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The effects of two paradigms of intermittent hypoxia on human cardio-ventilatory responses and cerebral… Foster, Glen Edward 2004

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The effects of two paradigms of intermittent hypoxia on human cardio-ventilatory responses and cerebral tissue oxygenation. by Glen Edward Foster B.H.K., The University of British Columbia, 2002 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF T H E REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE In T H E F A C U L T Y OF G R A D U A T E STUDIES SCHOOL OF H U M A N KINETICS T H E UNIVERSITY OF BRITISH COLUMBIA December, 2004 © Glen E. Foster, 2004 A B S T R A C T The purpose of this study was to determine the ventilatory, cardiovascular, and cerebral tissue oxygen responses to two paradigms of normobaric, isocapnic, intermittent hypoxia (IH). Eighteen male subjects were randomly assigned to one of two I H groups; short duration I H (SDIH) was exposed to 5 minutes of 12% O 2 separated by 5 minutes of normoxia for one hour, and long duration IH (LDIH) was exposed to 30 minutes of 12% O2. Both groups had 10 daily exposures over a twelve day period. The isocapnic hypoxic ventilatory response was measured before (preHVR) and after (postHVR) each daily exposure on day 1, 3, 5, 8, 10, 12 and again 3 and 5 days following the end o f I H . The hyperoxic hypercapnic ventilatory response ( H C V R ) was determined following rest on days 1, 12, 15, and 17. During all procedures, ventilation, beat-by-beat blood pressure, heart rate (HR) arterial oxyhemoglobin saturation (SaO-2), and cerebral tissue oxygenation ( SCO2 ) were measured. The p reHVR increased throughout I H exposure regardless o f paradigm and returned to resting levels by day 17 (Day 1: 0.84 ± 0.50; Day 12: 1.20 ± 1 . 0 1 ; Day 17: 0.95 ± 0.58 1 min" 1 %Sa02"'; p= 0.002). The H C V R did not change throughout I H . The pos tHVR was blunted compared with the p r e H V R (p= 0.02). There were no differences in the change in systolic blood pressure sensitivity (ASBP/ASa02), diastolic blood pressure sensitivity ( A D B P / A S a 0 2 ) , heart rate sensitivity (AHR/ASaCh), cardiac output sensitivity (ACO /ASa0 2 ) , stroke volume sensitivity (ASV/ASaC>2), and total peripheral resistance sensitivity (ATPR/ASaO^) to hypoxia following IH. The change in cerebral tissue oxygen saturation sensitivity to hypoxia (ASc0 2 /ASa0 2 ) was less on day 12 (Day 1: -0.51 ± 0.13; Day 12: -0.64 ± 0.181 p= 0.0002) and the change in cerebral tissue deoxyhemoglobin concentration (AHHb /ASa0 2 ) i i was more on day 12 (Day 1: 0.34 ± 0.21; Day 12: 0.44 ± 0.14 uM %Sa.02']; p= 0.007). These differences had returned to baseline by day 17. Acute exposure to SDIH increased mean arterial pressure (MAP; p= 0.005) but LDIH did not (p>0.05). Intermittent hypoxia did not improve exercise ventilatory efficiency during exercise. In conclusion, exposures to SDIH and LDIH have similar effects on the ventilatory, cardiovascular, and cerebral oxygen responses to acute progressive hypoxia. However, acute exposure to SDIH increases MAP while LDIH does not. iii TABLE OF CONTENTS Abstract 1 1 List of Tables v List of Figures vi Introduction 1 Materials and Methods 8 Results 14 Discussion 22 Appendix A. Review of Literature 64 Appendix B. Individual Raw Data 76 References "113 iv LIST OF TABLES Table 1. Descriptive and resting pulmonary function data 38 Table 2. Peak exercise values during maximal cycle ergometry tests 39 Table 3. Ventilatory efficiency at submaximal exercise intensities 40 Table 4. Effects of intermittent hypoxia on basal ventilatory and cardiovascular variables during eupnea 41 Table 5. Heart rate variability data throughout intermittent hypoxia 42 Table 6. Average level of isocapnia maintained throughout each preHVR and postHVR 43 Table 7. Effects of intermittent hypoxia on systolic, diastolic, and mean arterial blood pressure sensitivity to hypoxia 44 Table 8. Relationship between the changes in cardiovascular responses and changes in the ventilatory response to hypoxia for all subject, SDIH, LDIH, and that reported by Katayama et al. (2001) 45 Table 9. Effects of intermittent hypoxia on cardiac output, heart rate, stroke volume, and total peripheral resistance sensitivity to hypoxia....' 46 Table 10. Effects of intermittent hypoxia on NIRS variables 47 Table 11. Effects of exposure to SDIH and LDIH on respiratory variables during hypoxia 48 Table 12. Effects of exposure to SDIH and LDIH on cardiovascular function during hypoxia 49 v L I S T O F F I G U R E S Figure 1. Displays the experimental protocol 50 Figure 2. Raw data trace during the first day of the experimental protocol. A. Individual subject from LDIH 51 B. Individual subject from SDIH 52 Figure 3. Typical hypercapnic ventilatory response for one representative subject 53 Figure 4. Effects of intermittent hypoxia on the hypercapnic ventilatory response for SDIH and LDIH subjects 54 Figure 5. Typical hypoxic ventilatory response for one representative subject on day 1 prior to TH exposure and again on day 12 on the last day of exposure 55 Figure 7. Displays the hypoxic ventilatory response for one individual subject prior to each exposure throughout intermittent hypoxia and the H V R measured on one occasion and 5 days later for 5 consecutive days for the same subject during a different study 56 Figure 6. Effects of intermittent hypoxia on the hypoxic ventilatory response occurring prior to each hypoxic exposure for all subjects 57 Figure 8. Displays the effects of intermittent hypoxia on preHVR and postHVR. 58 Figure 9. Displays the relationships and sensitivities to hypoxia of (A) systolic (SBP) and (B) diastolic blood pressure (DBP), (C) heart rate (HR), (D) stroke volume (SV), (E) cardiac output (CO), (F) total peripheral resistance (TPR) for one individual subject 59 Figure 10. Effects of intermittent hypoxia on SBP and DBP sensitivity to hypoxia 60 v i Figure 11. Displays the relationship and sensitivity to hypoxia of cerebral (A) tissue oxygen saturation (ScCh), (B) oxyhemoglobin concentration (O^Hb) (C) deoxyhemoglobin concentration (HHb) (D) total hemoglobin concentration (cHb) for. one individual subject 61 Figure 12. Effects of intermittent hypoxia on cerebral oxygen saturation sensitivity to hypoxia for all subjects 62 Figure 13. Displays the change in cerebral oxygen saturation during the preHVR on day 1 and day 12 for all subjects in (A) SDIH and (B) LDIH 63 vn I N T R O D U C T I O N Exposure to hypoxia affects animal and human physiology in numerous ways. In response to acute isocapnic hypoxia, ventilation, blood pressure and muscle sympathetic nerve activity increase (Xie et al, 2000). Two types of hypoxic exposure can be distinguished: continuous hypoxia (CH) and intermittent hypoxia (IH). Continuous hypoxia can be described as a single exposure to a sustained hypoxic stimulus over a prolonged period. There are two forms of IH: long duration intermittent hypoxia (LDIH) and short duration intermittent hypoxia (SDIH) (Peng & Prabhakar, 2004). From the available studies, LDIH is typically defined as a single daily episode of hypoxia lasting 30 minutes to five hours that occurs every day for more than five days, while SDIH typically involves several daily bouts of hypoxia (3-12 bouts) lasting less than 5-7 minutes with each bout of hypoxia being separated by normoxia. Like LDIH, SDIH involves daily exposures that continue for more than five days. Continuous hypoxia typically occurs in individuals who inhabit environments at high-altitude, while IH seems to occur more frequently in daily life, as in situations of brief episodic sojourns to high-altitude or during repeated apneas, such as in sleep apnea. In both animal and human studies, LDIH and SDIH affect the control of breathing (Gozal & Gozal, 2001; Mitchell et al, 2001; Prabhakar, 2001; Mitchell & Johnson, 2003; Morris et al, 2003), the cardiovascular system (Earley & Walker, 2002; Gonzales & Walker, 2002; Jernigan & Resta, 2002), and the autonomic nervous system (Morgan et al, 1995; Smith & Muenter, 2000; Yasuma & Hayano, 2000). Unlike CH, IH may contribute to the effects of pathological conditions, such as sleep apnea and chronic obstructive pulmonary disease (Prabhakar, 2001). Intermittent exposure to hypoxia for a prolonged period of time (i.e. several years) is associated with secondary conditions including systemic hypertension, myocardial and brain infarctions, and cognitive dysfunction (Prabhakar, 2001). Recurrent episodes of hypoxia are also common in humans without pathophysiologies, such as those who voluntarily engage in breath-holding -1 -activities (i.e. breath-hold diving) (Andersson et al, 2002) or travel to high altitude regularly (Powell & Garcia, 2000). These individuals display characteristics in respiratory and cardiovascular control that may be advantageous to them. Breath-hold divers demonstrate a reduced ventilatory response to hypoxia and have an enhanced diving response that allows them to sustain longer breath-hold dives and conserve oxygen (Lindholm et al, 1999; Andersson et al, 2002). On the contrary, individuals who travel to high altitude regularly demonstrate an enhanced ventilatory response to hypoxia; this quality has been suggested to reduce the incidence of acute mountain sickness (Beidleman et al, 2004). It is important to note that individuals with sleep apnea or breath-hold divers are not exposed exclusively to hypoxia. The physiological outcomes of their activities, whether pathological or not, are complicated by marked hypercapnia. However, several animal studies do show that exposure to SDIH, modeled after sleep apnea, leads to secondary hypertension and that hypercapnia is not necessary [reviews: (Fletcher, 2001; Neubauer, 2001; Prabhakar et al, 2001)]. Respiratory function is altered following exposure to hypoxia and is referred to as respiratory neural plasticity (Powell et al, 1998). Various animal studies have demonstrated respiratory neural plasticity within the central nervous system in response to hypoxia (Morris et al, 2003). Interestingly, the response to C H is different from IH. In the rodent model, chronic IH enhances hypoxic sensitivity and leads to sensory long-term facilitation in the carotid body (Peng et al, 2001; Prabhakar, 2001), while sustained hypoxia does not (Mitchell et al, 2001). The study of the control of breathing in humans is ethically limited; as a result, animal models play a major role in the interpretation and analysis of human studies. Studies involving normal human subjects also demonstrate respiratory neural plasticity. As in the rodent model, human hypoxic sensitivity increases with repeated exposure to hypoxia (Katayama et al, 1998; Tansley etal, 1998; Katayama et al, 1999; Garcia et al, 2000b; Katayama et al, 2001a; Katayama et al, 2001b; Mahamed & Duffm, 2001; Katayama et al, 2002; Mateika et al, 2004) although long - 2 -term facilitation cannot be detected (Mateika et al, 2004). Other human studies involving patients who have undergone carotid body resection as a treatment for asthma or carotid body tumors (Gross et al, 1976; Honda et al, 1988; Timmers et al, 2003) indicate that the carotid body plays an inhibitory role for the heart rate response and an excitatory role for the ventilatory response to hypoxia. Timmers et al (2003) reported an abolished ventilatory response to hypoxia following bilateral carotid body resection. Similarly, Honda et al (1988) noted the absence of the ventilatory response to progressive eucapnic hypoxia in bilateral carotid body resected subjects; an enhanced tachycardic heart rate response was also seen in these patients. Making direct comparisons between studies is difficult as there appears to be no standard IH protocol. Some studies expose human subjects to isocapnic hypoxia [controlled end-tidal partial pressure of CO2 (PetC02)] (Garcia et al, 2000a) while others expose subjects to poikilocapnic hypoxia (uncontrolled P e t C 0 2 ) (Tansley et al, 1998; Katayama et al, 2001b). Patterns, durations, and hypoxic intensities vary throughout all IH studies and may involve normobaria (Serebrovskaya et al, 1999; Mahamed & Duffin, 2001; Ainslie et al, 2003; Mateika et al, 2004) or hypobaria (Sato et al, 1992; Sato et al, 1994; Katayama et al, 1998; Katayama et al, 1999; Garcia et al, 2000c; Katayama et al, 2001a; Katayama et al, 2001b). Intermittent hypoxic studies have even involved simultaneous exercise, training (Levine et al, 1992; Katayama et al, 1998; Katayama et al, 1999, 2001a). Whether or not the changes in respiratory and cardiovascular physiologies are similar among all of these conditions is unknown and requires further study. In contrast to the rodent model, human studies involving high altitude CH for a week or more have demonstrated an increase in the hypoxic ventilatory response (HVR) that subsequently returns to normal within a week of descent to sea-level (Sato et al, 1992; Sato et al, 1994). More similar to the rodent model are the human studies involving both LDIH and SDIH and equivocally demonstrate increases in HVR (Katayama et al, 1998; Garcia et al, 2000b, 2000c; Katayama et al, 2001b; Katayama et al, 2002). Garcia et al (2000c) compared - 3 -five days of hypo-baric IH at rest (two hours daily at 3800m) with eight weeks of CH (also at 3800m). Both LDIH and C H induced similar changes in magnitude of HVR; however, two weeks of C H were necessary to reach the same change in HVR seen after only five days of LDIH. Most paradigms of IH in humans evoke an increase in HVR; however, the available data on the HCVR is not so clear. The HC V R has been reported to either remain unchanged (Katayama et al, 1998; Katayama et al, 1999, 2001a; Mahamed & Duffm, 2001) or increase following IH (Ainslie et al, 2003). Several studies involve IH with concurrent exercise training (Katayama et al, 1998; Katayama et al, 1999) and each study involves a different method for determining HCVR making it difficult to directly compare studies. The first and most common method of determining H C V R is the rebreathing method (Read, 1967) which is thought to be a measure of CO2 sensitivity at the central chemoreceptor (Mohan et al, 1999). Using this method and exercise training during IH, 30 min of hypobaric hypoxia at 432 mmHg for either six days or two weeks, shows no change in the central chemoreceptor response to CO2 (Katayama et al, 1998; Katayama et al, 1999). However, Ainslie et al. (2003) showed an increase in the hypercapnic ventilatory response following five nights of normobaric poikilocapnic hypoxia (13.8% O2) using the rebreathing method. Other investigators have used the single breath CO2 response test (HCVRsb), which is thought to be a measure of the peripheral chemoreceptor response to CO2 (McClean et al, 1988). No change in HCVRsb was seen following 30 minutes of hypobaric hypoxia at 432 mmHg for six days with concurrent exercise training (Katayama et al, 1999) and also following 1 hour of hypobaric hypoxia at 432 mmHg for two weeks without exercise training (Katayama et al, 2002). Finally, a novel approach of determining the central chemoreceptor response to CO2 has been employed by Mahamed et al. (2001). This method involves prior hyperventilation before commencing the rebreathe at different iso-oxic levels and allows for the determination of the chemoreflex threshold to C 0 2 . Using the modified - 4 -rebreathing technique, changes in the peripheral chemoreflex to CO2 were measured in hyperoxia and in hypoxia. Following twenty minutes of isocapnic hypoxia daily for 14 consecutive days, an increase in the CO2 threshold occurred only in the presence of hypoxia, but not hyperoxia (Mahamed & Duffin, 2001). The authors interpreted this result as indicating changes in the peripheral chemoreflex and not the central chemoreflex. The acute cardiovascular response to" hypoxia involves an increase in cardiac output (CO), systemic arterial vasodilation, and pulmonary arterial vasoconstriction (Semenza, 1999). Cerebral blood flow velocity (Vovk et al, 2002), heart rate (HR), and arterial blood pressure increase with progressive isocapnic hypoxia and hyperoxic hypercapnia (Yasuma & Hayano, 2000). Twenty minutes of sustained isocapnic hypoxia elicits increases in heart rate, limb blood flow, blood pressure, and muscle sympathetic nerve activity (Morgan et al, 1995; Xie et al, 2000). Intact peripheral chemoreceptors appear to be necessary for the blood pressure in rats to increase in response to SDIH patterned after that of sleep apnea in humans (Fletcher et al, 1992). Few studies have examined the cardiovascular response to intermittent hypoxic exposure in humans. Katayama et al. (2001b) studied the cardio-ventilatory response to progressive isocapnic hypoxia before and after one hour of daily exposure to 4,500 m (~12 % O2) for 7 days. Resting ventilation, blood pressure, and heart rate did not change after IH. There was, however, an increase in the systolic (SBP) and diastolic (DBP) blood pressure response to progressive hypoxia. These changes in cardiovascular sensitivity were accompanied by an increase in HVR. Alternatively, in a cat model, no changes in the blood pressure response to hypoxia were present following four days of chronic intermittent hypoxia (hypoxic episodes lasting for ~ 90s, 8 hours/day, inspired PO2 ~ 75 mmHg) (Rey et al, 2004). Recently published animal work suggests IH may alter both peripheral and cerebrovascular vasomotor activity as a result of a hypoxia associated endothelial dysfunction (Earley & Walker, 2002; Gonzales & Walker, 2002; Jernigan & Resta, 2002; Altay et al, 2004; - 5 -Phillips et al, 2004). These alterations in vasomotor activity may differ depending on the location of the vascular bed. Mesenteric resistance arteries isolated from rats exposed to 48 hours of hypobaric hypoxia (380 mmHg) have attenuated vasoconstrictor reactivity (Earley & Walker, 2002; Gonzales & Walker, 2002). On the other hand, rats exposed to a similar level of hypobaric hypoxia for four weeks have an attenuated endothelium-derived nitric oxide-dependent pulmonary vasodilation (Jernigan & Resta, 2002). Another study exposed rats to SDIH and assessed endothelial function of resistance vessels in skeletal muscle and cerebral circulations and found that exposure to chronic IH severely blunts vasodilator responsiveness to acute hypoxia (Phillips et al, 2004). Impaired blood flow regulation caused by endothelial dysfunction could limit oxygen delivery during acute episodes of hypoxia. No similar studies have been performed in humans. One study does assess, however, the effects of five consecutive nocturnal hypoxic exposures in humans (Kolb et al, 2004). Using an end-tidal forcing technique, cerebral blood flow velocity responses to acute variations in O2 and CO2 were determined before and after the nocturnal hypoxic episode. Their results show that discontinuous hypoxia (nocturnal hypoxia separated by daytime normoxia) elicits an increase in the sensitivity of cerebral blood flow velocity to acute variations in O2 and CO2. In another study, the cerebral blood flow velocity response to 5-minute steps of isocapnic hypoxia and hyperoxic hypercapnia were measured before and during a 5-day sojourn at 3,810 m altitude (Jensen et al, 1996). The results from this study indicate that the cerebral vascular response to acute isocapnic hypoxia may increase during acclimatization at high altitude. However, it is unknown if IH affects cerebral oxygenation. Hypothesis The primary purpose of this study was to compare normobaric, isocapnic SDIH with LDIH exposure and to follow changes in ventilatory, cardiovascular, and cerebral tissue oxygen responses over a twelve-day period and again over a five-day period after hypoxic exposure had ended. It was hypothesized that IH would increase the cardio-ventilatory responses to acute hypoxia, but not to hypercapnia, and that those individuals exposed to SDIH would have a greater response than those exposed to LDIH. It was further hypothesized that the change in cerebral oxygenation during acute hypoxia would increase over the twelve-day period and would remain increased for at least five days after hypoxic exposure had been completed. M A T E R I A L S AND M E T H O D S All procedures and methods were approved by the clinical research ethics board of the University of British Columbia and conformed to the Declaration of Helsinki. All testing occurred within the Health and Integrative Physiology Laboratory at the University of British Columbia. Subjects Eighteen active, healthy male volunteers were randomly assigned to one of two intermittent hypoxia groups. All subjects had normal cardiopulmonary function and were excluded from participation if they had been diagnosed with sleep apnea, had a history of smoking, or if they were hypertensive (systolic>140mmHg; diastolic>90mmHg). All subjects were life-long residents at sea-level and had not sojourned to altitude (>3,000m) in the year prior to testing. None of the subjects participated in breath-hold diving or trained/competed as endurance athletes, as this has been known to affect ventilatory responses (Byrne-Quinn et al, 1971;Ferretti, 2001). Experimental Protocol The experimental protocol is displayed in Figure 1. Subjects reported to the laboratory, on the first day of testing when procedures were explained and informed consent was obtained. Anthropometric measures and pulmonary function tests were determined on Day 1 prior to ventilatory response testing and IH. Subjects were exposed to a total of ten intermittent hypoxic exposures throughout a twelve-day period. Following the twelve-day IH period, subjects returned three and five days later to determine the time course of recovery for the cardio-ventilatory responses. The H C V R was determined after ten minutes of rest (eupnea) on Days 1, 12, 15, and 17. The H V R was determined immediately before intermittent hypoxic exposure - 8 -(preHVR) and five minutes following exposure (postHVR) on Days 1, 3, 5, 8, 10, 12, 15, and 17. On Days 1, 12, 15, and 17 the H C V R preceded the preHVR test by a minimum of five minutes or until cardio-ventilatory parameters returned to eupneic levels. A maximal cycle exercise test occurred on Days 1 and 12 to determine the subjects' maximal oxygen consumption (V02msx) and to determine if intermittent hypoxia improves ventilatory efficiency during submaximal and maximal exercise. For both experimental groups, IH exposure involved isocapnic exposure to a fraction of inspired O2 ( F i 0 2 ) of 12% (balance N2) for a total duration of 30 minutes. The SDIH group (n=9) was exposed to a five-minute hypoxia to five-minute normoxia cycle for one hour, while the LDIH group (n=9) was exposed to 30 minutes of sustained hypoxia. Measurements and Procedures All data was acquired in real-time using an analog-to-digital converter (Powerlab/16SP M L 795, AD Instruments, Colorado Springs, CO, USA) interfaced with a personal laptop computer (Satellite, Toshiba, Irvine, CA, USA). During the measurement of heart rate variability all data was sampled at 1000 Hz; during all other procedures data was sampled at 200 Hz and stored for subsequent analysis. Commercially available software was used to analyze ventilatory and near-infrared spectroscopy variables (Powerlab V5.02, A D Instruments, Colorado Springs, CO, USA) and cardiovascular variables (Beatscope VI . 1, FMS, Arnhem, Netherlands). Pulmonary Function Testing. Subjects performed three forced vital capacity (FVC) maneuvers using a calibrated spirometer (Spirolab II, Medical International Research, Via del Maggiolino, Roma, Italy). Recorded parameters included F V C , forced expiratory volume in one second ( F E V 1 . 0 ) , and the ratio of F E V 1 . 0 to F V C ( F E V 1 . 0 / F V C ) . The above parameters were tested in accordance with the procedures outlined by the American Thoracic Society (1995). Predicted values were determined for each individual based on European Respiratory Society prediction equations for adult men (Quanjer et al, 1993). Maximal Cycle Exercise Test. Maximal oxygen consumption was determined using a ramped exercise test on an electronically braked cycle ergometer (Excalibur, Lode, Groningen, Netherlands). Workload was increased in a ramped fashion (30-watts/min) until subjects reached volitional fatigue. Metabolic and ventilatory parameters were recorded using a calibrated open-circuit system (Physio-Dyne, Max-1, Fitness Instrument Tech., NY, USA). Heart rate was obtained using a telemetric HR monitoring system (S410, Polar Electro Inc., Kempele, Finland). In addition to volitional exhaustion, all subjects fulfilled at least two of the following criteria for V02m3X: 1) heart rate > 220-age, 2) respiratory exchange ratio > 1.10, 3) no further increase in V02 with increasing workload. Hyperoxic Hypercapnic Ventilatory Response (HCVR). HCVR was assessed by a modified rebreathing technique (Read, 1967). Subjects were asked to maximally expire and were then switched to a rebreathing bag (6% CO2; 94% O2) and took three full breaths to facilitate mixing between the lungs and bag (Rebuck, 1976), after which they were asked to "breathe as you feel necessary". Rebreathing continued until PetC02 reached 60-65 mmHg or for a maximal duration of five minutes. Gas was sampled at the mouth and analyzed using an infrared CO2 analyzer (CD-3 A, AEI, Pittsburgh, Pennsylvania, USA). Inspired minute ventilation (V,) was plotted as a function of PetC02 and the linear regression relating these two variables was used to represent the HCVR (i.e. the slope of the line expressed as 1 min' "'mmHg"1). V, andPetC0 2 were averaged over 10 second intervals prior to plotting HCVR. - 10-Isocapnic Hypoxic Ventilatory Response (HVR). HVR was assessed by modifications of a method previously described (Weil et al, 1970; Harms & Stager, 1995; Derchak et al, 2000; Guenette et al, 2004; Koehle et al, In Press). Subjects breathed room air from a mixing chamber (13.5 liters) and 100% N 2 was gradually added to the inspiratory circuit to evoke a gradual drop in Sa02 to 75% over an approximate 5 minute period. Sa02 was measured at the finger using a pulse oximeter (3740, Ohmeda, Louisville, CO, USA). Isocapnia was maintained during the test by the addition of 100% CO2 through a 25 gauge needle inserted into the inspiratory circuit 30 cm from the inspiratory valve. Resting PetC02 was determined during a ten-minute rest period which occurred at the beginning of each day. The F i 0 2 was determined by analyzing gas sampled from the proximal side of the inspiratory valve (S-3A, AEI, Pittsburgh, Pennsylvania, USA). CO2 was sampled at the mouth and analyzed as described above. V, was plotted as a function of Sa02 and the slope of this line was taken to represent the HVR (expressed as 1 min' '' % S a 0 2 " ' ) . V, and S a 0 2 were averaged over 10 second intervals prior to plotting HVR. Cardiovascular Parameters. Beat-by-beat SBP,. DBP, and mean arterial pressure (MAP) were obtained during rest, HCVR, HVR, and IH using finger pulse photoplethysmography (Finometer, FMS, Arnhem, Netherlands). MAP was calculated from SBP and DBP using the following formula: MAP = DBP + 1/3(SBP-DBP). The photoplethysmograph was placed on the mid-phalanx of the middle digit of the left hand. Beat-by-beat blood pressure was calibrated against an automated blood pressure measurement (BPM-100, V S M Medtech Ltd., Vancouver, Canada) taken from the right arm at the level of the heart every three minutes. Cardiovascular analysis included determination of heart rate (HR), cardiac output (CO), stroke volume (SV), and total peripheral resistance (TPR), all obtained from arterial pressure using a three-element model of arterial input impedance (Wesseling et al, 1993; Harms et al, 1999; Houtman et al, 1999; Remmen et al, 2002; Van Lieshout et al, 2003). Cardiovascular sensitivity to hypoxia was determined as per previously published studies and was expressed as ASBP/ASa02, ADBP/ASa0 2, AMAP/Sa0 2 , AHR/ASa0 2 , ACO/ASa0 2 , ASV/ASa0 2 , and ATPR/ASa0 2 (Insalaco et al, 1996; Katayama et al, 2001b). Similar analyses during hypercapnia were not undertaken because of the inability to demonstrate linearity of the cardiovascular variables and PetC0 2. Al l cardiovascular parameters were averaged over 10 second intervals. Near-infrared Spectroscopy (NIRS). Cerebral tissue oxygen saturation (Sc02) and changes in oxyhemoglobin concentration (0 2Hb), deoxyhemoglobin concentration (HHb), and total hemoglobin concentration (cHb) were determined using near-infrared spectroscopy at a sampling rate of 2 Hz (Niro 300, Hamamatsu Phototonics K. K., Sunayama-Cho, Hamamatsu-city, Japan). The cerebral optodes were applied so that the detection probe sat toward the middle of the forehead and the emission probe was 4-5 cm away, towards the right side, avoiding the temporal muscles, sinuses, and the hairline as previously described (Madsen & Secher, 1999). Optodes were placed in a black plastic holder and applied to the head with a bandage to shield the light and maintain optode separation. The path-length value was determined as the product of the source-detector probe spacing (in cm) multiplied by the differential path-length factor (DPF) for the brain (Madsen & Secher, 1999). A DPF of 5.92 was used for the brain as determined by Van der Zee et al. (1992) where a 4 or 5 cm probe spacing would have a pathlength of 23.7 cm or 29.6 cm respectively. Like the other cardiovascular parameters, Sc0 2 , 0 2 Hb, HHb, and cHb sensitivity to hypoxia was expressed as ASc0 2/ASa0 2 , AOiHb/ASa0 2 , AHHb/ASa0 2, and AcHb/ASa0 2. - 12-Heart Rate Variability (HR V). Heart rate variability was determined during the ten-minute resting (normoxia) period on days 1, 12, 15, and 17. HRV was measured in order to determine if resting shifts in autonomic function occurred through intermittent hypoxia exposure. Subjects were monitored via an E C G (ML 132, ADInstruments, Colorado Springs, CO, USA), configured in the standard bipolar limb lead I and sampled at 1 kHz. Analysis occurred off-line as described previously (Task Force, 1996). Measured R-R intervals were determined from the electrocardiogram and the resulting tachogram was fast Fourier transformed (FFT). The high frequency (HF), low frequency (LF), and very low frequency (VLF) bands were defined as 0.15-0.4 Hz, 0.04-0.15 Hz, and <0.04 Hz respectively. HRV calculations were performed on normal R-R intervals and ectopic intervals. If it was too difficult to accurately select the R-wave from the E C G signal, then a 45 Hz low pass filter was applied. In addition, a derivative function was applied when necessary to correct for shifts in the E C G baseline. Statistical Analysis All data are expressed as means ± SD unless otherwise indicated. Statistical software (Statistica V.6.1, Statsoft Inc., Tulsa, OK, USA) was applied to detect differences between groups, between subjects, and between pre and post measures using repeated measures M A N O V A . When significant F-ratios were detected, Tukey's post hoc analysis was applied to determine where the differences lay. Pearson product moment correlations were implemented to determine relationships between selected dependent variables. Statistical significance was set at p<0.05. - 13 -R E S U L T S Subject Characteristics All eighteen subjects completed 10 intermittent hypoxic exposures over the twelve-day period. One subject did not complete the final day 17 ventilatory response testing and another subject did not complete either maximal exercise test. Missing (incomplete) data on day 17 for this one subject was replaced with the group mean. Mean subject characteristics are displayed in Table 1. Subjects were not statistically different from each other based on age, mass, or pulmonary function; however, the SDIH group was slightly taller than the LDIH group (F= 7.17; df= 16; p= 0.01). Effects of IH on maximal exercise performance and on the ventilatory response to exercise Maximal exercise data is displayed in Table 2. There were no differences in any maximal or submaximal exercise data between SDIH and LDIH conditioned individuals. Therefore, all data was pooled together. Maximal V02, VC02, RER, and the ventilatory equivalents for oxygen and C 0 2 were not affected by exposure to LDIH or SDIH. In addition, peak power, maximal ventilation and heart rate were also unaffected by exposure to either paradigm of intermittent hypoxia. The ventilatory response to exercise was determined at 20, 40, 60, 80, and 100% of maximal oxygen uptake and CO2 production and is displayed in Table 3. V,, tidal volume (V t), and breathing frequency (FD) were not affected at any exercise intensity. Effects of IH on basal ventilatory and cardiovascular variables Basal ventilatory and cardiovascular variables measured during eupnea are displayed in Table 4. Also displayed in Table 4 are the coefficients of variation for each variable across 8 - 14-days. There were no differences between groups for any resting ventilatory or cardiovascular variable. Slight increases in resting breathing frequency (+2-3 breaths min"1) were detected on day 8 and 10 (F= 2.44; df= 1, 112; p= 0.02), but tidal volume and overall minute ventilation were not different (p>0.05). Furthermore, PetCC>2 was not different on any day and the mean coefficient of variation was 3.2 %. Basal blood pressure did not differ on each experimental day; however, resting HR was slightly elevated (+7 bpm) at day 10 compared to days 1 and 3 (F= 2.34; df= 7, 112; p= 0.03). Although HR was slightly elevated, there was no difference in CO, suggesting that SV was slightly reduced even though not detectable by statistical analysis. In addition, heart rate variability did not change over the course of the intermittent hypoxic exposures. The HF and LF spectral components of HRV normalized to total power and the LF/HF ratio are displayed in Table 5. Resting TPR and Sc02 did not change throughout the course of the experiment. Effects of I H on the ventilatory response to hyperoxic progressive hypercapnia Raw data traces for selected variables are shown in Figure 2a and 2b for the duration of the first experimental day for one representative subject from the SDIH group and one subject from the LDIH group. During the H C V R procedure, inspiratory flow increases with increasing PetC02 and the relationship between PetC02 and V, is linear. A typical H C V R is plotted in Figure 3 for one representative subject. This ventilatory response is mediated largely by an increase in V t while Fb remains relatively unchanged. The means for each group is displayed in Figure 4. The H C V R was not different on days 1, 12, 15, or 17 and was not different between SDIH conditioned individuals or LDIH conditioned individuals. The means ± SD for all subjects pooled together on day 1, 12, 15, and 17 were 2.49 ± 1.49, 1.74 ± 2.37, 2.35 ± 1.88, and 2.12 ± ' 1.15 1 min"1 mmHg"1 respectively. - 15 -Effects of I H on the ventilatory response to progressive isocapnic hypoxia During the H V R procedure, the FiC>2 was reduced from 21% to approximately 5 % over approximately a 5-minute period, thus evoking an increase in inspiratory flow (Figure 2a and 2b). The increase in ventilation is mediated largely by increases in V t and is linearly related to the reduction in SaO"2. Displayed in Figure 5 is an example of the preHVR for one subject on day 1 prior to intermittent hypoxic exposure and again on day 12 on the last day of exposure to IH. The preHVR and postHVR were not different between groups on any day of its measurement. Therefore, the HVR data for all subjects was pooled together. Displayed in Figure 6 is the mean preHVR data for all subjects. There were significant increases in preHVR following 10 intermittent hypoxic exposures over a twelve-day period (F= 3.42; df= 7, 112; p= 0.002). This increase in preHVR was at a maximum by day 12 and subsequently returned to baseline by five days after the exposure to IH had ended. Figure 5 shows the preHVR for one individual subject on day 1 and again on day 12. This subject's preHVR had nearly doubled by day 12, increasing from 1.01 on day 1 to 1.99 on day 12. Several of the subjects (n = 4) involved in this study took part in another study completed in our laboratory 4 -6 months earlier (Koehle et al, In Press). During that study, the subject's HVR was measured during an isolated occasion, and then five days later, the HVR was measured repeatedly over five consecutive days. The methods used in that study are identical to the method used during this study. Displayed in Figure 7 are the HVR's for one subject who took part in both studies. In this Figure the dotted trace indicates the repeated H V R measurements and the solid trace indicates the preHVR for each day of its measurement throughout and following exposure to LDIH. This subject does not display a peak in his H V R on day 12 and instead the HVR reaches a maximum on day 15. This - 16-was true for several subjects. Not all subjects display a peak in their preHVR on day 12. Instead some show a peak on day 10 (n = 3) or 15 (n = 1). The increase in preHVR at day 12 was mediated by a greater increase in V t (F= 2.44; df= 7, 112; p= 0.02); on day 1, V t increased by 0.74 ± 0.38 liters but on day 12, the change in V t was 0.92 ± 0.41 liters at identical levels of SaCV The Fb did not change over the course of IH. The 4 average PetCG*2 at which each preHVR was maintained was not different throughout the course of the study (Table 6). Displayed in Figure 8 are the mean preHVR and postHVR for all subjects throughout the 12-day IH protocol. The postHVR measured five minutes following each IH exposure was significantly less than the preHVR (F=13.99; df= 1, 16; p=0.02). The V, occurring immediately before the preHVR and the postHVR were not different. Also, the average levels of isocapnia that were maintained during each preHVR and each postHVR were the same (Table 6). Accompanying the blunted postHVR was a blunted V t response (F= 5.27; df= 1, 16; p= 0.04). On day 1 the change in V t during the preHVR was 0.74 ± 0.38 liters and during the postHVR it was 0.60 ± 0.42 liters. Similarly, on day 12 the change in V t during the preHVR was 0.92 ± 0.41 liters and during the postHVR it was 0.79 ± 0.45 liters. Effects of IH on the cardiovascular response to progressive isocapnic hypoxia Displayed in Figure 9 are the cardiovascular sensitivities to hypoxia for one individual subject on the first day of study. There were no differences between the SDIH and LDIH conditioned individuals for any cardiovascular sensitivity to hypoxia; therefore, all subjects will be discussed as one group throughout this section. Shown in Table 7 are the sensitivities to hypoxia for SBP, DBP, and MAP during both the preHVR and the postHVR. During the HVR, as Fi02 is progressively lowered there is an increase in both systolic and diastolic blood pressures. This increase in blood pressure was - 17-linearly related to the change in SaC>2 (Figure 9). The mean ASBP/ASaO-2 and the mean ADBP/ASa02 during the preHVR are displayed in Figure 10. The ASBP/ASa02 was not significantly different on day 12; nor was the ADBP/ASa02. As shown in Table 7, the ASBP/ASaO-2 and ADBP/ASaCh during the postHVR were significantly less than that occurring during the preHVR (SBP: F= 28.38; df= 1, 16; p= 0.0007, DBP: F= 37.73; df= 1, 16; p= 0.00001). The SBP and DBP immediately prior to each postHVR were greater than immediately before the preHVR (SBP: F= 25.67; df= 1, 16; p= 0.0001, DBP: F= 58.40; df= 1, 16; p= 0.000001). The mean SBP occurring prior to the preHVR on day 1 was 125 ± 8 mmHg and prior to the postHVR it was 132 ± 7 mmHg; and on Day 12 it was 123 ± 7 and 132 ± 11 respectively. The mean DBP occurring prior to the preHVR on day 1 was 73 ± 7 mmHg and on day 12 was 72 ± 7; prior to the postHVR it was 78 ± 6 mmHg on day 1 and 76 ± 8 on day 12. The change in ASBP/ASaO-2 (6: day 12- day 1) and the change in ADBP/ASa0 2 (5: day 12- day 1) were correlated to the change in H V R and are displayed in Table 8. The change in ASBP/ASaO^ and HVR was positively correlated (r = 0.68; p<0.05) as was the change in ADBP/ASaC^ and HVR (r = 0.73; p<0.05). When the relationships were analyzed separately as SDIH and LDIH groups the significant correlations remained for SDIH but not LDIH (Table 8). During progressive hypoxia, cardiac output increases with SaC>2 in a linear manner (Figure 9). The ACO/ASa0 2 during both the preHVR and the postHVR on each day is displayed in Table 9. In addition, the ACO/ASaCh during the preHVR was not significantly different from the ACO/ASaO-2 occurring during the postHVR. Heart rate increased linearly with decreasing SaO-2 as displayed in Figure 9. The AHR/ASaC>2 during the preHVR was not different from the postHVR and was not affected by intermittent hypoxia (Table 9). The change in AHR/ASaCh was not significantly correlated to the change in HVR (Table 8). -18-The SV response to progressive hypoxia was variable; some subjects show a linear increase in SV when plotted against SaCh (as displayed in Figure 9), while others show a decrease or no change at all. The mean ASV/ASa02 during the preHVR was not different from the postHVR and was not affected by intermittent hypoxia (Table 9). Total peripheral resistance decreases linearly with decreasing SaCh (Figure 9). The mean ATPR/ASa0 2 during the preHVR and during the postHVR on each day of measurement is displayed in Table 9. The ATPR/ASaC^ during the preHVR was unaffected by intermittent hypoxia; however, the ATPR/ASa02 during the postHVR was much less than the ATPR/ASaC>2 during the preHVR (F= 7.08; df= 1, 16; p= 0.02). The TPR occurring immediately prior to the postHVR was greater than the TPR occurring prior to the preHVR (F= 16.34; df= 1, 16; p= 0.0009). On day 1 the TPR prior to the preHVR was 0.87 ± 0 . 1 8 PRU but immediately prior to the postHVR it was 0.94 ± 0.25 PRU. Similarly, on day 12 the TPR prior to the preHVR was 0.77 ± 0.14 PRU; but, immediately before the postHVR it was 0.91 ± 0.21 PRU. Effects of IH on cerebral tissue oxygenation As arterial oxyhemoglobin saturation decreased so did Sc0 2 (Figure 2a and b) and 02Hb, while both HHb and cHb increased. The relationships for each of these variables for one individual subject are displayed in Figure 11. There were no differences between the LDIH and SDIH conditioned individuals for the following variables: ASc02/ASa0 2, A02Hb/ASa02, AHHb/ASa02, and AcHb/ASa02. As a result, the NIRS data for all subjects was pooled together. Displayed in Figure 12 is the group mean ASc02/ASa02 during the preHVR for each day of its measurement. The ASc02/ASa02 during the preHVR was significantly less on day 12 and subsequently returned to baseline by day 17 (F= 4.44; df= 7, 112; p= 0.0002). This change in ASc02/ASa02 corresponds to a reduction in Sc0 2 (at similar levels of Sa02) of-8.4 ± 2.8 % on day 1, -10.0 ± 2.7 % on day 12, and -8.3 ± 2.3 % on day 17. As displayed in Figure 13, a greater - 19-reduction in ScC^ on day 12 was consistent for 8 of 9 subjects in the SDIH group and 5 of 9 subjects in the LDIH group. The AScCVASaO^ during the preHVR tended to be greater during the preHVR than during the postHVR; however, this difference was not significant (p=0.06). The ScO"2 prior to the preHVR was not different than immediately prior to the postHVR. The AO"2Hb/ASa02 during the preHVR was not different from the postHVR and did not change over the course of intermittent hypoxia. On the other hand, the AHHb/ASa02 during the preHVR (Table 10) became progressively greater throughout exposure to intermittent hypoxia and was significantly different on day 12 compared with days 1 and 3 (F= 2.94; df= 7, 112; p= 0.007). In addition, the AHHb/ASa02 during the postHVR was significantly greater than the AHHb/ASa02 during the preHVR (F= 6.32; df= 1, 16; p= 0.02) (Table 10). The AcHb/ASa02 during the preHVR was not different from the postHVR and did not display significant changes over the course of intermittent hypoxia. Effects of ventilatory and cardiovascular variables in hypoxia to IH exposure During each exposure, ventilation, blood pressure, heart rate, cerebral oxygen saturation, and arterial oxyhemoglobin saturation were averaged over a three-minute period at the end of the first 5 minutes of hypoxia (H-l) and at the end of the last 5 minutes of hypoxia (H-2). Displayed in Table 11 are the ventilatory variables and, in Table 12, the cardiovascular variables for the SDIH and LDIH group during H - l and H-2 for each day of its measurement. None of the ventilatory or cardiovascular variables on day 12 was different from those on day 1. Ventilation was not different between the SDIH and the LDIH conditioned individuals. In addition, ventilation during H - l was not significantly different than that of H-2. Breathing frequency was, however, significantly less during H-2 for both groups of IH (F= 7.82; df= 1,16; -20-p= 0.01). Tidal volume tended to be greater during H-2 when compared with the first 5 minutes, although this difference was not statistically significant (p= 0.16). Mean arterial pressure was not different between groups during H - l . During H-2, MAP was significantly greater than during H- l for SDIH conditioned individuals, but not for LDIH conditioned individuals (F= 10.87; df= 1, 16; p= 0.005). Heart rate was not different between groups during H - l or during H-2. But, heart rate did increase significantly throughout exposure (F= 13.5; df= 1, 16; p= 0.002). Arterial oxyhemoglobin saturation was not different between conditions during H - l ; however, during H-2, the LDIH group had an Sa0 2 that was significantly less than that of the SDIH conditioned group (F=21.74; df= 1,16; p=0.0003). The Sa0 2 during each exposure was unaffected by IH even though there were large increases in the HVR. During H - l , Sc0 2 was similar between conditions; but, during H-2, the LDIH conditioned individuals had an Sc0 2 that was significantly less than the SDIH conditioned individuals (F= 32.75; df= 1,16; p= 0.00003). The Sc0 2 during hypoxic exposure was unaffected by 12 days of IH. -21 -D I S C U S S I O N This is the first study to compare ventilatory, cardiovascular, and cerebral tissue oxygen responses to SDIH and LDIH in humans. The principal findings of this study are five-fold: (1) twelve days of exposure to isocapnic intermittent hypoxia reversibly enhanced the hypoxic ventilatory response, regardless of paradigm,, and had no effect on the hypercapnic ventilatory response; (2) following acute exposure to SDIH and LDIH, the hypoxic ventilatory response is blunted compared to immediately before exposure; (3) cardiovascular sensitivity to hypoxia was not affected by exposure to either SDIH or LDIH; however, during exposure to SDIH, MAP was significantly greater than during LDIH; (4) exposure to intermittent hypoxia resulted in a greater reduction in cerebral tissue oxygenation compared to baseline measures and (5) no differences occur in submaximal or maximal exercise ventilatory efficiency following intermittent hypoxia. Ventilatory Effects of Intermittent Hypoxia. The hypoxic ventilatory response was significantly increased on day 12. This increase in HVR occurred regardless of the intermittent hypoxic paradigm (i.e. LDIH or SDIH). Five days following the end of intermittent hypoxia, the HVR had returned to baseline, indicating that the change in HVR is transient. The increase in HVR is attributed to an enhanced tidal volume response to hypoxia. On day 1, V t increased by 0.74 ± 0.38 liters (~ +52%) but on day 12, the change in V t was 0.92 ± 0.41 liters (~ +57%) at identical levels of Sa02. Other studies involving human subjects have reported results similar to this study (Katayama et al, 1998; Katayama et al, 1999; Garcia et al, 2000b, 2000c; Katayama et al, 2001a; Katayama et al, 2001b; Mahamed & Duffin, 2001; Mateika et al, 2004). Katayama et al (2001b) exposed human subjects to an hour daily of hypobaric hypoxia (432 mmHg) and demonstrated a 62%> increase in HVR after 7 days. In the current study, subjects were exposed to thirty minutes of a similar level of isocapnic hypoxia for 10 episodes -22-(over 12 days) and improved their HVR by 70% (range: -42%-108%). Several human studies have used similar SDIH methods to ours and have also reported increases in H V R (Serebrovskaya et al, 1999; Bernardi et al, 2001). In contrast to the results from the current study are the findings from Peng and Prabhakar (2004) who clearly showed in the rat that LDIH does not enhance carotid body chemosensitivity, while SDIH does. A possible explanation for the differences in results is that the rats in Peng and Prabhakar's study were exposed to a substantially greater hypoxic stimulus (5% O2 versus 12% O2). In addition, the rats in the SDIH group were exposed to hypoxia for 15 seconds every 5 minutes, 8 hours per day, while the rats in the LDIH group received 4 hours of hypoxia per day (0.4 atm). In the present study, human subjects were exposed to either 30 minutes of sustained normobaric isocapnic hypoxia (LDIH; 12% O2) or 5 minutes of normobaric isocapnic hypoxia separated by 5 minutes of normoxia for an hour (SDIH; 12% 0 2). In this study, the H V R was measured immediately before each exposure to intermittent hypoxia and again 5 minutes following each exposure. The HVR occurring after each exposure was significantly less than the HVR occurring immediately prior to, indicating a form of hypoxic desensitization (Figure 8). Similar results were found in other human studies (Easton et al, 1986, 1988) and cat studies (Long et al, 1994). In these studies, an initial exposure to isocapnic hypoxia decreased the ventilatory response to a subsequent hypoxic exposure. The results from the current study agree with these studies and indicate that the reduced ventilatory response to hypoxia was largely due to alterations in the tidal volume response to hypoxia. On day 1 the change in V t during the preHVR was 0.74 ± 0.38 liters and, during the postHVR, it was 0.60 ± 0.42 liters. From the data obtained throughout this study, it is difficult to discern the mechanism responsible for the apparent hypoxic desensitization; however, others suggest that the hypoxic ventilatory depression is mediated by relatively slowly reversible neurochemical -23 -events that are specific to the central neural structures concerned with the hypoxic ventilatory response (Long et al, 1994). While the results indicate an increase in HVR following intermittent hypoxia, no change in the hypercapnic ventilatory response was evident. This finding is similar to the results of almost all other studies which have measured the HCVR using the Read rebreathing method and the single breath CO2 response test (Katayama et al, 1998; Katayama et al, 1999; Katayama et al, 2002). However, some studies have found increases in H C V R following intermittent hypoxia (Mahamed & Duffin, 2001; Ainslie et al, 2003). Ainslie et al (2003) showed an increase in the hypercapnic ventilatory response following five nights of normobaric hypoxia (13.8% O2). A novel approach of determining the central chemoreceptor response to CO2 has been employed by Mahamed et al (2001). This method involves prior hyperventilation before commencing the rebreathe at different iso-oxic levels and allows for the determination of the chemoreflex threshold to CO2. Using the modified rebreathing technique, changes in the peripheral chemoreflex to CO2 were measured in hyperoxia and in hypoxia. Following twenty minutes of isocapnic hypoxia daily for 14 consecutive days, an increase in the CO2 threshold occurs only in the presence of hypoxia, but not hyperoxia (Mahamed & Duffin, 2001). The authors interpreted this result as indicating changes in the peripheral chemoreflex and not the central chemoreflex. It may be that marked respiratory alkalosis is necessary to elicit changes in HCVR. In the majority of the studies that measure HCVR, the hypoxic exposure is usually no more than an hour per day for less than two weeks. In the current study, it may be no surprise that the H C V R did not change; our subjects were exposed to isocapnic hypoxia and, thus, no respiratory alkalosis occurred. During acute exposure to sustained hypoxia (similar to LDIH) and during several short repeated bouts of hypoxia (similar to SDIH), several phenomena are known to occur. At the onset of hypoxia there is an immediate increase in ventilation. Following 5-30 minutes of -24-sustained hypoxia, a decrease in ventilation is observed and is referred to as hypoxic ventilatory decline (HVD) (Powell et al, 1998). H V D occurs even during isocapnic hypoxia. In contrast, during short repeated bouts of hypoxia (similar to SDIH), progressive augmentation is known to occur (Powell et al, 1998). Progressive augmentation refers to the increase in the magnitude of the hypoxic ventilatory response seen in each successive episodes of an identical hypoxic stimulus. Following exposures to successive episodes of hypoxia, respiratory motor output progressively increases during the normoxic intervals and is referred to as long term facilitation (Powell et al, 1998). This condition can last for many minutes to several hours after the final stimulus episode. The results from this study suggest that, during exposures to SDIH and LDIH, HVD, progressive augmentation, and long term facilitation did not occur or were undetectable. During exposure to LDIH, there was no difference in ventilation during H- l when compared with H-2 (Day 1: 14 ± 2 and 13 ± 2 1 min"1 respectively). During SDIH, ventilation during the first bout of hypoxia was not different from the final bout of hypoxia (Dayl: 14 ± 3 and 13 ± 3 1 min"1 respectively). This was true for all days of exposure. While overall minute ventilation did not change throughout exposure, our results do indicate a small but significant increase in Fb (+ ~1 breaths min"1; p<0.05) during H-2 of both LDIH and SDIH. Tidal volume did not change significantly. The results from the present study suggest that long term facilitation did not occur. There was no difference in resting ventilation nor in the ventilation occurring in normoxia immediately prior to the final HVR procedure of each day. If long term facilitation did occur, any increase in ventilation should have returned to resting levels within the five-minute period prior to the postHVR measurement. This study is not the first study to suggest that long-term facilitation does not occur in human subjects following exposure to successive episodes of hypoxia (McEvoy et al, 1996; Jordan et al, 2002; Mateika etal, 2004). -25 -Cardiovascular Sensitivity to Intermittent Hypoxia. The results showed a transient increase in resting heart rate on day 10 (+7 bpm), although there were no concomitant changes in cardiac output or stroke volume. Our subjects, resting in a supine position, had a mean CO of 6.88 1 min"1 (range: 4.7-9.0 1 min"1). This result is similar to other studies which have determined cardiac output using the thermodilution technique during supine rest and found it to range from 5.3-8.7 1 min"1 (Harms et al, 2003). Blood pressure and total peripheral resistance did not systematically change throughout the intermittent hypoxic protocol. While there were fluctuations in resting normoxic heart rate, we did not detect any changes in the high and low frequency spectral components of heart rate variability, indicating that baseline autonomic control of the heart did not change throughout experimentation and that all subjects were in a comparable autonomic state prior to each hypoxic trial. There were no changes in the sensitivity to hypoxia for any cardiovascular variables including: systolic, diastolic, and mean arterial pressure, and cardiac output, stroke volume, and total peripheral resistance. Very few studies have studied cardiovascular sensitivity and intermittent hypoxia. In contrast to the results found here, Katayama et al (2001b) found a 68% increase in systolic blood pressure sensitivity and a 44% increase in diastolic blood pressure sensitivity. The results from the present study are comparable, but did not show statistically significant differences. In this study, systolic blood pressure sensitivity increased by 70% and diastolic blood pressure sensitivity increased by 67%. Katayama et al (2001b) also showed a significant relationship between the change in SBP (r = 0.66) and DBP (r = 0.62) sensitivity and the change in HVR (Table 8). Interestingly, the data from the present study showed similar significant relationships between the same variables. Our data suggests that the increase in SBP and DBP are positively related to the increase in H V R (r = 0.68 and.r = 0.73 respectively). Our correlational coefficients are very similar to those of Katayama et al. (2001b) but, appear to only be significant and comparable for either all subjects or only those exposed SDIH. In agreement - 26 -with the study of Katayama et al. (2001b), the present study's results did not illustrate changes in the heart rate sensitivity to hypoxia or a relationship to the change in HVR. There are several differences between the methods used in this study and the methods used by Katayama et al. (2001b). While the hypoxic intensity was similar for both studies (12% O2 vs. a simulated altitude of 4,500 m), the subjects in the present study were exposed to thirty minutes of normobaric, isocapnic hypoxia while the subjects in the study by Katayama et al. (2001b) were exposed to an hour of poikilocapnic, hypobaric hypoxia. The results of a study by Insalaco et al. (1996) also differ from this study's results; however, their results involved exposure to 24 days of continuous hypoxia. They found increases in blood pressure sensitivity following one day at 5,050m that continued to increase by the 24th day at high-altitude. In their study they found a slight reduction in heart rate sensitivity. In support of our findings are two studies, both involving exposure to a variant of SDIH. In one study, humans were exposed to 3-4 periods of 7 minutes of isocapnic progressive hypoxia (end-tidal PO2 was allowed to drop to 35-40 mmHg) in 1 hour each day for 14 days; no changes in the blood pressure or heart rate sensitivity to hypoxia occurred (Bernardi et al, 2001). Similarly, in another study, cats were exposed to a cyclic hypoxic episode (~ 2 min each; inspired PO2 ~ 75 mmHg) repeated during 8 hours for 2-4 days; no changes in arterial pressure or heart rate during acute hypoxia were found (Rey et al, 2004). Interestingly, Rey et al. (2004) also found a marked increase in the resting, normoxic LF/HF ratio and an increase of the power spectral distribution toward the LF spectral component of heart rate variability indicating sympathetic predominance. In our study there was no change in the resting HF, LF, or the LF/HF ratio, indicating that there was no change in autonomic control of the heart throughout intermittent hypoxia. Clearly, the daily exposure to hypoxia used for this study (30 minutes) was much less than that displayed in the study by Rey et al (2004); therefore, direct comparisons are difficult. -27-Cardiovascular sensitivity measures occurred during both the preHVR and the postHVR procedure (Table 7). When the ASBP/ASa0 2 during the preHVR are compared with the postHVR, our results indicate a reduction in the SBP sensitivity to hypoxia following the daily acute exposure to LDIH or SDIH. This was true for the ADBP/ASa0 2 and the AMAP/ASa0 2 . No other study has done a similar comparison. This blunted blood pressure sensitivity can be explained by the increase in normoxic SBP, DBP, or MAP during the five-minute period following the daily acute exposure to hypoxia. The SBP, DBP, and MAP were significantly greater immediately before the postHVR compared with those before the preHVR. In addition, the peak increase in SBP, DBP, and MAP at similar levels of Sa0 2 during the postHVR were not different from the preHVR. The results can, therefore, not be interpreted as indicating a reduction in blood pressure sensitivity to hypoxia following exposure to an acute episode of hypoxia. Similar analysis was undertaken for the CO, HR, SV, and TPR sensitivity to hypoxia (Table 9). Cardiac output, HR, and SV sensitivity were not different during the postHVR when compared with the preHVR. The ATPR/ASa0 2 during the preHVR was significantly less during the postHVR. Like the blood pressure sensitivities, this can be explained by an increase in the normoxic TPR occurring immediately prior to the postHVR when compared with the preHVR. Cardiovascular Function during Exposure to Intermittent Hypoxia. A significant increase in mean arterial pressure (+ ~5 mmHg; p<0.05) was found throughout acute exposure to SDIH. This increase in MAP did not occur during acute exposure to LDIH (+ ~ 2 mmHg; p>0.05). The change in MAP was not greater following 12 days of exposure to intermittent hypoxia. Heart rate was similar between both groups throughout exposure to either LDIH or SDIH. There were small but significant increases in HR over the duration of exposure (+ ~1 bpm; p - 0.002). No previous study has documented a similar finding. It is not understood why -28-SDIH results in a rise in M A P while LDIH does not. It may be that exposure to SDIH resulted in a greater carotid body stimulation. While the repeated deoxygenation-reoxygenation states may have provided increased carotid body stimulation, the subjects in the SDIH group were exposed to significantly less hypoxaemia. During the first 5 minutes of hypoxic exposure, SaC>2 was similar between both intermittent hypoxic groups (SDIH = 92%; LDIH = 91%); but, during the final 5 minutes of hypoxia, Sa0 2 was significantly less for those subjects exposed to LDIH (SDIH = 91%; LDIH = 87%). It is possible that repeated states of deoxygenation-reoxygenation are more important than sustained hypoxemia for increasing blood pressure. Furthermore, this phenomenon may relate to the secondary hypertension that is present in patients with obstructive sleep apnea (Morgan & Joyner, 2002). Although under somewhat different circumstances, Fletcher and colleagues (1992), using a rat model, demonstrated increases in resting, normoxic daytime blood pressure following exposure to 35 days of SDIH patterned after that of sleep apnea. This increase in resting daytime blood pressure was dependent upon intact carotid chemoreceptors. In a different study, sympathetic responsiveness to hypoxia and hypercapnia were increased following 30 days of SDIH, also modeled after sleep apnea syndrome (Greenberg et al, 1999). Or perhaps more simply, LDIH conditioned individuals did not display an increase in MAP because the sustained systemic hypoxia experienced by them mediated a local vasodilatory response that prevented the increase in blood pressure (Doherty & Liang, 1984; Blauw et al, 1995). Effects of Intermittent Hypoxia on Cerebral Tissue Oxygenation. During acute exposure to progressive hypoxia, cerebral tissue oxygen saturation decreases. This includes an increase in oxyhemoglobin concentration and total hemoglobin concentration, while deoxyhemoglobin concentration decreases. The change in each variable is linearly related to the change in arterial oxyhemoglobin saturation (Figure 11). In the cerebral circulation, -29-vascular autoregulation is responsible for the vasodilator response to hypoxia. Several lines of evidence suggest that exposure to intermittent hypoxia affects vascular function negatively (Earley & Walker, 2002; Gonzales & Walker, 2002; Jernigan & Resta, 2002; Altay et al, 2004; Phillips et al, 2004). Exposure to chronic intermittent hypoxia markedly attenuates the acute vasodilator responses to hypoxia in isolated vessels (Phillips et al, 2004). Phillips et al. (2004) exposed rats (n = 6) to chronic intermittent hypoxia (Fi02 = 10% for 1 min at 4-min intervals, 12h/day) for 14 days. After 14 days the middle cerebral arteries were isolated and placed in a tissue bath. The arteries were pressurized to 90 mmHg, and vessel diameters were measured via a video micrometer before and after exposure to acetylcholine (ACh) (10~7-10~4 M) and acute reduction of PO2 in the perfusate and superfusate (from 140 to 40 mmHg). Dilation of the middle cerebral artery induced by ACh was greatly attenuated while dilation-induced by acute reductions in PO2 was virtually abolished in animals exposed to chronic intermittent hypoxia. These results suggest that vascular regulation is altered following intermittent hypoxia and may affect the ability to oxygenate cerebral tissue. In the current human study, the sensitivity of the cerebral vasculature was assessed by determining the ability to oxygenate cerebral tissue during acute exposure to progressive hypoxia using near-infrared spectroscopy. Changes in SCO2, 0 2 Hb, HHb, and cHb per change in Sa02 were used to represent the sensitivity of the cerebral vasculature to hypoxia (Table 10). The results indicate that the ASc02/ASa02 became significantly less following exposure to both SDIH and LDIH (Day 1 = -0.51 ± 0 . 1 3 ; Day 12 = -0.64 ± 0.18). This change in SCO2 sensitivity was mediated by an increase in the AHHb/ASa02 (Day 1 = 0.34 ± 0.21; Day 12 = 0.44 ± 0.12). These changes in the ability to oxygenate the brain were reversible and, following the end of exposure to intermittent hypoxia, had returned to baseline. There were no differences in the A02Hb/ASa02 or the AcHb/ASa02 response. In addition, the change in SCO2 sensitivity throughout intermittent hypoxia cannot be explained by shifts in resting SCO2, as it did not change. The resting Sc02 was very reproducible and the -30-mean coefficient of variation was 4.7 ± 2 . 1 %. Taken together, the results indicate that there was a greater reduction in cerebral tissue oxygen saturation following exposure to both SDIH and LDIH. This was a consistent observation where 8 of 9 subjects in the SDIH group and 5 of 9 subjects in the LDIH group demonstrate a greater reduction in cerebral tissue oxygen saturation (Figure 13). To more fully understand what this means in terms of % change, we determined the change in ScC<2 for each subject at an SaC>2 that was similar on each day (i.e. iso-SaCh). On day 1 the subjects demonstrate a -8 ± 3 % change in Sc02 and on day 12 the change in S c 0 2 is -10 ± 3 %. From the experimental design used here it is difficult to understand the mechanism leading to the greater reduction in Sc02. While the results seem to suggest cerebral vascular dysregulation in the human subject following exposure to SDIH and LDIH and support the findings of results seen in the rat model (Phillips et al, 2004), the results of this study differ from two human studies of the cerebral blood flow velocity response to acute hypoxia (Jensen et al, 1996; Kolb et al, 2004). Jensen et al. (1996) studied the cerebral blood flow velocity response from the control value with 5-minute steps of isocapnic hypoxia and hyperoxic hypercapnia before and during a 5-day sojourn at 3,810 m altitude. Their results indicate an increase in the cerebral vascular response to acute isocapnic hypoxia. Similarly, Kolb et al. (2004) studied the cerebral blood flow responses to acute variations in O2 and CO2 prior to, immediately after, and five days following exposure to five consecutive nocturnal exposures of 13.8 % O2 (8 hours during the night). Their results also indicate an increase in the sensitivity of cerebral blood flow velocity to acute variations in O2 and CO2. Several key differences may account for the variations between the results of the current study and the results from Jensen et al (1996) and Kolb et al (2004). The hypoxic exposure used in the present study was more intense (12% O2) and involved isocapnia. In addition, the hypoxic protocol lasted for 12 days while it lasted only 5 days during the other two studies. In fact, following the 3r d and 5th day of this study's protocol there were no significant decreases in Sc02 sensitivity to hypoxia; if -31 -anything, there was an increase in AScCVASaO^ on day 3 (not significant) (Figure 12). Furthermore, fourteen days of intermittent hypoxia were needed to demonstrate vascular dysfunction in the rat model (Phillips et al, 2004). It is possible that had these researchers {Jensen et al, 1996; Kolb et al, 2004) continued their hypoxic protocol for 5 more days they may have discovered decrements in cerebral blood flow sensitivity. The change in cerebral tissue oxygen sensitivity was measured during the HVR and, therefore, the results also include the cerebral tissue oxygen sensitivity during the postHVR. The results from this analysis indicate that the AScOVASaC^ was less and the AHHb/ASaCh was greater on each day of measurement during the postHVR (Table 10). The change in ScC»2 sensitivity cannot be explained by an increase in normoxic ScC»2 immediately prior to the postHVR when compared with immediately prior to the preHVR, as it was not different. It is more likely that the blunted postHVR (Figure 8) is the cause of the cerebral tissue oxygen sensitivity being less following hypoxic exposure. Effects of Intermittent Hypoxia on Submaximal and Maximal Exercise. Several studies suggest that exposure to intermittent hypoxia during rest improves exercise efficiency (Katayama et al, 2001a; Katayama et al, 2003; Katayama et al, 2004); others do not (Katayama et al, 2002). The results from this study do not indicate any improvement in maximal or submaximal exercise ventilatory efficiency. Maximal V02, VC02, ventilatory equivalents for O2 and CO2, V,, peak power, and HR were not different following intermittent hypoxia compared with immediately before (Table 2). In addition, there were no differences in V,, F b , or V t at 20, 40, 60, 80, or 100 % of maximal V02 and VC02 (Table 3). Katayama et al (2002) found similar results; there was no change in either minute ventilation or the ventilatory equivalent for oxygen during maximal and submaximal exercise following intermittent hypoxia. -32-In other studies, submaximal V02, and 3,000m running time improved (Katayama et al, 2003; Katayama et al, 2004). In these studies, intermittent hypoxia involved either hypobaric hypoxia at 4,500 m for 90 minutes, 3 days a week for 3 weeks (Katayama et al, 2003), or normobaric hypoxia (12.3 % O2) for 3 hours per day for 14 consecutive days (Katayama et al, 2004). While the hypoxic intensity is similar to the current study, the total time in hypoxia is significantly greater and may account for the discrepancy between studies. Furthermore, the subjects involved in both of these studies were trained athletes continued to train throughout participation in the study. Katayama et al. (2002) used active healthy subjects with similar peak exercise values to our subjects; they also used a similar IH protocol. Their protocol involved 1 hour daily of exposure to hypobaric hypoxia (4,500m) for 7 days while our protocol involved 30 minutes exposure to normobaric isocapnic hypoxia (12% O2). Critique of Methods. The HVR measurement can be associated with large day-to-day variability (Sahn et al, 1977; Beidleman et al, 1999). The coefficient of variation for HVR can range from 26% to 76% (Zhang & Robbins, 2000; Fahlman et al, 2002). Using similar methods described in this study, repeated HVR measurements were performed in our laboratory over 5 consecutive days (n ='8; male subjects) and the mean individual C V was found to be 27 ± 4 % (Koehle et al, In Press). This coefficient of variation is identical to that of Zhang and Robbins (2000) who found a C V of 26%. In addition to having a low coefficient of variation, several subjects involved in the current study also took part in our repeated HVR study (Koehle et al, In Press). As a result, there is additional reassurance that the increase in HVR seen throughout this study was not due to either the repeated measure of H V R or day-to-day variability. Arterial oxygen saturation was measured by pulse oximetry and not determined from arterial blood. Changes in arterial pH and body temperature affect the haemoglobin-oxygen -33-dissociation curve. Pulse oximetry fails to account for this. During this study subjects were at rest, so there were not likely changes in temperature during the experiment and changes in pH were minimized by maintaining subjects' isocapnic throughout all hypoxic exposures. The measurement of cardiac output and stroke volume was evaluated using a pulse wave analysis method that calculates beat-to-beat flow from non-invasive arterial pressure by simulating a non-linear, time-varying model of human aortic input impedance (Van Lieshout et al, 2003). This model incorporates three elements to calculate aortic flow: aortic impedance, aortic compliance, and total peripheral resistance (Wesseling et al, 1993). Using this method for obtaining continuous cardiac output and stroke volume has not been embraced by clinical studies because its methods, although based on strong physical principles, are also based on some weaker physiological models (Van Lieshout & Wesseling, 2001). Some major concerns include a non-linear aortic compliance, using finger pressure to determine stroke volume instead of proximal aortic pressure, inadequate pulse detection, and an inability to accurately obtain an absolute cardiac output (Van Lieshout & Wesseling, 2001). This method has now been compared with thermodilution, whole-body impedance cardiography, CO2 rebreathing, and Doppler ultrasound techniques for determining cardiac output. Generally, the studies have determined that pulse wave analysis may not be appropriate for determining absolute values of cardiac output (Hirschl et al, 1997; Houtman et al, 1999; Nieminen et al, 2000; Remmen et al, 2002). However, if calibrated against an invasive method, pulse wave analysis can produce accurate measurements (Jansen et al, 2001; Remmen et al, 2002). Pulse wave analysis calibrated against thermodilution measures accurately reflects changes in cardiac output over a range of cardiac output values when compared with thermodilution techniques in mechanically ventilated patients with septic shock (Jellema et al, 1999). A study which tracked the changes in stroke volume and cardiac output during different phases of a tilt-table test determined that pulse wave analysis can track the changes in cardiac output and stroke volume but, for absolute values, -34-is not appropriate (Nieminen et al, 2000). Changes in stroke volume can be adequately assessed using pulse wave analysis when compared with stroke volume obtained by Doppler ultrasound during tilt-table testing (Van Lieshout et al, 2003). Houtman et al (1999) showed that pulse wave analysis derived cardiac output reflects the cardiac output determined using the CO2 rebreathing method at rest and during exercise up to 60% of the individual peak power output. Unfortunately, the methods used in this study do not involve calibrating our pulse wave analysis derived cardiac output with an invasive method. However, our measurements were performed during supine rest and are within the range of resting cardiac output determined using the thermodilution technique in other supine resting individuals (5.3 - 8.7 1 min"1) (Harms et al, 2003). The range of cardiac output values in our study was 4.7-9.0 1 min"1. Near-infrared spectroscopy provides a unique and detailed measurement of cerebral oxygenation. NIRS reflects cerebral oxygenation during arterial hypotension, hypoxic hypoxemia, and hypo- and hypercapnia (Madsen & Secher, 1999). Some important limitations to NIRS include insufficient light shielding, optode displacement, and a sample volume that includes muscle or the frontal sinus mucous membrane (Madsen & Secher, 1999). During this study, optodes were placed just below the hairline in the center of the forehead to ensure that the sample volume was not affected by the frontal sinus or temporal muscles. Contained within the sampled volume is information about the hemoglobin contained within arterioles, capillaries, and venules, and the relative position of pigments determined by NIRS cannot be determined. In the brain, approximately 5% of the blood is situated in the capillaries, 20% in the arteries, and the remainder is in the venous circulation (Madsen & Secher, 1999). The hemoglobin measured by NIRS is therefore 'post cellular' and it can be argued that NIRS determines local venous oxygen saturation rather than tissue oxygen content. While some degree of co-variation is present between regional cerebral oxygen saturation and internal jugular venous oxygen content, the -35 -contribution from capillaries and arterioles is significant and the NIRS signal provides the best non-invasive method of monitoring cerebral tissue oxygenation (Madsen & Secher, 1999). Another limitation to this study is that the methods did not include a control group that was exposed to the experimental set-up but not to intermittent hypoxic exposure. While this does provide a limitation, it is unlikely that the results of this study would be different. As described earlier in a previous study, HVR was measured in subjects over five consecutive days (Koehle et al, In Press). Four subjects involved in the current.study also were involved in this repeated H V R study. These subjects had, therefore, been previously exposed to the identical experimental setup without exposure to intermittent hypoxia. During this repeated HVR study, there was no effect of measuring HVR over 5 consecutive days. In addition, several other investigations have studied the effects of intermittent hypoxia on H V R and on cardiovascular responses and have included a control group (Bernardi et al, 2001; Katayama et al, 2001b; Mahamed & Duffin, 2001; Katayama et al, 2002; Katayama et al, 2003; Katayama et al, 2004). In these studies, having a control group had no effect on the outcome of their studies. Conclusion. The results from this study indicate that exposure to twelve days of isocapnic intermittent hypoxia will transiently increase hypoxic chemosensitivity regardless of how the hypoxic stimulus is patterned (i.e. SDIH or LDIH), when the hypoxic intensity and total duration are the same. The increase in hypoxic chemosensitivity is short-lived as HVR returns to baseline 5 days after intermittent hypoxia has ended. Hypercapnic chemosensitivity is not altered following isocapnic intermittent hypoxia, likely because respiratory alkalosis is necessary to evoke changes in hypercapnic chemosensitivity. The HVR that occurrs following acute exposure to hypoxia was blunted and suggests hypoxic desensitization. The mechanism leading to hypoxic desensitization is unknown and requires further study. While intermittent hypoxia led to increases in hypoxic chemosensitivity, the cardiovascular sensitivity to hypoxia (SBP, DBP, -36-CO, SV, HR, and TPR) was not affected. This finding is in contrast with other studies and it is suspected that a longer duration of exposure is necessary to evoke changes in cardiovascular sensitivity to hypoxia. Several animal studies have suggested that intermittent hypoxia may affect the ability to oxygenate cerebral tissue due to vascular dysregulation. The results from this study suggest that the vascular processes required to control blood flow and to oxygenate cerebral tissue in the human have been affected in a way that inhibits the ability to oxygenate the cerebral tissue in response to progressive isocapnic hypoxia following exposure to twelve days of isocapnic intermittent hypoxia. This is the first study to show that acute exposure to SDIH results in a rise in MAP that is not present during acute exposure to LDIH. This suggests that exposure to SDIH may be a useful model when studying the effects of sleep-disordered breathing and intermittent hypoxia on the cardiovascular system, including systemic hypertension. -37-Table 1. Descriptive and resting pulmonary function data. Percent of predicted values are contained within parentheses. Values are means ± SD. Definitions of abbreviations: FVC = forced vital capacity; F E V i . o = forced expired volume in 1 second. * Significantly different from SDIH (p<0.05). SDIH (n=9) LDIH (n=9) Age (years) 25.8 ±4 .3 25.6 ±4 .5 Height (cm) 177.9 ±7 .0 174.0 ± 18.7* Mass (kg) 81.3 ±7 .4 81.4 ± 10.9 FVC (liters) 4.99 ±0.83 (95 ± 12) 4.96 ±0.51 (107 ± 4 3 ) F E V L 0 (liters) 4.14 ±0.47 (94 ± 9) 4 .16±0 .50 (105 ± 4 0 ) FEV,. 0 /FVC (%) 84.25 ±5.92 (102 ± 7 ) 83.49 ±5.67 (101 ± 7 ) -38-Table 2. Peak exercise values during maximal cycle ergometry tests. Values are means ± SD. Definition of abbreviations: V02 = maximal oxygen consumption; VC02 = maximal CO2 production; RER = respiratory exchange ratio; V, IV02 = ventilatory equivalent for oxygen; V, IVC02 = ventilatory equivalent for CO2; V, = ventilation; HR = heart rate. Day 1 (n=17) Day 12 (n=17) V02 (ml kg 1 min"') 42.2 ±7.5 42.9 ±7 .5 V02 (1 min1) 3.47 ±0.59 3.53 ±0 .66 VC02 (lmin1) 4.31 ±0.68 4.32 ±0 .74 RER 1.25 ±0.07 1.24 ±0 .08 VjlV02 34.02 ±4.81 33.83 ±4.95 v,ivco2 26.75 ± 1.72 27.37 ±3.08 V, (lmin"1) 118.3 ± 21.9 115.1 ±23 .4 Power (watts) 322 ± 67 327 ± 67 HR (bpm) 179 ± 10 181 ± 10 -39 -Table 3. Ventilatory efficiency at submaximal exercise intensities. Values are means ± SD. Definition of abbreviations: V, = ventilation; Fb = breathing frequency; V t = tidal volume; V02 = % of maximal oxygen consumption; VC02 = % of maximal CO2 production. vo2 vco2 Variable Intensity (%) Day 1 Day 12 Day 1 Day 12 Vj (liters min"1) 20 17.3 ± 1.0 17.1 ± 1.1 21.8 ± 1.1 22.0 ± 1.0 40 29.2 ± 1.7 29.0 ± 1.7 38.3 ±2 .1 40.0 ± 2 . 0 60 47.3 ±3 .4 47.7 ±2 .6 58.8 ± 3 . 2 60.1 ±3 .3 80 69.9 ±5 .4 73.5 ±3 .5 83.2 ±4 .9 84.7 ±4 .6 100 116.3 ±5 .4 116.0 ± 5 . 4 117.3 ± 5.2 117.2 ±5 .4 F b (breaths min"1) 20 18± 1 18± 1 19 ± 1 20 ± 1 40 22 ± 1 21 ± 1 24 ± 1 22 ± 1 60 27 ± 2 27 ± 2 30 ± 1 31 ± 2 80 33 ± 3 35 ± 2 37 ± 3 38 ± 2 100 52 ± 3 53 ± 3 54 ± 4 52 ± 3 V, (liters) 20 0.99 ± 0.05 0.99 ± 0.07 1.24±0.10 1.14 ±0.08 40 1.40 ±0.06 1.43 ±0 .09 1.62 ±0 .06 1.82 ±0.08 60 1.78 ±0.06 1.82 ±0 .09 2.02 ± 0.07 1.98 ±0.09 80 2.13 ±0.07 2.16 ±0.09 2.31 ±0 .09 2.27 ±0.11 100 . 2.37 ± 0.09 2.34 ±0 .10 2.30 ±0 .10 2.29 ± 0.09 - 4 0 -Table 4. Effects of intermittent hypoxia on basal ventilatory and cardiovascular variables during eupnea. Values are means ± SD. *Significantly different from day 1 (p<0.05). f Significantly different from day 3 (p<0.05). Definition of abbreviations: V, = ventilation; Fb= breathing frequency; V t= tidal volume; PetC02= end-tidal partial pressure of C 0 2 ; SBP= systolic blood pressure; DBP= diastolic blood pressure; MAP= mean arterial pressure; CO= cardiac output; HR= heart rate; SV= stroke volume; TPR= total peripheral resistance; Sc0 2= cerebral oxygen saturation. Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 CV (%) Vj (lmin1) 11.1 ± 2 . 4 11.8 ± 2.1 11.9±2.3 12.4 ±2 .4 12.1 ±2 .6 11.7 ± 2.2 11.7 ± 1.9 11.8 ± 1.9 9.7 ±0.5 F b (breaths min"1) 16.8 ± 3 . 8 18.1 ±3 .6 17.8 ±4 .0 18.4 ±3 .2* 18.7 ±3 .4* 17.7 ±2.7 17.6 ± 3.1 17.9 ±3 .0 8.6 ±4.5 Vt(liters) 0.69 ±0 .12 0.67 ±0.11 0.69 ±0 .10 0.69 ±0.11 0.67 ±0.13 0.68 ±0.12 0.69 ± 0.07 0.68 ±0 .10 10.6 ±0 .7 PetCC-2 (mmHg) 43.6 ± 3 . 8 43.2 ± 3 . 0 43.6 ±3 .6 43.0 ±3 .3 42.4 ± 2.6 43.6 ±3.3 43.6±3.1 43.1 ± 3 . 0 3.2 ± 1.2 SBP (mmHg) 124 ± 9 120 ± 11 121 ± 9 121 ± 10 118 ± 9 122 ± 7 123 ± 11 121 ± 12 5.4 ± 2 . 0 DBP (mmHg) 71 ± 7 70 ± 7 71 ± 6 71 ± 8 70 ± 8 70 ± 6 70 ± 9 70 ± 9 6.5 ± 1.9 MAP (mmHg) 89 ± 7 87 ± 8 87 ± 6 88 ± 9 86 ± 8 88 ± 6 88 ± 9 87 ± 10 5.7 ± 1.8 CO (1 min"1) 6.88 ± 1.10 6.64 ± 1.26 6.61 ± 1.46 6.70 ± 1.40 6.91 ± 1.12 7.33 ± 1.21 7.02 ± 1.19 6.94 ± 1.34 10.6 ±3 .8 HR(bpm) 66 ± 11 66 ± 12 68 ± 13 67 ± 13 73 ± 15*| 70 ± 12 68 ± 13 68 ± 11 8.9 ±3 .2 SV (ml) 106 ± 17 101 ± 19 101 ± 18 101 ± 19 99 ± 19 106 ± 15 106 ± 18 104 ± 18 7.6 ±3 .6 TPR (PRU) 0.83 ±0 .14 0.84 ±0.17 0.86 ±0.21 0.86 ±0.27 0.79 ±0.15 0.76 ±0.15 0.79 ±0.16 0.81 ± 0.23 13.0± 1.2 Sc02 (%) 70 ± 5 68 ± 7 69 ± 4 69 ± 5 69 ± 6 70 ± 6 70 ± 5 69 ± 4 4.7 ±2.1 -41 -Table 5. Heart rate variability data throughout intermittent hypoxia. Values are means ± SD. Definition of abbreviations: H F = high frequency power normalized to total power; L F = low frequency power normalized to total power; n.u.= normalized units (HF/total power). Day Day Day Day 1 12 15 17 HF (n.u.) 44.7 ± 15.2 47.3 ± 15.4 45.5 ± 18.8 54.34 ±20.5 LF (n.u.) 45.9 ± 15.3 32.2 ± 17.4 31.8 ± 19.1 37.7 ± 12.7 LF/HF 1.06 ±0.55 0.83 ± 1.12 0.85 ±0 .86 0.83 ± 0.44 - 4 2 -Table 6. Average level of isocapnia maintained throughout each preHVR and postHVR. Values are means ± SD. Definition of abbreviations PetCCh = end-tidal partial pressure of C 0 2 ; preHVR = hypoxic ventilatory response occurring prior to each intermittent hypoxic exposure; postHVR = hypoxic ventilatory response occurring following each intermittent hypoxic exposure. PetC02 (mmHg) Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 preHVR 42.4 ± 3.4 42.7 ±2 .8 42.8 ±3 .4 42.5 ±2 .9 42.0 ±2 .3 42.3 ±2 .9 42.4 ±2.7 42.2 ±2 .9 postHVR 42.8 ±3 .5 42.4 ±3.1 42.9 ±3 .3 42.5 ±2 .9 42.2 ± 2 . 0 42.8 ±2 .7 - 4 3 -Table 7. Effects of intermittent hypoxia on systolic, diastolic, and mean arterial blood pressure sensitivity to hypoxia. Values are means ± SD. * Significantly different from preHVR (p<0.05). Definition of abbreviations: ASBP/ASa0 2 = change in systolic blood pressure per change in arterial oxyhemoglobin saturation; ADBP/ASa0 2 = change in diastolic blood pressure per change in arterial oxyhemoglobin saturation; AMAP/ASa0 2 = change in mean arterial pressure per change in arterial oxyhemoglobin saturation; preHVR = hypoxic ventilatory response prior to each hypoxic exposure; postHVR = hypoxic ventilatory response following each hypoxic exposure. Variable HVR Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 - Day 15 Day 17 ASBP/ASa02 preHVR 0.74 ± 0.44 0.77 ± 0.70 0.76 ± 0.64 0.92 ± 0.57 0.83 ± 0.44 1.05 ±0.98 0.74 ±0.88 0.85 ± 0.62 (mmHg %Sa02" ') postHVR 0.46 ±0.59* 0.47 ± 0.42* 0.69 ± 0.74* 0.39 ±0.37* 0.45 ± 0.47* 0.50 ±0.49* ADBP/ASa02 preHVR 0.32 ± 0.20 0.35 ±0.38 0.34 ± 0.38 0.45 ± 0.36 0.35 ±0.29 0.48 ±0.50 0.32 ±0.40 0.37 ±0.29 (mmHg %Sa02" *) postHVR 0.16±0.28* 0.20 ±0.24* 0.25 ±0.32* 0.14 ±0.22* 0.18 ±0.25* 0.22 ±0.31* AMAP/ASa02 preHVR 0.47 ±0 .26 0.49 ± 0.47 0.48 ± 0.45 0.60 ± 0.42 0.51 ±0.33 0.67 ± 0.65 0.45 ± 0.55 0.53 ±0.38 (mmHg %Sa02" ') postHVR 0.26 ±0.37* 0.29 ±0.26* 0.40 ±0.45* 0.22 ± 0.24* 0.27 ± 0.32* 0.31 ±0.35* - 4 4 -Table 8. Relationship between the changes in cardiovascular responses and changes in the ventilatory response to hypoxia for all subject, SDIH, LDIH, and that reported by Katayama et al. (2001). Variable vs. 5HVR All SDIH LDIH Katayama et al, (n=18) (n = 9) (n = 9) (2001) 5ASBP/ASa0 2 r = 0.68* r = 0.93* r = -0.05 r = 0.66* 5ADBP/ASa0 2 r = 0.73* r = 0.85* r = 0.09 r = 0.62* 5AHR/ASa0 2 r = 0.32 r = 0.49 r = -0.05 r = 0.11 5 = Day 12 - Day 1, * p<0.05. - 45 -Table 9. Effects of intermittent hypoxia on cardiac output, heart rate, stroke volume, and total peripheral resistance sensitivity to hypoxia. Values are means ± SD. * Significantly different from preHVR (p<0.05). Definition of abbreviations: ACO/ASaC>2 = change in cardiac output per change in arterial oxyhemoglobin saturation; AHR/ASaO-2 = change in heart rate per change in arterial oxyhemoglobin saturation; ASV/ASaG*2 = change in stroke volume per change in arterial oxyhemoglobin saturation; ATPR/ASaC»2 = change in total peripheral resistance per change in arterial oxyhemoglobin saturation; preHVR = hypoxic ventilatory response occurring immediately prior to each hypoxic exposure; postHVR = hypoxic ventilatory response occurring following each hypoxic exposure. Variable HVR . Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 ACO/ASa02 preHVR 0.12 ±0.05 0.10 ±0 .04 0.12 ±0.05 0.11 ±0.06 0.12 ±0 .06 0.11 ±0.09 0.13 ±0.09 0.11 ±0 .06 (1 min 1 %Sa02'') postHVR 0.13 ±0.08 0.09 ± 0.06 0.12 ±0 .06 0.11 ±0.06 0.11 ±0 .06 0.12 ± 0.08 AHR/ASa02 preHVR 1.11 ±0 .36 1.02 ±0 .46 1.15 ±0.45 1.10 ±0.53 1.08 ±0.46 1.13 ±0.54 1.16±0.16 0.96 ± 0.70 (bpm o/oSaCY1) postHVR 1.16± 0.79 1.06 ±0 .34 0.97 ±0.74 1.06 ±0.56 1.02 ±0.57 1.18 ± 0.61 ASV/ASa02 preHVR -0.02 ± 0.52 -0.11 ±0 .64 0.06 ± 0.49 -0.07 ± 0.44 0.24 ± 0.49 0.02 ± 0.48 0.03 ± 0.54 0.14 ±0 .58 (ml %Sa02:i) postHVR -0.0? ±0.37 -0.13 ±0.63 0.07 ±0.48 0.06 ±0.51 0.07 ±0 .39 -0.04 ±0.57 ATPR/ASaCV preHVR -0.007 ± -0.006 ± -0.008 ± -0.006 ± -0.009 ± 0.007 -0.005 ± -0.007 ± -0.006 ± (PRU o/oSaOz"1) 0.007 0.004 0.005 0.008 0.006 0.009 0.007 postHVR -0.022 ± -0.010 ± -0.010 ± -0.010 ± -0.008 ± -0.009 ± 0.043* 0.011* 0.005* 0.007* 0.014* 0.006* - 46 -Table 10. Effects of intermittent hypoxia on near-infrared spectroscopy variables. Values are means ± SD. * Significantly different from preHVR. f Significantly different from day 1 and 3. Definition of abbreviations: ASc0 2/ASa0 2 = change in cerebral oxygen saturation per change in arterial oxyhemoglobin saturation; A0 2 Hb/ASa0 2 = change in oxyhemoglobin concentration per change in arterial oxyhemoglobin saturation; AHHb/ASa0 2 = change in deoxyhemoglobin concentration per change in arterial oxyhemoglobin saturation; AcHb/ASa0 2 = change in total hemoglobin concentration per change in arterial oxyhemoglobin saturation; preHVR = hypoxic ventilatory response occurring prior to hypoxic exposure; postHVR = hypoxic ventilatory response occurring following each hypoxic exposure. Variable HVR Day Day Day Day Day Day Day Day 1 3 5 8 10 12 15 17 ASc02/ASaOz preHVR -0.51 ±0 .13 -0.44 ±0 .19 -0.53 ±0.12 -0.55 ±0.15 -0.55 ±0.15 -0.64±0.18t -0.59 ±0.11 -0.51 ±0.13 (yoScCV/oSaO;,-1) postHVR -0.58 ±0 .15* -0.50 ±0.18* -0.56 ±0.15* -0.52 ±0.14* -0.60 ±0.13* -0.64 ±0.19* A02Hb/ASa02 preHVR -0.29 ± 0.08 -0.22 ±0 .13 . -0.25 ± 0.08 -0.27 ±0.13 -0.27 ±0.12 -0.26 ±0.19 -0.28 ±0.13 -0.25 ±0.15 (uM% Sa02"') postHVR -0.22 ±0 .18 -0.26 ±0.12 -0.29 ±0.12 -0.26 ±0.11 -0.27 ± 0.09 -0.33 ±0.14 AHHb/ASa02 preHVR 0.34 ±0.21 0.34 ±0 .09 0.38 ±0.09 0.39 ±0.11 0.36 ±0.10 0.44±0.12t 0.43 ±0.11 0.38 ±0.10 (uM %Sa02-') postHVR 0.43 ±0 .11* 0.38 ± 0.09* 0.40 ±0 .11* 0.39 ±0.09* 0.41 ± 0.09* 0.43 ± 0.09* AcHb/ASa02 preHVR 0.10 ±0.07 0.12 ±0.14 0.12 ±0.07 0.12±0.10 0.08 ±0.09 0.18 ±0.24 0.15 ±0.14 0.13 ±0.12 (uM %Sa02_1) postHVR 0.17 ± 0.13 0.11 ±0 .10 0.11 ±0.09 0.13 ±0.09 0.14 ± 0.11 0.10±0.14 - 4 7 -Table 11. Effects of exposure to SDIH and LDIH on respiratory variables during hypoxia. Values are means ± SD. * Significantly different from H- l (p<0.05). Definition of abbreviations: V, = ventilation; F b = breathing frequency; V t = tidal volume; H- l = average over the last 3 minutes of the first 5 minute period of hypoxic exposure; H-2 = average over the last 3 minutes of the last 5 minute period of hypoxic exposure. Variable Group Day 1 H-l H-2 Day 3 H-l H-2 Day 5 H-l H-2 Day 8 H-l H-2 Day 10 H-l H-2 Day 12 H-l H-2 V, SDIH 13.6 ± 13.1 ± 12.5 ± 12.6± 13.6 ± 13.7 ± 13.0 ± 12.7 ± 13.7± 13.6 ± 13.9 ± 14.0 ± 1 3.1 2.5 2.6 2.4 3.2 2.5 3.0 4.3 3.3 2.1 2.8 2.3 (1 min"1) LDIH 14.0 ± 13.3 ± 13.9 ± 13.2 ± 13.8 ± 13.7 ± 15.1 ± 14.2 ± 13.2 ± 13.3 ± 14.8 ± 13.5 ± 2.0 2.3 ' 1.9 2.3 2.2 2.0 2.8 2.4 2.4 2.9 ' 2.4 2.4 F b SDIH 18.0 ± 17.0 ± 18.6 ± 17.5 ± 18.1 ± 17.7 ± 17.7 ± 16.5 ± 18.8 ± 18.0 ± 17.9 ± 17.4 ± (breaths 3.8 4.4* 4.2 3.7* 4.8 4.3* 4.1 4.7* 4.1 3.4* 3.4 3.8* min"1) LDIH 18.4 ± 18.0 ± 19.1 ± 17.9 ± 18.6 ± 18.2± 19.6 ± 18.9± 19.8 ± 17.6± 19.4 ± 17.9 ± 2.0 2.9* 2.7 . 3.5* 2.4 2.6* 2.1 3.6* 2.9 4.3* 2.7 2.9* V, (liters) SDIH 0.80 ± 0.83 ± 0.70 ± 0.75 ± 0.80 ± 0.84 ± 0.76 ± 0.81 ± 0.75 ± 0.80 ± 0.81 ± 0.85 ± 0.12 0.18 0.13 0.17 0.20 0.27 0.16 0.31 0.18 0.21 0.21 0.19 LDIH 0.81 ± 0.77 ± 0.75 ± 0.77 ± 0.76 ± 0.78 ± 0.79 ± 0.79 ± 0.70 ± 0.86 ± 0.78 ± 0.78 ± 0.14 0.11 0.06 0.21 0.07 0.11 0.14 0.25 0.14 0.45 0.11 0.17 - 4 8 -Table 12. Effects of exposure to SDIH and LDIH on cardiovascular function during hypoxia. Values are means ± SD. * Significantly different from H - l (p<0.05). Definition of abbreviations: MAP = mean arterial pressure; HR = heart rate; Sa0 2 = arterial oxyhemoglobin saturation; Sc0 2 = cerebral oxygen saturation. Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Variable Group H-l H-2 H-l H-2 H-l H-2 H-l H-2 H-l H-2 H-l H-2 MAP SDIH 94.6 ± 99.8 ± 89.7 ± 96.7 ± 94.0 ± 99.4 ± 90.1 ± 97.7 ± 91.4 ± 98.0 ± 96.4 ± 99.4 ± (mmHg) 9.3 9.5* 8.3 5.9* 6.8 8.6* 7.2 7.6* 10.3 8.4* 8.5 11.9* LDIH 95.1 ± 98.5 ± 88.8 ± 91.8 ± 87.0 ± 90.2 ± 90.8 ± 91.9 ± 89.2 ± 89.3 ± 91.3 ± 92.9 ±6 .2 11.3 15.4 10.5 10.6 8.0 6.6 11.4 13.1 6.6 9.0 7.6 HR (bpm) SDIH 68.1 ± 71.2 ± 67.0 ± 72.5 ± 71.1 ± 73.1 ± 68.0 ± 70.2 ± 69.8 ± 69.4 ± 69.6 ± 70.8 ± 14.2 17.5 14.3 21.6 17.1 13.3 12.2 13.2 11.5 11.5 13.4 12.1 LDIH 72.9 ± 73.9 ± 71.7 ± 70.6 ± 70.1 ± 72.4 ± 71.5 ± 73.7 ± 78.4 ± 81.6 ± 76.4 ± 77.2 ± 9.2 10.6 10.7 10.2 9.8 11.5 13.4 12.6 14.1 15.1 9.4 12.7 Sa02 (%) SDIH 91.4± 89.9 ± 92.2 ± 90.8 ± 92.1 ± 91.8 ± 91.6 ± 91.4± 92.5 ± 92.7 ± 92.0 ± 92.2 ±2 .1 3.7 4.7 2.7 3.7 1.9 2.2 2.1 2.2 1.5 2.1 1.6 LDIH 91.1 ± 87.1 ± 91.1 ± 86.9 ± 91.3 ± 87.3 ± 92.2 ± 89.1 ± 90.6 ± 84.8 ± 91.6 ± 87.3 ± 2.1 6.1* 2.5 3.0* 1.9 3.8* 2.0 3.8* 1.1 2.4* 1.2- 4.3* Sc02 (%) • SDIH 67.9 ± 67.6 ± 65.3 ± 67.0 ± 66.4 ± 67.9 ± 65.1 ± 65.7 ± 68.1 ± 69.1 ± 67.8 ± 68.1 ±7 .0 5.9 6.5 6.4 8.1 5.2 5.0 5.7 6.2 6.0 6.0 5.9 LDIH 65.1 ± 62.6 ± 62.3 ± 60.1 ± 63.6 ± 61.9± 65.0 ± 63.1 ± 62.3 ± 59.1 ± 63.7 ± 61.3 ± 6.9 8.0* 6.3 7.2* 5.3 5.4* 3.6 4.8* 4.7 6.7* 6.4 6.7* - 4 9 -Figure 1. Displays the experimental protocol. Each day of measurement is indicated along the top bar. Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 Anthropometric measures, pulmonary function testing HCVR HCVR HCVR HCVR 1 | preHVR preHVR preHVR preHVR preHVR preHVR HVR • HVR IH* IH IH IH IH IH IH IH IH IH 1 postHVR postHVR postHVR postHVR postHVR postHVR V 0 2 m a x - Test V 0 2 m a x - Test -50-Figure 2a. Raw data trace of one individual subject from the LDIH group on the first day of the experimental protocol. Data was sampled at 1000Hz. Definition of abbreviations: F i 0 2 = fraction of inspired oxygen; Sa0 2 = arterial oxyhemoglobin saturation; Sc0 2 = cerebral oxygen saturation; HCVR = hypercapnic ventilatory response; HVR = hypoxic ventilatory response. T i m e ( s ) -51 -Figure 2b. Raw data trace of one individual subject from the SDIH group on the first day of the experimental protocol. Data was sampled at 1000Hz. Definition of abbreviations: F i 0 2 = fraction of inspired oxygen; Sa0 2 = arterial oxyhemoglobin saturation; Sc0 2 = cerebral oxygen saturation; H CV R = hypercapnic ventilatory response; HVR = hypoxic ventilatory response. Figure 3. A typical hypercapnic ventilatory response (HCVR) for one representative subject. Data points are 10-second averages. Definition of abbreviations: Vi = minute ventilation;. PetCCh = end-tidal partial pressure of CO2. 60 n PetC0 2 (mmHg) - 5 3 -Figure 4. Effects of intermittent hypoxia on the hypercapnic ventilatory response (HCVR) for subjects in the SDIH group (n=9) and subjects in the LDIH group (n=9). Data points are means ± S.E. -54-Figure 5. Displays the hypoxic ventilatory response (preHVR) for one individual subject on day 1 (pre-IH) prior to intermittent hypoxic exposure and again on day 12 (post-IH) on the last day of intermittent hypoxic exposure. Definition of abbreviations: Vi = minute ventilation; SaC»2 = arterial oxyhemoglobin saturation. 0 n 1 :—r 1 1 1 100 95 90 85 80 75 S a 0 2 (%) -55-Figure 6. Effects of intermittent hypoxia on the hypoxic ventilatory response occurring prior to each hypoxic exposure (preHVR) for all subjects. Data points are means ± SE. * Significantly different from day 1 and day 3. -56-Figure 7. Displays the hypoxic ventilatory response (preHVR) for one individual subject prior to each exposure throughout intermittent hypoxia and the HVR measured on one occasion and 5 days later for 5 consecutive days for the same subject during a different study (Koehle et al, In press). 1.5 (M o re </) 1 'c E 0.5 > X Q. 0 0 ~~1 r 5 post-1 H - Repeated HVR — IH HVR 10 15 Days - 57 -Figure 8. Displays the effects of intermittent hypoxia on preHVR and postHVR for all subjects. Data points are means ± SE. * Significantly different from postHVR (p<0.01). Definition of . abbreviations: H V R = hypoxic ventilatory response; preHVR = HVR occurring prior to each hypoxic exposure; postHVR = HVR occurring following each hypoxic exposure. o ns or > X 1.4 1.2 1 -0.8 -0.6 -0.4 0.2 5 8 Day preHVR postHVR 10 12 -58-Figure 9. Displays the relationships and sensitivities to hypoxia of (A) systolic (SBP) and (B) diastolic blood pressure (SBP), (C) heart rate (HR), (D) stroke volume (SV), (E) cardiac output (CO), and (F) total peripheral resistance (TPR) for one individual subject during a hypoxic ventilatory response on the first day of its measurement. Data points are 10-second averages. Definition of abbreviations: SBP/Sa02 = change in systolic blood pressure per change in arterial oxyhemoglobin saturation; DBP/Sa02 = change in diastolic blood pressure per change in arterial oxyhemoglobin saturation; HR/Sa02 = change in heart rate per change in arterial oxyhemoglobin saturation; SV/Sa0 2 = change in stroke volume per change in arterial oxyhemoglobin saturation; CO/Sa02 = change in cardiac output per change in arterial oxyhemoglobin saturation; TPR/Sa02 = change in total peripheral resistance per change in arterial oxyhemoglobin saturation. 180 -I X 160 -E E, 140 -Q. CQ 120 -(/> 100 -SBP/Sa0 2= 1.61 R 2 = 0.87 B 100 D) X E E, 80 Q_ m a 60 DBP/SaO 2 = 0.50 R 2= 0.82 -59-Figure 10. The effects of intermittent hypoxia on systolic blood pressure sensitivity and on diastolic blood pressure sensitivity, for all subjects. Data points are means ± SE. Definition of abbreviations: BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; pre-IH = pre intermittent hypoxia; post-IH = post intermittent hypoxia. Q. CQ 0 -I 1 1 1 1 1 : 1 1 — < 1 1 3 5 . 8 10 12 15 17 Day -60-Figure 11. Displays the relationship and sensitivity to hypoxia of cerebral (A) oxygen saturation (ScC»2), (B) oxyhemoglobin concentration (uM), (C) deoxyhemoglobin concentration (HHb), and (D) total hemoglobin concentration (cHb) during a hypoxic ventilatory response for one individual subject. Data points are 10-second averages. Definition of abbreviations: dScCVdSaC^ = the change in cerebral oxygen saturation per change in arterial oxyhemoglobin saturation.; dC»2Hb/dSa02 = change in oxyhemoglobin concentration per change in arterial oxyhemoglobin saturation; dHHb/dSa02 = change in deoxyhemoglobin saturation per change in arterial oxyhemoglobin saturation; dcHb/dSa02 = change in total hemoglobin concentration per change in arterial oxyhemoglobin saturation; SaC»2 = arterial oxyhemoglobin saturation. 100 95 90 85 80 75 100 95 90 85 80 75 Sa02(%) Sa0 2(%) -61 -Figure 12. The effects of intermittent hypoxia on cerebral oxygen saturation sensitivity (dScCVdSaC^) to hypoxia for all subjects. Cerebral oxygen saturation sensitivity is the change in cerebral oxygen saturation (dSc02) per change in arterial oxygen saturation (dSaC^). Data points are means ± SE. * Significantly different from day 1 and day 3 (p<0.05). Definition of abbreviations: pre-IH = pre intermittent hypoxia; post-IH = post intermittent hypoxia. 1 3 5 8 10 12 15 17 Day -62-Figure 13. Displays the change in cerebral oxygen saturation (ScO-2) during the preHVR on day 1 and on day 12 for all subjects in (A) SDIH and (B) LDIH. The preHVR is the hypoxic ventilatory response occurring prior to exposure to daily hypoxia. -63 -APPENDIX A Review of Literature - Intermittent Hypoxia Introduction Intermittent exposure to hypoxia has been shown to affect the control of breathing (Gozal & Gozal, 2001; Mitchell et al, 2001; Prabhakar, 2001; Mitchell & Johnson, 2003; Morris et al, 2003), the cardiovascular system (Earley & Walker, 2002; Gonzales & Walker, 2002;.Jernigan & Resta, 2002), and the autonomic nervous system (MacDonald et al, 1992; Morgan et al, 1995; Smith & Muenter, 2000; Yasuma & Hayano, 2000). Unlike continuous hypoxia (CH), intermittent hypoxia (IH) may contribute to the effects of certain pathological conditions, such as sleep apnea and chronic obstructive pulmonary disease. Chronic exposure to IH can lead to secondary conditions including systemic hypertension, myocardial and brain infarctions, and cognitive dysfunction (Prabhakar, 2001). Recurrent episodes of hypoxia are also common in individuals who do not display pathophysiologies. This includes individuals who voluntarily engage in breath-holding activities (i.e. breath-hold diving) (Andersson et al, 2002) or sojourn to altitude (Powell & Garcia, 2000). These healthy individuals display adaptations as a result of repetitive hypoxemia (Ferretti, 2001). The purpose of this review is to examine the consequences of IH on ventilatory, cardiovascular, and autonomic systems in healthy humans and to compare these findings to animal models and to individuals who have been exposed to IH as a result of disease. Several extensive reviews already exist which describe intermittent hypoxia in the animal model (Fletcher et al, 1992; Fletcher, 2001; Gozal & Gozal, 2001; Mitchell et al, 2001; Prabhakar, 2001; Prabhakar et al, 2001); the reader is referred to them as a supplement to this review. For the purpose of this review, three types of exposure to hypoxia are distinguished. Continuous hypoxia is defined as a single exposure to a sustained hypoxic stimulus for a - 64 -duration greater than 48 hours with no subsequent exposure to hypoxia. Continuous hypoxia is contrasted to two forms of IH: long duration intermittent hypoxia (LDIH) and short duration intermittent hypoxia (SDIH) (Peng & Prabhakar, 2004). LDIH is defined as exposure to a single daily episode of hypoxia for 30 minutes to five hours that occurs every day for 5 days or more, while SDIH is several daily exposures (3-12 bouts) to less than five minutes of hypoxia separated by normoxia. Like LDIH, SDIH involves daily exposures that continue for 5 days or more. This review is divided into three sections. The first section describes the ventilatory consequences of IH with particular emphasis on the acute ventilatory response to hypoxia and hypercapnia. The subsequent section describes the cardiovascular consequences of IH and discusses changes in blood pressure, cardiac output, stroke volume, heart rate, and total peripheral resistance. This section also describes changes in endothelial function in response to hypoxia. The final section discusses the consequences of IH on autonomic function. Ventilatory Consequences of Intermittent Hypoxia The control of breathing in humans is often studied by quantifying the ventilatory response to chemical stimuli. The hypoxic ventilatory response (HVR) is measured by progressively reducing the inspired fraction of oxygen to evoke a change in the partial pressure of oxygen in arterial blood (Pa02) and, thus, an increase in minute ventilation (Weil et al, 1970). Using this method, the H V R is the slope of the linear regression relating ventilation and arterial oxygen saturation (Harms & Stager, 1995; Derchak et al, 2000; Guenette et al, 2004; Koehle et al, In Press). Another method of assessing HVR involves plotting the hyperbolic curve that results when the partial pressure of oxygen is related to ventilation (Weil et al, 1970; Byrne-Quinn etal, 1971). These two methods of assessing HVR are qualitatively similar but quantitatively different. The hypercapnic ventilatory response (HCVR) is measured by -65-quantifying the increase in ventilation as the individual's end-tidal partial pressure of C02 is increased (Read, 1967). A linear regression relates the change in ventilation to the change in end-tidal partial pressure of C O 2 ; the slope of this line is termed the HCVR. Various methods exist for measuring the HCVR; however, the rebreathing method developed by Read (Read, 1967) is the most common. Other methods are simply variations of this method that may involve previous hyperventilation and varying levels of oxygen (hyperoxic, normoxic, or hypoxic) (Mohan & Duffin, 1997; Mohan et al, 1999; Mahamed & Duffm, 2001; Duffin & Mahamed, 2003; Mateika et al, 2004). The mechanisms are qualitatively similar for both responses; changes in the partial pressure of oxygen and C02 are sensed by the peripheral chemoreceptor and a ventilatory correction is made reflexively to maintain homeostasis (Duffm & Mahamed, 2003). Changes in HVR and H C V R (i.e. changes in slope) indicate changes in the sensitivity of the respiratory control system to hypoxia and hypercapnia respectively. Ventilatory responses have been determined in a broad spectrum of individuals. In comparison to healthy normal controls, endurance athletes (Martin et al, 1979; Mahler et al, 1982; Miyamura & Ishida, 1990; Harms & Stager, 1995), breath-hold divers (Masuda et al, 1981; Grassi et al, 1994; Delapille et al, 2001), and sleep apnea patients (Garcia-Rio et al, 2002) have a reduced ventilatory response to hypercapnia and hypoxia. Blunted ventilatory responses in breath-hold divers and sleep apnea patients might be explained by their chronic exposure to intermittent hypoxic conditions; however, individuals involved in mountain climbing who repeatedly sojourn to altitude demonstrate an enhanced ventilatory response to hypoxia (Powell & Garcia, 2000). Also, in healthy humans with no breath-holding experience and no previous exposure to altitude, intermittent hypoxic exposure for a duration of one to two weeks increases the ventilatory response to hypoxia (Prabhakar & Kline, 2002). Respiratory control in the animal model is similar in that chemical stimuli may be used to evoke respiratory compensation; however, direct nerve recordings can be obtained from either -66-the carotid sinus nerve or the phrenic nerve rather than quantifying ventilation itself (Daly, 1997). Chemical stimuli include changes in the partial pressures of oxygen and C02, changes in pH and application of pharmacological agents. Direct electrical stimulation of the carotid sinus nerve is also a popular method for evoking respiratory changes in the animal model. For the purpose of this review only those respiratory responses that result from changes in oxygen and C02 partial pressures will be discussed. Various studies on the control of breathing using animal models have demonstrated respiratory neural plasticity within the central nervous system in response to hypoxia (Mitchell & Johnson, 2003; Morris et al, 2003). Long term facilitation occurs following exposure to successive episodes of hypoxia and is characterized by a progressive increase in respiratory motor output during the normoxic intervals (Powell et al, 1998). Respiratory motor output can remain elevated for many minutes to several hours following the final stimulus episode (Powell et al, 1998). In the rodent model, SDIH enhances hypoxic sensitivity and leads to long-term facilitation in the sensory discharge of the carotid nerve while continuous hypoxia does not (Peng et al, 2001; Prabhakar, 2001; Peng & Prabhakar, 2004). Peng and Prabhakar (2004) exposed rats to SDIH and LDIH for ten days and determined carotid body sensory activity in vivo and ex vivo to graded isocapnic hypoxia. The hypoxic sensory activity was enhanced in SDIH animals but not in LDIH animals. Studies involving normal human subjects also demonstrate respiratory plasticity. As in the rodent model, human hypoxic sensitivity increases with repeated exposure to hypoxia (Katayama et al, 1998; Katayama et al, 1999; Garcia et al, 2000b; Katayama et al, 2001a; Katayama et al, 2001b); but, long term facilitation does not occur. Other human studies involve patients who have undergone carotid body resection as a treatment for asthma or carotid body tumors (Gross et al, 1976; Honda et al, 1988; Timmers et al, 2003). From these studies it appears that the carotid body plays an obligatory, excitatory role in the ventilatory response to - 67 -hypoxia. Bilateral carotid body resected patients have no ventilatory response to progressive hypoxia (Honda et al, 1988; Timmers et al, 2003). Making direct comparisons between studies is difficult as there appears to be no standard method of intermittent hypoxia protocols. Some studies expose human subjects to isocapnic hypoxia (controlled PetCCh) (Garcia et al, 2000a), while others expose subjects to poikilocapnic hypoxia (uncontrolled PetC02) (Tansley et al, 1998; Katayama et al, 2001b). Patterns, durations, and hypoxic intensities vary throughout many IH studies and may involve normobaria (Serebrovskaya et al, 1999; Mahamed & Duffin, 2001; Ainslie et al, 2003; Mateika et al, 2004) or hypobaria (Sato et al, 1992; Sato et al, 1994; Katayama et al, 1998; Katayama et al, 1999; Garcia et al, 2000c; Katayama et al, 2001a; Katayama et al, 2001b). Some intermittent hypoxic studies have involved simultaneous exercise training (Levine et al, 1992; Katayama et al, 1998; Katayama et al, 1999, 2001a). Whether or not the changes in respiratory and cardiovascular physiologies are similar among all of these conditions is unknown and requires further study. In contrast to the rodent model, human studies involving C H for a week or more have demonstrated an increase in the HVR that subsequently returns to normal within a week of descent to sea-level (Sato et al, 1992; Sato et al, 1994). More similar to the rodent model are the human studies involving both LDIH and SDIH which equivocally demonstrate increases in HVR (Katayama et al, 1998; Garcia et al, 2000b, 2000c; Katayama et al, 2001b; Katayama et al, 2002). Garcia et al. (2000c) compared five days of hypobaric IH at rest (two hours daily at 3800m) with eight weeks of C H (also at 3800m). Both LDIH and C H induced similar changes in magnitude of HVR; however, two weeks of C H were necessary to reach the same change in HVR seen after only five days of LDIH. Most paradigms of IH in humans evoke an increase in HVR; the available data on the HCVR is not so clear. The H C V R has been reported to either stay the same or increase following IH (Katayama et al, 1998; Katayama et al, 1999, 2001a; Mahamed & Duffin, 2001; - 68 -Ainslie et al, 2003). Some of these studies involve IH with concurrent exercise training and involve three different methods for determining HCVR, making it difficult to compare studies. The first and most common method of determining HCVR is the rebreathing method (Read, 1967) which is thought to be a measure of CO2 sensitivity at the central chemoreceptor (Mohan et al, 1999). Using this method and exercise training during IH, 30 min of hypobaric hypoxia at 432 mmHg for either six days or two weeks shows no change in the central chemoreceptor response to CO2 (Katayama et al, 1998; Katayama et al, 1999). However, Ainslie et al (2003) showed an increase in the hypercapnic ventilatory response following five nights of normobaric hypoxia (13.8% O2) using the rebreathing method. Other investigators have used the single breath CO2 response test (HCVRsb) which is thought to be a measure of the peripheral chemoreceptor response to CO2 (McClean et al, 1988). No change in HCVRsb was seen following 30 minutes of hypobaric hypoxia at 432 mmHg for six days with concurrent exercise training (Katayama et al, 1999) and also following 1 hour of hypobaric hypoxia at 432 mmHg for two weeks without exercise training (Katayama et al, 2002). Finally, a novel approach of determining the central chemoreceptor response to C02 has been employed by Mahamed et al. (2001). This method involves prior hyperventilation before commencing the rebreathe at different iso-oxic levels and allows for the determination of the chemoreflex threshold to CO2. Using the modified rebreathing technique, changes in the peripheral chemoreflex to C02 were measured in hyperoxia and in hypoxia. Following twenty minutes of isocapnic hypoxia daily for 14 consecutive days, an increase in the C02 threshold occurs but only in the presence of hypoxia, not hyperoxia (Mahamed & Duffin, 2001). The authors interpreted this result as indicating changes in the peripheral chemoreflex and not the central chemoreflex. It may be that marked respiratory alkalosis is necessary to elicit changes in HCVR. In the majority of the studies that measure HCVR, the hypoxic exposure is usually no more than an hour per day for -69-less than two weeks. Furthermore, it is likely that no change in H C V R occurs in studies where the subjects are exposed to isocapnic hypoxia because no respiratory alkalosis occurs. Cardiovascular Consequences of Intermittent Hypoxia The acute cardiovascular response to hypoxia involves an increase in cardiac output (CO), systemic arterial vasodilation, and pulmonary arterial vasoconstriction (Semenza, 1999). Cerebral blood flow (Vovk et al., 2002), heart rate (HR), and arterial blood pressure increase with progressive isocapnic hypoxia and hyperoxic hypercapnia (Yasuma & Hayano, 2000). Twenty minutes of isocapnic hypoxia elicits increases in heart rate, limb blood flow, blood pressure, and muscle sympathetic nerve activity (Morgan et al., 1995; Xie et al., 2000). Intact peripheral chemoreceptors are necessary for arterial blood pressure in rats to increase in response to SDIH patterned after that of sleep apnea in humans (Fletcher et al, 1992). Few studies have examined the cardiovascular response to intermittent hypoxic exposure in humans. Katayama et al. (2001b) studied the cardio-ventilatory response to progressive isocapnic hypoxia before and after one hour of daily exposure to 4,500 m for 7 days. Resting ventilation, blood pressure, and heart rate did not change after IH. There was, however, an increase in the systolic (SBP) and diastolic (DBP) blood pressure response to progressive hypoxia. These changes in cardiovascular sensitivity were accompanied by an increase in HVR. Similar results were found in men at high-altitude (5,050M) for 24 days (Insalaco et al, 1996). They found increases in blood pressure sensitivity following one day at high-altitude that continued to increase by the 24th day at high-altitude. They also observed a slight reduction in heart rate sensitivity. In contrast to these studies, several studies using SDIH did not observe changes in cardiovascular function (Bernardi et al, 2001; Rey et al, 2004). Bernardi et al. (2001) studied the change in SBP and DBP in response to progressive hypoxia before and after 14 days of exposure to three to four 7-minute isocapnic rebreathing sessions daily (P0 2 was progressively reduced to -35-40 - 70 -mmHg). They found no changes in SBP or DBP sensitivity to isocapnic hypoxia. Similarly, in another study, cats were exposed to cyclic hypoxic episodes (P02 ~ 75 mmHg) repeated during 8 hours for 2 to 4 days; no changes in arterial pressure or heart rate sensitivity during acute hypoxia were found (Rey et al, 2004). Studies involving sleep apnea patients show that an elevated resting normoxic blood pressure and, in many cases, a hypertensive condition are present (Fletcher, 2001). Recently published animal work suggests IH may alter both peripheral and cerebrovascular vasomotor activity as a result of a hypoxia associated endothelial dysfunction (Earley & Walker, 2002; Gonzales & Walker, 2002; Jernigan & Resta, 2002; Altay et al, 2004; Phillips et al, 2004). These alterations in vasomotor activity may differ depending on the location of the vascular bed. Mesenteric resistance arteries isolated from rats exposed to 48 hours of hypobaric hypoxia (380 mmHg) have an attenuated vasoconstrictor reactivity (Earley & Walker, 2002; Gonzales & Walker, 2002). On the other hand, rats exposed to a similar level of hypobaric hypoxia for four weeks have an attenuated pulmonary vasodilation (Jernigan & Resta, 2002). Another study exposed rats to SDIH and assessed endothelial function of resistance vessels in skeletal muscle and cerebral circulations and found that exposure to chronic IH severely blunts vasodilator responsiveness to acute hypoxia (Phillips et al, 2004). None of the above studies have determined if blood flow or tissue oxygenation is affected by the altered endothelial function. No similar studies have been performed in humans. One study does assess, however, the effects of five consecutive nocturnal hypoxic exposures in humans (Kolb et al, 2004). Using an end-tidal forcing technique, cerebral blood flow responses to acute variations in O2 and CO2 were determined before and after the nocturnal hypoxic episode. Their results show that discontinuous hypoxia elicits an increase in the sensitivity of cerebral blood flow to acute variations in oxygen and CO2. In a similar study where cerebral blood flow responses to 5-min steps of isocapnic hypoxia were measured before and during 5 days at 3, 810 m, increases in -71-cerebral blood flow responses occurred (Jernigan & Resta, 2002). Perhaps maladaptive effects occur following a greater duration of intermittent hypoxia. Autonomic Consequences of Intermittent Hypoxia Intermittent exposure to hypoxia produces sustained systemic hypertension in a rat model that is preventable by denervating the carotid body (Fletcher et al, 1992). Researchers have hypothesized that long-term exposure to intermittent hypoxia increases sympathetic responsivity to chemoreflex stimulation and leads to long-lasting sympathetic activation and vasoconstriction in sleep apnea patients (Morgan & Joyner, 2002). This was true following a simple acute exposure to combined hypoxia (SaC>2 = 80%) and hypercapnia (PetCd + 5 mmHg) (Morgan et al, 1995). Muscle sympathetic nerve activity increased in response to the asphyxic exposure and about 2/3 of the sympathetic activation persisted in excess of twenty minutes (Morgan et al, 1995). The exposure was repeated with hyperoxic hypercapnia and also caused an increase in sympathetic activity; but, unlike the asphyxic exposure, there was no after-effect. This study demonstrates that even relatively brief periods of asphyxic stimulation can cause a substantial increase in sympathetic vasomotor outflow that outlasts the chemical stimuli. Following this study, the researchers looked at the effects of intermittent asphyxia on sympathetic activation (Xie et al, 2000). In this study, healthy subjects (n=7) were exposed to an intermittent asphyxic (Sa02 = 79-85%; PetCCh = +3-5 mmHg) intervention consisting of 20-second asphyxic periods alternating with 40-second periods of room-air breathing for a total of 20 minutes. Like 20 minutes of sustained asphyxia, 20 minutes of intermittent asphyxia resulted in MSNA activity that remained elevated for at least 20 minutes after the removal of the chemical stimuli. While both these studies show an elevated sympathetic activation after exposure to combined hypoxia and hypercapnia, it is not known whether hypoxia alone would have similar results. Therefore, Xie et al (2001) performed a study to determine the relative contributions of hypoxia and -72-hypercapnia in causing persistent sympathoexcitation. In this study, healthy subjects (n=9) were exposed to 20 minutes of isocapnic hypoxia (SaCh = 77-87%) or twenty minutes of normoxic hypercapnia (PetCC>2 = +5.3-8.6 mmHg) in random order on two separate days. The results indicated that both hypoxia and hypercapnia cause substantial increases in sympathetic outflow to skeletal muscle; but, hypercapnia-evoked sympathetic activation is short-lived, whereas hypoxia-induced sympathetic activation outlasts the chemical stimuli. To more clearly understand if this response is true for intermittent exposure and not just sustained exposure, Cutler et al. (2004) undertook a study. In this study, the effects of 20 minutes of intermittent voluntary hypoxic apneas (30-second hypoxic apnea performed every minute) on MSN A during 180 minutes of recovery were determined. In addition, the effects of 20 minutes of intermittent hypercapnic hypoxia (30-seconds hypercapnic hypoxia every minute), and isocapnic hypoxia (30-seconds isocapnic hypoxia every minute) on MSNA during 180 minutes of recovery were determined. The results indicate that short-term exposure to intermittent hypoxic apnea results in sustained elevation of M S N A and that hypoxia is the primary mediator of this response. It is now well documented that hypoxic exposure, whether intermittent or sustained, can induce sympathetic activation that remains elevated following the removal of the chemical stimuli. This response is not dependent on the presence of hypercapnia. To date no long-term intermittent hypoxia studies have assessed sympathetic activity in humans. An animal study does, however, assess the sympathetic response to chronic intermittent hypoxia (Fi02 nadir = 6.5-7% each minute separated by 1-minute of 21% O2 occurring 8 hours/day during the night for 30 days) (Greenberg et al., 1999). Preganglionic cervical sympathetic activity was measured directly in rats spontaneously breathing 100% 0 2 , room air, 10% O2, 12%C02, and 10% 02-12% CO2. In addition, baroreceptor function was assessed during phenylephrine infusion. The results indicate that baroreceptor function was not different; but, the chronic intermittent hypoxia led to increased sympathetic responsiveness to chemoreflex -73-stimulation. In addition, there was an increase in resting normoxic mean arterial pressure. This is the first study to indicate that exposure to chronic intermittent hypoxia leads to systemic hypertension that may have been mediated by increased sympathetic responsiveness to chemoreflex stimulation. Summary In summary, the hypoxic ventilatory response increases following both SDIH and LDIH in human subjects (Katayama et al, 1998; Katayama et al, 1999; Garcia et al, 2000b; Katayama et al, 2001b); but in the animal model, only SDIH leads to enhanced chemosensitivity (Peng & Prabhakar, 2004). The hypercapnic ventilatory response has been described to either stay the same or increase (Katayama et al, 1998; Katayama et al, 1999; Mahamed & Duffin, 2001; Ainslie et al, 2003). It is likely that marked respiratory alkalosis is necessary for changes in the hypercapnic ventilatory response to occur. The blood pressure response to isocapnic hypoxia has been reported to increase following both LDIH and sustained high altitude human studies, while the heart rate response is unaltered (Insalaco et al, 1996; Katayama et al, 2001b). This is not true for SDIH exposure in the human or the cat (Bernardi et al, 2001; Rey et al, 2004), even though SDIH in the rat for 30-35 days results in systemic hypertension (Fletcher et al, 1992; Rey etal, 2004). Several recent rat studies have suggested that exposure to SDIH leads to vasomotor dysfunction in cerebral, skeletal, and mesenteric resistance arteries (Gonzales & Walker, 2002; Phillips et al, 2004). This is true for the pulmonary circulation as well (Jernigan & Resta, 2002). Human studies, however, suggest that hypoxic exposure leads to an increase in the blood flow response to both hypoxia and hypercapnia following 5 days of intermittent or sustained hypoxia (Jensen et al, 1996; Kolb et al, 2004). It is likely that longer exposures are necessary to evoke the maladaptive effects of SDIH. Elevated sympathetic activity is apparent for a short time following exposure to short sustained periods of isocapnic hypoxia and - 74 -intermittent isocapnic hypoxia, and is not present following similar exposures to normoxic hypercapnia (Morgan et al, 1995; Xie et al, 2000; Xie et al, 2001; Cutler et al, 2004). In addition, the sympathetic response to hypoxia is elevated following 30 days of exposure to SDIH (Greenberg et al, 1999). Intermittent hypoxic exposure is a powerful stimulus to the ventilatory, cardiovascular, and autonomic system. The effects of intermittent hypoxia are still not fully understood. -75 -APPENDIX B - Individual Raw Data Subject characteristics and resting pulmonary function. Age Height Mass Forced vital capacity Forced expired volume in 1 second F E V , / F V C Subject (years) (cm) (kg) (FVC, liters) (FEV,, liters) (%) SDIH 01 23 172 90 4.27 3.79 88.8 SDIH 02 24 170 76 3.88 3.48 92.7 SDIH 03 23 170 72 4.21 3.62 86.1 SDIH 04 22 181 79 4.46 3.89 87.2 SDIH 05 23 182 70 5,81 4.81 82.8 SDIH 06 23 172 90 4.77 4.39 88.0 SDIH 07 33 186 84 5.93 4.25 76.0 SDIH 08 32 188 86 5.80 4.34 75.0 SDIH 09 29 181 85 5.74 4.69 81.7 LDIH 01 21 185 93 5.24 4.00 76.4" LDIH 02 23 126 69 5.10 4.64 91.0 LDIH 03 26 186 86 4.56 3.38 74.1 LDIH 04 33 177 76 5.08 4.34 85.3 LDIH 05 23 177 67 4.28 3.52 82.2 LDIH 06 28 182 96 5.12 4.25 82.0 LDIH 07 21 177 76 5.40 4.60 85.0 LDIH 08 32 171 93 4.20 3.92 90.6 LDIH 09 23 186 77 5.68 4.82 84.9 -76-Maximal exercise data day 1. VO-2 Predicted V 0 2 VO-2 v c o 2 RER V i / V C 0 2 Power v , HR Subject (ml kg"1 min"1) (ml kg"1 min"1) (1 min"1) (1 min"1) (watts) (liters) (bpm) SDIH 01 37.1 41.2 4.20 5.28 1.29 33.3 26.5 255 140.0 158 SDIH 02 39.4 39.1 3.77 4.65 1.25 35.7 28.9 230 134.5 192 SDIH 03 44.3 42.3 3.19 3.87 1.21 29.1 24.0 305 94.8 169 SDIH 04 36.4 45.1 2.93 3.75 1.28 34.0 26.6 283 97.6 172 SDIH 05 52.1 43.7 3.61 4.52 1.25 34.3 27.4 364 136.3 189 SDIH 06 27.6 34.2 2.56 3.60 1.40 37.4 26.7 257 86.1 188 SDIH 07 56.1 51.0 4.72 5.63 1.19 30.3 25.4 486 148.2 182 SDIH 08 48.7 48.2 4.19 4.85 1.16 30.0 25.9 412 139.1 175 SDIH 09 37.7 43.9 3.20 4.08 1.27 35.8 28.2 341 114.8 193 LDIH 01 41.8 42.9 2.87 3.72 1.31 48.5 29.0 279 139.2 180 LDIH 02 41.8 28.4 2.88 3.56 1.23 31.6 25.6 265 91.0 191 LDIH 03 42.8 43.5 3.69 4.20 1.14 26.7 23.5 337 97.9 168 LDIH 04 — 43.8 — — — — — — — — LDIH 05 ' 48.5 44.8 3.38 4.09 1.21 36.0 29.8 294 116.7 187 LDIH 06 39.2 42.1 3.74 5.12 1.37 37.7 27.5 388 141.1 176 LDIH 07 38.4 44.8 2.92 3.53 1.21 30.8 25.4 287 89.8 179 LDIH 08 33.0 35.7 3.07 3.75 1.22 34.0 27.8 315 110.2 172 LDIH 09 52.5 . 50.8 4.04 5.05 1.25 33.2 26.5 381 133.9 176 -77-Maximal exercise data day 12. V 0 2 v o 2 v c o 2 RER V i / V 0 2 V I A Vr C 0 2 Power V i HR Subject (ml kg"1 min"1) (1 min"1) (1 min"1) (watts) (liters) (bpm) SDIH 01 40.5 4.62 5.35 1.20 29.7 25.6 256 137.2 165 SDIH 02 35.3 2.69 3.40 1.31 43.6 34.5 256 117.4 208 SDIH 03 44.5 3.17 3.89 1.23 29.9 24.3 300 95.6 173 SDIH 04 . 43.5 3.18 3.54 1.14 27.1 23.7 286 88.9 171 SDIH 05 52.5 3.49 4.75 1.36 41.0 30.2 353 143.8 184 SDIH 06 30.0 2.70 3.80 1.41 37.1 26.3 - 275 110.3 190 SDIH 07 58.1 4.88 5.70 1.17 30.0 25.7 504 146.3 185 SDIH 08 48.7 4.49 5.12 1.22 32.3 26.4 426 144.5 180 SDIH 09 39.7 3.43 4.05 1.18 38.2 32.4 340 129.4 183 LDIH 01. — — — — — — — — LDIH 02 — • . . . — — — . . . — LDIH 03 40.9 3.52 3.90 1.11 26.3 23.7 355 97.2 173 LDIH 04 _— ___ — — — — — — . . . LDIH 05 44.2 2.94 3.53 1.20 33.2 27.7 295 97.7 184 LDIH 06 40.7 3.85 4.84 1.26 32.4 25.8 380 125.5 172 LDIH 07 36.9 .2.95 3.87 1.31 36.9 28.1 285 102.7 177 LDIH 08 36.4 3.39 4.09 1.21 34.3 28.4 317 116.8 173 LDIH 09 52.4 3.95 5.04 1.28 35.5 27.8 383 142.8 186 -78 -Normoxic resting ventilation (VT) and coefficient of variation ( C V ) . v , C V (1 min"1) (%) Subject Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 SDIH 01 8.43 9.13 8.77 8.64 9.64 8.45 10.37 9.99 8.07 SDIH 02 9.12 10.80 11.50 9.31 7.32 9.10 9.20 9.93 13.17 SDIH 03 9.27 9.69 7.98 10.62 8.76 9.20 9.59 9.08 8.22 SDIH 04 14.86 14.00, 12.66 15.29 11.48 11.42 12.44 13.31 11.02 SDIH 05 10.96 11.33 ' 12.53 13.17 13.05 12.00 13.30 12.63 7.01 SDIH 06 11.39 12.22 .14.32 10.26 11.55 14.91 14.66 11.60 13.97 SDIH 07 12.34 10.79 13.04 13.75 14.54 13.82 13.05 11.79 9.41 SDIH 08 12.24 11.50 13.70 13.52 15.64 12.55 11.63 12.39 10.54 SDIH 09 6.26 . 7.91 7.13 9.10 8.84 7.56 7.32 7.79 11.83 LDIH 01 13.126 13.71 12.95 13.56 11.71 12.83 11.78 13.30 5.85 LDIH 02 7.89 10.52 9.61 9.62 10.10 10.39 10.40 10.55 9.00 LDIH 03 14.04 10.82 11.77 13.84 10.78 13.51 12.12 11.90 10.52 LDIH 04 9.80 10.63 12.20 10.90 10.74 10.23 10.80 10.68 6.41 LDIH 05 10.69 14.75 13.64 15.73 14.58 12.77 12.31 12.69 12.02 LDIH 06 14.51 14.25 12.81 15.98 14.96 11.80 14.67 14.69 9.21 LDIH 07 9.91 11.00 11.06 12.96 13.74 12.69 11.93 11.77 11.18 LDIH 08 12.58 13.97 12.08 13.14 15.37 11.86 12.44 12.98 8.78 LDIH 09 12.18 15.08 16.09 14.60 15.47 15.24 13.13 14.84 8.86 -79-Normoxic resting breathing frequency (Fb) and coefficient of variation ( C V ) . F b C V (breaths min") (%) Subject Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 SDIH 01 14.6 14.8 14.9 14.6 15.3 14.8 14.6 14.7 1.6 SDIH 02 20.2 21.3 21.5 19.3 20.2 18.7 17.8 18.8 6.6 SDIH 03 10.1 11.9 10.4 12.4 11.1 13.4 12.4 11.6 9.5 SDIH 04 22.5 24.1 22.8 22.6 23.2 22.2 22.8 22.8 2.5 SDIH 05 15.7 16.1 18.5 17.5 15.8 17.0 19.5 18.6 8.2 SDIH 06 18.7 17.5 17.9 15.0 18.9 15.8 19.1 17.4 8.4 SDIH 07 18.4 19.2 18.6 17.9 20.3 18.9 19.3 19.0 3.9 SDIH 08 19.6 20.5 22.0 23.0 21.7 17.4 18.5 19.1 9.5 SDIH 09 7.3 11.3 7.8 12.7 13.3 11.4 10.2 11.8 20.2 LDIH 01 17.7 20.0 19.1 20.7 20.1 17.2 16.6 18.6 7.8 LDIH 02 11.6 17.7 13.3 17.3 17.3 17.8 16.7 17.1 14.3 LDIH 03 20.4 14.9 15.3 18.1 16.4 17.4 17.8 16.1 10.4 LDIH 04 17.9 20.9 20.6 18.7 19.0 17.6 15.5 17.7 9.4 LDIH 05 17.2 15.9 19.2 18.4 23.2 19.7 17.8 19.8 11.5 LDIH 06 20.0 20.1 19.8 22.5 21.8 21.7 22.3 21.6 5.2 LDIH 07 16.9 15.6 18.0 19.7 17.2 19.3 17.7 17.9 7.8 LDIH 08 17.2 20.9 18.0 20.0 22.6 18.8 19.7 22.0 8.9 LDIH 09 17.1 22.6 21.6 21.2 19.1 19.5 18.0 18.5 9.9 -80-Normoxic resting tidal volume ( V t ) and coefficient of variation ( C V ) . v t . C V (liters) (%) Subject Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 SDIH 01 0.59 0.62 0.59 0.49 0.63 0.57 0.71 0.68 10.96 SDIH 02 0.45 0.54 0.53 0.48 0.36 0.49 0.52 0.53 11.82 SDIH 03 0.94 0.82 0.77 0.86 0.79 0.69 0.78 0.79 9.03 SDIH 04 0.67 0.59 0.56 0.71 0.50 0.52 0.55 0.59 12.26 SDIH 05 0.71 0.71 0.69 0.76 0.84 0.71 0.69 0.68 7.31 SDIH 06 0.62 0.71 0.83 0.69 0.62 0.99 0.80 0.68 16.88 SDIH 07 0.68 0.56 0.71 0.78 0.74 0.74 0.68 0.62 10.34 SDIH 08 0.63 0.56 0.62 0.59 0.73 0.73 0.63 0.65 9.44 SDIH 09 0.89 0.71 0.92 0.75 0.67 0.67 0.73 0.67 13.28 LDIH 01 0.75 0.69 0.68 0.66 0.58 0.76 0.71 0.72 8.19 LDIH 02 0.71 0.60 0.73 0.56 0.60 0.59 0.63 0.63 9.33 LDIH 03 0.69 0.73 0.77 0.77 0.66 0.78 0.69 0.74 6.11 LDIH 04 0.56 0.52 0.61 0.60 0.58 0.59 0.72 0.62 9.65 LDIH 05 0.64 0.94 0.76 0.93 0.63 0.67 0.71 0.66 16.94 LDIH 06 0.77 0.76 0.66 0.75 0.75 0.54 0.69 0.71 10.85 LDIH 07 0.59 0.71 0.61 0.67 0.80 0.66 0.68 0.67 10.23 LDIH 08 0.75 0.68 0.64 0.67 0.69 0.64 0.63 0.60 6.93 LDIH 09 0.77 0.70 0.81 0.70 0.87 0.84 0.80 0.98 11.38 - 81 -Normoxic resting end-tidal partial pressure of CO2 (PetC02) and coefficient of variation (CV). PetCG-2 CV (mmHg) (%) Subject Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 SDIH 01 46.18 44.63 44.88 44.03 47.20 45.76 46.10 45.36 2.21 SDIH 02 43.13 43.80 45.11 45.05 44.17 43.71 42.06 43.32 2.31 SDIH 03 42.42 43.18 44.71 43.97 43.22 45.04 43.72 42.98 2.04 SDIH 04 42.11 43.49 43.17 46.18 45.31 44.90 45.17 43.63 3.06 SDIH 05 42.85 44.20 42.80 44.52 43.42 42.36 43.30 41.46 2.28 SDIH 06 43.95 44.76 43.98 41.40 40.30 44.28 46.04 41.52 4.56 SDIH 07 41.80 41.56 42.23 43.14 40.71 43.21 42.49 42.21 1.96 SDIH 08 38.31 39.06 38.55 35.42 41.75 39.14 39.89 40.03 4.64 SDIH 09 53.74 50.54 51.17 48.86 47.73 48.82 49.72 47.93 3.98 LDIH 01 42.68 42.89 41.64 45.32 40.70 41.86 41.03 42.55 3.40 LDIH 02 47.36 46.78 50.54 45.09 43.26 51.83 48.76 49.81 5.99 LDIH 03 40.97 42.13 45.46 41.72 40.00 41.46 42.60 40.73 3.96 LDIH 04 45.23 44.52 44.48 45.33 44.44 45.37 45.58 44.64 1.05 LDIH 05 43.50 43.51. 43.03 40.13 40.27 41.02 42.75 43.18 3.44 LDIH 06 49.04 45.40 44.82 45.52 42.76 46.20 45.16 46.85 3.93 LDIH 07 44.18 41.39 42.05 40.77 39.32 41.52 43.57 43.13 3.94 LDIH 08 37.08 38.25 37.43 38.59 38.92 39.35 38.08 37.67 2.01 LDIH 09 40.91 38.17 37.89 39.04 40.28 39.75 39.32 39.34 2.56 -82-Normoxic resting cardiac output (CO) and coefficient of variation (CV). Cardiac Output CV (1 min" ) (%) Subject Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 SDIH 01 6.34 6.28 6.31 6.11 7.16 7.62 7.00 7.10 8.12 SDIH 02 6.68 7.42 7.53 6.47 7.50 7.84 6.40 6.89 7.72 SDIH 03 5.48 4.66 4.10 6.15 5.11 6.67 5.72 5.55 14.96 SDIH 04 6.42 7.22 6.64 6.45 6.16 6.02 6.06 7.01 6.75 SDIH 05 6.24 6.59 7.28 9.31 6.62 7.25 7.80 8.21 13.60 SDIH 06 8.16 8.68 8.75 7.79 7.45 8.76 9.59 8.31 7.86 SDIH 07 4.73 4.71 4.90 5.75 5.12 5.00 5.74 4.03 11.30 SDIH 08 5.86 5.75 5.41 5.52 6.67 6.68 6.20 6.28 8.09 SDIH 09 8.15 7.73 8.08 7.59 7.52 7.55 7.55 8.04 3.46 LDIH 01 9.01 9.25 9.12 9.37 8.19 9.82 8.77 8.28 6.12 LDIH 02 5.96 4.86 5.86 4.13 5.13 5.52 5.98 4.37 13.88 LDIH 03 7.27 6.36 8.39 6.56 7.91 7.08 7.40 7.21 9.08 LDIH 04 6.65 5.74 6.06 6.60 5.88 7.37 8.88 6.63 15.10 LDIH 05 7.01 7.11 5.78 7.28 6.67 8.68 7.57 7.55 11.49 LDIH 06 6.40 6.49 5.88 4.18 6.75 7.79 5.83 6.70 16.56 LDIH 07 8.20 6.20 7.00 6.92 8.88 7.92 6.85 6.94 12.57 LDIH 08 7.54 7.01 4.39 6.63 7.20 6.05 5.77 6.48 15.58 LDIH 09 7.79 7.51 7.48 7.72 8.38 8.27 7.26 9.37 8.57 - 83 -Normoxic resting heart rate (HR) and coefficient of variation. Heart Rate CV (bpm) (%) Subject Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 SDIH 01 64.9 62.0 62.9 59.4 64.3 61.08 64.27 71.77 5.80 SDIH 02 69.8 86.2 91.9 72.4 89.1 90.16 71.93 78.79 11.23 SDIH 03 64.4 62.1 66.5 70.6 67.8 71.83 65.66 67.19 4.72 SDIH 04 66.1 71.4 64.5 66.0 65.1 " 63.21 62.10 65.28 4.23 SDIH 05 65.7 71.7 76.5 84.7 69.0 72.12 76.21 81.67 8.36 SDIH 06 79.1 78.0 76.5 71.8 69.1 76.36 88.94 76.17 7.58 SDIH 07 46.6 44.9 44.3 52.5 53.1 45.88 46.60 40.86 8.79 SDIH 08 41.6 41.1 44.1 43.9 47.6 52.38 42.19 45.78 8.37 SDIH 09 69.3 64.5 63.5 62.7 90.5 59.88 63.26 64.19 14.49 LDIH 01 69.5 85.3 82.2 98.3 83.4 90.52 84.14 82.32 9.62 LDIH 02 87.5 73.6 80.4 74.3 81.9 78.97 81.50 75.16 5.96 LDIH 03 62.6 53.7 68.1 55.5 69.4 65.86 60.79 57.21 9.51 LDIH 04 59.3 52.9 58.6 56.3 66.5 64.66 77.05 62.12 11.97 LDIH 05 68.0 69.5 55.5 67.9 67.5 81.14 66.62 67.29 10.15 LDIH 06 64.2 67.9 62.0 65.7 70.3 70.67 65.72 74.43 5.98 LDIH 07 86.6 73.0 . 84.5 81.1 115.1 86.67 86.10 68.06 14.94 LDIH 08 64.3 61.9 51.1 58.1 76.2 60.59 55.26 68.33 12.63 LDIH 09 64.4 75.0 67.9 73.9 72.8 73.03 66.48 78.45 6.70 -84-Normoxic resting stroke volume (SV) and coefficient of variation (CV). Stroke Volume CV (ml) (%) Subject Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 SDIH 01 98.0 103.5 101.1 103.7 112.1 126.1 109.6 99.3 8.6 SDIH 02 96.3 86.4 81.9 89.5 84.4 87.1 89.1 87.6 4.8 SDIH 03 85.6 75.5 62.2 87.3 75.9 92.8 87.5 83.0 11.9 SDIH 04 97.3 101.2 103.2 97.8 95.0 95.4 97.7 107.6 4.3 SDIH 05 95.5 92.2 95.6 110.1 95.0 100.9 102.4 100.8 5.8 SDIH 06 103.5 111.6 114.7 108.9 108.2 115.0 108.3 109.5 3.4 SDIH 07 101.8 105.4 110.7 110.2 97.0 .109.3 123.5 99.4 7.8 SDIH 08 140.9 139.8 122.5 125.9 140.4 127.9 147.1 137.5 6.4 SDIH 09 118.2 120.3 128.1 121.6 126.1 126.6 119.8 125.7 3.0 LDIH 01 130.1 108.9 111.3 95.6 98.4 108.7 104.6 101.1 10.0 LDIH 02 68.4 66.3 73.0 55.7 62.7 69.9 73.5 58.2 10.0 LDIH 03 116.7 119.6 123.9 118.6 114.4 107.9 122.1 126.7 5.0 LDIH 04 112.5 109.3 103.9 117.6 88.5 114.4 115.4 107.1 8.6 LDIH 05 103.3 102.4 104.8 107.7 99.1 107.2 114.1 112.4 4.8 LDIH 06 99.8 67.9 95.1 63.9 96.3 110.5 89.1 90.1 17.7 LDIH 07 95.1 85.1 83.3 85.6 77.3 91.7 79.8 103.6 7.3 LDIH 08 117.6 113.6 86.1 114.1 94.5 100.1 104.5 . 95.0 10.9 LDIH 09 122.0 100.3 110.6 104.8 115.6 113.7 110.0 119.8 6.5 -85 -Normoxic resting mean arterial pressure (MAP) and coefficient of variation (CV). Mean arterial pressure CV (mmHg) (%) Subject Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 SDIH 01 92.1 89.0 87.3 85.0 85.4 91.4 93.3 87.9 3.5 SDIH 02 84.6 82.1 86.9 88.2 84.9 98.4 87.0 90.5 5.7 SDIH 03 87.8 92.3 86.3 86.7 86.1 91.8 83.7 87.7 3.3 SDIH 04 90.9 89.8 90.9 85.8 81.0 84.2 87.2 88.3 4.0 SDIH 05 81.4 92.2 86.0 84.3 85.1 84.8 84.1 79.9 4.3 SDIH 06 92.9 85.1 91.2 89.8 95.1 83.0 99.6 86.7 6.1 SDIH 07 78.0 74.6 87.7 81.7 72.9 85.4 79.2 81.0 6.3 SDIH 08 83.6 74.1 83.1 81.7 76.0 82.1 74.1 80.1 5.1 SDIH 09 96.1 94.2 88.5 98.8 90.4 95.8 95.2 91.3 3.6 LDIH 01 95.7 94.5 93.6 83.2 90.2 81.2 85.8 79.5 7.3 LDIH 02 95.6 91.9 80.1 93.8 94.8 88.6 90.5 92.0 5.4 LDIH 03 84.2 83.5 83.9 85.6 82.7 85.1 82.6 73.9 4.5 LDIH 04 77.8 79.4 82.5 85.0 84.4 78.7 76.7 77.5 4.1 LDIH 05 96.7 88.3 80.3 83.1 73.0 84.3 84.1 81.1 8.1 LDIH 06 97.6 100.2 104.1 116.9 100.7 89.9 107.1 105.7 7.6 LDIH 07 92.7 74.9 77.0 78.4 86.1 82.1 87.7 87.1 7.8 LDIH 08 94.9 98.7 95.3 82.8 98.5 100.1 104.6. 114.7 9.2 LDIH 09 79.2 81.1 90.0 92.9 80.2 92.0 80.4 82.2 6.9 -86-Normoxic resting total peripheral resistance (TPR) and coefficient of variation (CV). Total peripheral resistance CV (PRU) (%) Subject Day 1 Day 3 Day 5 Day 8 Day 10 Day 12 Day 15 Day 17 SDIH 01 1.08 0.87 0.86 0.88 0.73 0.74 0.77 0.71 14.72 SDIH 02 0.80 0.69 0.71 0.84 0.70 0.78 0.85 0.82 8.46 SDIH 03 0.99 1.21 1.28 0.88 1.04 0.86 0.90 0.97 15.20 SDIH 04 0.92 0.74 0.87 0.81 0.80 0.84 0.87 0.75 7.53 SDIH 05 0.80 0.85 0.72 0.55 0.77 0.72 0.66 0.60 14.28 SDIH 06 0.71 0.61 0.66 0.74 0.80 0.59 0.65 0.65 10.30 SDIH 07 1.00 0.98 1.08 0.86 0.89 1.04 0.82 1.23 13.49 SDIH 08 0.87 0.82 0.94 0.93 0.71 0.74 0.73 0.8 10.94 SDIH 09 0.73 0.75 0.68 0.81 0.75 0.79 0.79 0.70 6.09 LDIH 01 0.66 0.63 0.63 0.55 0.68 0.51 0.60 0.59 9.25 LDIH 02 1.03 1.22 0.85 1.38 1.18 0.99 0.93 1.36 17.63 LDIH 03 0.71 0.83 0.63 0.82 0.64 0.74 0.70 0.64 11.06 LDIH 04 0.71 0.86 0.83 0.80 0.87 0.66 0.53 0.72 15.55 LDIH 05 0.83 0.77 0.87 0.71 0.68 0.60 0.69 0.66 12.47 LDIH 06 0.94 0.93 1.06 1.71 0.97 0.71 1.10 0.95 27.90 LDIH 07 0.70 0.75 0.69 0.70 0.60 0.64 0.79 0.81 9.12 LDIH 08 0.78 0.87 1.34 0.77 0.84 1.03 1.12 1.10 20.45 LDIH 09 0.63 0.66 0.74 0.74 0.60 0.69 0.69 0.55 10.07 -87-Normoxic resting cerebral saturation of oxygen (Sc02) and coefficient of variation (CV). Sc0 2 CV (%, Subject Day 1 Day 3 Day 5 Day 8 y/o) Day 10 Day 12 Day 15 Day 17 \/0) SDIH 01 72.2 69.0 67.9 65.8 67.3 83.7 71.8 63.4 8.8 SDIH 02 69.2 66.1 68.3 67.8 67.7 69.5 69.5 68.8 1.7 SDIH 03 69.2 68.0 67.9 72.9 74.5 71.7 73.8 68.9 3.8 SDIH 04 71.1 70.1 70.5 71.5 71.9 73.8 71.8 71.0 1.5 SDIH 05 81.3 78.8 72.1 68.9 81.7 66.0 74.8 74.0 7.6 SDIH 06 68.0 69.6 71.3 70.4 65.4 67.5 72.6 68.2 3.3 SDIH 07 67.6 60.0 66.1 69.1 72.2 71.6 69.0 67.0 5.6 SDIH 08 76.1 78.3 79.4 79.0 76.7 77.4 73.7 77.9 2.4 SDIH 09 65.3 58.2 63.4 58.4 61.3 63.8 61.4 62.3 4.0 LDIH 01 66.5 69.1 70.7 70.7 67.5 69.1 69.3 67.9 2.1 LDIH 02 71.6 73.9 71.2 69.3 6.7.4 67.5 73.1 76.0 4.3 LDIH 03 71.4 63.4 64.5 66.0 70.8 74.0 67.8 70.6 5.4 LDIH 04 63.7 65.8 65.5 69.4 59.2 56.5 64,5 65.2 6.3 LDIH 05 58.4 54.5 59.0 62.1 60.4 67.0 59.9 61.9 5.9 LDIH 06 74.6 71.8" 73.5 69.3 68.4 73.1 72.1 71.8 2.9 LDIH 07 73.2 65.4 67.0 66.1 72.0 62.1 74.0 69.0 6.6 LDIH 08 67.3 73.2 70.4 74.2 73.5 68.0 76.8 67.2 5.1 LDIH 09 74.3 60.5 70.0 74.6 68.6 73.2 69.5 70.5 6.4 -88-Change in cerebral tissue oxygen saturation (Sc02) per change in arterial oxyhemoglobin saturation (Sa02) during both the preHVR and the postHVR. ASc0 2/ASa0 2 Day 1 3 5 8 10 12 15 17 HVR Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 -0.62 -0.69 -0.46 -0.42 -0.63 -0.42 -0.45 -0.40 -0.50 -0.67 -0.83 -1.26 -0.63 -0.57 SDIH 02 -0.52 -0.84 -0.42 -0.49 -0.51 -0.43 -0.44 -0.51 -0.62 -0.64 -0.79 -0.80 -0.60 -0.35 SDIH 03 -0.40 -0.39 -0.44 -0.40 -0.41 -0.48 -0.67 -0.52 -0.49 -0.56 -0.41 -0.40 -0.48 -0.46 SDIH 04 -0.51 -0.82 -0.32 -0.67 -0.54 -0.79 -0.62 -0.58 -0.65 -0.59 -0.74 -0.64 -0.63 -0.63 SDIH 05 -0.28 -0.49 -0.27 -0.49 -0.42 -0.49 -0.35 -0.36 -0.26 -0.45 -0.65 -0.72 -0.54 -0.57 SDIH 06 -0.55 -0.65 -0.50 -0.51 -0.65 -0.75 -0.71 -0.55 -0.50 -0.65 -0.51 -0.62 -0.62 -0.60 SDIH 07 -0.39 -0.39 -0.32 -0.62 -0.40 -0.54 -0.71 -0.84 -0.57 -0.79 -1.16 -0.58 -0.76 -0.41 SDIH 08 -0.70 -0.74 -0.62 -0.77 -0.70 -0.75 -0.72 -0.64 -0.63 -0.64 -0.71 -0.76 -0.53 -0.76 SDIH 09 -0.65 -0.50 -0.59 -0.50 -0.54 -0.54 -0.52 -0.53 -0.53 -0.55 -0.61 -0.64 -0.60 -0.54 LDIH 01 -0.41 -0.64 -0.42 -0.44 -0.63 -0.57 -0.49 -0.54 -0.54 -0.60 -0.57 -0.55 -0.51 -0.35 LDIH 02 -0.38 -0.54 -0.36 -0.39 -0.37 -0.40 -0.27 -0.32 -0.27 -0.65 -0.46 -0.53 -0.56 -0.35 LDIH 03 -0.52 -0.49 -0.38 -0.48 -0.49 -0.57 -0.51 -0.61 -0.46 -0.47 -0.51 -0.66 -0.33 - -0.45 LDIH 04 -0.51 -0.40 -0.32 -0.30 -0.42 -0.24 -0.40 -0.31 -0.49 -0.46 -0.49 -0.38 -0.53 -0.30 LDIH 05 -0.57 -0.66 -0.52 -0.44 -0.65 -0.62 -0.42 -0.44 -0.55 -0.43 -0.76 -0.51 -0.62 -0.67 LDIH 06 -0.74 -0.73 -0.75 -0.86 -0.62 -0.71 -0.57 -0.65 -0.61 -0.62 -0.71 -0.67 -0.69 -0.65 LDIH 07 -0.67 -0.60 -0.69 -0.57 -0.64 -0.61 -0.82 -0.64 -0.96 -0.90 -0.63 -0.69 -0.81 -0.51 LDIH 08 -0.53 -0.53 -0.68 -0.57 -0.61 -0.71 -0.74 -0.64 -0.67 -0.72 -0.52 -0.52 -0.66 -0.46 LDIH 09 -0.32 -0.33 -0.06 -0.04 -0.30 -0.39 -0.48 -0.34 -0.54 -0.39 -0.43 -0.60 -0.46 -0.55 -89-Change in cerebral oxyhemoglobin concentration (0 2Hb) per change in arterial oxyhemoglobin saturation (Sa02) during both the preHVR and the postHVR. A0 2 Hb/ASa0 2 (uM %Sa02"') Day 1 3 5 8 10 12 15 17 H V R Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 -0.33 -0.15 -0.19 -0.04 -0.30 -0.24 -0.20 -0.18 -0.24 -0.16 -0.12 -0.21 -0.12 -0.28 SDIH 02 -0.24 -0.28 -0.27 -0.40 -0.26 -0.17 -0.21 -0.05 -0.31 -0.29 -0.30 -0.42 -0.31 -0.14 SDIH 03 -0.30 -0.31 -0.28 -0.19 -0.29 -0.46 -0.27 -0.29 -0.33 -0.33 -0.24 -0.23 -0.32 -0.32 SDIH 04 -0.23 0.36 -0.22 -0.40 -0.19 -0.55 -0.34 -0.37 -0.36 -0.40 -0.45 -0.46 -0.26 -0.36 SDIH 05 -0.25 -0.20 -0.20 -0.21 -0.20 -0.27 -0.24 -0.22 -0.33 -0.27 -0.36 -0.37 -0.41 -0.41 SDIH 06 -0.26 -0.30 -0.32 -0.20 -0.33 -0.35 -0.24 -0.42 -0.26 -0.38 -0.05 -0.00 -0.45 -0.42 SDIH 07 -0.16 -0.05 0.16 -0.28 -0.20 -0.20 -0.39 -0.20 -0.20 -0.15 0.27 -0.34 0.00 -0.04 SDIH 08 -0.20 -0.30 -0.24 -0.35 -0.23 -0.23 -0.23 -0.21 -0.14 -0.28 -0.35 -0.41 -0.36 -0.43 SDIH 09 -0.41 -0.29 -0.31 -0.18 -0.22 -0.27 -0.26 -0.26 -0.24 -0.22 -0.29 -0.33 -0.28 -0.18 LDIH 01 -0.35 -0.35 -0.20 -0.41 -0.38 -0.43 -0.20 -0.39 -0.25 -0.28 -0.30 -0.29 -0.23 -0.18 LDIH 02 -0.23 -0.09 -0.13 -0.09 -o:o4 -0.18 0.00 -0.08 -0.00 -0.16 0.02 -0.22 -0.15 0.15 LDIH 03 -0.18 -0.19 -0.16 -0.19 -0.16 -0.17 -0.12 -0.18 -0.15 -0.18 -0.17 -0.24 -0.16 -0.18 LDIH 04 -0.27 -0.16 -0.16 -0.13 -0.25 -0.07 -0.27 -0.18 -0.19 -0.18 -0.29 -0.24 -0.33 -0.23 LDIH 05 -0.36 -0.44 -0.30 -0.23 -0.32 -0.42 -0.45 -0.36 -0.53 -0.36 -0.57 -0.56 -0.45 -0.37 LDIH 06 -0.32 -0.41 -0.39 -0.48 -0.34 -0.37 -0.26 -0.35 -0.29 -0.32 -0.41 -0.39 -0.43 -0.29 LDIH 07 -0.45 -0.35 -0.42 -0.38 -0.34 -0.35 -0.58 -0.39 -0.46 -0.44 -0.40 -0.51 -0.39 -0.25 LDIH 08 -0.28 -0.27 -0.19 -0.22 -0.23 -0.33 -0.33 -0.19 -0.30 -0.30 -0.28 -0.26 -0.16 -0.22 LDIH 09 -0.35 -0.22 -0.18 -0.30 -0.29 -0.24 -0.37 -0.30 -0.36 -0.24 -0.32 -0.52 -0.32 -0.38 -90-Change in cerebral deoxyhemoglobin concentration (HHb) per change in arterial oxyhemoglobin saturation (SaC^) during both the preHVR and the postHVR. AHHb/ASaO-2 (uM %Sa(V) Day 1 3 5 8 10 12 15 17 HVR Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 0.40 0.57 0.42 0.36 0.41 0.35 0.33 0.31 0.35 0.41 0.35 0.49 0.40 0.52 SDIH 02 0.30 0.42 0.37 0.43 0.35 0.28 0.29 0.32 0.36 0.34 0.43 0.45 0.34 0.25 SDIH 03 0.34 0.37 0.32 0.35 0.33 0.34 0.35 0.32 0.35 0.35 0.32 0.28 0.29 0.32 SDIH 04 0.32 0.54 0.24 0.38 0.43 0.47 0.32 0.36 0.33 0.36 0.43 0.40 0.41 0.32 SDIH 05 0.22 0.24 0.25 0.34 0.29 0.32 0.25 0.30 0.22 0.36 0.42 0.48 0.41 0.43 SDIH 06 0.42 0.53 0.32 0.41 0.57 0.61 0.56 0.47 0.32 0.49 0.45 0.57 0.46 0.49 SDIH 07 0.45 0.40 0.46 0.56 0.34 0.47 0.47 0.51 0.40 0.57 0.77 0.33 0.54 0.40 SDIH 08 0.37 0.36 0.34 0.48 0.39 0.41 0.37 0.42 0.38 0.41 0.44 0.51 0.49 0.42 SDIH 09 0.41 0.46 0.36 0.37 0.39 0.41 0.37 0.35 0.32 0.36 0.37 0.40 0.37 0.35 LDIH 01 0.45 0.52 0.35 0.36 0.47 0.44 0.47 0.49 0.43 0.48 0.48 0.42 0.42 0.25 LDIH 02 0.27 0.53 0.26 0.31 0.28 0.29 0.29 0.30 0.20 0.46 0.33 0.37 0.33 0.26 LDIH 03 0.28 0.26 0.25 0.31 0.23 0.29 0.22 0.24 0.23 0.24 0.28 0.41 0.23 0.25 LDIH 04 0.34 0.26 0.22 0.19 0.30 0.20 0.30 0.26 0.29 0.25 0.36 0.28 0.40 0.32 LDIH 05 0.52 0.54 0.37 0.29 0.47 0.54 0.58 0.46 0.57 0.49 0.65 0.52 0.68 0.59 LDIH 06 0.50 0.48 0.47 0.52 0.43 0.48 0.43 0.45 0.43 0.48 0.48 0.49 0.49 0.46 LDIH 07 0.54 0.49 0.54 0.45 0.47 0.45 0.61 0.50 0.56. 0.54 0.47 0.51 0.61 0.38 LDIH 08 0.38 0.33 0.35 0.33 0.41 0.54 0.45 0.44 0.38 0.42 0.39 0.35 0.41 0.32 LDIH 09 0.45 0.54 0.32 0.31 0.27 0.33 0.44 0.44 0.45 0.44 0.48 0.52 0.42 0.47 -91 -Change in cerebral total hemoglobin concentration (cHb) per change in arterial oxyhemoglobin saturation (Sa02) during both the preHVR and the postHVR. AcHb/ASa0 2 (uM %Sa02"1) Day 1 3 5 8 10 12 15 17 HVR Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 0.07 0.42 0.23 0.33 0.11 0.11 0.13 0.13 0.11 0.25 0.23 0.28 0.28 0.24 SDIH 02 0.06 0.14 0.10 0.03 0.09 0.11 0.08 0.27 0.05 0.05 0.13 0.02 0.03 0.11 SDIH 03 0.04 0.06 0.03 0.15 0.03 -0.12 0.08 0.03 0.03 0.02 0.08 0.05 -0.02 -0.00 SDIH 04 0.09 0.18 0.02 -0.02 0.24 0.08 -0.03 -0.01 -0.03 -0.04 -0.02 -0.06 0.15 -0.04 SDIH 05 -0.03 0.04 0.06 0.13 0.08 0.05 0.01 0.08 -0.12 0.09 0.05 0.11 -0.01 0.02 SDIH 06 0.17 0.23 0.00 0.20 0.24 0.26 0,32 0.05 0.05 0.10 0.40 0.57 0.01 0.07 SDIH 07 0.29 0.35 0.61 0.28 0.14 0.27 0.08 0.31 0.20 0.42 1.04 -0.00 0.55 0.36 SDIH 08 0.17 0.06 0.10 0.13 0.16 0.18 0.14 0.21 0.24 0.12 0.09 0.09 0.13 -0.01 SDIH 09 0.06 0.17 0.05 0.19 0.17 0.14 0.11 0.09 0.09 0.13 0.08 0.07 0.09 0.17 LDIH 01 0.10 0.16 0.15 -0.04 0.09 0.00 0.27 0.10 0.18 0.20 0.17 0.13 0.19 0.07 LDIH 02 0.03 0.44 0.13 0.22 0.23 0.11 0.29 0.22 0.20 0.29 0.35 0.15 0.18 0.41 LDIH 03 0.10 0.07 0.09 0.12 0.07 0.11 0.10 0.05 0.07 0.06 0.11 0.16 0.07 0.07 LDIH 04 0.07 0.09 0.07 0.06 0.05 0.13 0.02 0.08 0.11 0.07 0.07 0.03 0.06 0.09 LDIH 05 0.16 0.10 0.07 0.06 0.15 0.11 0.13 0.10 0.04 0.14 0.08 -0.04 0.23 0.22 LDIH 06 0.17 0.07 0.08 0.04 0.08 0.11 0.16 0.11 0.14 0.16 0.06 0.11 0.06 0.17 LDIH 07 0.08 0.14 0.11 0.07 0.13 0.09 0.03 0.10 0.10 0.10 0.06 0.01 0.22 0.13 LDIH 08 0.10 0.06 0.16 0.10 0.19 0.21 0.11 0.24 -0.08 0.12 0.11 0.09 0.35 0.11 LDIH 09 0.09 0.32 0.14 0.00 -0.02 0.09 0.07 0.14 0.09 0.19 0.16 0.00 0.11 0.09 -92-Hypercapnic ventilatory response (HCVR). HCVR (1 min"1 mmHg"1) Subject Day 1 Day 12 Day 15 Day 17 SDIH 01 1.71 1.31 1.49 1.53 SDIH 02 1.26 0.12 0.75 0.80 SDIH 03 1.26 1.25 1.66 1.48 SDIH 04 2.74 2.07 1.63 3.24 SDIH 05 3.19 3.89 5.51 4.93 SDIH 06 1.02 1.32 1.51 1.26 SDIH 07 4.71 4.12 5.87 1.38 SDIH 08 2.60 3.88 5.56 3.80 SDIH 09 2.70 3.57 3.40 1.22 LDIH 01 2.07 2.13 1.99 2.02 LDIH 02 0.62 1.16 0.52 0.76 LDIH 03 3.05 3.60 2.81 1.92 LDIH 04 1.91 1.62 2.15 2.06 LDIH 05 0.89 1.62 0.88 1.74 LDIH 06 1.91 0.29 1.89 1.20 LDIH 07 6.74 6.15 1.39 2.12 LDIH 08 3.45 3.05 3.37 2.90 LDIH 09 2.96 3.02 2.75 3.73 -93 -The hypoxic ventilatory response (HVR) prior to acute intermittent hypoxia (preHVR) and following acute intermittent hypoxia (postHVR). HVR (1 min"1) Day 1 3 5 8 10 12 15 17 HVR Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 0.67 0.82 1.10 0.83 1.12 1.15 0.89 0.90 0.96 1.14 1.26 1.13 1.14 1.57 SDIH 02 0.48 0.51 0.24 0.36 0.55 0.12 0.20 0.28 0.65 0.44 0.28 0.70 0.52 0.26 SDIH 03 0.31 0.31 0.10 0.21 0.50 0.44 0.74 0.48 0.82 0.44 0.56 0.42 0.37 0.30 SDIH 04 0.43 0.33 0.25 0.27 0.39 0.31 0.38 0.29 0.46 0.44 0.49 0.30 0.31 0.36 SDIH 05 0.84 0.50 0.66 0.67 0.66 0.59 0.60 0.72 0.78 0.63 0.86 1.07 1.26 0.94 SDIH 06 0.60 0.58 0.56 0.69 0.69 0.45 0.64 0.65 0.67 0.80 0.60 0.78 0.44 0.46 SDIH 07 2.39 1.61 2.04 1.97 2.33 2.11 2.57 2.50 2.76 2.10 4.78 2.15 3.61 2.32 SDIH 08 0.71 1.52 1.31 0.8.6 1.59 0.77 1.60 0.92 1.47 1.43 1.26 0.95 1.34 1.70 SDIH 09 1.00 0.68 1.01 0.76 1.09 1.05 0.91 0.91 0.95 0.82 1.26 1.11 1.10 1.18 LDIH 01 0.53 0.55 0.52 0.24 0.32 0.23 0.70 0.79 0.52 0.29 1.10 0.52 0.81 0.65 LDIH 02 0.76 1.12 0.73 0.66 0.79 0.70 0.84 0.53 0.76 0.85 0.95 0.87 0.62 0.99 LDIH 03 0.61 0.35 0.72 0.53 0.51 0.79 0.50 0.22 0.65 0.26 0.76 0.76 0.62 0.49 LDIH 04 0.63 0.39 0.84 0.59 0.63 0.35 0.68 0.49 0.64 0.32 0.93 0.62 0.89 0.65 LDIH 05 0.36 0.23 0.21 0.24 0.07 0.16 0.24 0.28 0.25 0.20 0.39 0.03 0.37 0.31 LDIH 06 1.05 1.21 0.84 0.79 0.78 0.68 0.86 0.79 0.73 0.45 1.13 0.57 1.00 0.99 LDIH 07 1.01 0.76 1.20 . 0.80 1.18 1.36 2.12 1.11 0.83 0.97 1.99 1.07 1.66 0.95 LDIH 08 1.61 0.94 1.19 0.72 1.33 1.42 1.83 1.78 1.47 1.27 1.91 1.45 1.63 1.47 LDIH 09 1.14 1.15 1.16 0.44 1.14 0.84 1.34 1.31 1.31 1.14 1.08 1.45 0.85 1.42 -94-Ventilation ( V i ) occurring in normoxia immediately before each preHVR and postHVR. Values are 30 second averages. V i (1 min"1) Day 1 3 5 8 10 12 15 17 H V R Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 8.59 9.71 9.11 10.97 10.14 10.85 9.99 6.73 9.54 8.11 7.96 7.73 10.49 8.91 SDIH 02 8.49 11.91 8.73 10.19 11.31 15.11 8.03 11.28 7.42 10.51 10.13 11.76 10.82 10.63 SDIH 03 9.19 9.97 10.74 12.10 8.61 9.48 11.31 9.37 8.91 12.37 6.77 9.22 9.61 9.44 SDIH 04 10.14 11.73 10.92 11.57 11.76 11.11 15.03 13.78 10.46 9.65 10.95 11.51 12.42 11.67 SDIH 05 9.57 10.54 11.83 10.58 11.88 11.18 13.00 10.75 11.46 10.94 11.60 10.48 12.28 13.32 SDIH 06 11.49 9.05 • 11.52 10.68 13.61 11.12 10.20 13.15 9.93 11.89 13.21 15.10 12.17 13.26 SDIH 07 14.29 13.04 11.41 10.94 20.25 12.24 11.88 10.16 22.35 12.05 12.12 14.51 14.64 10.66 SDIH 08 13.61 15.29 10.25 22.64 12.90 17.21 15.36 14.52 16.58 12.32 12.67 12.33 12,21 11.49 SDIH 09 6.54 7.03 7.86 6.28 5.80 10.70 9.76 7.66 6.16 8.91 7.99 8.78 9.27 9.38 LDIH 01 11.87 9.61 14.16 14.21 14.22 14.83 13.37 15.12 11.51 10.47 12.65 11.48 13.12 13.29 LDIH 02 8.53 9.77 9.71 7.97 8.53 9.46 8.15 9.14 10.57 7.65 10.52 11.30 8.26 11.50 LDIH 03 13.90 11.63 9.86 10.43 11.47 8.29 12.70 12.82 10.45 11.67 6.67 9.32 13.30 11.73 LDIH 04 11.70 11.50 12.13 12.11 12.08 11.88 10.55 11.60 11.09 16.24 9.51 10.53 9.67 9.68 LDIH 05 11.01 8.62 15.31 13.66 12.35 11.79 15.93 10.24 13.36 12.27 11.04 10.73 12.21 11.50 LDIH 06 16.78 15.75 11.74 11.03 11.32 9.73 14.27 11.86 13.28 12.52 14.17 13.34 13.40 12.41 LDIH 07 7.44 9.87 10.24 9.10 9.81 9.89 11.35 14.19 13.85 12.34 9.99 11.16 10.20 11.28 LDIH 08 12.38 14.70 14.53 10.38 13.19 9.94 10.71 11.26 13.62 13.22 11.02 8.40 11.47 9.59 LDIH 09 12.39 12.96. 14.83 18.81 11.66 13.33 14.22 15.13 17.49 15.12 15.96 12.83 13.12 13.36 -95 -Change in heart rate (HR) per change in arterial oxyhemoglobin saturation (Sa02) during preHVR and postHVR. AHR/ASa0 2 (bpm %Sa02"1) Day 1 3 5 8 10 12 15 17 HVR Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDfflOl 1.39 0.22 1.33 1.37 1.30 1.10 1.52 -0.23 1.03 0.90 1.47 1.56 0.97 1.06 SDIH 02 1.07 1.66 0.69 1.08 0.53 1.07 0.77 0.76 1.01 0.76 0.55 1.08 0,94 0.64 SDIH 03 0.60 0.53 0.31 0.84 0.78 0.61 0.54 0.72 0.78 0.55 0.53 0.06 0.50 0.44 SDIH 04 0.66 0.83 0.47 0.84 0.81 1.12 0.87 0.79 0.81 0.87 0.52 0.67 0.60 0.81 SDIH 05 0.78 0.81 0.64 0.62 0.71 0.57 0.71 0.80 1.02 0.83 0.93 0.99 1.08 1.00 SDIH 06 1.32 1.27 0.98 1.56 1.32 1.28 1.16 1.65 1.24 1.50 0.93 1.48 0.92 1.24 SDIH 07 1.92 1.74 1.50 1.19 1.85 1.35 1.80 1.91 2.38 1.92 2.24 1.37 2.99 1.52 SDIH 08 1.46 2.69 1.99 1.74 1.89 2.06 2.09 1.70 1.94 2.34 2.26 2.95 2.31 2.78 SDIH 09 1.25 1.46 1.76 0.96 1.37 1.45 1.82 1.50 1.15 1.19 1.34 1.51 1.26 1.20 LDIH 01 1.06 1.47 0.84 0.66 0.93 0.94 0.79 0.82 1.00 0.84 0.96 1.12 0.83 0.77 LDIH 02 1.22 2.29 1.08 1.48 1.06 1.04 0.81 1.25 0.85 1.80 0.99 1.25 1.22 1.11 LDIH 03 0.97 0.66 0.73 0.72 0.45 0.80 0.62 0.48 0.63 0.59 0.79 1.55 0.81 -0.77 LDIH 04 1.05 1.15 1.45 1.45 1.75 1.48 1.53 1.45 1.34 1.17 1.40 1.33 1.31 1.23 LDIH 05 1.47 1.66 1.14 0.82 1.65 1.52 1.30 1.36 1.15 0.09 0.97 0.59 1.55 1.38 LDIH 06 0.40 0.82 0.46 0.74 0.67 0.59 0.03 0.20 0.52 0.37 0.47 0.43 0.01 0.14 LDIH 07 1.20 1.01 1.15 1.21 1.35 1.57 1.38 1.16 0.75 1.14 1.33 0.98 1.46 0.96 LDIH 08 1.12 0.84 0.80 0.79 0.93 1.26 1.12 1.35 0.63 0.61 0.86 0.97 0.94 0.63 LDIH 09 0.97 1.42 0.95 1.07 1.28 0.88 0.95 1.34 1.18 0.90 1.75 1.25 1.15 1.07 -96-Heart rate (HR) occurring in normoxia immediately before each preHVR and postHVR. Values are 30 second averages. Day 1 3 5 H V R Pre Post Pre Post Pre Post HR (bpm) 8 1 0 - 1 2 Pre Post Pre Post Pre Post 15 17 SDIH 01 SDIH 02 SDIH 03 SDIH 04 SDIH 05 SDIH 06 SDIH 07 SDIH 08 SDIH 09 67.00 70.76 64.00 62.00 63.67 79.00 42.67 42.33 69.67 78.95 80.42 62.00 84.00 66.67 80.67 39.00 46.00 71.00 62.41 83.80 65.00 72.67 69.67 77.33 43.33 40.67 63.67 60.24 77.62 62.33 73.67 68.00 78.00 47.33 47.00 69.00 75.12 88.33 67.00 64.00 75.00 77.67 47.00 50.67 63.00 58.08 90.33 69.00 65.00 79.33 79.33 48.00 44.67 63.00 60.47 73.67 70.67 64.67 85.00 72.00 49.67 50.33 62.00 62.44 78.33 63.67 62.67 80.67 77.00 48.33 43.00 59.67 65.97 84.33 65.33 65.00 65.33 64.00 52.67 52.00 59.00 59.73 84.67 61.00 63.67 75.00 68.67 50.33 48.33 61.00 55.65 90.00 70.67 67.00 74.00 77.00 48.33 52.00 64.00 57.94 85.33 65.33 57.33 69.00 78.33 45.33 41.67 63.67 69.18 72.33 63.67 64.33 77.00 93.00 53.00 42.00 65.33 64.59 81.33 62.67 66.67 83.33 74.67 41.33 44.67 69.33 78.00 LDIH 01 LDIH 02 LDIH 03 LDIH 04 LDIH 05 LDIH 06 LDIH 07 LDIH 08 LDIH 09 71.53 80.33 63.00 63.33 66.00 62.33 85.67 62.67 65.67 73.14 69.00 61.33 50.00 53.33 62.00 86.00 62.33 63.67 89.91 72.00 57.00 55.33 69,33 64.67 70.67 62.67 77.00 78.40 67.00 54.33 47.33 58.00 61.67 66.00 60.67 69.67 82.67 78.33 68.00 55.00 52.00 64.67 85.00 52.00 68.33 82.33 73.67 59.67 59.00 56.67 61.33 72.67 49.67 66.67 96.67 81.00 60.00 51.00 72.00 66.00 80.33 58.33 75.67 100.33 72.33 55.67 51.00 55.00 67.67 76.00 54.33 72.67 80.67 82.67 65.00 65.33 65.67 68.00 113.00 75.67 75.00 80.00 68.00 53.67 53.67 55.00 67.67 110.33 72.67 77.33 91.67 81.00 65.00 61.67 78.00 75.67 85.33 61.33 72.67 83.00 77.33 52.00 54.00 70.33 71.33 83.00 61.67 74.00 91.00 78.33 60.33 65.00 61.67 67.33 83.33 57.00 69.33 70.00 54.33 64.00 61.00 73.33 66.74 66.00 79.33 -97-Change in cardiac output (CO) per change in arterial oxyhemoglobin saturation (Sa02) during preHVR and postHVR. ACO/ASa0 2 (1 min' %Sa02") Day H V R 1 3 5 8 10 12 15 17 Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 0.08 0.02 0.09 -0.05 0.10 -0.06 0.13 -0.03 0.03 0.1.1 0.15 0.17 0.13 0.21 SDIH 02 0.11 0.15 0.07 0.11 0.04 0.17 0.08 0.06 0.11 0.09 0.02 0.02 0.12 0.06 SDIH 03 0.05 0.05 0.01 0.04 0.07 0.05 0.00 0.05 0.07 0.04 0.06 0.05 0.05 0.03 SDIH 04 0.07 0.09 0.07 0.08 0.11 0.13 0.12 0.09 0.11 0.11 0.06 0.08 0.07 0.12 SDIH 05 0.09 0.09 0.09 0.08 0.09 0.09 0.12 0.10 0.14 0.11 0.11 0.12 0.13 0.12 .. SDIH 06 0.23 0.13 0.19 0.22 0.11 0.14 0.12 0.25 0.18 0.18 0.15 0.17 0.11 0.16 SDIH 07 0.17 0.16 0.14 0.12 0.14 0.15 0.19 0.16 0.26 0.16 0.24 0.09 0.42 0.09 SDIH 08 0.16 0.35 0.15 0.10 0.16 0.20 0.20 0.17 0.18 0.25 0.31 0.36 0.25 0.23 SDIH 09 0.14 0.17 0.12 0.15 0.19 0.16 0.14 0.13 0.07 0.11 0.07 0.08 0.11 0.15 LDIH 01 0.02 0.06 0.11 0.02 0.06 0.09 0.08 0.07 0.10 0.08 0.14 0.14 0.09 0.10 LDIH 02 0.11 0.19 0.10 0.10 0.13 0.09 0.07 0.11 0.07 0.15 0.09 0.11 0.11 0.10 LDIH 03 0.10 0.07 0.04 0.07 0.03 0.07 0.06 0.06 0.05 0.05 0.07 0.14 0.06 0.06 LDIH 04 0.12 0.12 0.14 0.17 0.22 0.19 0.18 0.18 0.17 0.15 0.18 0.13 0.17 0.17 LDIH 05 0.17 0.16 0.09 0.10 0.18 0.12 0.15 0.12 0.15 0.06 -0.07 0.05 0.16 0.12 LDIH 06 0.05 0.07 0.12 0.11 0.10 0.14 0.01 0.05 0.15 -0.01 . 0.13 0.08 0.01 0.03 LDIH 07 0.14 0.11 0.08 0.06 0.09 0.12 0.15 0.09 0.06 0.06 0.05 0.06 0.12 0.11 LDIH 08 0.11 0.07 0.05 0.05 0.09 0.13 0.10 0.10 0.09 0.07 0.04 0.06 0.05 0.03 LDTH 09 0.18 0.23 . 0.15 0.14 0.20 0.11 0.14 0.17 0.16 0.15 0.21 0.22 0.19 0.17 -98-Cardiac output (CO) occurring in normoxia immediately before each preHVR and postHVR. Values are 30 second averag. CO (1 min"1) Day 1 3 5 8 ' 10 12 15 17 J H V R Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 6.44 8.01 6.95 7.02 7.79 6.91 6.30 6.54 7.27 7.07 7.11 7.79 8.98 6.17 SDIH 02 6.59 7.91 7.00 6.37 7.99 7.54 6.43 7.00 7.30 6.99 7.30 6.76 6.22 7.18 SDIH 03 5.64 5.37 5.22 5.09 4.78 5.05 6.06 4.76 4.87 5.00 6.74 5.71 5.50 5.75 SDIH 04 5.82 8.58 7.37 7.68 6.35 6.82 6.23 5.86 6.26 5.93 6.47 5.29 6.36 7.41 ' SDIH 05 5.94 6.05 6.68 6.39 7.39 7.72 9.78 8.38 6.28 7.37 7.80 6.35 7.80 8.49 SDIH 06 8.02 8.95 8.89 9.22 9.01 9.93 8.00 7.45 7.63 7.54 8.43 8.41 9.34 7.68 SDIH 07 4.24 3.60 4.54 4.49 5.39 5.28 5.54 5.16 5.17 4.33 5.29 4.82 5.86 4.12 SDIH 08 6.25 6.96 5.56 6.84 6.15 6.27 6.14 6.27 7.09 6.50 6.78 6.14 6.22 5.67 SDIH 09 7.78 7.31 7.48 7.02 7.93 7.65 7.47 7.06 7.43 7.56 7.46 6.98 7.81 7.97 LDIH 01 9.57 6.53 9.50 8.40 9.61 8.37 9.69 10.31 7.72 8.15 10.56 11.02 9.53 7.98 LDIH 02 4.98 4.22 4.96 4.03 5.66 5.10 4.88 4.39 5.33 4.55 5.60 4.63 5.64 4.38 LDIH 03 7.22 7.63 6.89 6.28 8.30 7.23 6.7.8 6.54 7.31 6.50 7.07 5.65 7.49 6.35 LDIH 04 6.75 5.94 6.21 5.71 5.75 6.65 6.01 6.20 6.22 5.22 6.67 6.58 7.66 7.24 LDIH 05 7.49 6.85 7.53 6.06 5.88 6.39 7.70 5.81 6.71 5.36 8.08 7.54 7.65 7.38 LDIH 06 6.11 6.53 6.31 5.94 6.19 6.44 4.42 4.90 6.30 5.79 7.75 8.34 6.01 5.71 LDIH 07 7.81 8.09 6.31 5.70 7.25 6.42 6.77 6.63 8.45 7.96 7.70 8.23 6.55 6.78 LDIH 08 7.10 6.97 7.07 7.12 4.62 4.63 6.56 6.26 7.12 7.43 5.82 5.50 5.86 6.40 LDIH 09 7.91 7.58 7.46 6.41 7.51 6.89 7.90 6.73 8.45 7.88 8.09 7.41 7.96 9.38 -99-Change in stroke volume (SV) per change in arterial oxyhemoglobin saturation (SaC>2) during preHVR and postHVR. ASV/ASa0 2 (ml %Sa02]) Day 1 3 5 8 10 12 15 17 HVR Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 -0.58 -0.02 -0.60 0.06 -0.37 -0.16 -0.29 -0.16 -0.14 -0.17 -0.50 0.44 -0.03 1.23 SDIH 02 0.14 0.05 0.09 0.23 -0.04 0.75 0.19 -0.01 0.20 0.27 -0.22 -0.67 0.41 0.02 SDIH 03 0.00 -0.02 -0.18 -0.44 0.12 0.02 -0.58 -0.05 0.08 -0.14 ' 0.06 -0.00 0.09 -0.14 SDIH 04 0.06 0.08 0.22 -0.05 0.42 0.13 0.51 0.18 0.37 0.27 0.17 0.28 0.14 0.40 SDIH 05 0.17 0.20 0.40 0.23 0.19 0.35 0.46 0.22 0.49 0.35 0.12 0.31 0.22 0.18 SDIH .06 0.94 -0.09 0.85 0.35 0.43 0.18 -0.10 0.92 0.43 0.16 0.55 0.01 0.10 0.24 SDIH 07 -0.25 -0.15 -0.18 -0.01 -1.07 0.03 -0.23 -0.70 0.22 -0.18 0.01 -1.00 1.21 -0.97 SDIH 08 -0.80 -0.72 -1.51 -2.23 -0.94 -0.98 -0.84 1.14 1.15 -0.84 0.14 0.88 -1.12 1.47 SDIH 09 -0.03 0.19 -1.09 0.59 0.18 0.20 -0.98 -0.64 -0.91 0.43 -0.99 -1.00 -0.48 0.09 LDIH 01 -1.28 -0.78 0.16 -0.51 -0.52 -0.10 0.00 -0.09 -0.01 -0.06 0.23 -0.09 -0.05 0.25 LDIH 02 0.37 0.44 0.25 0.12 0.53 0.22 0.23 0.30 0.12 0.31 0.22 0.31 0.19 0.30 LDIH 03 -0.20 -0.27 -0.65 -0.13 0.36 -0.38 -0.27 0.12 -0.31 -0.28 -0.23 -0.36 -0.49 -0.45 LDIH 04 0.09 -0.19 -0.24 -0.02 0.41 0.28 -0.06 -0.03 0.35 0.35 0.20 -0.33 0.14 0.27 LDIH 05 -0.03 -0.50 -0.36 0.23 -0.10 -0.71 0.10 -0.23 0.38 -0.41 -0.37 -0.20 -0.38 -0.65 LDIH 06 0.15 -0.18 1.01 0.60 0.51 1.13 0.17 0.46 1.32 0.61 1.08 0.46 0.43 0.06 LDIH 07 0.30 0.19 -0.25 -0.50 0.23 -0.26 0.39 -0.12 -0.01 -0.23 -0.74 -0.37 0.05 0.14 LDIH 08 -0.16 -0.26 -0.46 -0.60 0.16 0.21 -0.40 -0.73 0.37 0.13 0.45 -0.39- -0.68 -0.36 LDIH 09 0.77 0.71 0.57 -0.19 0.62 0.26 0.49 0.59 0.26 0.66 0.14 1.02 0.77 0.45 - 100-Stroke volume (SV) occurring in normoxia immediately before each preHVR and postHVR. Values are 30 second averages. SV (ml) Day 1 3 5 8 10 12 15 17 HVR Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post \ SDIH 01 96.33 101.70 112.13 117.42 104.52 119.86 104.93 105.72 111.06 118.93 129.22 134.61 130.52 96.26 SDIH 02 93.70 98.39 83.87 82.38 91.00 84.00 87.67 89.67 86.67 83.00 81.67 79.33 86.67 88.67 SDIH 03 88.33 87.33 80.67 82.33 72.00 73.33 85.67 75.00 74.67 82.33 95.00 87.33 86.33 92.00 SDIH 04 94.00 102.00 101.67 104.67 99.00 105.33 97.00 93.33 96.67 93.67 97.00 93.00 98.33 112.00 SDIH 05 93.67 91.33 96.33 94.33 98.67 98.00 115.33 104.67 96.67 99.50 106.00 92.33 101.33 102.67 SDIH 06 101.67 111.33 115.67 119.00 116.33 125.67 111.67 97.67 119.67 110.33 109.33 108.00 100.67 103.33 SDIH07 99.67 93.33 105.67 98.00 114.33 110.67 112.67 107.00 98.33 86.33 110.33 107.00 111.00 100.67 SDIH 08 147.33 151.33 136.33 146.67 121.33 140.33 122.33 144.67 136.33 135.00 130.00 147.00 148.67 127.33 SDIH 09 112.33 103.67 117.67 101.67 126.67 122.00 121.00 118.33 127.00 124.00 116.67 109.67 120.00 115.33 LDIH 01 134.33 89.42 106.07 107.43 115.67 101.67 100.00 103.00 96.00 102.33 115.33 133.67 105.00 103.00 LDIH 02 62.00 61.33 69.00 61.00 72.67 69.67 60.33 60.67 64.67 67.00 69.33 60.00 72.00 63.00 LDIH 03 115.00 125.33 122.33 117.00 122.67 122.33 113.33 117.33 113.00 121.33 109.00 110.00 124.67 118.00 LDIH 04 106.67 119.67 112.67 120.33 105.00 113.00 118.67 121.33 95.67 99.33 109.33 123.33 118.33 113.67 LDIH 05 114.33 128.67 109.33 105.00 113.67 113.00 107.33 105.67 102.00 97.33 103.33 107.67 124.67 122.00 LDIH 06 99.00 106.33 98.00 97.00 95.67 106.00 67.67 72.33 92.00 86.00 102.33 117.00 89.33 77.67 LDIH 07 91.67 94.67 89.33 87.00 86.00 89.00 84.33 88.00 75.00 72.33 90.33 99.33 78.33 103.01 LDIH 08 113.00 112.67 113.67 118.67 89.00 93.00 112.67 115.33 94.67 102.67 94.67 89.67 102.00 97.33 LDIH 09 121.00 119.33 97.33 93.00 110.67 104.00 104.33 92.67 113.33 103.33 112.00 100.33 115.33 118.33 -101 -Change in total peripheral resistance (TPR) per change in arterial oxyhemoglobin saturation (Sa02) during preHVR and postHVR. ATPR/ASa0 2 (PRU %Sa<V) Day 1 3 5 10 12 15 17 HVR Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 -0.007 0.000 -0.010 0.010 0.000 0.000 -0.010 0.008 -0.004 -0.010 0.006 -0.012 -0.005 -0.010 SDIH 02 -0.008 -0.189 -0.004 -0.012 -0.003 -0.005 -0.008 -0.009 -0.006 -0.007 -0.002 0.001 -0.012 -0.003 SDIH 03 -0.007 -0.011 -0.003 -0.007 -0.014 -0.010 0.002 -0.010 -0.010 -0.006 -0.005 -0.006 -0.005 -0.004 SDIH 04 -0.008 -0.008 -0.005 -0.007 -0.012 -0.012 -0.010 -0.010 -0.009 -0.013 -0.007 -0.010 -0.007 -0.008 SDIH 05 -0.008 -0.011 -0.008 -0.011 -0.005 -0.007 -0.004 -0.006 -0.010 -0.009 -0.007 -0.013 -0.007 -0.006 SDIH 06 -0.010 -0.008 -0.005 -0.010 -0.004 -0.004 -0.005 -0.018 -0.010 -0.013 -0.005 -0.008 -0.002 -0.005 SDIH 07 -0.024 -0.037 -0.013 -0.045 -0.012 -0.016 -0.014 -0.024 -0.021 -0.025 -0.015 -0.006 -0.026 -0.008 SDIH 08 -0.011 -0.025 -0.009 -0.006 -0.013 -0.016 -0.016 -0.015 -0.009 -0.017 -0.015 -0.022 -0.016 -0.019 SDIH 09 -0.005 -0.011 0.002 -0.012 -0.005 -0.009 -0.003 -0.006 0.002 -0.003 0.004 -0.006 -0.002' -0.006 LDIH 01 0.000 -0.008 -0.002 0.002 -0.004 -0.007 0.001 -0.003 -0.005 -0.005 -0.002 -0.005 -0.006 -0.005 LDIH 02 -0.015 -0.028 -0.009 -0.021 -0.007 -0.007 -0.006 -0.016 -0.005 -0.023 -0.002 -0.017 -0.009 -0.011 LDIH 03 -0.004 -0.006 -0.002 -0.007 0.000 -0.005 -0.005 -0.008 -0.002 -0.005 -0.004 -0.018 -0.003 -0.004 LDIH 04 -0.007 -0.013 -0.013 -0.016 -0.016 -0.015 -0.012 -0.016 -0.013 -0.015 -0.010 -0.010 -0.006 -0.008 LDIH 05 -0.011 -0.012 -0.007 -0.011 -0.016 -0.014 -0.010 -0.014 -0.010 -0.009 -0.003 -0.005 -0.015 -0.009 LDIH 06 0.015 -0.006 -0.002 -0.011 -0.005 -0.012 0.021 -0.001 -0.030 0.041 -0.004 -0.005 0.020 0.017 LDIH 07 -0.010 -0.009 -0.008 -0.009 -0.008 -0.011 -0.011 -0.010 -0.003 -0.004 -0.004 -0.006 -0.011 -0.006 LDIH 08 -0.006 -0.005 -0.002 -0.001 -0.012 -0.021 -0.003 -0.007 -0.004 -0.005 0.004 -0.002 -0.000 0.000 LDIH 09 -0.007 -0.011 -0.007 -0.014 -0.011 -0.009 -0.008 -0.015 -0.005 -0.008 -0.014 -0.013 -0.011 -0.006 -102-Total peripheral resistance (TPR) occurring in normoxia immediately before each preHVR and postHVR. Values are 30 second averages. Day HVR 1 Pre Post 3 Pre Post 5 Pre Post TPR (PRU) 8 10 Pre Post Pre Post 12 Pre Post 15 17 SDIH 01 1.06 0.81 0.79 0.90 0.76 0.88 0.87 1.01 0.71 0.90 0.80 0.94 0.69 0.85 SDIH 02 0.79 0.79 0.71 0.91 0.73 0.70 0.88 0.90 0.72 0.86 0.88 1.02 0.87 0.80 SDIH 03 1.03 1.16 1.13 1.16 1.12 1.02 0.88 1.21 1.06 1.23 0.82 0.98 0.96 0.97 SDIH 04 1.03 0.80 0.73 0.75 0.92 0.90 0.83 0.95 0.79 0.96 0.83 0.99 0.88 0.69 SDIH 05 0.88 0.96 0.85 0.99 0.71 0.80 0.53 0.74 0.80 0.78 0.69 0.96 0.66 0.59 SDIH 06 0.72 0.67 0.60 0.65 0.67 0.67 0.72 0.85 0.84 0.88 0.69 0.79 0.71 0.71 SDIH 07 1.14 1.47 1.02 1.91 0.95 1.01 0.88 1.04 0.89 1.24 0.94 1.10 0.88 1.14 SDIH 08 0.82 0.77 0.83 0.82 0.87 0.90 0.81 0.85 0.70 0.78 0.73 0.83 0.80 0.94 SDIH 09 0.77 0.86 0.77 0.97 0.69 0.82 0.82 0.83 0.76 0.80 0.72 0.98 0.76 0.74 L U I I l U 1 V.IJ l . ^ - O U.UU \J.I-I KI.^S \ J . i - r . LDIH 02 1.28 1.52 1.20 1.66 0.86 1.12 1.22 1.32 1.14 1.38 1.05 1.41 0.98 1.38 LDIH 03 0.72 0.78 0.79 0.90 0.64 0.80 0.80 0.86 0.71 0.89 0.77 1.02 0.72 0.77 LDIH 04 0.74 0.93 0.81 0.91 0.83 0.84 0.85 0.82 0.84 1.04 0.73 0.85 0.60 0.68 LDIH 05 0.79 0.90 0.78 0.93 0.89 0.91 0.65 0.93 0.68 0.94 0.63 0.69 0.75 0.72 LDIH 06 1.00 0.93 0.92 0.99 0.98 0.89 1.66 1.43 1.52 0.95 0.71 0.72 1.06 1.12 LDIH 07 0.72 0.69 0.78 0.90 0.70 0.76 0.73 0.74 0.63 0.66 0.67 0.65 0.86 0.84 LDIH 08 0.83 0.85 0.89 0.82 1.26 1.31 0.77 0.85 0.87 0.88 1.05 1.13 1.12 1.05 LDIH 09 0.63 0.71 0.70 0.84 0.74 0.82 0.71 0.82 0.58 0.68 0.73 0.80 0.69 0.55 - 103 -Change in systolic blood pressure (SBP) per change in arterial oxyhemoglobin saturation (Sa02) during preHVR and postHVR. ASBP/ASa0 2 (mmHg %Sa02 ) Day H V R 1 3 5 8 10 12 15 17 Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 0.68 0.23 0.06 1.02 1.87 2.02 1.62 0.22 1.08 0.69 1.17 0.52 0.11 2.43 SDIH 02 0.45 -0.03 0.47 0.41 0.47 2.24 0.35 -0.04 0.88 0.64 0.22 0.15 0.24 0.71 SDIH 03 0.35 -0.39 0.10 -0.15 0.03 0.02 0.09 0.14 0.38 0.08 0.21 0.27 0.46 0.07 SDIH 04 0.34 -0.19 0.40 0.09 0.31 0.45 0.68 0.28 0.63 0.05 0.16 0.44 0.31 0.62 SDIH 05 0.21 0.12 0.24 0.11 0.34 0.22 0.81 0.49 0.50 0.24 0.31 0.09 0.59 0.59 SDIH 06 1.61 0.18 1.45 0.91 1.09 1.07 1.16 0.89 1.16 0.80 1.40 1.09 1.44 1.40 SDIH 07 1.14 0.60 1.19 0.78 1.49 1.32 1.64 0.11 1.66 1.26 3.62 0.88 3.15 0.88 SDIH 08 0.52 0.81 1.45 0.09 0.78 0.67 1.71 0.21 0.77 0.51 1.09 0.90 0.74 1.08 SDIH 09 1.71 1.24 2.57 1.02 2.05 1.09 2.21 1.26 1.82 1.34 2.69 1.06 1.77 1.31 LDIH 01 0.20 0.19 1.07 0.76 0.23 -0.23 1.22 0.54 0.71 0.02 1.46 0.16 0.27 0.56 LDIH 02 0.85 1.86 1.33 0.43 1.27 1.26 0.84 0.60 0.86 0.96 1.30 0.69 0.93 1.22 LDIH 03 0.98 0.11 0.32 0.41 0.45 0.31 0.20 0.11 0.23 0.04 0.32 0.28 0.71 0.35 LDIH 04 0.43 -0.07 0.29 0.18 0.49 -0.01 0.59 0.06 0.16 0.17 0.30 0.30 0.55 0.42 LDIH 05 0.62 0.24 0.05 0.32 0.58 -0.46 0.47 0.21 0.73 -0.38 0.25 -0.26 0.90 0.41 LDIH 06 0.85 0.81 1.41 1.17 0.77 0.78 0.76 0.84 1.06 0.27 1.76 0.58 1.58 1.56 LDIH 07 0.41 0.49 0.08 -0.05 0.12 0.14 0.61 -0.14 0.40 -0.02 0.11 -0.52 0.19 0.85 LDIH 08 0.98 0.68 0.72 0.81 1.18 1.06 1.04 0.61 1.03 0.60 1.54 1.29 1.02 0.86 LDIH 09 1.03 1.39 0.88 0.07 0.80 0.52 0.55 0.57 0.91 0.84 1.13 1.06 0.73 0.74 - 104-Systolic blood pressure (SBP) occurring in normoxia immediately before each preHVR and postHVR. Values are 30 second averagi SBP (mmHg) Day 1 3 5 8 10 12 15 17 H V R Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 125 133 135 125 140 117 113 113 126 131 114 138 126 117 SDIH 02 112 134 109 125 124 113 124 136 116 128 138 147 114 126 SDIH 03 120 123 132 132 118 113 116 127 109 127 124 120 118 125 SDIH 04 120 140 128 120 125 125 119 125 112 124 125 121 125 124 SDIH 05 119 129 131 124 121 123 127 125 119 121 126 122 120 117 SDIH 06 126 139 122 138 133 138 120 144 145 149 130 150 136 120 SDIH 07 112 120 109 127 123 127 114 126 107 122 116 129 126 107 SDIH 08 124 127 103 134 130 131 115 122 114 122 120 125 121 121 SDIH 09 135 142 135 154 126 146 138 133 130 139 118 157 134 134 LDIH 01 139 138 121 124 129 135 115 128 117 123 114 134 124 114 LDIH 02 127 121 116 131 113 124 132 130 122 116 122 117 129 124 LDIH 03 120 137 123 124 118 133 123 129 118 130 125 127 122 110 LDIH 04 117 131 118 115 113 128 122 122 122 126 117 136 113 119 LDIH 05 134 136 136 131 121 133 115 125 107 118 118 124 140 130 LDIH 06 136 135 134 133 140 131 159 158 136 122 125 140 146 143 LDIH 07 126 125 106 110 110 106 108 108 113 109 112 120 120 123 LDIH 08 132 131 143 130 128 134 115 121 136 149 132 132 146 147 LDIH 09 119 122 117 119 125 125 124 120 112 120 131 131 126 118 - 105 -Change in diastolic blood pressure (DBP) per change in arterial oxyhemoglobin saturation (Sa02) during preHVR and postHVR. ADBP/ASaG-2 (mmHg VoSaO/) Day 1 3 5 8 10 12 15 17 H V R Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 0.48 0.18 0:19 0.50 0.88 0.81 1.05 0.21 0.51 0.33 0.69 0.19 0.27 0.76 SDIH 02 0.30 -0.16 0.17 0.01 0.24 0.79 0.09 -0.08 0.29 0.21 0.12 0.38 0.24 0.30 SDIH 03 0.17 -0.23 -0.07 0.08 -0.11 -0.04 0.19 0.02 0.04 0.07 0.05 0.07 0.20 0.07 SDIH 04 0.10 -0.16 0.03 -0.01 -0.06 -0.02 0.20 -0.00 0.20 -0.17 -0.01 0.09 -0.01 -0.03 SDIH 05 0.06 -0.03 -0.01 -0.10 0.11 -0.04 0.26 0.09 0.09 -0.03 0.06 -0.09 0.20 0.13 SDIH 06 0.50 0.08 0.50 0.18 0.54 0.46 0.48 0.21 0.40 0.20 0.55 0.50 0.43 0.61 SDIH 07 0.65 0.44 0.80 0.52 1.06 0.63 0.82 0.35 0.95 0.77 1.88 0.96 1.39 0.91 SDIH 08 0.42 0.39 0.74 0.59 0.64 0.35 0.89 0.22 0.60 0.43 0.43 0.38 0.52 0.75 SDIH 09 0.63 0.38 1.45 0.20 0.98 0.53 1.20 0.71 0.98 0.62 1.32 0.55 0.78 0.57 LDIH 01 0.37 0.37 0.49 0.52 -0.08 -0.12 0.73 0.14 0.28 -0.05 0.45 -0.00 -0.08 0.24 LDIH 02 0.31 0.89 0.61 0.26 0.56 0.51 0.46 0.26 0.57 0.36 0.88 0.27 0.45 0.63 LDIH 03 0.42 0.02 0.31 0.19 0.32 0.17 0.16 -0.04 0.19 0.01 0.26 .0.04 0.40 0.24 LDIH 04 0.19 -0.05 0.17 0.09 0.17 -0.03 0.24 -0.03 0.00 -0.04 0.04 0.09 0.24 0.13 LDIH 05 •0.19 0.04 0.05 0.02 0.27 -0.16 0.11 -0.01 0.10 -0.08 0.23 -0.06 -0.50 -0.12 LDIH 06 0.29 0.24 0.17 0.17 0.07 0.11 0.19 0.06 0.25 0.06 0.41 -0.00 0.40 0.39 LDIH 07 -0.07 -0.11 -0.04 -0.01 -0.14 -0.01 0.18 -0.17 0.12 0.03 0.10 -0.30 0.03 0.37 LDIH 08 0:52 0.31 0.47 0:51 0.57 0.41 0.68 0.49 0.36 0.26 0.87 0.73 0.69 0.49 LDIH 09 0.32 0.36 0.34 -0.19 0.16 0.09 0.11 0.08 0.45 0.22 0.40 0.19 0.14 0.22 -106-Diastolic blood pressure (DBP) occurring in normoxia immediately before each preHVR and postHVR. Values are 30 second averagl DBP (mmHg) Day HVR 1 3 5 8 10 12 15 17 Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post SDIH 01 74 80 70 76 78 78 67 86 77 90 77 80 76 73 SDIH 02 68 79 67 78 76 70 75 83 70 81 86 93 72 76 SDIH 03 78 78 81 80 73 71 71 79 70 89 74 68 71 74 SDIH 04 81 85 72 73 79 76 69 76 65 78 73 72 75 66 SDIH 05 69 77 75 91 69 80 67 82 67 75 70 83 68 65 SDIH 06 76 78 68 77 77 88 74 85 83 87 76 88 79 71 SDIH 07 65 72 61 73 67 70 63 71 60 75 65 71 69 62 SDIH 08 64 67 58 69 70 72 64 67 62 64 63 64 62 68 SDIH 09 78 83 74 89 69 81 78 76 72 77 69 89 76 77 LDIH 01 90 93 76 74 75 84 72 79 73 77 66 72 80 69 LDIH 02 83 83 77 92 61 75 81 79 81 83 78 76 72 76 LDIH 03 68 75 70 73 68 75 70 73 68 75 72 76 69 63 LDIH 04 63 69 63 60 61 56 64 63 69 70 62 69 57 62 LDIH 05 75 76 75 73 66 74 63 69 57 66 66 68 72 67 LDIH 06 78 80 79 80 83 77 99 98 81 75 72 78 87 87 LDIH 07 75 74 65 69 68 64 66 65 73 73 68 70 91 71 LDIH 08 76 78 81 75 80 82 66 69 83 86 81 84 87 88 LDIH 09 62 69 69 72 72 74 73 74 62 70 77 77 71 64 - 107-Ventilation during the first (Hi) and last (H2) 5 minutes of hypoxic exposure to SDIH and LDIH. Values are 3-minute averages of the end of each 5-minute period. Vi (1 min"1) Day 1 3 5 8 10 12 H V R Hi H 2 Hi H 2 Hi H 2 Hi H 2 Hi H 2 Hi SDIH 01 14.98 14.16 13.38 16.69 10.64 14.97 9.60 9.63 10.75 12.92 10.39 13.74 SDIH 02 11.19 11.00 8.60 11.21 12.24 12.20 10.12 10.61 10.32 10.42 13.38 14.02 SDIH 03 11.59 10.95 10.30 11.30 13.43 11.32 13.60 12.60 13.59 15.28 12.52 11.97 SDIH 04 14.11 13.10 16.75 13.46 13.59 12.02 15.26 15.06 11.29 12.79 13.42 13.39 SDIH 05 13.98 12.64 13.21 12.63 13.62 14.89 13.61 14.53 14.29 14.38 13.23 12.99 SDIH 06 12.45 12.98 12.49 15.22 18.23 18.97 13.24 16.24 15.06 13.40 16.46 16.52 SDIH 07 19.74 16.81 14.53 11.04 18.29 15.05 17.37 17.72 20.59 16.85 19.31 18.02 SDIH 08 15.54 16.59 13.75 12.84 14.12 13.51 15.66 14.40 16.05 15.61 15.41 15.04 SDIH 09 9.04 9.26 9.77 8.72 8.20 10.79 8.58 3.55 11.11 11.15 11.15 10.27 LDIH 01 10.77 11.90 14.23 12.71 10.46 11.08 14.72 15.18 10.25 10.55 14.73 12.59 LDIH 02 11.84 10.52 11.33 11.68 13.82 13.93 10.44 11.87 9.71 10.31 12.53 13.22 LDIH 03 14.24 11.00 11.80 9.59 12.16 11.42 14.75 12.45 11.66 10.75 12.34 10.78 LDIH 04 15.68 17.50 16.26 15.52 17.53 15.42 15.41 14.38 14.35 12.81 17.65 15.76 LDIH 05 13.02 12.17 14.18 13.79 13.80 15.94 16.68 13.44 13.52 12.44 11.12 10.31 LDIH 06 16.37 16.14 15.88 14.01 14.86 14.47 20.23 18.39. 15.30 17.42 16.79 16.25 LDIH 07 13.33 13.18 11.42 10.46 11.94 11.91 12.31 12.48 12.15 12.03 14.39 15.77 LDIH 08 16.54 14.23 15.08 14.16 13.23 12.42 14.53 12.15 14.69 17.06 15.71 11.16 LDIH 09 14.17 13.39 15.12 16.61 16.56 16.26. 16.50 17.32 16.91 16.41 17.82 15.60 - 108-Mean arterial pressure (MAP) during the first (Hi) and last (H2) 5 minutes of hypoxic exposure to SDIH and LDIH. Values are 3-minute averages of the end of each 5-minute period. MAP (mmHg) Day 1 3 5 8 10 12 HVR Hi H 2 Hi H 2 Hi H 2 Hi H 2 Hi H 2 H t H 2 SDIH 01 111.47 109.76 95.55 103.73 101.11 105.89 98.74 109.11 97.53 107.47 106.84 117.63 SDIH 02 86.95 107.24 88.12 90.32 101.63 98.95 98.16 102.95 89.42 104.00 108.68 115.58 SDIH 03 96.65 97.56 95.37 96.28 94.49 87.37 86.54 94.89 103.96 103.63 102.51 90.61 SDIH 04 100.46 112.70 97.63 98.89 99.40 109.91 87.47 94.02 85.00 94.33 87.46 87.26 SDIH 05 92.35 93.42 90.35 101.82 86.82 101.82 81.54 101.07 88.65 90.75 91.96 97.00 SDIH 06 98.21 102.77 92.19 97.35 98.40 110.09 95.40 100.96 108.51 108.53 94.05 105.42 SDIH 07 83.96 86.11 76.16 93.05 85.05 89.30 86.33 88.68 79.70 89.96 95.77 92.07 SDIH 08 82.14 87.47 75.91 86.12 85.02 91.12 80.12 85.21 78.11 85.21 83.42 85.09 102.39 94.11 100.54 96.70 102.70 91.35 97.67 97.14 103.49 LDIH 01 115.17 134.82 100.49 110.70 91.84 91.00 92.16 87.68 92.53 98.26 90.37 89.74 LDIH 02 108.05 105.32 103.21 104.56 84.28 90.18 99.00 101.42 99.00 101.42 100.75 98.70 LDIH 03 87.28 90.88 78.35 83.14 83.89 87.70 87.35 87.42 78.46 79.04 89.14 88.11 LDIH 04 84.55 90.16 84.07 87.33 89.00 88.82 84.58 91.33 86.26 87.74 88.82 97.58 LDIH 05 96.02 94.82 84.46 85.18 80.96 95.19 87.16 90.74 85.88 80.47 82.04 85.72 LDIH 06 98.54 101.95 98.54 96.07 100.33 95.88 117.21 121.42 95.16 95.16 89.86 90.44 LDIH 07 95.58 95.30 73.44 78.30 72.70 75.54 77.72 76.70 84.84 82.39 80.93 85.74 LDIH 08 92.14 93.09 93.53 94.88 93.68 98.12 85.21 79.93 95.05 98.56 103.18 99.60 LDIH 09 78.98 79.86 82.74 86.42 86.35 89.51 86.88 90.02 85.25 80.95 96.19 100.67 -109-Heart rate (HR) during the first (Hi) and last (H2) 5 minutes of hypoxic exposure to SDIH and LDIH. Values are 3-minute averages of the end of each 5-minute period. HR (bpm) Day 1 3 5 8 10 12 H V R Hi H 2 Hi H 2 Hi H 2 - Hi H 2 -H i H 2 Hi H 2 SDIH 01 75.47 76.83 66.34 71.05 72.00 69.84 62.89 63.58 64.95 66.24 70.68 68.53 SDIH 02 80.15 81.47 83.76 80.86 95.11 90.05 78.37 79.47 89.84 89.84 95.63 95.05 SDIH 03 65.79 60.21 62.05 68.00 74.00 77.37 72.05 77.32 74.42 68.26 75.79 71.89 SDIH 04 70.21 94.21 82.32 79.11 74.00 78.68 71.05 73.63 68.95 74.16 64.68 61.58 SDIH 05 68.89 68.63 70.07 74.84 80.63 79.32 83.11 89.53 74.00 73.32 72.79 70.05 SDIH 06 89.74 89.16 81.32 119.05 86.95 87.47 75.74 77.42 81.32 77.68 78.26 80.74 SDIH 07 50.84 42.84 50.16 41.37 44.74 53.32 55.89 52.95 60.68 55.11 50.37 72.74 SDIH 08 42.95 49.32 42.89 51.53 44.89 52.89 43.47 48.53 51.79 51.68 56.00 52.05 SDIH 09 68.95 77.68 64.37 67.05 67.32 . 68.74 69.26 69.42 62.00 68.00 62.00 64.95 LDIH 01 77.81 81.70 88.49 83.73 79.68 87.63 101.11 98.63 85.32 89.63 92.21 96.47 LDIH 02 77.84 76.16 78.37 75.11 81.29 83.89 72.47 82.05 72.47 82.05 73.37 71.68 LDIH 03 67.79 65.42 53.95 54.63 63.37 59.68 63.84 67.84 67.16 64.14 61.00 59.26 LDIH 04 66.11 68.53 64.74 62.79 70.11 75.74 63.26 62.68 62.63 70.00 76.89 75.37 LDIH 05 .74.00 83.84 73.53 72.79 65.79 73.05 67.68 70.00 79.05 78.16 80.11 83.00 LDIH 06 62.84 62.74 69.26 65.26 65.32 66.26 59.74 65.26 71.16 72.32 74.11 69.63 LDIH 07 92.79 92.79 72.95 70.89 79.37 77.58 76.58 79.11 110.58 116.26 85.53 91.37 LDIH 08 64.89 61.84 61.58 63.68 51.21 51.37 58.42 57.21 74.00 77.00 66.11 62.63 LDIH 09 71.89 71.63 82.37 86.42 75.16 76.05 80.53 80.53 83.11 85.00 78.47 85.16 -110-Cerebral tissue oxygen saturation (Sc02) during the first (Hi) and last (H2) 5 minutes of hypoxic exposure to SDIH and LDIH. Values are 3-minute averages of the end of each 5-minute period. Sc0 2 (%) Day 1 3 5 8 10 12 HVR Hi H 2 Hi H 2 Hi H 2 Hi H 2 H, H 2 H, H 2 SDIH 01 70.3 68.4 67.0 70.8 64.8 66.9 63.0 64.9 64.1 67.5 80.1 83.4 SDIH 02 61.1 66.4 65,2 64.2 67.5 68.5 61.7 64.5 65.2 66.7 65.7 66.1 SDIH 03 64.2 64.1 64.7 66.2 64.1 65.3 66.1 66.0 70.6 73.8 68.0 68.4 SDIH 04 67.9 64.5 65.8 63.3 66.7 66.7 67.0 66.1 66.7 66.3 68.5 66.9 SDIH 05 79.5 81.7 74.5 81.8 66.4 67.3 63.9 65.2 79.5 79.7 60.9 59.6 SDIH 06 67.9 67.3 64.8 66.8 69.5 71.5 65.3 66.3 63.9 63.6 64.8 66.1 SDIH 07 64.6 62.6 58.3 60.3 62.5 64.8 65.8 64.6 69.9 70.3 67.5 67.0 SDIH 08 73.5 73.4 73.5 75.0 77.4 78.9 77.4 78.9 73.5 73.8 72.9 73.7 SDIH 09 61.8 60.1 54.2 54.4 58.6 61.0 55.7 54.6 59.6 59.9 61.9 61.7 LDIH 01 61.8 60.5 64.5 62.5 64.7 59.9 66.1 66.3 63.2 62.3 66.7 61.8 LDIH 02 70.9 68.2 70.2 68.7 68.4 67.9 67.2 66.6 63.6 62.0 66.0 65.8 LDIH 03 63.8 61.7 60.4 57.5 60.3 57.8 61.2 54.4 64.5 60.1 65.7 62.4 LDIH 04 58.4 55.5 60.0 59.7 61.4 58.7 63.4 62.7 52.9 46.3 51.8 50.5 LDIH 05 52.1 46.5 48.7 43.3 52.9 52.6 59.8 56.8 56.4 50.4 58.3 51.4 LDIH 06 72.0 72.3 68.2 66.0 70.8 70.1 67.1 67.5 65.8 64.3 70.9 68.9 LDIH 07 68.4. 65.3 60.9 59.3 61.9 61.9 61.5 61.0 63.0 •58.9 57.0 58.8 LDIH 08 65.1 62.9 66.3 63.2 65.0 63.0 69.5 66.5 68.4 67.2 66.3 63.2 LDIH 09 73.0 70.5 61.8 60.9 66.7 65.4 69.3 66.7 63.1 60.2 70.0 69.0 - I l l -Arterial oxygen saturation (Sa02) during the first (H,) and last (H2) 5 minutes of hypoxic exposure to SDIH and LDIH. Values are 3-averages of the end of each 5-minute period. Sa0 2 (%) Day 1 3 5 8 10 12 H V R H , H 2 H , H 2 Hi H 2 H, H 2 Hi H 2 Hi H 2 SDIH 01 93.8 90.8 93.5 94.5 93.6 94.3 91.1 93.6 91.2 94.9 93.8 94.9 SDIH 02 81.8 89.2 96.5 92.9 93.9 91.5 87.9 90.6 94.1 94.0 90.3 89.7 SDIH 03 91.4 90.9 92.6 89.1 93.4 90.6 93.3 90.5 91.8 95.1 91.6 90.3 SDIH 04 92.3 91.7 87.4 82.1 88.4 88.4 89.4 89.0 89.6 90.0 90.1 90.4 SDIH 05 93.4 77.8 91.2 91.1 90.4 88.8 91.5 88.7 93.2 89.3 92.1 90.8 SDIH 06 91.3 91.4 89.5 90.5 93.3 94.3 91.7 92.6 93.8 92.2 92.2 93.4 SDIH 07 92.6 91.9 94.3 93.7 92.4 93.1 93.4 92.1 94.0 94.5 94.5 95.5 SDIH 08 93.2 93.8 92.9 92.3 93.1 93.6 94.8 95.5 93.0 92.9 90.5 91.9 SDIH 09 93.0 92.0 91.7 90.7 90.2 92.2 91.4 90.4 91.9 91.5 93.0 93.0 LDIH 01 89.5 86.7 88.3 84.1 88.8 80.2 88.6 88.8 90.2 86.1 90.5 82.7 LDIH 02 94.7 91.0 93.6 88.3 93.4 88.8 94.5 91.6 91.1 84.8 94.0 93.7 LDIH 03 89.0 87.6 94.8 88.1 92.8 89.2 90.8 80.4 89.0 81.3 90.1 80.5 LDIH 04 90.0 87.5 88.9 88.5 88.8 81.7 93.0 90.8 92.0 82.0 91.3 89.5 LDIH 05 88.2 71.9 88.0 80.3 89.2 86.8 95.0 91.8 91.2 83.2 91.4 82.8 LDIH 06 93.4 93.6 93.5 88.9 93.1 90.5 92.7 91.6 90.5 85.9 92.0 88.5 LDIH 07 91.6 87.4 91:6 90.2 91.0 90.5 91.6 91.2 88.8 85.1 90.4 88.9 LDIH 08 92.2 89.2 90.4 85.9 92.6 90.3 93.1 90.2 91.6 89.2 92.4 90.0 LDTH 09 91.4 88.5 90.6 87.4 91.8 87.4 90.6 85.3 90.9 85.2 92.2 89.5 - 112-R E F E R E N C E S AINSLIE PN, K O L B JC, IDE K & POULIN MJ. 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