 second. These projections are then combined to form a single image. This image is also known as a slice. A rotate-fixed scanner is one where the detectors (sometimes more than 2000) completely surround the patient while the x-ray tube rotates around, allowing faster scans. Speed is necessary to image moving objects such as vessels and the heart. Image reconstruction is completed using a computer, which represents the tissue as a matrix of tiny blocks called voxels. These boxes are then each assigned a number according to the tissues attenuation for x-rays using the equation for exponential attenuation: N = N0e -(µ 1 + µ 2 +… µ n )x Where e is known as the base of the natural logarithm, the initial number of photons (N0), transmitted photons (N) and voxel thickness (x) are all known so the attenuation coefficient (µ) is the only unknown. By combining the projections from each different angle, the equation can be solved for each individual attenuation coefficient. Image quality of a CT scan is a combination of factors including noise, patient exposure, and resolution. Noise is the result of a statistical fluctuation caused by a variation in the number of x- ray photons absorbed by a detector and is reduced by increasing the number of projections in a slice. Resolution is composed of spatial resolution and contrast resolution. Spatial resolution is 74  the scans ability to differentiate between two small objects that sit near each other. Contrast resolution is the ability to differentiate between two objects with very similar densities (and therefore similar attenuation coefficients). Spatial resolution is improved through the scanner design, computer reconstruction and display output. Contrast resolution is increased by reducing noise [114]. CT and Exercise Several studies have used CT to investigate development of EVLW during exercise at sea-level or in hypoxia (See Table A1). In female subjects exercising maximally in normobaric hypoxia (15% O2), Guenette et al. found no change in lung density. Lung density at 44 min post exercise (0.137 ± 0.011 g*ml -1) was not significantly different than baseline (0.138 ± 0.014 g*ml -1) [22]. MacNutt et al. measured lung density in males exercising maximally in normobaric hypoxia. There was no change in lung density between baseline (0.18 ± 0.02 g*ml -1) and post-exercise (0.18 ± 0.04 g*ml -1) [23]. Caillaud et al. measured lung density in eight male subjects after a triathlon. Lung density increased significantly from 0.21 ± 0.009 g/cm3 at baseline to 0.25 ± 0.01 g/cm3 [108]. In nine trained runners who ran at 75% of their VO2max for two hours, no change in lung density was observed (0.37 ± 0.04 vs. 0.35 ± 0.03, not significant) [111]. While results are conflicting, it is possible that the increase in lung density after exercise occurs in only a small sub-sample of the population. It is possible that individuals susceptible to HAPE or IPE are more likely to be included in this sample. 75  Spirometric Pulmonary Diffusion Capacity According to the laws of diffusion, we know that the amount of gas which crosses a tissue is proportional to the area of the tissue, the difference in partial pressure, a constant, and inversely proportional to the thickness of the tissue. This is Fick’s equation:                    Because it is not possible to measure these parameters in vivo, the equation is rewritten so that DL is the diffusion capacity of the lung which includes the area, thickness and constant of the tissue and gas.        D L  (P1 – P2) Because factors other than just tissue area and thickness can affect the diffusion capacity of oxygen, carbon monoxide (CO), with its high affinity for hemoglobin, is used in its place. The diffusion capacity for carbon monoxide (DLco) is shown below: DL =           [49] Using the single-breath method, a mixture of gas including a small amount of carbon monoxide (0.3%) is inhaled during a single inspiration. The inhalation must be within 10% of the largest previously measured vital capacity. The patient is instructed to hold their breath for 10 seconds while the carbon monoxide is allowed to diffuse across the barrier. The breath hold must involve no Valsalva or Muller maneuvers and the exhalation must be quick and smooth. On exhalation, 76  the remaining carbon monoxide is calculated by the spirometer and compared to the inhaled concentration to give the diffusion capacity in ml*min -1 *mmHg -1.  A minimum of two tests are necessary and averaged to find the mean DLco. Tests should be five minutes apart and are included when within 3 ml*min -1 *mmHg -1 of each other [29, 115].  DLco is normally separated into its two components which act as resistances in series to diffusion. The “extra-Hb resistance” refers to the passage of gas by way of passive diffusion from the alveolar space through the epithelial cells, the basement membrane, the capillary endothelium, the plasma, red blood cell membrane and  red blood cell cytoplasm. This pathway is termed the membrane diffusion component (DM). The second resistance is related to the capillary blood volume (VC) that is exposed to alveolar air and the conductance of the blood for CO transfer (Ø) [116]. The DM and VC are combined to determine DLco using the equation: 1/ DLco = 1/DM + 1/( Ø VC) [30] In order to partition these two components, it is necessary to make a second measure of single breath DLco using a gas at a different PAO2 (10% He, 0.3% CO, Balance O2). These are plotted on a graph and a line is fitted. The y-intercept is equal to 1/ DM and the slope is equal to 1/ VC. Because Ø and therefore DLco are directly related to the concentration of hemoglobin (Hb) in the blood, it is necessary to measure Hb during each test [116]. Normal diffusion capacity at rest is 25 ml*min -1*mmHg-1 and can increase with exercise [49].  Stewart et al. found that DLco in the supine position was significantly higher than in the seated position [28]. Several studies have looked at the effect of exercise on DLco, DM, and VC; these 77  are summarized in Table A2. Exercise was found to cause a depression in DLco, specifically in the membrane diffusion component, following maximal exercise [27]. This is believed to be caused by a thickening of the alveolar-capillary membrane which causes a decrease in the rate of gas transfer. This could be caused by the onset of pulmonary edema. The higher DLco in the supine position could be due to increased pulmonary lymph flow which serves to remove and fluid which has accumulated in the alveolar-capillary membrane. It is also thought that the depressed DLco in the seated position could be due to redistribution of perfusion which is concentrated primarily in the lower parts of the lung. This would be more evenly spread out in the supine position and result in less of a depression in DLco [28]. 78  Table A2. Changes in pulmonary diffusion capacity as measured in different populations performing different types of exercise. Maximal oxygen consumption (VO2max), duration of exercise protocol, type of exercise, gender of participants, and significant change in pulmonary diffusion capacity (DLco), membrane diffusion (DM), and capillary blood volume (VC). Study VO2max Duration Type Gender Time to Test DLco DM VC Unit (l*min -1) (min)  (m/f) (min) (p < 0.05) (p < 0.05) (p < 0.05) Filley et al. (1954)[117] Healthy 6 Treadmill M/F During Increase N/A N/A Ross et al. (1959) [118] Healthy N/A Leg Flexion M During Increase N/A N/A Miles et al. (1983) [119] Trained 210 Run M 5-10 min Decrease Decrease N/C Rasmussen et al. (1986) [120] N/A 6-10 Canoe N/A 130 Decrease N/A N/A Manier et al. (1991) [121] Trained 180 Run M 28 ± 14 Decrease Decrease Decrease Rasmussen et al. (1992) [122] N/A 6 Rowing N/A 120-180 Decrease N/A N/A Manier et al. (1993) [123] Professional 20-22 Handball M Post Decrease Decrease N/C Hanel et al. (1994)[124] Trained 6 Rowing M 360 Decrease N/C Decrease 79  Study VO2max Duration Type Gender Time to Test DLco DM VC Unit (l*min -1) (min)  (m/f) (min) (p < 0.05) (p < 0.05) (p < 0.05) Caillaud et al. (1995) [108] 4.8 ± 0.12 120 Run M Post Decrease† N/A N/A McKenzie et al. (1999) [125] 67 ± 3.6‡ 2 x 60 Cycle M 60 Decrease Decrease Decrease Sheel et al. (1998) [27] 3.73 ± 0.37 Ramp Cycle M 60 Decrease† Decrease Decrease “ 4.45 ± 0.5 Ramp Cycle M 60 Decrease† Decrease Decrease “ 4.93 ± 0.34 Ramp Cycle M 60 Decrease† Decrease Decrease McKenzie et al. (2005) [13] 4.8 ± 0.14 45 Cycle M 60 Decrease No Change Decrease Snyder et al. (2006) [112] 38 ± 8‡ Ramp Cycle M/F N/A Increase* Increase* Increase* Present Study (2011) 3.75 ± 1.12 3 x 5 Cycle M/F 23 ± 4 Decrease† Decrease† Decrease† *Indicates test was performed under hypoxic (reduced FIO2) conditions. †Change also significant when corrected for VA. ‡Units are ml*min* -1kg-80  APPENDIX B: INDIVIDUAL DATA Table B1. Individual anthropometric and spirometric characteristics of 18 subjects. Subject Age (years) Height (cm) Weight (kg) FVC (L) FEV1 (L) 1 40 187 87.6 5.69 4.23 2 53 189 91.6 6.35 4.5 3* 27 187 78.1 8.81 7.01 4* 46 179 79.9 4.98 4.06 5* 55 160 54.7 4.9 3.37 6‡ 30 179 85.9 4.83 4.21 7‡ 22 164 54.5 3.87 3.62 8 30 167 64.3 4.66 3.62 9* 55 171 83.3 4.66 3.8 10* 21 169 65.9 6.85 4.4 11* 46 174.5 89.5 6.87 4.36 12 21 171 76.5 5.92 4.04 13 24 180 73.2 5.95 4.89 14 27 183 93.3 4.99 3.7 15 52 175 78.3 5.08 4.29 16 28 166 65.1 4.25 3.49 17‡ 40 165 54.9 3.95 1.99 18 61 164 66.6 3.16 2.5 *Indicates susceptibility to HAPE; ‡ indicates susceptibility to IPE. 81  Table B2. Maximal oxygen consumption (VO2max), peak power, maximum heart rate (MHR) and minimum arterial oxygen saturation (SPO2). Subject VO2max (L*min) VO2max (mL*min*kg) Peak Power (watts) MHR (bpm) Min SPO2 (%) 1 5.38 56.4 432 185 88 2 3.97 43.4 322 152 99 3* 5.40 69.2 442 187 99 4* 3.34 41.9 284 183 95 5* 2.81 51.4 270 169 78 6‡ 3.00 35.0 344 187 98 7‡ 2.29 41.9 234 191 98 8 3.07 47.7 311 183 79 9* 3.37 40.4 280 181 98 10* 3.71 56.2 335 189 98 11* 4.65 51.9 373 188 92 12 5.29 69.2 362 175 98 13 4.94 68.6 410 189 98 14 4.80 55.2 389 184 93 15 4.31 55.2 343 170 98 16 2.55 39.2 235 181 65 17‡ 2.60 47.3 270 183 79 18 2.12 32.1 202 174 98 *Indicates susceptibility to HAPE; ‡ indicates susceptibility to IPE. 82  Table B3. Maximum heart rate (MHR), minimum arterial oxygen saturation (SPO2), during third interval, mean interval power (INT Power), mean percent maximal power (INT Intensity). Subject MHR (bpm) Min SPO2 (%) INT Power (watts) INT Intensity (%) 1 182 88 N/A N/A 2 160 98 236 73.41 3* 188 94 350 79.12 4* 185 88 204 71.91 5* 171 92 186 68.94 6‡ 188 99 260 75.44 7‡ 200 86 146 62.54 8 179 N/A 226 72.78 9* 188 98 232 82.73 10* 188 97 261 77.81 11* 190 79 266 71.20 12 179 98 267 73.81 13 194 98 314 76.51 14 179 92 237 60.90 15 176 99 263 76.63 16 197 91 162 68.79 17‡ 193 88 192 71.15 18 180 98 133 65.76 *Indicates susceptibility to HAPE; ‡ indicates susceptibility to IPE.83  Table B4. Individual CT reconstruction algorithms and slice thicknesses for lung density pre- and post- exercise. Density (g*mL -1) For Each Spatial Frequency Reconstruction Algorithm Sub # B35 1mm B35 2mm B45 1mm B45 2mm B45 5mm B60 1mm B60 2mm B60 5mm Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post 1 0.178 0.177 0.178 0.178 0.173 0.172 0.175 0.174 0.178 0.177 0.177 0.175 0.178 0.176 0.174 0.174 2 0.198 0.205 0.198 0.205 0.193 0.200 0.194 0.201 0.198 0.203 0.195 0.202 0.196 0.202 0.194 0.200 3* 0.217 0.188 0.217 0.189 0.213 0.184 0.214 0.185 0.215 0.186 0.211 0.182 0.213 0.184 0.213 0.183 4* 0.249 0.215 0.249 0.216 0.243 0.210 0.244 0.211 0.254 0.215 0.246 0.214 0.249 0.215 0.251 0.213 5* 0.156 0.161 0.157 0.161 0.151 0.155 0.152 0.156 0.154 0.159 0.149 0.154 0.150 0.155 0.151 0.155 6‡ 0.208 0.200 0.208 0.200 0.203 0.195 0.204 0.196 0.210 0.202 0.206 0.198 0.206 0.200 0.205 0.197 7‡ 0.185 0.157 0.186 0.158 0.184 0.148 0.181 0.153 0.185 0.155 0.170 0.144 0.172 0.150 0.181 0.151 8 0.250 0.249 0.251 0.250 0.248 0.246 0.249 0.247 0.251 0.249 0.249 0.246 0.251 0.249 0.257 0.255 9* 0.151 0.156 0.152 0.157 0.146 0.151 0.147 0.152 0.151 0.156 0.150 0.154 0.150 0.155 0.147 0.152 10* 0.234 0.205 0.234 0.206 0.234 0.201 0.235 0.203 0.237 0.205 0.237 0.199 0.240 0.202 0.243 0.211 11* 0.160 0.152 0.161 0.153 0.158 0.150 0.159 0.151 0.163 0.153 0.165 0.153 0.165 0.154 0.160 0.149 12 0.237 0.250 0.238 0.250 0.233 0.246 0.234 0.247 0.237 0.251 0.236 0.250 0.238 0.251 0.235 0.250 13 0.238 0.216 0.238 0.217 0.234 0.212 0.235 0.213 0.238 0.215 0.233 0.210 0.235 0.212 0.237 0.213 14 0.260 0.240 0.260 0.240 0.257 0.237 0.258 0.237 0.258 0.239 0.262 0.241 0.263 0.241 0.257 0.237 15 0.193 0.187 0.193 0.188 0.187 0.181 0.188 0.182 0.193 0.187 0.190 0.184 0.190 0.185 0.190 0.184 16 0.227 0.208 0.227 0.208 0.224 0.204 0.224 0.205 0.226 0.208 0.226 0.207 0.228 0.209 0.232 0.214 17‡ 0.179 0.189 0.180 0.189 0.174 0.183 0.175 0.184 0.176 0.186 0.170 0.179 0.172 0.180 0.173 0.183 18 0.183 0.167 0.184 0.168 0.178 0.163 0.179 0.164 0.182 N/A 0.177 0.163 0.179 0.162 0.179 0.162 *Indicates susceptibility to HAPE; ‡ indicates susceptibility to IPE; Sub, subjects.   84  Table B5. Individual CT reconstruction algorithms and slice thicknesses for lung mass pre- and post- exercise. Mass (g) For Each Spatial Frequency Reconstruction Algorithm Sub # B35 1mm B35 2mm B45 1mm B45 2mm B60 1mm B60 2mm Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post 1 157.856 162.483 118.033 163.462 153.740 158.879 154.719 160.051 157.298 161.178 157.677 161.679 2 164.583 166.096 164.571 165.678 160.707 162.908 161.708 163.140 162.763 164.553 163.005 164.535 3* 176.977 163.212 176.715 163.690 174.230 159.725 174.368 160.702 173.506 158.925 173.948 160.122 4* 138.302 124.223 136.424 124.487 134.618 121.938 134.028 122.323 136.129 124.446 136.851 124.372 5* 101.949 103.420 102.210 103.586 98.443 100.277 99.052 100.744 97.688 99.877 98.046 100.117 6‡ 160.560 143.987 159.866 143.692 157.934 140.779 157.283 141.041 158.833 143.166 158.323 143.562 7‡ 120.624 107.934 120.774 108.111 117.328 101.459 118.006 104.896 110.487 98.877 111.333 103.100 8 131.044 133.301 131.276 133.896 130.622 132.453 128.034 132.980 131.531 132.635 132.186 134.054 9* 116.730 118.294 116.914 118.681 112.567 114.823 112.689 114.791 116.070 117.199 115.278 116.738 10* 125.665 125.629 125.863 125.893 127.133 123.195 127.896 124.051 129.490 121.575 131.084 123.326 11* 129.327 133.730 129.161 133.619 128.588 132.869 128.764 133.422 131.162 134.021 131.309 133.750 12 156.577 157.641 156.238 155.392 154.369 154.781 154.444 155.144 156.886 158.213 157.088 157.373 13 154.157 150.642 153.789 150.756 152.187 148.062 152.087 148.426 151.881 146.982 146.647 148.038 14 168.962 178.466 168.405 177.809 167.546 176.524 167.338 176.238 171.572 180.071 171.283 179.636 15 127.494 131.868 127.288 131.300 124.774 128.221 124.424 128.183 125.847 129.494 125.818 129.462 16 126.566 120.939 126.522 118.065 125.489 119.324 125.512 119.790 127.073 121.342 127.935 122.433 17‡ 113.850 124.926 114.217 125.183 110.685 121.995 111.347 122.191 108.565 119.562 109.559 119.855 18 107.041 105.902 107.494 105.979 104.275 103.448 105.105 103.727 104.320 103.681 104.961 102.819 *Indicates susceptibility to HAPE; ‡ indicates susceptibility to IPE; Sub, subjects.  85  Table B6. Individual CT reconstruction algorithms and slice thicknesses for lung volume pre- and post- exercise. Volume (mL) For Each Spatial Frequency Reconstruction Algorithm Sub # B35 1mm B35 2mm B45 1mm B45 2mm B60 1mm B60 2mm Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post 1 881.539 916.721 673.509 914.326 883.163 918.722 880.231 916.345 884.798 921.403 881.437 917.656 2 831.143 809.525 829.549 806.499 832.598 811.471 830.746 808.607 835.080 814.070 832.421 810.859 3* 819.859 868.433 816.862 866.397 822.098 870.490 819.065 868.450 824.146 872.293 820.676 870.414 4* 551.724 587.025 546.991 585.707 552.322 589.280 549.438 587.439 554.112 591.548 551.096 588.905 5* 652.715 642.298 650.837 640.407 654.359 644.141 652.321 642.255 656.164 646.254 653.888 644.217 6‡ 766.002 722.231 761.763 718.463 768.558 724.324 764.116 720.675 767.173 725.588 763.208 722.289 7‡ 652.303 693.467 651.198 692.357 653.756 691.757 652.763 693.772 650.541 692.556 649.068 695.157 8 404.466 412.090 375.094 382.772 249.630 414.524 222.349 384.306 251.076 415.812 232.829 385.752 9* 774.203 763.844 770.830 761.152 775.167 765.658 771.353 762.079 776.377 766.705 772.434 763.125 10* 414.644 468.279 384.649 434.411 418.925 469.345 388.864 435.593 421.071 467.949 390.950 434.315 11* 799.139 874.008 795.573 870.369 804.204 879.121 800.497 875.903 801.606 876.673 798.551 873.330 12 659.327 635.051 655.685 628.980 661.387 636.408 657.684 633.047 663.783 640.124 659.679 634.897 13 649.892 697.505 647.726 696.326 652.956 699.645 650.225 698.264 655.228 701.410 627.155 700.369 14 651.023 742.249 648.189 739.489 653.373 744.943 650.596 742.216 655.908 747.822 652.509 744.340 15 647.753 694.844 645.246 691.427 650.409 696.469 646.664 693.029 651.652 698.378 648.535 695.156 16 427.614 447.027 396.656 404.779 429.839 449.089 398.330 416.658 431.437 450.712 400.041 418.206 17‡ 634.379 662.541 632.822 661.205 636.003 664.703 634.301 662.948 637.849 666.142 636.113 664.100 18 585.003 632.999 584.370 631.015 586.971 635.359 586.024 633.240 589.144 637.685 587.980 634.353 *Indicates susceptibility to HAPE; ‡ indicates susceptibility to IPE; Sub, subjects.86  De ns ity  (g *m l-1 ) Pre Po st 0.0 0.1 0.2 0.3 PEr - 1mm PEs - 1mm  Figure B1. CT lung density pre and post exercise. B35 spatial frequency reconstruction algorithm, 1mm slice thickness. M ass  (g ) Pre Pos t 0 50 100 150 2 0 PEr - 1mm PEs - 1mm  Figure B2. CT lung mass pre and post exercise. B35 spatial frequency reconstruction algorithm, 1mm slice thickness. 87  Vo lum e ( ml ) Pre Pos t 0 500 1000 PEr - 1mm PEs - 1mm  Figure B3. CT lung volume pre and post exercise. B35 spatial frequency reconstruction algorithm, 1mm slice thickness. 88  Table B7. Pulmonary diffusion capacity of carbon monoxide breathing 21% oxygen (DL-21%), alveolar volume measured breathing 21% oxygen (VA), diffusion capacity of the alveolar membrane (DM) and capillary blood volume (VC) in each participant, pre and post exercise. Subject DL-21% (mL*min -1 *mmHg -1) VA (mL) VC (mL) DM (mL*min -1 *mmHg -1)  Pre Post Mean Pre Post Pre Post 1 36.23 37.47 8.13 84.56 83.16 49.35 51.29 2 40.99 34.81 7.89 122.48 74.11 52.23 51.15 3 47.42 45.61 10.73 81.88 80.22 67.82 68.39 4 31.59 27.94 6.42 105.85 87.49 39.84 34.44 5 22.94 21.13 5.25 69.63 45.51 29.02 29.93 6 29.35 26.39 7.06 66.87 50.15 42.48 42.42 7 24.19 23.54 5.48 56.24 44.68 34.09 37.05 8 26.88 23.19 4.84 85.41 63.98 34.31 29.94 9 23.89 21.52 6.05 67.17 62.46 31.43 27.42 10 36.98 34.49 5.77 144.74 69.46 43.34 45.75 11 43.46 42.44 8.22 148.46 105.98 54.99 56.44 12 49.36 43.44 7.12 108.46 94.84 67.58 60.49 13 37.76 38.92 8.26 67.57 59.34 58.45 63.47 14 32.34 27.02 6.09 110.90 166.42 40.36 30.19 15 30.88 26.23 5.10 79.71 67.44 36.31 28.95 16 22.88 19.37 5.49 38.77 35.66 34.45 28.89 17 27.48 21.83 7.05 96.11 53.80 39.03 35.82 18 26.14 19.97 4.87 87.47 57.83 32.86 26.76  89   D L -2 1% (m l *m in- 1 * mm Hg -1 ) Pre Pos t 0 10 20 30 40 50 PEr PEs  Figure B4. Pulmonary diffusion capacity of carbon monoxide breathing 21% oxygen (DL-21%) in each participant, pre and post exercise.  D M (m l *m in- 1 * mm Hg -1 ) Pre Pos t 0 20 40 60 80 PEr PEs  Figure B5. Pulmonary membrane diffusion capacity of carbon monoxide breathing 21% oxygen (DM) in each participant, pre and post exercise.  90   V C (m l) Pre Pos t 0 50 100 150 200 PEr PEs  Figure B6. Pulmonary capillary blood volume (VC) in each participant, pre and post exercise.   

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