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The effects of a six week sea level exposure on the cardiac output of high altitude Quechua natives Davidson, Robert Bruce 1989

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THE EFFECTS OF A SIX WEEK SEA LEVEL EXPOSURE ON THE  CARDIAC OUTPUT OF HIGH ALTITUDE QUECHUA NATIVES by ROBERT BRUCE DAVIDSON A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF PHYSICAL EDUCATION in THE FACULTY OF GRADUATE STUDIES Department of Sport Science School of Physical Education We accept this thesis as conforming to the required standard: THE UNIVERSITY OF BRITISH COLUMBIA September 1989 © Robert Bruce Davidson, 1989 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of P h y s i c a l E d u c a t i o n The University of British Columbia Vancouver, Canada Date Otf rQ  DE-6 (2/88) ABSTRACT Six healthy males (mean age 34 +/- 1.9) from La Raya, Peru served as subjects in a study of the effects of a six week sea level exposure on the cardiac output of high altitude natives. The subjects had resided, as had their ancestors, at or above 13,000 ft for their entire lives. Cardiac output was measured upon exposure to sea level, three weeks later, and after six weeks at sea level using a C0 2 rebreathing protocol, and also upon exposure and six weeks later using a nuclear ventriculogram protocol. Measurements of cardiac output, stroke volume, and heart rate, were taken at rest and then workloads corresponding to 40%, 60%, (and in the case of the ventriculograms) 90% of maximal oxygen consumption. The results were analyzed using repeated measures ANOVA to determine if significant changes occurred over time. Stroke volume increased 21% and cardiac output increased 28% averaged across intensity, for the nuclear ventriculogram protocol, but neither of these changes were found to be significant (p=.089 and .095 respectively). For the C0 2 rebreathing protocol cardiac output was found to increase significantly over time (p=.042), while the increase in stroke volume was non significant (p=.073). Non significant changes were also found in HR (p=.291), and 0 2 delivery (p=.342), while significant changes were found in Hgb (which decreased an average of 16%) and V 0 2 (which decreased an average of 23%) (p=.0001 and .023 respectively). It was found that over time at sea level slight in most cases non significant, increases in cardiac output, stroke volume, and heart rate all had the additive effect of compensating for the significant decrease found in the haemoglobin values. These contrary changes had the net effect of allowing the oxygen delivery to the tissues to remain essentially constant. ii TABLE OF CONTENTS ABSTRACT ii TABLE OF CONTENTS iii LIST OF SYMBOLS v LIST OF TABLES vi ACKNOWLEDGEMENTS vii INTRODUCTION 1 METHODOLOGY 4 STATISTICAL ANALYSIS 9 RESULTS 10 PHYSICAL CHARACTERISTICS 10 NUCLEAR VENTRICULOGRAM MEASUREMENTS 11 NUCLEAR VENTRICULOGRAM DATA 13 C0 2 REBREATHING MEASUREMENTS 16 C0 2 REBREATHING DATA 16 PROTOCOL COMPARISONS 19 DISCUSSION 20 HEART RATE RESPONSE 20 STROKE VOLUME AND CARDIAC OUTPUT RESPONSES 22 HAEMODYNAMIC CHANGES 26 V 0 2 DATA 27 OXYGEN DELIVERY 28 C0 2 REBREATHING DATA 28 NUCLEAR VENTRICULOGRAM AND C 0 2 REBREATHING COMPARISON 31 iii SUMMARY 32 REFERENCES 33 APPENDIX A -Relevant Literature 40 APPENDIX B 43 MEASUREMENT OF CARDIAC OUTPUT 43 VALIDITY AND RELIABILITY OF TECHNIQUES 44 SAMPLE PLATEAU'S AND CALCULATIONS 47 APPENDIX C -Basic Anthropometric Data (Table Al) 50 APPENDIX D -V0 2 Data (Table A2) 51 APPENDLX E -Individual Subject Data (Table A3) 52 iv LIST OF SYMBOLS A Alveolar a Arterial C a C 0 2 Content of C0 2 in arterial blood C v C 0 2 Content of C0 2 in venous blood C ( ¥ . a ) C0 2 Venous-arterial C0 2 content difference F b a g C 0 2 Fraction of C0 2 in bag at equilibrium HGB Haemoglobin HR Heart rate PC0 2 Partial pressure of carbon dioxide P0 2 Partial pressure of oxygen P„C0 2 Partial pressure of arterial C0 2 PVC02 Partial pressure of mixed venous C0 2 P«,C0 2 Partial pressure of end-tidal C0 2 Q Cardiac output QT Cardiac output per body surface area SI Stroke index SV Stroke volume v Mixed venous V C 0 2 Volume CO, V 0 2 max Maximal oxygen consumption Vt Tidal volume v LIST OF TABLES SUMMARY OF PHYSIOLOGICAL CHARACTERISTICS . . . . 10 SELECTED PHYSIOLOGICAL VARIABLES FROM THE NUCLEAR VENTRICULOGRAM DATA 13 ANOVA RESULTS FOR SELECTED PHYSIOLOGICAL VARIABLES FROM THE NUCLEAR VENTRICULOGRAM DATA 14 SELECTED PHYSIOLOGICAL VARIABLES FROM THE NUCLEAR VENTRICULOGRAM DATA WITH SUBJECT SIX REMOVED 15 ANOVA RESULTS FOR SELECTED PHYSIOLOGICAL VARIABLES OF THE NUCLEAR VENTRICULOGRAM DATA WITH SUBJECT SIX REMOVED 15 SELECTED PHYSIOLOGICAL VARIABLES FROM THE C0 2 REBREATHING DATA 17 3 X 2 ANOVA RESULTS FOR SELECTED PHYSIOLOGICAL VARIABLES OF THE CO, REBREATHING DATA 18 2 X 3 ANOVA RESULTS FOR SELECTED PHYSIOLOGICAL VARIABLES OF THE CO, REBREATHING DATA 18 COMPARISON CORRELATIONS 19 CARDIAC OUTPUT VALUES FROM THE LITERATURE . . . 25 vi ACKNOWLEDGEMENTS The compilation of this thesis was made possible by the efforts of several people. I would like to sincerely thank the six subjects: Santiago Ccallo, Bertin Ccallo, Leonidas Hancco, Luis Barrios, Manuel Navarro, and Mariano Kana for their kind cooperation, efforts, and patience. I extend my sincere appreciation to my committee members: Drs. Peter Hochachka, Don McKenzie, and Jack Taunton for their guidance and support during all phases of the project. Special thanks is given to Dr. Jack Taunton for inspiring me to pursue graduate studies, and Dr. Don McKenzie for firstly allowing me to join this exciting project and then tirelessly putting up with my revisions. I dedicate this work to the memory of my parents: Park and Sheena Davidson who unknowingly instilled in me the desire to learn. vii 1 INTRODUCTION Man has long been mystified by the demands of survival at altitude. As early as the 1600's scientists and balloonist's were writing and recording observations about altitude physiology. More recently, a great deal of interest has been shown in the adaptations that occur at altitude. One of the main challenges of surviving at altitude is in compensating for the decreased partial pressure of oxygen. As one ascends from sea level the density of the air becomes less, and subsequently the pressures of the respective gases decrease. When the ambient PO z is reduced to approximately 107 mm Hg, optimal tissue oxygenation becomes difficult and mechanisms must be invoked to increase the oxygen supply (McArdle et al., 1986). Increases in ventilation and cardiac output occur, resulting in increased arterial saturation and oxygen transport respectively; these are part of the acclimatization process that occurs at altitude. After an adequate period of time the native lowlander can function sufficiently at altitude but regardless of the length of the stay, he can never achieve the level or efficiency of work of the native highlander (Balke et al., 1968; Bushkirk, 1971; Faulkner et al., 1971; Heath and Williams, 1981; Houston, 1983; Loeppky and Bynum, 1970; Pugh, 1964). The adaptations to altitude experienced by the lowlander seem to be qualitatively similar to that of the highlander but quantitatively different (Heath and Williams, 1981). Most of the adaptations are concerned with improvements in oxygen transport and supply to the peripheral tissues. If an altitude native is capable of normal functioning in the strenuous environment that exists at altitude, what will his function be in the substantially less demanding environment present at sea-level? This question has been very rarely examined and the answers are not clear. 2 Hartley et al. (1967) studied this issue on altitude natives of European descent, thus not truly "high altitude man". Banchero et al. (1970), and Sime et al. (1971) used Peruvian subjects but separated their pre- and post-tests by two years. Vogel et al. (1974) studied Peruvian altitude natives, over an 8 to 10 day period, but as in the other studies compared post-test (sea-level) to the pre-test values (altitude). While the results of Hartley et al., Banchero et al., and Sime et al. were all quite similar, the more acceptable study of Vogel et al. came up with slightly different results. The trends found in these studies seem to indicate that the cardiac output increases over time at sea-level (see Appendix A). A common feature of all of the above studies is that the sea level values were compared to altitude values, not prior sea level values. Therefore little indication is given as to what the time frame or order of these changes were. To examine this aspect a large study was initiated in which altitude natives were brought to a sea level environment for a six week acclimatization (altitude de-acclimatization) period. This paper examines the cardiodynamic aspects of the acclimatization process of this larger study. Cardiac output was chosen because it has been said to be the main indicator of the functional capacity of the circulation to meet the demands of activity (McArdle et al., 1986). Thus, as the demands of activity change, such as exercising in a hypoxic to a normoxic environment, these changes should be reflected in measurement of cardiac output. If high altitude natives are different and/or advantaged as compared to sea-level natives, this should be reflected in the cardiac output. 3 The purpose of this investigation is therefore to determine the cardiac output changes over time, as they occur in high altitude natives acclimatizing to a sea-level environment. 4 METHODOLOGY Six healthy male high altitude natives from La Raya, Peru served as subjects in this study. The subjects have resided, as have their ancestors, above 13,000 ft for their entire lives, so they are truly altitude natives. The subjects were thoroughly informed of the exercise protocol prior to initiating the tests, gave their consent to participate, and were allowed to withdraw at any point during the experimental procedure. As the subjects in this study were from a very distinctive population, generalizations to other populations such as different sexes, ages, fitness levels, or habitat must be considered carefully. Also, because of the radical lifestyle change that occurred when the subjects came to Vancouver, generalizations must also be made cautiously. The lifestyle change and/or diet change could have an effect on the findings but were unavoidable due to laboratory and expense requirements. Physical characteristics were recorded before cardiac output measurements were initiated. Cardiac output was measured using two different techniques, nuclear ventriculogram (invasive), and C0 2 rebreathing (non-invasive). Prior to starting the cardiac output measurements, the subjects were tested on an electronically braked cycle ergometer (Mindjhardt model 402) to determine their maximal oxygen uptake (V0 2 Max). This test was part of a concurrent study using the same subjects. The protocol used involved cycling at 60 rpm with increasing resistances of 30 watts every 2 minutes, until volitional fatigue. Heart rate was monitored using a three lead ECG (Lifepac 6) interfaced with a Medical Graphics system 2001 metabolic cart. Throughout the protocol ventilatory gases were collected by the metabolic cart and analyzed for ventilatory volumes and partial 5 pressures of 0 2 and C0 2 . The subjects were then brought into the lab on a subsequent day for the cardiac output measurements. The cardiac measurements themselves involved determinations at rest and then at workloads corresponding to 40%, 60%, and (in the case of the ventriculograms) 90% of maximal oxygen consumption. The exercise values for the C0 2 rebreathing protocol were obtained while cycling on the same cycle as the V 0 2 max test. For the ventriculograms, exercise values were obtained on a semi-reclined cycling chair. The cycle resistance was set, while pedalling at 80 rpm, to cause a heart rate calculated to correspond to the prescribed percentage of the heart rate at V 0 2 Max. The C0 2 rebreathing method used was the equilibrium method of Collier (1956), with the Jones modifications (1969, 1973, 1982). In this method the subject exercised, breathing into a low resistance one way valve connected to a Hans Rudolph slide valve with a five litre rebreathing bag attached. The rebreathing bag contained approximately 1.5 times the subjects tidal volume of a gas containing a high concentration of C0 2 , 21% 02, and the balance N 2. The concentration of C0 2 in the bag was estimated to be 6-8% greater than the subjects expired PC0 2 (Jones and Campbell, 1982). In most cases this meant that for the rest sample 9% C0 2 was used and for the 60% exercise value a 14% C0 2 mixture was utilized. The concentration for the 40% exercise value was generally an estimation of two parts of 14% C0 2 mixture to one part of the 9% C0 2 mixture. Respiratory gases were collected and analyzed by a Medical Graphics System 2001 Metabolic cart. Breath by breath analysis of C0 2 , 0 2, and minute ventilation were recorded and presented on screen as they occurred, throughout the experiment. Resting values were obtained once the subject had maintained a steady state condition for at least three minutes. Steady state was defined as changes of less than 5 beats per minute in heart rate, 3 6 millimeters mercury in end tidal C0 2 , and less than .1% variation in expired concentration of 0 2 (Jones and Campbell, 1982; McArdle et al., 1986). Once these requirements had been met by the subject the first cardiac output value was initiated by having the subject signal when he was at an end-expiration. The rebreathing valve was then opened and the subject was encouraged to take two quick breaths and then continue to breathe normally, from the bag, until either an equilibrium plateau was reached or 30 seconds passed. The valve was then closed and the. subject resumed breathing room air. The equilibrium plateau was then examined to determine if it fit the following criteria; 1) a difference of less than .1% in the C0 2 pressure between the inspiration and expiration of two successive breaths, and 2) occurred within 15 seconds of the opening of the valve, but not before the completion of the second breath (Collier, 1956). If the plateau was not acceptable, or was not reached, the bag C0 2 concentration and/or volume was adjusted and the procedure repeated. Once an acceptable plateau had been obtained, the data was recorded and the subject moved on to the next work level. After the completion of the test the fraction of the C0 2 in the bag at equilibrium (FbagC02) was used to estimate the partial pressure of the C0 2 in the venous blood (PvCOJ for that work level. The obtained P vC0 2 was then corrected for the alveolar to arterial PC0 2 difference by the empirical formula of Jones and this value then used to calculate a venous content for the Fick equation (Jones et al., 1969, 1982). The pressure of the C0 2 in the arterial blood (PaC02) at the same workload, was derived from the pressure of the end tidal C0 2 (PetC02), on the assumption that lung function was normal. The venous-arterial C0 2 content difference (C(v.a)C02) was then calculated and a conversion factor applied that took into account the subject's haemoglobin level. The total volume of 7 C0 2 was then divided by this corrected C ( v . a )C0 2 and a value of cardiac output obtained for that work level. Calculations were then repeated for each work level. To examine the test-re test reliability of this protocol a reliability study was performed. In this study rest values for eight subjects were obtained using the above mentioned protocol. These values were then compared to rest values obtained several minutes later with the same subjects. The test-retest correlation was very high (r = .93), and the range of variation was 100-400 ml (mean 125 ml). This value converts to a percent variation of 1%. At the beginning and end of the six week period, the subjects had cardiac output measurements done via nuclear ventriculograms. These measures were performed at the U.B.C. Health Sciences Centre, Nuclear Medicine Facility. This procedure involved first preparing the subject's blood with a tinning agent that adheres to the red blood cells (Amerscan Stannous agent). Technetium" (Tc99), which binds to these prepared cells, was then infused and allowed to equilibrate. Measurements subsequently began with a ten minute rest period, while seated on the cycle, with sampling occurring for the full ten minutes (the term sampling refers to the time when data is collected). Exercise periods were then initiated starting with 40% V 0 2 max followed by 60%, and lastly, 90%. The exercise periods, which lasted 5 minutes each, began by having the subject pedal at 80 rpm and then increasing the workload to obtain the desired heart-rate. Once at this heart-rate, * steady state was maintained and sampling occurred during the last two minutes of each level. During each sampling period the computer timed the subjects R waves and took 24 images between successive waves. After the test, each image was then averaged for the 8 entire sampling period and a radiographic image presented. The technician then indicated to the computer the "region of interest" on this image, in this case the left ventricle, and the computer calculated the number of radio-active counts in this region. This was then subtracted from a "background" region, also drawn on the image, and a value for the number of actual counts was obtained. The values of counts in the end-diastolic and end-systolic phases of the cardiac cycle were then compared to the number of actual counts found in a 5 ml blood sample, drawn from the subject at the end of the test. Once the ventricular values were corrected for radioactive decay, and distance effects, they were subtracted, giving a value for stroke volume. This stroke volume value was then multiplied by the heart rate to obtain cardiac output. Haemoglobin was measured two days after the subjects arrived at sea level, after three weeks, and then again after six weeks. This procedure was done at the U.B.C. Health Sciences Center using a Coulter Stacker S+ blood analyzer. A value of oxygen delivery was calculated for each subject for both protocols. This was done by multiplying the subject's current haemoglobin value (in gram/litre) by the oxygen capacity of haemoglobin (1.34 ml Oj/gram) assuming 100% saturation. This product was then multiplied by the cardiac output for each exercise intensity, giving a value of tissue oxygen delivery for that workload. A value of oxygen pulse was also calculated for each subject for the CO z rebreathing protocol. This was done by dividing the volume of 0 2 ventilated (in mis) by the corresponding heart rate. This value gives an indication of cardiac efficiency (ml Oj/heart beat). 9 STATISTICAL ANALYSIS: The nuclear ventriculogram data was treated as a two-factor design with repeated measures on both independent variables; intensity (4 levels) and time (2 levels). The analysis of variance (ANOVA), was performed using BMDP statistical software (UCLA, 1981) with the level of significance set a priori at .05. The C0 2 rebreathing data was missing the sixty percent values for week one, so the data was subsequently analyzed using both a 3 X 2 repeated measures ANOVA (all three time periods X rest and forty percent values) and then 2 X 3 repeated measures ANOVA (week 3 and week 6 periods X all three intensity conditions). The actual calculations were once again performed using BMDP statistical software with the level of significance once again .05. The two test protocols were compared using the BMDP, P:8D missing value correlation program. This program was also used in the C0 2 rebreathing reliability study. 10 RESULTS PHYSICAL CHARACTERISTICS; The subjects all remained in good health throughout the study. The average values for some of the basic physiological data is presented in Table 1 below. The subjects ages ranged from 31 to 37 years. The heights ranged from 155 to 164 centimeters. The average weight increased over the duration of the study, but this change was not significant (P > .05). TABLE 1: SUMMARY OF PHYSIOLOGICAL CHARACTERISTICS (n=6) MEAN +/- S.D AGE (yrs) 34 1.9 HEIGHT (cm) 158.5 3.1 WEIGHT (PRE) (kg) 58.8 5.8 WEIGHT (POST) (kg) 62.8 4.1 V02 MAX (PRE) (1) 3.45 0.5 V02 MAX (MID) (1) 3.21 0.6 V02 MAX (POST) (1) 3.11 0.5 HAEMOGLOBIN (WEEK 1) (g/dl) 15.7 1.1 HAEMOGLOBIN (WEEK 3) (g/dl) 15.3 1.3 HAEMOGLOBIN (WEEK 6) (g/dl) 13.5 1.2 In terms of the haemoglobin values, there was a highly significant change over time (p=.0001). The subjects started at a value classified as high normal (sea-level normal hgb = 14-16 g/dl), and over the six weeks changed to a level considered below normal by sea-level standards. 11 NUCLEAR VENTRICULOGRAM MEASUREMENTS: The Ventriculogram measurements were performed successfully on all levels, for all subjects, except the ninety percent level in the first week, on two subjects. One of these subjects (S4) had an inverted R wave on the ECG, which caused the computer to confuse background noise for heart beats at the ninety percent intensity. This problem lead to an erroneous count of the radioactivity for that level causing the test to be aborted. For the subsequent test on this subject (week 7), the ECG leads were reversed allowing the computer to count properly and complete the level. The other subject (S6) found the condition very difficult and moved his upper body around too much for the camera to get accurate readings. This problem was corrected on the post-test by strapping the subject in more securely, and constantly reminding him to keep still. For the statistical analysis of the ninety percent condition, stroke volume values were estimated for these two subjects for the pre test, based on the mean score on this test, and these subjects deviation from the mean on the post-test. Subject four's values deviated little from the mean on the post-test, so his pre-test volumes were also normal. Subject six on the other hand, deviated immensely from the mean on all of the conditions for both pre- and post-tests. To estimate this subject's values the deviation from the mean was kept constant and his resultant estimated values were notably below the mean. 12 HEART RATE VALUES: Heart rate values at rest are subject to natural variation and due to their nature can not be controlled. With a few exceptions the values did however remain within +/- 5 beats per minute for most subjects. One subject of interest however was subject #2. This subject was the only subject who had a large variation in both test protocols, possibly indicating that the subject was a little more excitable than the others. Though the target heart rate was set for each exercise intensity, from the initial maximum V 0 2 tests, heart rates varied slightly from test to test. Some of this variation was simply due to the fact that the target heart rate was set +/- 5 beats per minute, causing some change from test to test. Another unexpected problem was that directions had to be given to the subjects in Spanish, therefore requiring the use of a translator. The delay in translation was variable and sometimes led to changes in the subjects pedalling cadence and/or speed. During the ventriculograms however, the need for instructions and therefore subsequent translation was minimal and not a problem. This was reflected in a small non significant variation in heart rate from test to test that did not adversely affect calculated cardiac output values (p > .05). 13 NUCLEAR VENTRICULOGRAM DATA: Individual subjects results are found in Table A3 in Appendix F. The group mean values for heart rate, stroke volume, cardiac output, and oxygen delivery are found in Table 2. Table 2A contains the results of the four, 2 X 4 repeated measures ANOVAs performed on this data. TABLE 2: SELECTED PHYSIOLOGICAL VARIABLES FROM THE NUCLEAR-VENTRICULOGRAM DATA*. PRE TEST POST TEST REST 40% 60% 90% REST 40% 60% 90% vo2 (ml) 669 1224 2062 3452 (105) (340) (352) (530) 511 951 1719 3107 (302) (288) (384) (465) HR 55 98 129 170 (bpm) (5.5) (7.5) (13) (17) 58 104 132 174 (7.1) (5.9) (6.8) (7.0) SV 78 93 98 112 (ml) (14) (14) (17) (33) 90 123 119 132 (20) (14) (17) (38) Q 4.2 9.0 12.8 19.1 (1/min) (.48) (.84) (2.4) (5.9) 5.3 12.8 15.7 22.7 (1.6) (1.9) (2.4) (6.4) 0 2 Delivery (ml/min) 88 189 269 401 96 232 284 410 * values are Mean, (S.D.) 14 TABLE 2A: ANOVA RESULTS FOR SELECTED PHYSIOLOGICAL VARIABLES FROM THE NUCLEAR VENTRICULOGRAM DATA. VARIABLE INTENSITY TIME INTENSITY X TIME (df, p) (df, p) (df, p) VO, 3,15 (.000)* 1,5 (.023)* 3,15 (.215) HR 3,15 (.000)* 1,5 (.291) 3,15 (.903) SV 3,15 (.009)* 1,5 (.089) 3,15 (.088) Q 3,15 (.000)* 1,5 (.095) 3,15 (.308) * indicates significant at alpha set at p < .05 Subject six had values that deviated markedly from the mean in several intensities, for both the stroke volume and cardiac output variables. To determine how these deviant scores affected the group mean, repeated measures ANOVAs were performed a second time for these variables, with this subject's data excluded. Results of the selected physiological variables with subject six omitted are tabulated in Table 3 and the ANOVA table for stroke volume and cardiac output in Table 3A. 15 TABLE 3: SELECTED PHYSIOLOGICAL VARIABLES FROM THE NUCLEAR-VENTRICULOGRAM DATA WITH SUBJECT SIX DELETED*. PRE TEST POST TEST REST 40% 60% 90% REST 40% 60% 90% HR 57 98 128 170 56 102 129 172 (bpm) (5.5) (7.4) (11) (17) (6.9) (4.9) (4.3) (6.7) SV 73 91 95 115 91 128 120 140 (ml) (7) (16) (17) (36) (22) (7) (18) (36) Q 4.1 9.0 12.3 19.7 5.4 13.3 15.8 24.3 (l/min) (-33) (.94) (2.4) (6.4) (1.8) (1.5) (2.7) (5.8) * values are Mean, (S.D.) TABLE 3A: ANOVA RESULTS FOR SELECTED PHYSIOLOGICAL VARIABLES OF THE NUCLEAR VENTRICULOGRAM DATA WITH SUBJECT SIX DELETED. VARIABLE INTENSITY TIME INTENSITY X TIME (df, p) (df, p) (df, p) SV 3,12 (.008)* 1,4 (.089) 3,12 (.088) Q 3,12 (.000)* 1,4 (.088) 3,12 (.348) * indicates significant at alpha set at p < .05 The results, with subject six omitted, did not change significantly, and once again only the intensity main effects were found to be statistically significant. 16 CO, REBREATHING MEASUREMENTS: Values were not obtained on any subjects for the sixty percent exercise level during week one, due to experimental error. It was found that the subjects' equilibrium CQ exceeded the maximal scale limits set on the metabolic cart (10% maximum on the Y-axis), resulting in inaccurate plateau curves. The metabolic cart was successfully reconfigured after this testing session, by changing the C0 2 voltage equivalent, and altering the scale to have a maximum of 12% C0 2 on the Y-axis of the cardiac output program. This enabled data to be attained for all of the levels on the subsequent tests. CO, REBREATHING DATA: Individual subjects results are found in Table A3 in Appendix E. The group mean values for heart rate, stroke volume, cardiac output, and oxygen delivery are found in Table 4. Table 4A contains the results of the 3 X 2 repeated measures ANOVA, and Table 4B contains the results of the 2 X 3 repeated measures ANOVA. 17 TABLE 4: SELECTED PHYSIOLOGICAL VARIABLES FROM THE C0 2 REBREATHING DATA*. WEEK ONE WEEK THREE WEEK SIX REST 40% 60% REST 40% 60% REST 40% 60% V02 (ml) 669 (105) 1224 (340) 2062 (352) 647 1079 (189) (221) 1774 (396) 511 951 (302) (288) 1719 (384) HR (bpm) 67 (9) 102 (5) N/A 65 (6) 100 (10) 128 (5) 71 (6) 104 (7) 129 (6) SV (ml) 116 (24) 129 (28) N/A 88 (33) 124 (17) 141 (12) 117 (19) 145 (30) 133 (15) Q (l/min) 7.6 (1) 13.2 (3) N/A 5.7 (2) 12.5 (2) 18.0 (1) 8.1 (1) 14.9 (3) 17.1 (2) o2 Delivery (ml/min) 159 276 N/A 117 256 369 147 270 310 o2 PULSE (ml Oj/bt) 9.99 12.0 N/A 9.90 10.8 13.8 7.20 9.14 13.4 values are Mean, (S.D.) 18 TABLE 4A: 3 X 2 ANOVA RESULTS FOR SELECTED PHYSIOLOGICAL VARIABLES OF THE CO, REBREATHING DATA. VARIABLE INTENSITY TIME INTENSITY (Rest, 40%, 60%) (Week 3, Week 6) X TIME (df, p) (df, p) (df, p) HR 2,16 (.000)* 1,5 (.124) 2,16 (.224) SV 2,16 (.003)* 1,5 (.123) 2,16 (.031)* Q 2,16 (.000)* 1,5 (.042)* 2,16 (.050)* indicates significant at alpha set at p < .05 TABLE 4B: 2 X 3 ANOVA RESULTS FOR SELECTED PHYSIOLOGICAL VARIABLES OF THE C0 2 REBREATHING DATA. VARIABLE INTENSITY TIME INTENSITY (Rest, 40%) (Weeks 1, 3, 6) X TIME (df, p) (df, p) (df, p) HR 2,16 (.000)* 1,5 (.124) 2,16 (.224) SV 2,16 (.006)* 1,5 (.073) 2,16 (.273) Q 2,16 (.000)* 1,5 (.026)* 2,16 (.594) * indicates significant at alpha set at p < .05 19 PROTOCOL COMPARISONS: Due to the difference in exercise heart rates between the C0 2 rebreathing and nuclear ventriculogram protocols, the stroke volume values for each subject, for each intensity, were multiplied by the average heart rate to obtain a standardized cardiac output. TABLE 5: COMPARISON CORRELATIONS; C0 2 REBREATHING vs NUCLEAR VENTRICULOGRAMS. CORRELATION INTENSITY WEEK ONE WEEK SIX % of V 0 2 max REST FORTY% STXTY% 0.75 0.77 N/A -0.35 0.88 0.43 20 DISCUSSION The acclimatization processes that a native lowlander undergoes when ascending to altitude are much more commonly studied than those that the altitude native experiences when descending to sea level. In both cases the adaptive processes involved include both short and long term changes in the respiratory and cardiovascular systems. The changes of interest in the cardiovascular system include cardiodynamic changes such as heart rate, stroke volume, and cardiac output, and haemodynamic changes such as blood volume and haematocrit. HEART RATE RESPONSE ALTITUDE ACCLIMATIZATION: In terms of heart rate changes, the initial response is that of a seemingly inappropriate tachycardia. Acute exposure may lead to heart rates that are up to 50% greater than sea level values during both rest and submaximal exercise conditions (Klausen, 1966; Vogel et al., 1967). Maximal heart rate remains unaltered but occurs at a lower work load. The effects of long term altitude exposure on heart rate are not so clear and seem to be a topic of some debate. Reeves et al. (1967), Paton et al. (1970), and Vogel et al. (1974) found that the tachycardia was maintained for the duration of the stay at altitude. 21 On the other hand, Asmussen and Consolazio (1941), Alexander et al. (1967), and Hartley et al. (1974) have indicated that the initial tachycardia resolved over 7-10 days at altitude. Grover et al. (1985) explained this apparent discrepancy as being due to individual variability. He postulated that some individuals would experience an initial tachycardia that would be maintained during the stay at altitude, others would experience a decrease in this tachycardia over time, and still others would experience an enhanced tachycardia. The group average therefore would be greatly affected by these individual variations and could parallel any of the above patterns. SEA L E V E L ACCLIMATIZATION: A decrease in resting heart rate in high altitude natives after acclimatization to a sea level environment is a common finding. Vogel et al. (1974) documented similar results in that his altitude subjects had a decrease of 10 bpm at sea level as compared to their altitude values. Hartley et al. (1967), Banchero et al. (1970), and Sime et al. (1971) also found a decrease in heart rate after acclimatization to sea level. Of note in these studies is that they all involved a comparison of the sea level value with an altitude value, not a prior sea level value. In the present study altitude values were not available and sea level values were compared to prior sea level values to get an idea of the progression of change over time. Also, the post testing in this study was done one day prior to the departure of the subjects for home, which could mean that the baseline heart rate values were elevated due to excitement and/or anticipation. 22 CURRENT DATA: The resting heart rate for both the nuclear ventriculogram data and the C0 2 rebreathing data demonstrated a slight increase over stay at sea level. The increases were an average of 3 bpm and 4 bpm for the nuclear ventriculogram and C0 2 rebreathing data respectively. Due to the test protocol utilized, with exercise intensity set at a certain target heart rate, comparison of exercise heart rates is of no benefit in this study. STROKE VOLUME AND CARDIAC OUTPUT RESPONSES ALTITUDE ACCLIMATIZATION: In terms of stroke volume, a sharp decrease in value is seen immediately upon ascent to altitude. This decrease is evident during rest (Grover et al., 1976) and both submaximal (Alexander et al., 1967) and maximal work levels (Vogel et al., 1974). The stroke volume continues to decrease during the first week at altitude after which time it appears to stabilize (Klausen, 1966; Stenberg et al., 1966; Alexander et al., 1967; Vogel et al., 1974; Grover et al., 1976; and Alexander et al., 1983). The reason for the decrease in stroke volume is not clearly understood. It was previously believed that the reduction in stroke volume was due to myocardial hypoxia, but Grover et al. (1976) demonstrated this not to be the case. Grover found that the large decrease in coronary blood flow (32%) was largely offset by a large increase in coronary 23 artery oxygen extraction (22%). This increase in extraction occurred in spite of a constant oxygen tension, therefore implying a decreased haemoglobin affinity for oxygen in the coronary tissue. Graver also found a decrease in myocardial lactate extraction and, with the evidence of increased oxygen extraction, theorized that myocardial hypoxia did not occur. That stroke volume decreases with exposure to altitude is not disputed but, unfortunately, an adequate theory to explain this phenomenon has not yet evolved. For cardiac output, an acute rise in volume during rest and submaximal exercise intensities can be attributed to the initial rise in heart rate. Maximal output is not altered but once again is attained at a lower maximal work load. The decrease in stroke volume over the subsequent week, with or without a decrease in the heart rate, leads to a decline in cardiac output to levels below that attained at sea level for all exercise intensities (Graver, 1986). At the end of the first week the values seem to balance and remain stable at the new levels (Graver, 1986). SEA L E V E L ACCLIMATIZATION: Data for sea level acclimatization of altitude natives is scarce. Sime et al. (1971), Banchero et al. (1970), and Hartley et al. (1967) found that cardiac output increased over time while stroke volume decreased. A paper by Vogel (1974), which also demonstrated similar trends, found no significant difference in cardiac output over time, but did find a significant difference in stroke volume. 24 CURRENT DATA: The average trend for stroke volume and cardiac output values was to increase between weeks one and six, for all exercise intensities. These trends were very similar to those reported in the literature but in the present study the differences were not found to be statistically significant for the nuclear ventriculogram protocol. The small subject number in this study (n = 6) affected the power of the study, and as a result, could have had an influence on the significance of the results. Table 6 presents the heart rate, stroke volume and cardiac output values from the literature, standardized to the same units (heart rate, stroke index, cardiac index). The ventriculogram values are well below the values reported by Sime et al. (1971), but very similar to those of Vogel et al. (1974) for high altitude natives and Hartley et al. (1967) for altitude natives of European descent. When doing a comparison of these values from the literature one must keep in mind that in both the Sime et al. and the Hartley et al. papers, exercise was done in the supine position, which would result in higher outputs than the upright position utilized in this study and by Vogel et al.. The exercise position would help explain the difference between our results and those of Sime et al., and the different subject populations could be the factor explaining the difference from the Hartley paper. In terms of absolute value, the cardiac output volumes obtained from these subjects were very similar to those reported in the literature for sea level natives of similar age and fitness level (Pugh, 1964; Alexander et al., 1967; Muiesan et al., 1968; Ferguson et al., 1968; Zeidifard et al., 1972; and Reybrouck et al., 1978). Also the cardiac output response to exercise appeared to be very similar to that of sea level natives (Pugh, 1964; Alexander et al., 1967; Ferguson et al., 1968; and Zeidifard et al., 1972). TABLE 6: 25 CARDIAC OUTPUT VALUES FROM THE LITERATURE HIGH ALTITUDE NATIVES MEASURED AT SEA-LEVEL AUTHOR CONDITION HR SI (ml/bt/m2) QT (Vmin/m2) Sime et al. (1971) (supine) Rest Exercise {300kg} 59 (7) 114 (12.5) 74.2 (12) 77.4 (9.8) 4.32 (0.67) 8.79 (1.05) Vogel et al. (1974) (erect) Rest Exercise {50%} Exercise {70%} Exercise {100%} -59 (5) -99 (8) -130 (9) -180 (4) 69 (8) 70 (5) 66 (5) 60 (5) 3.9 (N/A) 7.0 (N/A) 9.0 (N/A) 10.6 (N/A) Hartley et al. (1967) (@) (supine) Rest Exercise {25w} Exercise {50w} Exercise {75w} Exercise {100w} 62 (8) 80 (10) 96 (12) 113 (17) 136 (21) 51 (18) 56 (12) 57 (14) 57 (16) 56 (17) 3.14 (1.1) 4.43 (.59) 5.45 (.91) 6.29 (.83) 7.40 (1.1) CURRENT DATA: CONDITION HR PRE POST SI PRE POST QT PRE POST Nuclear Ventriculograms (erect) Rest Exer. 40% Exer. 60% Exer. 90% 55 98 129 170 58 104 132 174 49 58 62 61 45 76 73 80 2.64 3.22 5.62 7.86 8.01 6.75 12.92 13.91 CO, REBREATHING (erect) Rest Exer. 40% Exer. 60% 67 71 102 104 N/D 129 72 79 80 89 N/D 82 4.72 8.18 N/D 5.46 9.18 10.50 N.B. All literature numbers given as Mean, (S.D.). @ Indicates subjects of European descent 26 HAEMODYNAMIC CHANGES ALTITUDE ACCLIMATIZATION: Blood volume and haematocrit also show changes during the acclimatization process. During the first week at altitude the haematocrit rises progressively due to a shrinkage in plasma volume, not a change in red cell mass (Jung et al., 1971; Surks et al., 1966). If altitude exposure is maintained over a period of weeks hypoxia stimulates the kidney to produce and secrete erythropoietin. Erythropoietin subsequently stimulates hematopoietic tissue in the bone marrow, leading to increased circulating red blood cells (polycythemia). Plasma volume is also eventually restored causing long term residents at altitude to have a comparatively larger total blood volume as well as an elevated haematocrit (Reynafarje, 1958). SEA L E V E L ACCLIMATIZATION: A decrease in haemoglobin upon exposure to sea level, in altitude natives, has been well documented in the literature (Banchero et al., 1970; Sime et al., 1971; Vogel et al., 1974). The proposed mechanism for this decrease is that upon descent to sea level the red blood cell count decreases (due to lack of hypoxic stimulation of the kidney and hematopoietic tissues), causing a proportionate increase in plasma volume due to the polycythemic hypervolemia found to be present at altitude (Hurtado et al., 1945; Merino, 1950). Over the next three to four months total blood volume decreases and red cell mass continues to decrease, reaching subnormal values (Reynafarje et al., 1959). As in the Banchero et al. (1966), Sime et al. (1971), and Vogel et al. (1974) studies, anemia occurred before the three to four months found by Reynafarje et al. (1959). 27 CURRENT DATA: In this study there was a highly significant decrease in haemoglobin over time at sea level (p = .0001), and some degree of anemia was present in all subjects but one (S2) after the six weeks. There is no proposed explanation for the speed of onset of the anemia in these subjects. Diet was not a explanation as the subjects were able to eat liberally, and every attempt was made to obtain the foods similar to the subjects regular diet. Also, phlebotomy should not have influenced the results as sampling was limited to less than 500 mis per subject over the six week period of the study. V P , DATA Decreases in V 0 2 over time at sea level, in altitude natives, have been reported in other previous studies on this topic (Hartley et al., 1967; Banchero et al., 1970; Sime et al., 1971; and Vogel et al. 1974). The decrease in max V 0 2 is possibly simply due to the decreased oxygen carrying capacity of the blood as a result of the decreased haemoglobin values. This reason is postulated because the decrease was present and essentially the same degree in all exercise intensities, and detraining was ruled out as a cause due to the heavy exercise demands placed on the subjects for other experimental purposes, during the duration of their stay. In addition, power output values did not change over time during the study. 28 OXYGEN DELIVERY The capacity of the heart to deliver oxygen to the tissues is determined by the blood flow (cardiac output) and the ability of the blood to carry oxygen (haemoglobin). As the subjects in this study acclimatized to the sea level environment their haemoglobin, and thus the ability of their blood to carry oxygen, decreased. To maintain a consistent oxygen delivery to the tissues the amount of blood circulated to the tissues per minute had to increase. This is exactly what happened. During the six weeks of the study the oxygen delivery did not change significantly, while the oxygen carrying capacity of the blood did. This would indicate that a receptor or sensor must exist that is sensitive to the amount of oxygen delivered to the tissues. This receptor would appear to have a certain 'set point* and adjusts the cardiac output accordingly. No such receptor has yet been identified. CO, REBREATHING DATA The C0 2 rebreathing values included an intermediate measure rather than simply a pre and post measurement. The pre to post trends in both cardiac output and stroke volume from the C0 2 rebreathing protocol, were similar to the nuclear ventriculogram data and the results previously mentioned from the literature (Hartley et al., 1967; Banchero et al., 1970; Sime et al., 1971; Vogel et al., 1974). The overall trend from the C0 2 rebreathing values was not however, one of a continual, gradual rise in volume. Between weeks one and three, for the rest and forty percent values, volumes actually decreased 29 before attaining an overall increase in week six (overall sixty percent intensity trends are unknown due to experimental error). The decrease and then subsequently greater increase in both stroke volume and cardiac output for these intensities was not mirrored by any similar trend in either haemoglobin or V0 2 . Haemoglobin values demonstrated a highly linear change over time (p = .002), as did V 0 2 (p = .04). The heart rate trend was similar, but not to nearly as great a degree (heart rate changes of ~3 bpm), as the cardiac output or stroke volume trend and thus is probably not the explanation. One possible explanation for this trend is that the second testing period coincided with a time during the red blood cell acclimatization cycle such that the polycythemia had been reduced, but the blood volume may have changed out of proportion to this reduction. If the reduction in haemoglobin occurred to a lesser extent than a theoretical reduction in blood volume, the blood oxygen carrying capacity would be proportionately greater. This would then mean that a lower cardiac output could maintain the same tissue oxygenation at a given work rate. This theory is given support by the fact that haemoglobin values in this study only decreased .42 g/dl between weeks one and three, while they decreased 1.75 g/dl between weeks three and six. This is reflected by the fact that while the change in haemoglobin was significantly linear, it was also significantly quadratic (p = .02), with most of the change occurring between weeks three and six. Unfortunately this explanation can not be confirmed as blood volume data was not obtained in this experiment, and therefore must simply remain as speculation. 30 In terms of absolute values the C0 2 rebreathing cardiac output results were higher than the nuclear ventriculogram values and the literature values of Hartley et al. (1967), Sime et al. (1971), and Vogel et al. (1974). Stroke volume values were very similar to those reported in the literature for the rest condition, but slightly higher than those reported for the exercise conditions (see Table 6). The reasons for the difference in values is not known. As the trends for the different protocols were the same, the difference is probably simply due to the measurement protocol used. A downstream correction factor was used in the C0 2 rebreathing protocol in our study to correct for a theoretical alveolar to blood PC0 2 difference. The use of this correction factor is controversial. Another reason could be that all other studies used a direct measure whereas, CO z rebreathing is indirect. It is possible that some physiological variable was different between the altitude natives and normal individuals that caused the rebreathing values to be systematically high. No validation or reliability study for C0 2 rebreathing could be found using high altitude natives as subjects. 31 NUCLEAR VENTRICULOGRAM AND CO, REBREATHING COMPARISON Although the correlations were relatively high, the C0 2 rebreathing values were systematically higher than the values obtained via the nuclear ventriculogram protocol. Several factors could have influenced these results: 1) the body position was not the same for each protocol. During the ventriculogram measurements the subject is strapped in a chair with a slightly reclined back whereas the position during the rebreathing experiment was a normal cycling position with the upper torso bent forward. 2) the muscle mass involved could have been slightly different. During the ventriculogram protocol the upper body was strapped to the chair and kept still, whereas no restriction was placed on upper body movement during the rebreathing protocol. This difference could have resulted in a larger muscle mass being utilized in the rebreathing protocol causing a subsequently larger cardiac output requirement. 3) neither technique had been validated for subjects of this type (i.e. high altitude natives). Altitude natives may have some slightly different physiological characteristics, which may have had a slight influence on the results of either of these tests. This study was not intended as a validation or comparison study for the two techniques and as such, little effort was put into making the protocol requirements similar. The values, though of different magnitude, reflected similar changes. 32 SUMMARY The changes in cardiac output demonstrated over time in altitude natives, during exposure to sea level, were quite similar but opposite to the changes that a native lowlander experiences during exposure to altitude. 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Vogel J.A., Hartley L.H., Cruz J.C.: Cardiac output during exercise in altitude natives at sea level and high altitude. J Appl Physiol (1974) 36:173-176. Winslow R.M., Samaja M., West J.B.: Red cell function at extreme altitude on Mount Everest. J Appl Physiol (1984) 56:109-116. Zeidifard E., Silverman M., Godfrey S.: Reproducibility of indirect (C02) Fick method for calculation of cardiac output. J Appl Physiol (1972) 33:141-143. Zink R.A., Lobenhoffer H.P. Heimhuber B., Rupp C , Schneider R.: Hemodilution: practical experiences in high altitude expeditions. In: High Altitude  Physiology and Medicine. Ed by W. Brendel and R.A. Zink. New York: Springer-Verlag, 1982. 40 APPENDIX A RELEVANT LITERATURE At altitude, the cardiac output and heart rate response to exercise in altitude natives has been reported to be normal by sea level standards whereas, the outputs of sea-level natives living at altitude even for extended periods of time, are never normal (Balke et al., 1968; Bushkirk, 1971; Faulkner et al., 1971; Heath and Williams, 1981; Houston, 1983; Loeppky and Bynum, 1970; Pugh, 1964). This has been taken to be indicative of a cardiovascular adaptation that takes place over several generations of life at altitude and has been used as the prime evidence for the existence of an adaptive difference between altitude and sea-level man (Harris, 1986; Heath and Williams, 1981; Heath, 1986; McArdle et al., 1986). Further evidence of this "adaptation" is substantiated in several studies where breathing of high concentrations of oxygen at altitude, thus effectively decreasing hypoxia, was shown to not change the cardiac output to the same extent that it changes at sea-level (Hartley et al., 1967; Sime et al., 1966; Sime et al., 1971). How this high altitude adaptation would affect life at sea-level is something very poorly understood. Sime et al., in 1966, found that altitude natives who had lived at sea-level for 2 years had a significant decrease in heart rate, an increase in cardiac output and, as a result, a significant increase in stroke index, in both rest and exercise conditions, as compared to their pre sea-level exposure values. In a subsequent paper by the same author (1971), it was found that the rise in cardiac output was not associated with a rise in oxygen uptake, but with a reduction in haemoglobin, arterial oxygen content, and arterio-venous difference of oxygen. Thus the change in cardiac output was a reflection of a decreased oxygen carrying capacity, rather that an increased oxygen delivery capability. A major limitation 41 of these papers is that there was a two year delay between original altitude testing and subsequent sea-level follow-up. During this two year period the subjects were involved in military training which of course would involve uncontrollable changes in physical activity, lifestyle, and also diet. Also, no information was gained concerning the time course of the changes. Hartley et al. (1967), studying high altitude subjects of European descent from Leadville Colorado (10,200 feet altitude), also observed a slight increase in cardiac output after 10 days of residence at sea-level. Of note in this study is the fact that these subjects did not possess the characteristic high altitude native's adaptations; their cardiac outputs at high altitudes were sub-normal compared to sea-level standards, and they did not possess polycythemia or pulmonary hypertension which are also considered characteristic (our subjects also did not have pulmonary hypertension). The authors used this decreased cardiac output at altitude, and the lack of any corresponding changes in pulmonary vascular resistance, acid-base balance, sympathetic activity, blood volume, or ventricular filling pressure, to indicate that chronic hypoxia could cause a depressant effect on the myocardium, thus resulting in reduced myocardial contractile force and stroke volume. This hypothesis was stated in spite of the fact that the administration of oxygen at altitude did not increase cardiac output significantly, and the fact that this reduction in output is unusual in altitude natives. In a more applicable paper, Vogel et al. (1974) studied the acute effects of exposure to sea-level. In this study eight subjects native to Cerro di Pasco, Peru (elevation 4,350 m), were tested at home, and then re-tested 8-13 days later in Lima (elevation -150 m). They found that at sea-level cardiac output was the same, heart rate decreased, and stroke 42 volume increased in both rest and submaximal exercise conditions, as compared to the values from the same subjects at altitude. During the maximal exercise condition, cardiac output was seen to increase 8%, and maximal oxygen uptake increased 9%, as compared to the maximal exercise altitude values. Though the cardiac output did not change significantly between altitude and sea-level, Vogel found that at altitude a relatively smaller stroke volume was compensated for by a higher heart-rate. This conclusion supported the previously mentioned findings, over a two year period, of Banchero et al. (1966), and Sime et al. (1966 and 1971) and lent some support to Hartley et al.'s (1967) contention of hypoxia induced myocardial limitation. Also of note in the Vogel paper is that concurrent tests were performed on lowland people both at high-altitude and sea-level. Comparing the obtained values of these two populations it was noted that the cardiac output response to exercise, between the two conditions (altitude and sea-level) for the altitude natives were very comparable, but subnormal when compared to sea-level natives measured at sea-level. Stroke volume, on the other hand, was comparable across both populations and conditions (high altitude native at altitude vs sea-level native at sea-level), thus suggesting that the high altitude adaptation in the natives has included a restoration in their stroke volume. The Vogel paper also only looked at pre and post sea-level exposure values leaving unanswered the question of what is the course or events of the processes involved. As can be seen a conclusive, proven answer to the question of what happens to the cardiac output of altitude natives at sea-level has yet to be obtained. The studies previously mentioned had some similar findings but, only showed the absolute changes and lacked information on the trends or time courses of the changes. These studies also all used invasive techniques which themselves could have an effect on the results. 43 APPENDIX B MEASUREMENT OF CARDIAC OUTPUT There are several different ways of measuring cardiac output. The standard method, by which other methods are usually judged, is based on the principle put forth by Fick in 1870. This principle states that the amount of a substance taken up or given off by an organ (or the whole body) per unit of time, is equal to the difference between the arterial and venous levels of the substance, times the blood flow. For example the Fick principle for carbon dioxide is: VC0 2 =(VENOUS - ARTERIAL C0 2 DIFFERENCE) X CARDIAC OUTPUT To determine a value for cardiac output one simply rearranges the equation to read: CARDIAC OUTPUT = VCQ 2 c v c o 2 - c A co 2 (C vC0 2 = Content of carbon dioxide in the venous blood, C a C0 2 = Content of carbon dioxide in the arterial blood). While this equation is very simple in theory, it is much more difficult in practice. The measurement of VC0 2 can be simply obtained by ventilatory gas analysis, but the measures C v C0 2 and CaCo2 are much more complex. These measures can be either obtained directly by invasive techniques (e.g. cardiac catheterization or subclavian vein and arterial catheterization) or indirectly, by various methods such as C0 2 rebreathing. Another method of obtaining cardiac output is the indicator dilution method which involves arterial and venous punctures, but not catheterization. In this method a known quantity of harmless dye, (such as Indocyanine green dye), is injected into a vein. Arterial 44 levels of the indicator are then measured and the average concentration of the indicator (Av[I]) is calculated from the area under the dilution-concentration curve. The cardiac output is then calculated as follows: Cardiac output = Quantity of dye injected Av[I] for duration of curve X duration of curve Early in this century C0 2 rebreathing was the most commonly used technique, but the obtained measures were rather rough estimates due to the equipment available. With the invention of modern catheters and more advanced techniques, these indirect Fick measurements were replaced by the direct Fick and dye-dilution methods. These methods, though accurate, involved catheterization and blood work and thus were time consuming, complicated and uncomfortable. The advent of fast accurate gas analyzers allowed for more precision when using the indirect methods and has thus caused a resurgence in interest in these techniques (Collier, 1956; Jones et al., 1969, 1973, 1982). VALIDITY AND RELIABILITY OF TECHNIQUES There are two main methods of obtaining mixed venous blood values through C0 2 rebreathing; the Defares method later modified by Jernerus et al. (1963), and the Collier method as modified by Jones et al. (Jones et al., 1969, 1973, 1982). The Defares method, otherwise known as the "exponential" method, is based on the principle that the time course of the percent CQ 2, in a closed lung-bag system, can be described by an exponential equation which can then be used to estimate the Venous C0 2 values (Klausen, 1965). The 45 procedure involves breathing from a bag containing little or no C0 2 and plotting the end-tidal PC02's for each breath. A line is then drawn through the points representing the line of identity for that work level and the P v C0 2 is estimated from the values obtained. The Collier method involves breathing from a bag with a very high initial concentration of C0 2 and allowing the bag and the lung C0 2 to equilibrate. The equilibrium C0 2 content is then measured and used as an estimation of P vC0 2. The advantages of the Defares method over the Collier method are that an equilibrium between the bag and the lungs does not have to be reached, therefore it is less uncomfortable at higher levels of exercise, and the fear that the recirculation of the blood might affect estimates does not exist in this method (as some feel it does in the Collier technique) (Clausen, 1970; Muiesan et al., 1968). The problems with this method are that it has proven to be unreliable at rest, and its accuracy is questionable in lower levels of exercise (Ferguson et al., 1968; Reybrouck et al., 1978). The main advantages of the Collier method over the Defares method is that in the Collier method success or failure may be accessed immediately and changes invoked and the procedure repeated in very little time, and the method has proven to be accurate during resting conditions (Franciosa, 1977; Jones et al., 1966, 1973, 1982; Kirby 1985, 1985; Zeidifard et al., 1972). The reliability of both of these methods is well established. In terms of the Collier method at rest, van Herwaarden et al. (1980) found on test-retest reliability, with the tests conducted on different days, that the standard error of observation was 3% which was somewhat higher than the 1.5% found by Godfrey et al. (1972) when the tests were conducted the same day. During exercise van Herwaarden found the variation increased to 4% which is very similar to the 5.7% found by Zeidifard et al. (1972). All of these values 46 compare very favorably to the values obtained for the direct measures obtained by many other authors (Franciosa et al., 1978; Zeidifard et al., 1972). In terms of validity, Franciosa, using the equilibrium method, compared values obtained by C0 2 rebreathing with those of the indicator dilution method in patients with either cardiovascular disease (n=17), hypertension (n=ll), or congestive heart failure (n=6) and found correlations ranging from .89-.95. Muiesan et al. (1968) compared the equilibrium and exponential method with the direct Fick method in both supine and seated rest and found a correlation of .94, though the direct Fick measures were generally higher (Muiesan did not use an alveolar-capillary correction factor, which tends to increase the indirect measured values slightly). These correlations are very high however, as mentioned previously, some authors have found unsatisfactory correlations when using the exponential method at rest which explains why the Collier method was chosen for this study (Ferguson et al., 1968; Reybrouck et al., 1978). For this study a reliability experiment was performed to compare test-retest values on the C0 2 rebreathing protocol. Eight subjects were used, and measurements were performed only in the rest condition. The test-retest correlation was very high (r =.93), and the range of variation was 100 to 400 ml (mean 125 ml). This value converts to a percent variation of 1%. 47 SAMBLE PLATEAU'S AND CALCULATIONS FOR THE COLLIER TECHNIQUE (USING JONES'S MODIFICATIONS) REBREATHING PATTERNS THAT INDICATE INCORRECT METHODS ARE: A CONTINUOUS AND STEEP RISE IN PC02. DUE TO A BAG C0 2 TOO LOW FOR EQUILIBRIUM TO BE OBTAINED 10.0-C02 % T - 1 0 . 0 - . i . 10 20 T i n t S t c onds . i 30 TOO HIGH INITIAL PC0 2. DUE TO BAG VOLUME BEING TOO LARGE, OR INAPPROPRIATE INITIAL C0 2 . EQUILIBRIUM NOT ATTAINED. JO.O-i COZ % T -j - h o.o- 10 Tiftt . i . 20 . i 30 S e c o n d s 48 LP ALL CONDITIONS ARE CORRECT YOU GET: 49 FROM THIS CARDIAC OUTPUT IS CALCULATED: 1) THE FRACTION OF END TIDAL AND EQUILIBRIUM C0 2 ARE CONVERTED TO PRESSURES; PC0 2 = FC0 2 X (Pb-47) 2) THE END TIDAL CO, IS USED TO CALCULATE THE ARTERIAL C0 2 VIA THE EQUATION; P aC0 2 = 5.5 + 0.9PetCO2 - 0.0021Vt 3) THE EQUILIBRIUM C0 2 IS USED TO CALCULATE THE MIXED VENOUS C0 2 , WITH A CORRECTION FACTOR TO ACCOUNT FOR THE DIFFERENCE BETWEEN THE ALVEOLAR AND BLOOD PC02; P vC0 2 = P^CO, - [ 0.24PeqCO2 - 11 ] 4) THE TWO PRESSURES ARE THEN CONVERTED TO A VENOUS ARTERIAL CONTENT DIFFERENCE; C ( v . a )C0 2 = 11.02 (P vC0 2 3 9 6 - P aC0 2 3 9 6) 5) A CORRECTION FACTOR IS THEN APPLIED TO ACCOUNT FOR ABNORMAL HAEMOGLOBIN (ie NOT 15g/dl) C ( v . a )C0 2 (actual) = C ( v . a )C0 2 - [(15-Hb) X 0.15 X (PvC02 - PaC02)] 6) CARDIAC OUTPUT IS THEN CALCULATED; Q = VCO, C ( v a ) C0 2 50 APPENDIX C T A B L E A l : BASIC ANTHROPOMETRIC DATA SUBJECT AGE HT (cm) WT (kg) HGB (g/dl) PRE POST PRE MID POST 51 30 160 59 59 17.1 16.8 14.2 52 35 168 66 68 17.1 17.3 15.8 53 37 161 60 62 14.4 13.9 12.3 54 33 155 55 55 15.7 14.3 12.9 55 34 152 64 65 15.7 14.5 12.7 56 35 163 58 59 14.2 14.9 13.3 * Weight units are to the nearest kg 51 APPENDIX D TABLE A2: V P , DATA SUBJECT V P 2 (ml) REST 40% 60% MAX vo^ SI PRE TEST 750 1220 2170 3600 61 MID TEST 746 1124 1916 3180 54 POST TEST N/A N/A N/A N/A N/A S2 PRE TEST 731 1229 2111 3750 57 MID TEST 286 1487 2538 3997 59 POST TEST 173 959 1759 3176 47 S3 PRE TEST 800 962 1771 3073 51 MID TEST 669 817 1347 2345 38 POST TEST 989 997 1588 2853 46 S4 PRE TEST 602 1862 2654 4100 75 MID TEST 559 1158 1513 2653 48 POST TEST 525 1300 2266 3874 70 S5 PRE TEST 600 1160 2012 3582 56 MID TEST 734 864 1483 3393 52 POST TEST 194 470 1176 3140 48 S6 PRE TEST 533 910 1654 2607 53 MID TEST 889 1024 1846 3669 62 POST TEST 587 821 1514 2456 42 * V02max units are in ml/kg/min 52 APPENDIX E INDIVIDUAL SUBJECT DATA TABLE A3 SUBJECT #1 REST 40% 60% 90% NVHR PRE 56 94 145 182 POST 53 100 134 172 NVSV PRE 77 94 89 107 POST 91 119 103 121 NVQT PRE 4.32 8.85 12.85 19.45 POST 4.83 11.87 13.77 20.73 o2 PRE .989 2.27 2.94 4.45 DELIVERY POST .918 2.26 2.62 3.94 RBHR TEST #1 70 96 N/D TEST #2 67 99 133 TEST #3 65 95 128 RBSV TEST #1 116 123 N/D TEST #2 107 120 129 TEST #3 139 171 139 RBQT TEST #1 8.13 11.76 N/D TEST #2 7.14 11.83 17.12 TEST #3 8.46 16.22 17.82 o2 TEST #1 1.86 2.69 N/D DELIVERY TEST #2 1.61 2.66 3.85 TEST #3 1.61 3.08 t 3.39 NVHR = NUCLEAR VENTRICULOGRAM HEART RATE NVSV = S T R O K E VOLUME (ML) NVQT = C A R D I A C OUTPUT (L) RBHR = CO, REBREATHING HEART RATE RBSV = S T R O K E VOLUME RBQT = C A R D I A C OUTPUT INDIVIDUAL SUBJECT DATA TABLE A3 CONTINUED SUBJECT #2 REST 40% 60% 90% NVHR PRE 48 89 115 166 POST 64 98 128 173 NVSV PRE 76 115 120 175 POST 81 127 141 187 NVQT PRE 3.64 10.19 13.77 29.01 POST 5.21 12.44 18.04 32.27 o. PRE .834 2.33 3.15 6.64 DELIVERY POST 1.10 2.64 3.82 6.84 RBHR TEST #1 63 105 N/D TEST #2 61 108 125 TEST #3 75 109 131 RBSV TEST #1 135 172 N/D TEST #2 133 156 163 TEST #3 143 153 157 RBQT TEST #1 8.50 18.06 N/D TEST #2 8.10 16.84 20.35 TEST #3 10.74 16.62 20.54 0 2 TEST #1 DELIVERY TEST #2 TEST #3 1.95 1.88 2.27 4.14 3.91 3.51 N/D 4.72 4.35 INDIVIDUAL SUBJECT DATA TABLE A3 CONTINUED SUBJECT #3 REST 40% 60% 90% NVHR PRE 56 108 112 140 POST 68 107 135 165 NVSV PRE 72 71 74 79 POST 123 137 135 170 NVQT PRE 4.04 7.70 8.27 ' 11.04 POST 8.38 14.63 18.17 27.98 o2 PRE .780 1.49 1.60 2.13 DELIVERY POST 1.38 2.41 2.99 4.62 RBHR TEST #1 65 102 N/D TEST #2 63 89 121 TEST #3 68 99 121 RBSV TEST #1 123 117 N/D TEST #2 66 113 133 TEST #3 93 121 122 RBQT TEST #1 7.97 11.89 N/D TEST #2 4.15 10.02 16.11 TEST #3 6.30 11.95 14.76 0 2 TEST #1 DELIVERY TEST #2 TEST #3 1.54 .772 1.04 2.30 1.86 1.97 N/D 2.99 2.44 INDIVIDUAL SUBJECT DATA TABLE A3 CONTINUED SUBJECT m REST 40% 60% 90% NVHR PRE 63 101 130 187* POST 59 100 121 186 NVSV PRE 61 85 95 105* POST 63 125 101 119 NVQT PRE 3.82 8.61 12.35 19.72* POST 3.70 12.49 12.25 22.12 o2 PRE .800 1.80 2.59 4.14 DELIVERY POST .644 2.16 2.12 3.83 RBHR TEST #1 77 111 N/D TEST #2 72 116 132 TEST #3 76 113 133 RBSV TEST #1 65 81 N/D TEST #2 44 104 147 TEST #3 103 121 112 RBQT TEST #1 5.04 8.99 N/D TEST #2 3.17 12.08 19.38 TEST #3 7.80 13.65 14.91 o2 TEST #1 1.06 1.89 N/D DELIVERY TEST #2 .610 2.32 3.74 TEST #3 1.35 2.36 2.58 * Indicates estimated data 56 INDIVIDUAL SUBJECT DATA TABLE A3 CONTINUED SUBJECT #5 REST 40% 60% 90% NVHR PRE 56 103 140 180 POST 53 114 140 175 NVSV PRE 79 92 101 107 POST 95 133 121 104 NVQT PRE 4.41 9.49 14.08 19.38 POST 5.02 15.16 16.95 18.14 o2 PRE .93 1.99 2.96 4.07 DELIVERY POST .85 2.58 2.88 3.08 RBHR TEST #1 67 104 N/D TEST #2 70 97 128 TEST #3 77 104 137 RBSV TEST #1 114 137 N/D TEST #2 118 117 131 TEST #3 101 110 128 RBQT TEST #1 7.61 14.27 N/D TEST #2 8.27 11.34 16.71 TEST #3 7.79 11.47 17.52 o2 TEST #1 1.6 2.99 N/D DELIVERY TEST #2 1.6 2.22 3.24 TEST #3 1.3 1.95 2.98 57 INDIVIDUAL SUBJECT DATA TABLE A3 CONTINUED SUBJECT #6 REST 40% 60% 90% NVHR PRE 49 91 134 67* POST 50 102 136 170 NVSV PRE 102 99 114 96* POST 87 99 112 89 NVQT PRE 5.00 9.04 15.25 16.13* POST 4.35 10.05 15.25 15.13 o2 PRE 1.06 1.92 2.23 3.42 DELIVERY POST .770 1.79 2.71 2.69 RBHR TEST #1 58 96 N/D TEST #2 55 93 131 TEST #3 63 102 122 RBSV TEST #1 140 145 N/D TEST #2 61 136 140 TEST #3 121 194 141 RBQT TEST #1 8.14 13.96 N/D TEST #2 3.33 12.68 18.32 TEST #3 7.65 19.74 17.23 o2 TEST #1 1.73 2.96 N/D DELIVERY TEST #2 .660 2.54 3.66 TEST #3 1.36 3.51 3.07 * Indicates estimated data 

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