uisirions and Aaquiaitions et raphii Services senrices bibliographiques

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ABSTRACT lncomplete recruiûnent of pulmonary capillaries could shorten right-to-left

ventricular red eell pulmonary transit üme (PTT) and explain exercise-induced arterial

hypoxemia (EIAH). Volume expansion cciutd dilate andior remit pulmonary capiflaries,

lengthen P T and improve gas exchange (reduce EIAH). The p u m e of this study

was to determine whether acute volume expansion using pentastarch hanged EIAH

and PTT during severe exercise. Twelve male endurance athletes (VO- = 69.6 i 7.4

ml . kg-' . min-'; weight = 74.8 k 8.0 kg; height = 180.6 i 7.0 cm) perfonned 6.5 minutes

constant, near-maximal cycling exercise (-92% Y 0 2 m d on fWa different days. Seven

subjects were classifieci as having ElAH [minimal arterial Pt& (PaOa) during exercise <

90 mm Hg ancilor alveolar-arterial oxygen pressure difference (AaD02) dunng the last

2.5 minutes of exercise > 25 mm Hg]. Pentastarch [(500 rnL, IO%), Infusion condition,

II or placebo [(60 mL nomal saline), non-infusion condition, NI were infused prior to

exercise in a randomized, double-blind fashion. Arterial blood gases, pulmonary transit

time, muitigatd acquisition technique (MUGA)derived cardiac output (QI, and oxygen

consumption (w2) were measured dunng exercise. Pentastarch increased plasma

volume significantly (+460 I 422 ml; P = 0.002; n = 12). PTT was measured during the

third minute of exercise by first-pass radionuclide cardiography using centroid and

deconvolution analysis, h i l e cardiac output (Q) was measured via a cwnt-basd ratio

method from MUGA technique. Pa02 (N = 89.5 I 9.0; 1 = 90.7 I 7.7 mm Hg), AaD02 (N

= 21.8 k 6.1; I = 22.7 I 6.8 mm Hg), and arterial oxyhemoglobin saturation [(%Sa&), N

= 93.9 2.4; I = 93.8 i 1.6%] at minute three of exercise did not d i i r between

conditions (P > 0.05; n = 12). PTT minute three of exercise was significantly greater in

the infusion than non-infusion conditions [l = 2.75 -I 0.32 seconds; N = 2.45 * 0.21

iii seconds (P = 0.002)]. Pulmonary blood volume was also greater in the infusion than

non-infusion conditions 11 = 1.35 I 0.21 : N = 1.22 k 0.1 3 liters (P = 0.01 511. \io2 (N =

4.56 * 0.54; I = 4.57 I 0.56 L min-') and Q (N = 30.6 f 4.2; 1 = 30.2 r 3.9 L . min-') did

not difFer between conditions. PTT at minute three of exercise was not correlated with

PaOz, AaD02, or %SaO2 in subjects with or without EIAH. However, PTf was

wrrelated with cardiac index (? = 0.22, P = 0.03) and pre-exercising white blood ceIl

wunt in the circulating pool (? = 0.31; P = 0.009) when wmbining data fmm both non-

infusion and infusion conditions. We conclude that volume expansion does not change

EIAH despite increasing PTT, and suggest that PTT (and thus pehaps pulmonary

capillary transit time) is not a significant mechanism of EIAH. These results also provide

evidence against a morphological limit in pulmonary capillary biood volume capacity

during severe exercise.

APPENDIX F . FlRST PASS M W DATA AND GAMMA VARIATE FIT FOR ............................... CALCULATION OF RED CELL PULMONARY TRANSIT TlME 1i2

APPENDIX G . ANALYSIS OF DATA ................................................................... 124 .................................................................................. . APPENDIX H REFERENCES 136

LIST OF TABLES

Table 1: Subject characteristics and resting pulmonary function (n = 12). ................... 22

fable 2: Classification of subjects with excessive AaD02 (> 25 mm Hg) andlor low Paon (< 90 mm Hg) during the 6.5 minutes, constant-load, severe cycling exercise

..................................................................................... in the non-infusion session 23

Table 3: Comparison of method and condition on assessment of red cell pulmonary transit times during minute 3 of the 6.5 minutes constant-load, severe cycling

........................ exercise, [n = 91; * P = 0.002 compared to non-infusion condition. 24

Table 4: Mean metabolic, arterial blood-gas (ABG), blood volume, and cardiac output data at minute 3 of intense cycling exercise (n = 12 except for P T and PBV where - t n-9). Pc0.05 .................................................................................................... 25

Table 5: Mean metabolic, arterial blood-gas (ABG), blood volume, and cardiac output data at minute 3 of intense cycling exercise in athletes with EIAH (minimal Pa02 < 90 mm Hg). [n = 7 except for P T and PBV where n = 61. * P < 0.05. ................... 26

Table 6: Comparison of mean pulmonary transit times during exercise. Also mesponding Q, HR. VO-, PBV. and Vc values from the literature. N = non- infusion condition; I = Infusion condition; BT = before training; AT = after training. 27

Table 7: Published studies that record changes in PaO2. AaD02. and %SaO2 within the first minute of constant-load, moderate to severe sea level exercise (65 - 97%

P c 0.05 campared to cycling; A = change. ......................................... 51

Table 8: Past definitions of EIAH ................................................................................... 53

Table 9: General subject characteristics and resting pulmonary function for each subject .................................................................................................................... 77

Table 10: Plasma volume changes between non-infusion and infusion sessions. ........ 78

Table 11: Ratings of perceived exertion for the ~0~~~ test. and both 6.5 minutes .............................................. exercise tests (non-infusion and infusion sessions). 79

.......................................................... Table 12: Repeated measures ANOVA for 8 0

... Table 13: PaiNvise multiple mparison procedures for \& (Bonferroni's method) 80

Table 14: Repeated measures ANOVA for VE. ............................................................ 81

....... Table 15: Pairwise multiple corn parison procedures for VE (Bonferroni's method) 81

vii Table 16: Repeated measures ANOVA for heart rate. ............................................. 82

Table 17: Pairwise multiple comparison procedures for heart rate (Bonferroni's method). .......................................................................... . ................................ ...... .............. 82

Table 18: Repeated measures ANOVA for %Sa02. .......... ....... ... .... . .. . . . . . . . . . . . . . .. . . . ... 83

Table 19: Pairwise multiple comparison procedures for %Sa02 (Bonferroni's mettiod).83

Table 20: Repeated measures ANOVA for Pa02 corrected to esophageal temperature. . ..................................................................................... . ............... 8 4

Table 21: Painnise multiple comparison procedures for Pa02 corrected to esophageal temperature (Bonferroni's method). ........................... ..... . ..........................*... .... .... 84

Table 22: Repeated measures ANOVA for AaD02 corrected to esophageal temperature. ....... . . . . .. ..... ... ..........,..... . . ... ...... . . . . . ........ . . . . . . 8 5

Table 23: Pairwise multiple comparison procedures for AaD02 corrected to esophageal temperature (Bonferroni's method). ................................................................. 85

Table 24: Repeated measures ANOVA for PaC02 corrected to esophageal temperature. ....................................................................................................... 86

Table 25: Pairwise multiple comparison procedures for PaC02 corrected to esophageal temperature (Bonferroni's method). ............................................................... ........ 86

Table 26: Repeated measures ANOVA for pH corrected to esophageal temperature. .87

Table 27: Pairwise multiple comparison procedures for pH corrected to esophageal temperature (Bonferroni's method). ................................................................... 87

Table 28: Repeated measures ANOVA for standard base excess ( S E ) corrected to esophageal temperature. ................................................................................... 88

Table 29: Paiwise multiple comparison procedures for standard base excess ( S E ) corrected to esophageal temperature (Bonferroni's method). ................................ 88

Table 30: Repeated measures ANOVA for bicarbonate (HCOj) corrected to esophageal temperature ....... .............................................. . ... ..... .. .-. ...- ... ............................. ..... 89

fable 31 : PaiMlise multiple comparison procedures for bicarbonate (HCO;) corrected to esophageal temperature (Bonferroni's method). ........................... ......................... 89

Table 32: Repeated measures ANOVA for esophageal temperature ............................ 90

Table 33: PairWise multiple comparison procedures for esophageal temperature (Bonfamni's method) ......................................................................................... 90

viii Table 34: Repeated measures ANOVA for Alveolar PO2. ............................................ 91

Table 35: Pairwise multiple comparison procedures for alveolar PO2 (Bonferroni's method). ......... ......................... ...,., ...... ...... ...... ............. ....... . . .. . . . . . 91

Table 36: Repeated measures ANOVA for PS. ..... ............... ........ ............ ......... . 9 2

Table 37: Pairwise multiple comparison procedures for PS0 (Bonferroni's method) ....... 92

Table 38: Repeated measures ANOVA for mean pulmonary transit times at 3rd minute of exercise during the 6.5 minute exercise tests. ................................................... 93

Table 39: Repeated measures ANOVA for distribution of pulmonary transit times at 3rd minute of exercise during the 6.5 minutes exercise tests ....................................... 93

Table 40: Pairwise multiple comparison procedures for distribution of pulmonary transit times at 3rd minute of exercise during the 6.5 minute exercise tests. .................... 93

Table 41: One way ANOVA for day-ta-day variability [intraobserver error] in assessing mean pulmonary transit times at 3rd minute of exercise during the 6.5 minutes exercise tests. ..................... ,., ............... ................................. ........ ........... 94

Table 42: One way ANOVA for day-to-day variability [intraobserver error] in assessing ejection fraction at 3rd minute of exercise during the 6.5 minutes exercise tests ... 94

Table 43: One way ANOVA for day-to-day variability [intraobserver error] in assessing mean end diastolic volume at 3rd minute of exercise during the 6.5 minutes exercise tests. ....................................................................................................... 94

Table 44: One way ANOVA for ratings of perceived exertion (RPE) beîween al1 three exercise sessions ................................................................................................ 94

Table 45: Summary of F values from the repeated measures ANOVA tables ............... 95

Table 46: MV raw data for both 6.5 minutes exercise tests. PaOz, PaC02, pH corrected to esophageal temperature. ........................... .. ............................................ 96

Table 47: JB raw data for both 6.5 minutes exercise tests. PaO2, PaC02, pH corrected to esophageal temperature. ............................................................................. 97

Table 48: ME raw data for both 6.5 minutes exercise tests. Paon, PaC02, pH corrected to esophageal temperature. ........................................................................... 98

Table 49: NC raw data for both 6.5 minutes exercise tests. Pa02, PaC02, pH corrected to esophageal temperature. ................................................................................... 99

Table 50: PC raw data for both 6.5 minutes exercise tests. Pa02, PaC02, pH corrected to esophageal temperature. .................... ... .................................................... 100

ix Table 51: LL raw data for both 6.5 minutes exercise tests. Paon, PaC02, pH cortected

.............................................................................. to esophageal temperature. 101

Table 52: BW raw data for both 6.5 minutes exercise tests. Pa02, PaC02, pH corrected ................................................................................ to esophageal temperature. 102

Table 53: AC raw data for both 6.5 minutes exercise tests. Pa02, PaC02, pH corrected ................................................................................. to esophageal temperature. 1 03

Table 54: SP raw data for both 6.5 minutes exercise tests. Paon, PaC02, pH corrected to esophageal temperature. ............................................................................... 104

Table 55: SS raw data for both 6.5 minutes exercise tests. PaOa, PaC02, pH corrected .......................................................................... to esophageal temperature. 1 0 5

Table 56: AF raw data for both 6.5 minutes exercise tests. Pa02, PaC02, pH corrected to esophageal temperature. ................................................................................. 106

Table 57: PG raw data for both 6.5 minutes exercise tests. Paon, PaC02, pH corrected ................................................................................. to esophageal temperature. 1 07

Table 58: Carâiac funcüon data obtained at minute 3 of severe exercise. Non-infusion ............................................................................................................... session. 1 08

Table 59: Cardiac function data obtained at minute 3 of severe exercise. Infusion ................................................................................................................ session. 109

Table 60: Red cell pulmonary transit times dunng minute 3 of constant-load, severe ........................................................ exercise: Comparing method and condition. 110

Table 61: Distribution descriptors of each subject's PTT transport function during minute ...................................................................... 3 of constant-load, severe exercise 11 1

LIST OF FIGURES

Figure 1: Mean transport functions created by deconvolution analysis companng distribution of PTT between non-infusion (N) and infusion (1) conditions. Mean PTT increased by 0.30 seconds (P = 0.002) behnreen the two conditions ...................... 28

Figure 2: Distribution of red cell pulmonary transit times during minute 3 of intense, constant-load exercise with (1) or without (N) volume infusion (n = 9). ' P = 0.02 between N and I within a g iven time interval. ...................................................... 29

Figure 3: Arterial PO2 (Pa02) and alveolar-oxygen difference (AaD02) during the 6.5 minutes severe, constant-load exerdse test for non-infusion (N) and infusion (1) conditions. different from minute O (corrected values only); * different from minute 1 (corrected values only; " different from minute 1 (corrected values only) [n = 121. Pa02 and &DO2 were temperature corrected at each time point by using

......... .................................... esophageal temperature at each time point. ..., 30

Figure 4: Arterial oxyhemogiobin saturation (%Saoz), arterial PC02 (PaC02), and esophageal temperature during the 6.5 minutes severe, constant-load exercise test for non-infusion (N) and infusion (1) conditions. a = difïerent from minute O; b = different from minute O to 1; c = different frorn minute O to 2; d = different from minute O to 3; e = different from minute O to 4 [values which are corrected to to temperature changes only; P c 0.051. # = main effect present between conditions. - ............................................................................................................ (n - 12) 3 1

Figure 5: Individual responses for Paon and &DO2 during the 6.5 minutes severe, constant-load exercise test collapsed across condition (n = 12). All values corrected to esophageal temperature. .................................................................................. 32

Figure 6: Minute ventilation, oxygen consumption, and heart rate during the 6.5 minutes severe, constant-load exercise test for non-infusion (N) and infusion (1) conditions. a = diierent fiom minute O; b = dihrent fmm minute O to 1; c = different from minute O to 2; d = dfirent from minute O to 3; [values which are corrected to temperature changes only; P < 0.051. ## = main effect present between conditions.

.....................................*.............*.........................-.....-.--...-..-.........-.--.---- -33

Figure 7: Arterial pH, bicarbonate (HCOj), and standard base excess (SBE) during the 6.5 minutes severe, constant-load exercise test for non-infusion (N) and infusion (1) conditions. a = different from minute 0; b = different from minute O to 1 ; c = different fiom minute O to 2; d = differentftom minute O to 3; e = different from minute O to 4 [values which are corrected tc temperature changes only; P < 0.051. ## = main efkct present between conditions. (n = 12). ......................................................... 34

Figure 8: Correlation between the change in AaDQ and the change in PTT with infusion at minute 3 of exercise in subjects with minimal Pa02 < 85 mm Hg and excessive gas exchange impairment (AaDa > 25mm Hg; n = 6) ......................... 35

xii Figure 24: Correlation between PaOz, AaD02, and %Sa02 versus pulmonary transit

time in both infusion and non-infusion conditions ........................................... 127

Figure 25: Correlation between %Sm2 and AaD02 versus Pa02, and %Sa02 versus AaD02 during minute 3 of constant-ioad, severe exercise in both non-infusion and . infusion condihons .............. ....., ........................................................................... 128

Figure 26: Comlation between Pa02, PaC02 venus VE 1- during minute 3 of ...... constant-load, severe exercise in both non-infusion and infusion conditions. 129

Figure 27: Correlation between alveolar PO2 (PAOZ) versus arterial PO2 (Paon), and between pulrnonary blood volume versus oxygen uptake and between during minute 3 of constant-load, severe exercise in both non-infusion and infusion . . conditions. .......................................................................................................... 130

Figure 28: Correlation behnreen arterial PO2 (Pa02) and arterial PC02 (PaC02) during minute 3 of constant-load, severe exercise in both non-infusion and infusion . . conditions. ............................................................................................................ 131

Figure 29: (A) Correlation between the change in arterial PC02 (APaCo2) and the change in arterial PO2 (APaOz) behiireen minute O and minute 1 of constant-load, severe exercise in both non-infusion and infusion conditions; (8) Correlation between red ceIl pulmonary transit time and pre-exercising circulating pool of white blood cells (WBC) in both infusion and non-infusion conditions. .......................... 132

Figure 30: Relationship behnreen pulmonary transit time (PTT) and cardiac index from the literature (means based on 152 diierent subjects from 13 different studies). The relationship obeys a single, 3 parameter exponential decay function. Shape of curve resembles that of Dempsey and Fregosi (46) and Warren et al. (213). No plateau in Vc is observeci as PlT fails to decrease in the face of increasing Q index. ............................................................................................................................. 133

Figure 31: Pooled data on the relationship between pulmonary transit time (PTT), pulmonary blood volume (PBV). and ardjac output (Q) h m 5 dikrent studies, including the present study. ................................................................................. 134

ACKNOWLEDGEMENTS

Since arriving at University of British Columbia in 1997, 1 pursued the idea of

doing my thesis research on ElAH and red cell pulmonary transit time via acute volume

expansion. However, I did not know how much preparation, collaboration, and funding

was needed to pursue this topic. Nevertheless, in the past fifteen months, good luck

sprung upon me and I managed to do this researdi. I would like to take this opportunity

to thank everyone who helped in the data collection, preparation, and editing of this

thesis. First, and foremost, I am deeply indebted to Dr. James Russell, my Ph.D.

supervisor, who decided to take me on as his student when I was in a difficult situation.

This project could not have been completed without his support, enthusiasm, and

valued suggestions. Second, I would like to thank Dr. George Sexsmith, (Nuclear

Medicine) who gave enthusiastic help in evaluating MUGA and first-pass cardiography

data of my subjects, and for reviewing my work. 1 also would like to show my

appreciation to Dr. Keith Walley (Critical Care Medicine) who provided me with

countless proofreading and suggestions. Furtherrnore, I would like to thank Dr. Don

McKenzie (Family Practice and Human Kinetics) who gave helpful advice on several

occasions, reviewing and critiquing several pieces of rny work. As well, I must give

sincere gratitude to the ICU research nurses Vince Dunlop and Tara Lehman, who were

by my side at almost every instance collecting the blood samples, and arranging the

randomized double-blind proœdure for this research. I would also like to thank Dr.

Garth Hunte, who helped me with arterial catheterization, proofreading several pieces of

my work, and just being my friend. Moreover, I would like to thank Dr. Norman Wong,

Director of Experimental Medicine, who allowed me to transfer into the department. I

would also like to thank al1 the staff of the Nudear Medicine Department at St. Paul's

xiv Hospital, who helped me with the cardiac imaging and bloodlplasma volume analysis.

Indeed, I am very grateful to Clive Gtover, Niklas Roëber, Dr. Sorel Bosan, and Dr.

Anna Celler who helped me with the mathematical software for calculating transit times

via centroid and deconvolution analysis, and calculating cardiac output via the manual

count-based ratio method. I would also iike to thank Erin Digitale for believing in me,

and Damn Warburton for helping me manage my references using €ndnoteQ software.

Last, but certainly not least, I would like to thank my father who has supporteci my

decision to continue through the ranks of academia.

CHAPTER 1. GENERAL INTRODUCTlON

In the past twenty years, evidence has been accumulating to suggest that the

lung can limit maximal oxygen consumption (\&,,,) and exercise performance (45,46,

215)- Respiratory limitations to exercise in healthy individuals, therefore, are of interest

to exercise physiologists. Published reviews that discuss the mechanisms of the

limitations of the respiratory system to maintain adequate oxygenation (93, 156)

suggest that rapid red cell velocity through the pulmonary capillary bed during exercise

may contribute to this limitation. This relationship has recently been given attention in a

featured review (185). This doctoral dissertation examines the relationship between

mean whole Iung red cell transit times (as a reflection of mean pulmonary capillary

transit times) and respiratory limitations to exercise as reflected by pulmonary gas

exchange variables. First, these topics are briefly introduced along with the general

hypotheses and specific aims of this intricate research experiment. Then, the details of

the experiment are described in the following chapter, followed by a general summary

and concluding chapter. Appendices are attached at the end of this dissertation.

1.1 EXERCISE-INDUCED ARTERIAL HYPOXEMIA

Sea level arterial oxyhemoglobin saturation (%Saoz) and arterial partial pressure

of oxygen (Pa04 are maintained during intense exercise in untrained and moderately

trained males (8, 52, 118, 220, 222). However, in approximately 50 - 60% of high

aerobic capacity athletes (Yoma 2 65 mL kg-' . min" or S L - min-') (23. 153). the Iung

is unable to fully oxygenate returning venous blood during exercise at near maximal (47,

118, 128) and maximal intensities (87, 145, 173, 222). Reœntly, it has also been

shown that %Saon (166) and PaOz (91) can drop significantiy in some individuals at

submaximal intensities (40 - 65% V O ~ ~ ) , and exercise-induced arterial hypoxemia

2 (EIAH), defined by %Sa@ s 91 % andIor Pa02 < 75 mm Hg, ensues (47, 1 18, 153,

155). Thus, when EIAH occurs, oxygen delivery (DO2) is diminished due to reduced

arterial oxygen content (Ca02), and maaw theoretically decreases. lndependent of

the exercise protocol (1 16), but not the mode of exercise (58, 167), arterial oxygen

saturation has been inversely related to V O ~ = (r = -0.49, - 0.71, and -0.77) (79, 143,

222). These correlative data demonstrate that individuals with higher i(02max values

have lower %SaO2 dunng intense exercise. In fact, a redudion in %Sa02 from 98% at

rest to 93% during severe exercise is suffÏcient to cause a measurable change in

maximal aerobic power and approximates a 1-2% decrement in mm, for each 1%

decrement in %SaO2 (78, 154). Thus, not only can EIAH affect maaxl but it can

impair exercise performance (as evaluated by total work output in kilojoules) lineariy

with %Sa02 reductions of > 6% from rest (1 IO). Moreover, it has been shown that

athletes who have displayed ElAH in normoxia have greater decreases in in

hypoxia compared to normoxemic athletes (33).

Mechanisms explaining EIAH include relative hypoventilation, venoarterial shunt,

ventilation-perfusion ( v ~ Q ) inequality, and pulmonary diffision limitation. Of the four

mechanisms, venoarterial shunts (47, 155) and relative hypoventilation (1 55, 156) have

been shown to play minor roleo in the development of EIAH, while VJQ inequality and

diffision limitation are main contributors of ElAH in dite male athletes (70, 91, 94, 156)

since each may account for about 50 - 60% of the increased alveolar-arterial oxygen

pressure difference (AaD02) during heavy exercise. In fact, a mathematical analysis

revealed that a combination of hlh inequality and diffusion Iimitation may lead to

greater decreases in Pa02 than the simple addition of their individual influences (201).

3 Hence, individuals who exhibit both mechanisms of ElAH could be seriously

performance limited.

Rapid pulmonary capillary transit times may also cause diffision limitation in very

fit individuals (45,46). High cardiac outputs achieved by elite endurance athletes dunng

strenuous exercise preclude red blood cells ffom reaching complete oxygen partial

pressure equilibriurn, which then predisposes the athlete to EIAH, This is discussed

below in more detail.

1.2 REDUCTION IN RED CELL TRANSIT TIMES

The average transit time of red cells in human pulrnonary capillaries is obtained

by the ratio of pulmonary capillary blood volume (Vc) to cardiac output (Q) and is about

0.75 seconds at rest (75 mUlOO m~~sec-') (106). Under normal conditions [e.g. mixed

venous PO2 = 40 mm Hg], partial pressure equilibrium of oxygen in a pulmonary

capillary is reached afler about 0.25 seconds (171, 202), or one-third along an average

capillary distance. If the complete 0.75 seconds normally available at rest were

required for partial pressure equilibrium, a large AaD02 during moderate exercise would

appear and. depending particularly on the Q. Vc. and ~ 0 2 . ElAH could develop (202).

Of the vast body of literature developing in the area of EIAH, the aspect of

diffision limitation consequent to increased red blood cell velocity through the

pulmonary capillaries is a possible, yet unstudied mechanism of ElAH in humans. The

theoretical scheme of rapid red blood cell velocity through the pulmonary capillaries as

a mechanism of ElAH is discussed eloquentîy by Dempsey and Fregosi (46) and again

in a later paper (45). They report that Q and Vc increase linearly up to 25 L min-' and

210 mL, respectively, thereby maintaining a sufiiciently long transit time to ensure

alveolar-end capillary equilibrium. As Q increases above -25 L min" in the

4 endurance-îrained individual, Vc achieves maximum dimensions and transit times fall

abruptly. They also suggest that the distribution of transit times around the mean may

result in even more reduced times in some parts of the lung 1.e. the more dependent

regions], and these transit times may be reduced even further, as capillary flow is not

unifom but pulsatile (93, 202).

However, there has b e n controversy over whether diffusing capacity of the lung

(DL), and therefore Vc, reaches an upper limit at submaximal or near-maximal

workloads (107). It even has been proposed that human pulmonary capillaries are

already 80% perfused at rest (121), so even minimal exercise would hilly recruit them.

Since DL is made up of two components arranged in series, that due to the diffusion

process itself [Membrane resistance (DM)], and that attributable to the time taken for

oxygen to react with hemoglobin [red cell resistance (WC)] (172), a morphological limit

in Vc reached during exercise will shorten transit times and reduce DL. VVhile there is

microscopic, morphometric, and physiological evidence to support Dempsey and

Fregosi's theory that Vc is maximally recniited during various exercise intensities (12,

109, 160, 184), other data on dogs (foxhounds) (97, 98, 107, 2241, and humans (100,

163, 213, 224), show DL (and therefore, Vc) does not plateau at severe exercise

intensities. As such, controversy remains on this topic.

1.3 STATEMENT OF THE PROBLEM

While red cell pulmonary capillary transit times cannot be measured directly in

healthy exercising humans, first-pass radionuclide cardiography can allow direct

measurement of right-to-left ventricular red cell pulmonary transit times (PTT) dun'ng

exercise. Previous research done in Our lab shows that PTT can be associateci with

gas exchange impairment during severe exercise, as signifiant carrelations were

observed benNeen Pa&, AaDOz, and PTT (r = 0.65, PaOz; r = -0.59, AaD02; P <

5 0.05)(88,90). As such, volume loading may alter pulmonary gas exchange by changing

PTT. An increase in blood volume by elevation in venous pressure (constant flow or

pressure) may increase transit time in the entire vasculature and perhaps in the

capillaries (67), whereas an increase in flow rate greater than an associated increase in

pulmonary blood volume diminishes transit time (67). If Vc is not at a morphological

limit during severe exercise, then plasma volume expansion should lengthen PTT due

to increased pulmonary capillary dilatationlrecruitment. As such, a prolonged PTT may

reduce the gas exchange impairment in elite exercising athletes with EIAH. On the

other hand, If Vc is at morphological limit during severe exercise, plasma volume

expansion should then reduce (shorten) PTT, and worsen pulmonary gas exchange in

athletes with EIAH. This thesis intends to further examine the relationship between

pulmonary gas exchange and PTT, and examines the issue of whether Vc reaches

maximal dimensions during severe exercise in endurance-trained athletes with high

aerobic capabilities.

1 A HYPOTHESES

The purpose of this study was to detemine the relationship between red cell PTT

and EIAH. Specifically, the hypotheses tested were:

1, Volume infusion improves gas exchange and prevents EIAH during severe exercise

in elite endurance athletes.

2. Volume infusion lengthens right-to-left ventncular red cell pulmonary transit time

during severe exercise in elite endurance athletes.

3. Pulmonary blood volume does not reach a limit at near-maximal exercise so that in

this setting, volume infusion increases pulmonary blood volume.

1.5 SPECIFIC AIMS

The hypotheses were tested by addressing these specific aims:

6 1. TO determine whether volume infusion alters pulmonary gas exchange during severe

exmise and whether volume infusion attenuates ElAH in elite endurances athletes.

2. To determine whether volume infusion lengthens right-to-left ventricular red celf

pulmonary transit time during severe exercise in elite endurance athletes.

3- To determine whether volume infusion increases pulmonary blood volume at near-

maximal exercise.

1.6 STATISTICS

In order to assess our hypotheses, Sigmastat 1.0 statistical software (Jandel

Scientific, CA) was used to estimate required sample size. In order to address the first

hypothesis, it was calculated that 12 subjects would be required for statistical ANOVA

power to be at 0.8 and alpha = 0.05. Group mean changes in arterial POn (Pa02) and

alveolar-arterial oxygen difference (AaDOz) between non-infusion and infusion

conditions was estimated to be -5 mm Hg (standard deviati~n of residuals = 4 mm Hg).

For the second hypothesis, it was calculated that 12 subjects would be required for

statistical paired t-test power to be 0.8 and alpha = 0.05. Group mean changes in right-

to-left red cell ventricular pulmonary transit time (PTT) was estimated at -0.33 seconds

between non-infusion and infusion conditions with an expected standard deviation of

change of 0.35 seconds. For the third hypothesis, it was calculated that 11 subjects

would be required for statistical paired t-test power to be 0.8 and alpha = 0.05. Group

mean changes in pulmonary blood volume was estimated at -165 mL between non-

infusion and infusion conditions with an expected standard deviation of change of 175

mL. Nonetheless, 12 subjects were used to address al1 three hypotheses.

CHAPTER 2. EIAH AND ACUTE HYPERVOLEMIA 2.1 INTRODUCTION

During heavy exercise, ventilation-perfusion (WQ) inequality and dimion

limitation are the main mechanisms of exercise-induced arterial hypoxemia [(EIAH)

arterial oxyhemoglobin saturation (%Sa02) s 91% andlor arterial POz (Pa02) < 90 mm

Hg] in endurance athletes with high aerobic capacities (w- 2 65 ml . kg-' . min-' or 5

L - min-') (70, 91, 94, 156). Both WQ inequality and diffusion limitation may aecornt

for about 50 - 60% of the increased alveolar-arterial oxygen pressure differenœ

(AaD02) in severe exercise. Diffusion limitation caused by rapid red cell velocity though

the lung may also partially explain EIAH (45, 46). lncomplete dilation andlor recruitment

of pulmonary capillaries could shorten red cell pulmonary transit time (PTT) and this

could partially explain EIAH. Previous studies of acute volume expansion prior to

exercise in elite athletes have found that Y 0 2 m a remains unaltered despite augmented

cardiac output (h) and stroke volume (SV) (108, 138, 211). However, none of these

previous studies have determined the effect of acute volume expansion on P ï l and

EIAH. Therefore, the first hypothesis was that acute volume expansion dilates andlor

recruits more pulmonary capillaries, lengthens PTT and prevents EIAH.

During exercise, if a morphological limit in pulmonary capillary blood volume (Vc)

is reached prior to reaching maximum cardiac output, pulmonary capillary transit times

could fall below the 0.25 seconds necessary for diffusion of oxygen, thereby limiting

oxygenation (93, 156, 185,202). Transit time is equal to volume (ml) divided by flow (ml

. sec-'), and thus any inuease in flow without a concomitant increase in volume will

shorten transit times (sec). While Vc does not plateau at severe exercise in some

studies (100, 213), Vc may plateau in athletes with cardiac outputs of > 25 1 min-' (45,

8 46). However, if Vc is not yet at a morphological lima during severe exercise, acute

hypervolemia may lengthen PTT because of increased distentiodrecruitment of Vc.

Thus, detemiining the effects of acute volume expansion prior to exercise on P T at

nearmaximal exercise in elite athletes provides insights into the morphologieal limit in

Vc dunng severe exercise. Therefore, the specific aims of this study were to detemine

whether acute volume infusion prior to exercise: (1) prevents ElAH and (2), lengthens

PTT in athletes with high aerobic capacities.

2.2 METHOOS

Twelve healthy male endurance athletes (v%, 2 65 ml - kg" min-' or 5 L .

min") wah no history of respiratory or cardiovascular disease were selected to

participate in the study. This study was approved by the St. Paul's HospitaIlUniversity

of British Columbia Ethics Committee. Subjects gave infomed written consent, and

corn pleted a Physical Activity Readiness Questionnaire (PAR-Q). Su bjeets performed

resting pulmonary lung function testing (Jaeger MasterSmen Body Ptethysmograph),

to assess baseline pulmonary function and then performed an incremental cycling

protocot to determine each subject's \IoZmw.

PreIiminary Incremental Cycling Exetmse Prolocol to Detemine vo2,r Prior

to al1 testing, subjects were asked not to partake in exhaustive exercise for 24 hr,

restrict theinselves from caifeine and alcohol consumption for 12 hours, and not

consume food or fluid other than water for 2 hours. \iO;>max was assessed using a

computer-aided electronically-braked load simulator (Cornputrainetm PRO 8001,

RacerMate, Seattle, WA). Metabolic variables were assessed with a Sensormedics

VMAX 29C metabolic a r t (Sensormedics, Yorba Linda, CA) using the breath-by-breath

9 system. Heart rate (HR) was recorded using a Marquette 12SLTU ECG monitor

(Maquette Electronics, Milwaukee, WI).

'IOaax was considered to have been obtained when at least three of the four

following criteria were met: (1) a plateau in with increasing workload, (2) respiratory

exchange ratio (RER) > 1 .IO, (3) attainment of 90% age-predicted maximal HR (HR,,),

and or (4), volitional fatigue. The highest three consecutive averaged 20 s interval's was

defined as V O ~ ~ . Rating of perceived exeriion (RPE) (21) was recorded immediately

post-exercise.

Experimental Design: The research design was a randomized, double-blinded,

crossover design, with subjects serving as their own control. Acute plasma volume

expansion was the intervention. A repeated measures ANOVA was used for measuring

the primary dependent variable, PTT: C2 x Mp, that is, condition (C; non-infusion,

infusion) crossed with method (M; centroid, deconvolution). A 2 x 8 repeated measures

ANOVA was used in the statistical analysis for the secondary dependent variables: Cz x

Ta, that is, condition (C; non-infusion, infusion) crossed with time (T; minute 0, 1-6, 6.5)

for arterial PO2 (Pa02), alveolar to arterial oxygen difference (AaDOp), and %Saoz.

Paired T-tests were used to compare cardiac output, and pulmonary blood volume

(PBV) between conditions at minute 3 of the constant-load exercise task.

Protocol: Subjects were randomized to receive 500ml of 10% pentaspana (Du

Pont Pharma, Kirkland, PQ) or -60 mL of intravenous normal saline infusion to keep the

vein open (TKVO) before sessions 1 and 2. During each of sessions 1 and 2, al1

research personnel and research subjects (except one research nurse and two medical

technicians) were blinded as to whether subjects received Pentaspana or saline. Each

of sessions 1 and 2 was identical in sequence, dufation, and protocol of measurements.

10 After a peripheral intravenous catheter was inserted, one research nurse infused either

500ml of entasp pan" [infusion session (l)] or 40mL saline [non-infusion session (N)]

(0.9% sodium chloride injection; Baxîer Corporation, Toronto, Ont.). The following line

diagram shows the protocol for sessions 1 and 2:

Arterial cannulation, blood volume or plasma volume measurement, esophageal probe insertion

Exercise at -92% ma,,,, (min)

-90min -60min -1 5min O 3 3.5 4 6.5

Baseline measurements iib, Hct

Randomized, double- Mind crossover infusion of 500 mL Pentaspan or 60 mL

- - First pass radionuclide acquisition cardiograph y

a ~0~ \jE, HR, RER, averaged every 20 s; ABG's, and esophageal temperature taken every minute and at 6.5 minutes

Sessions 1 and 2 4 . 5 minute Constant-load Severe Cycling Exercise: Sessions

1 and 2 consisted of repeated 6.5 minute, constant, near-maximal cycling exercise tests

(-92% Voamax) on separate days, with a minimum of 6 days between sessions 1 and 2.

Blood and Plasma volume. Pnor to arterial cathetenzation, subjects laid on a

stretcher and rested for -1.5 houts prior to exercise. An 18 gauge peripheral

intravenous catheter was inserted into an antecubital vein on both days, 1.5 hours prior

to exercise. During this time, hematocrit (Hct), hemoglobin (Hb), blood volume andlor

plasma volume were measured. Blood volume was measured using 2.7 MBq of ' ' ~ r

measure red blood cell (RBC) mass and plasma volume was measured using 0.17 MBq

'251 human serum by standard methadology (6). The quantity of plasma volume

11 expansion was deterrnined by comparing plasma volume post-infusion during the I

session to the plasma volume from the blood volume measurement of the N session

because train4 individuals have stable plasma volume (66) and RBC mass (63) over a

4 - 12 week period. Therefore, blood volume was only measured once (N session),

while plasma volume was only measured post-infusion (1 session).

Artenal Catheteniation, Esophageal Temperature Probe Insertion, Artenal Blood-

Gas Sampling: Within 10 minutes of having plasma volume or blood volume measured,

the subjects remained supine while a 20 gauge arterial catheter (Arrow International,

Erding, Gerrnany) was inserted into the left radial artery under local anaesthesia (2%

lidocaine hydrochloride).

An esophageal temperature probe was inserted to rneasure temperature

continuously during exercise so that arterial blood gases (ABG's) could be corrected for

the increase in temperature that occurs during exercise (48). In a sitting position,

subjects had a general purpose temperature probe (Sheridan Corporation, Argyle, NY)

inserted though a preferred nostril into the esophagus at a specified depth (135). The

temperature probe was then connected to a Yellow Springs 400 telethermometer

(Vellow Springs Instrument Company, OH).

PaOz, PaC02, and pH were measured directly via an ABL30 Acid - Base

Analyzer (Radiometer, Copenhagen, DK). %Sa02 was calculated from measurements

of pH, POa, and body temperature using a nomal 0 2 dissociation curve (186). ABG's

were sampled at rest (prior to warm-up), every minute during exercise, and at 6.5

minutes of the exercise test All ABG's samples were corrected for core temperature

(182). The ideal alveoîar gas equation was used to calculate alveolar partial pressure

(PA02) and AaD02, and the PC02 equation was used to calculate alveolar ventilation

(VA).

12 Detemination of Right-to-Lefl Pulmonary Transit Ti'mes by Fiist P a s

RadioNuclide Cadiogmphy: About 1 hr prior to the 6.5 minute exercise test, 10 ml of

venous blood were withdrawn into a 20mL heparinised luer-lock tip syringe (Shemood

Mediwl, St. Louis, Mo). The RBC's were labeled with 1110 MBq 99"Tc (~echneLite@

Molybdenum 99 - Technetium 99m Generator; Du Pont Pharma, Mississauga, Ontario)

by a standardized in vitro labeling procedure (13). The estimated radiation absorbed

dose for '*TC labeled -360 mR (180 mR per session) (68), which is equivalent to -3.6

mSv of effective radiation exposure (68). Prior to exercise, the researchers positioned

the bicyde (secured to the Computrainerm) in front of a Siemens Orbiter Gamma

Camera (wide field of view, low energy high resolution parallel hole collimator, 64 x 64

matrix, 0.65 cm per pixel). Subjects leaned fonnrard placing their chests directly in

contact with the Gantera and grasping the camera with the left hand while the gamma

camera acquired images at an approximate 30" left anterior oblique position. They

maintained this position for both 6.5 minute exercise tests. PTT and distribution of PTT

were assessed during a 30 second period (beginning at the third minute of severe

exercise) by first-pass radionuclide cardiography using previously validated centroid and

deconvolution methods (90, 123). Minute 3 was selected as the time-point to assess

PTT because first-pass radionuclide cardiography must precede the measurement of

cardiac output. Sinœ cardiac output measurement with nuclear medicine technology

takes about 2.5 minutes, and since athletes could only perform close to maximum

intensity for about 6 minutes, measurement PTT (which takes 30 seconds) occurred at

minute 3. For the assessment of PTT, one picture was taken every 0.2 seconds for a

total of 150 frames. Radioactivity was measured during first-pass of the injected bolus

of ' 9 c labeled RBC's through the central circulation via an antecubital vein. Time-

adivity curves for the nght ventricle (RV) and left ventride (LV) were generated allowing

13 calculation of mean right-to-left ventricular red cell PTT (œntroid method) and

distribution of PTT (deconvolution method).

Calculation of Mean PTT-Centroiû Method. Each time-activity curve (RV and

LV raw data) was fitted by a'gamma function of the form

where, k, a, I) are arbitrary parameters, ta = first appearance time, t = time in seconds,

and C(t) = indicator concentration at time t (190). This function has been shown to yield

good fits to unimodal curves (43, 55, 65). Parameters were estimated through manual

fitting of equation [ l] to RV and LV raw data. Mean PTT was determined by subtracting

the first moment of the LV curve (the center of mass of the LV curve) from the first

moment of the RV cunre, where the first moment of equation [il is given by

Distribution of PTT-Deconvolution Method. Deconvolution is a mathematical

process by which a distribution of PTT (calied a transport function) can be derived from

the input (RV) and output (LV) time-activity curves. The Fourier domain transport

function mapping RV to LV is the transport function that provided the frequency

distribution of PTT. The theory follows: Given that both input and output curves can be

described by a gamma fundion, then the transport function is also a gamma function.

Mathematically:

O(t) = h(t)*i(t) Pl

where I(t) = input function, o(t) = output function, h(t) is the transport function or

distribution of PTT, and * is the convolution operator. Since input and output functions

are obtained from the smoothed gamma-variate fitted RV and LV time-activity curves,

14 h(t) is the remaining function to be solved. This mathematical proœss was performed

using GLANSE computer software (22), developed by Vanderbilt University for

physiological transport madeling (174). Briefly, the software sets the area underneath

both RV input and LV output curves equal to one. GLANSE then actually directly

computes the transport function using a numerical deconvolution algorithm. Because

deconvolution is very noise-dependent, in can be a difficult process to do.

Consequently, al1 RV and LV raw data time-activity curves were smoothed by using a

three point smoothing technique and gamma variate fit (43) from the gamma-camera

wmputer software.

Theoretically, mean PTT obtained from the deconvolution of the gamma variated

fitted input and output curves, is the same as the mean PTT obtained via the centroid

method (123). Therefore, the close approximation of mean PTT obtained by both

methods should validate the application of both mathematicai processes and strengthen

evaluation of both estimates of PTT.

Ejection Fraction and Cardiac Output Measurement: Ejection fraction (EF) was

determined from Multigated Acquisition (MUGA) Technique ( a h called equilibrium

radionuclide ventriculography), obtained during the last 2.5 minutes of both 6.5 minute

tests. The MUGA technique was chosen for its relatively non-invasive procedure, and

for its compatibility of measuring PTT sequentially. Data from each cardiac cyde of the

final 2.5 minutes of the test was divided up into 16 frames of equal length, and data

from each portion of the cardiac cycle was put into the appropriate frames. The end

result was a final 16 images each of which showed a portion of the cardiac cycle.

Because of the inherent relianœ of gated methodology on ECG input, the success of

MUGA technique to determine EF (and thus cardiac output) is related to the consistency

of cardiac rate and rhythm in a given subject (137). Severe disturbances in ECG

1s waveform length cause distortion of the data obtained. Therefore, eomrnercially

available software (SIEMENS ICON) was used to generate a histogram of distribution of

the lengths of the R-R intervals over the last 2.5 minutes of acquisition time. These

histograms provide easy recognition of aberrant cardiac beats. In al1 subjects, the

validity of the data was preserved by arrhythmia filtering. This process allowed for the

rejection of cardiac cycles that did not conform to the average length of the cardiac

cycle during the last 2.5 minutes of the exercise test. Where the R-R interval was

outside the accepted Iimits (k 10% variation), beats were rejected and thus did not

wntribute to the final image set (137). Ejection fraction (EF) was calculated from the

MUGA scan where the LV region of interest (ROI) with the highest number of counts

was assigned as the end diastolic counts (EDC), the LV ROI with the lowest number of

wunts was the end systolic wunts (ESC), and "backgroundn was the correction factor

applied for the excess radioactive wunts from overlaying tissues due to recirculation:

EF = EDC -€SC

EDC - background

Left ventf'icular volumes were then calculated using a validated manuai wunt-based

ratio melhod originally derived by Massardo et al. (129) and modified by Levy et al.

(120). The count-based method of calculating left-ventricular volumes relies on the

theory that if radioactivity is completely mixed in a chamber, the nurnber of munts

recorded in a chamber is directly proportional to its volume. The count distribution is

directly related to the threedimensional activity distribution in front of a gamma camera

(144). Of course, the image itself is only pseudo-three-dirnensional because radiation

depais are superimposed (144). Nonetheless, a good volume estimate can be obtained

from the count-density distribution of the left ventricle that has radioactivity

homogeneously mixed, with a shape that is not too irregular (144). The manual count-

f 6 based method by Levy and colleagues (120) also assumes that the left-ventricle is a

prolate ellipsoid with the major axis 1.8 times the length of the minor axis (D), and uses

background correction. In fact, the left ventride has been shown to represent a prolate

ellipsoid for left-ventricular volumes of less than 300 ml (117, 177) [the volume of a

prolate ellipsoid = 0.3~~~1. Therefore, left ventricular EDV was obtained by manually

drawing a ROI of the left ventricle in the EDV image from MUGA scan, and then

calculating volume (Vt) from the formula:

L( = 2.02M3C3'2~3'2 151

where M is the pixel width in cm; R is the ratio of the total counts in the ROI (minus the

total background correction in that ROI), divided by the average of the four highest

count pixels (minus the average background count rate per pixel); and C is the

transmission factor of the highest count pixel fi), to the transmission factor of the

whole ROI fi). The absolute transmission factor decreases with distance, but does not

Vary over depths of 5 - 15 cm (120). In this study, it was assumed that the attenuation

of Tm and Tf were the same, and thus C was equal to 1. In addition, we determined the

pixel width from the Siemens Orbiter to be 0.65 cm per pixel. Thus, the final formula

used to calculate EDV was:

V, = 0.55R3" PI

SV was then calculated by multiplying EDV by the EF obtained from the MUGA scan,

and was then calculated by multiplying HR by SV.

2.3 RESULTS

Subject Characteristics and resting puimonary function: Subject characteristics

and resting pulmonary function data are shown in Table 1. All subjects were very fit as

mean VO- was 69.6 r 7.4 ml kg-' m i d These elite endurance-trained subjects

17 had predicted or somewhat better than predicted resting pulmonary function. No lung

function abnonnalities were present. From the 6.5 minutes, constant-load severe

exercise tests, seven subjects (58%) were classified as having ElAH (minimal Pa02 of

< 90 mm Hg andlor excessive AaD02 > 25 mm Hg; Table 2).

Effects of infusion on PTT: Pentastarch (500 mL of 10%) infusion significantly

increased blood volume (460 î 422 ml) compared to normal saline (P = 0.002). The

primary results of this study show that volume expansion lengthened right-to-left PTT by

0.30 + 0.20 seconds during severe exercise (range = +0.11 to +0.66 seconds; Table 3;

P = 0,002; n = 9). Paired measurements on three subjeds PTT data were omitted from

the overall PTT analysis because of technical problems. Neverthless, deconvolution

and centroid methods gave the same results (r = 0.96 between both methods). Day-to-

day intraobserver error in determining PTT (assessed by a one-way ANOVA (20) over

three blinded randomized trials) varied by 11 % or 0.28 seconds. Test-retest reliabitity of

manually fitting right and left time-activity cuwes had an intraclass correlation coefficient

of -0.50.

Acute volume expansion by pentastarch (500 mL of 10%) shifted the distribution

of PTT to the right during severe exercise (Figures 1 and 2). In the non-infusion

condition, 22.5 I 13.2% of RBC's had PTT of less than 2 seconds, h i l e volume

infusion shifted the distribution to the right as only 13.2 k 12.6% of RBC's had PTT less

than 2 seconds (P = 0.08). Furthemore, 75.0 k 8.7% of RBC's had PTT of less than 3

seconds, while 62.8 * 15.4% of red cells had PTT less than 3 seconds during the

infusion condition (P = 0.01). Acute hypervolemia also altered the distribution of PTT

within a time interval because there was significantly greater percentage of RBC's within

the 3 - 3.8 seconds time intewal after acute volume infusion than in the non-infusion

18 condition (Figure 1; P = 0.02). Red blood cell dispersion of the mean PTTs during

exercise (defined as SD of mean PTT t mean PTT) was also slightly altered between

conditions. The lengthened PTT during volume infusion increased mean red cell PTT

dispersion to 0.12 compared to 0.09 in the N condition. Therefore, the data shows that

acutely increased blood volume lengthened PTT causing red cell distribution to become

more heterogeneous compared to the non-infusion condition. In addition, there was a

strong trend for the blood volume (per kg of body weight) to be associated with PTT (r =

0.39; P = 0.08). Moreover, cardiac index was negatively associated with P lT (? = 0.22;

P = 0.03).

Artenal Wood Gases and Esophageal Temperature: Pa02 and AaD02 (Figure 3),

PaCO2 and %Sa02 (Figure 4), were not altered between infusion (1) and non-infusion

(N) conditions (P > 0.05). Pa02 (corrected to esophageal temperature) decreased from

105.2 i 6,b to 90.6 i 9.2 mm Hg (range = 69.7 - 102.3 mm Hg; Figure 5) within the first

minute of severe cycling exercise (P c 0.05) and did not significantly change throughout

the rest of exercise, irrespective of condition (PaOa at end of test was 88.2 + 7.4 mm

Hg). AaD02 (corrected to esophageal temperature) increased from 5.9 I 7.8 mm Hg at

minute O to 19.6 I 7.8 mm Hg (range = 9.8 - 34.4 mm Hg; Figure 5) at minute 1 of

severe cycling exercise (P < 0.05). Thereafter, was a significant increase of AaD02

throughout the rest of the 6.5 minute test such that at the end of exercise, AaD02 was

24.8 k 6.0 mm Hg (range = 16.2 - 35.2 mm Hg) (P c 0.05; Figure 3).

There was no significant relationship between PTT and pulmonary oxygenation

since PïT was not associated with Paon (r = 0.19; P = 0.43), AaDO2 (r = -0.24; P =

0.30) or %Saoz (r = 0.15; P = 0.53). Calculated %SaO2 decreased from 97.9 I 0.5% at

minute O to 90.6 k 2.4% (range = 86.0 - 93.5%) at minute 6.5, irrespective of vdume

19 infusion (P < 0.01 ; Figure 4). In order to determine what part of the mean 7.3% drop in

%SaO2 during the 6.5 minute cyding exercise was due to the Bohr effect (changes pH

and body core temperature) versus other factors (Le. T~aD02, L P ~ o ~ , ?PaCCI2, im2),

standardized formulas (181) were implemented to correct %Sa02 to a pH of 7.4 and

37% (Figure 4). It was found that at the end of the cycling exetcise, 41% of the total

dmp in %Sa02 from minute O to minute 6.5 was due to the increased core temperature

(as reflected by esophageal temperature, Tes) and decreased pH, while 59% of the

remaining 7.3% drop was due to other factors (Le fAaDO2, kPaO2). Esophageal

temperature increased significantly during exercise but there was no difïerenœ in the

increase in temperature between non-infusion and infusion conditions (Figure 4; P =

0.58). Arterial PC02 corrected for temperature did not change during exercise in either

the non-infusion nor infusion group (Figure 3; P = 0.71).

Metabolic variables, heart rate and ratings of perceived exertion: Acute volume

Infusion did not affect m2, VE (Figure 5) or RPE between sessions 7 and 2 (P > 0.05).

Oxygen consumption increased from 8.5 1.2.0 at rest to 63.E I 6.6 ml - kg-' - min-' at

minute 6.5 of severe cycling exercise, irrespective of volume infusion (p c 0.05). This

represented an intensity of about -92% of maximum when averaging the last 2.5

minutes of exercise. Minute ventilation increased from 18.6 * 2.8 at rest to 158.6 I: 27-4

L - min'' at minute 6.5 of exercise (P < 0.05). Ratings of perceived exertion (21) were

unchanged between the preliminary ~ 0 z m a x sessian (RPE = 17.8 k 0.8) and both 6.5

minutes cycling exercise sessions (N = 18.1 t 1.1 ; I = 18.3 k 0.6) (P > 0.05), suggesting

that the same effort was maintained during each exercise session. However, there was

a main efkct of condition on HR, as Hf? was about 2 beats min" lower at al1 time

intervals with volume infusion (Figure 6; P = 0.04).

20 Artenal pH, Standard Base Excess, and Bicanbonate concentration: Arterial pH,

bicarbonate and standard base excess decreased steadily and significantly during

severe exercise (Figure 7). Acute volume expansion decreased pH (P = 0.02) and

bicarbonate concentration (P = 0.01) during the 6.5 minute cycling exercise test by

about 4 - 5% (Figure 7), while calculated standard base excess was not affecied by

infusion (Figure 7; P = 0.16). Because there was no difkrence between non-infusion

and infusion condition in PaC02, and because arterial pH is negatively associated with

blood lactate levels (148), it is possible that peak blood lactate levels in this study rose

from -14.5 mmol r' in the non-infusion session to -15.5 mmol L" in the volume

infusion session (148) (P ~0.05).

Cardr'ac functjon data: Cardiac index was unchanged despite volume infusion in

al1 12 athletes (P = 0.73; Table 4) and in the subset of athletes with ElAH (P = 0.48;

Tabie 5). Cardiac index at minute 3 of constant-load severe exercise (-88% w-) was 15.8 k 2.0 and 15.6 -1.1.8 L + m2 min'' in the non-infusion and infusion conditions,

respectively (n = 12). There was a signifcant association between V O ~ and Q (r = 0.81 ;

P c 0.01), confiming the linear relationship between \j0* and Q during exercise.

In addition, predicted Q from VO* measurernents (221) demonstrated similar

values to Q measured wing radionuclide techniques (r = 0.68; P c 0.01). The average

Q was predided to be 32.1 I 3.5 L - min" (221) while the average calculated Q f m

the combined EDV estimation using the count-based ratio method (120) and the E f

from the MUGA scan, waç 30.4 I 4.1 L . min" (P > 0.05 between predicted and

calculated b). The 2 L . min'' underestimation of Q usirg radionuclide methods is in

agreement with a curent review (212), which indicates underestimation of Q by

radionuclide methods during exercise.

21 EDV assessed by the count-based ratio rneoiod (120) showed good

reproducibility (day-today intraobsewer error (19) by GSZ was 36 mL (15%)].

Repeated analysis of the same raw data indicated excellent correlation between EDV

measured on al1 twelve subjects measured on two occasions by GSZ (r = 0.91; P <

0.01). Furthemore, calculating ejedion fraction from the MUGA scan showed good

reproducibility as day-today intraobserver error (19) was 5%. Repeated measurement

of EF on two occasions showed good correlation (r = 0.92; P < 0.01).

Stroke volume, ejection fraction, EDV, and €SV were unaltered between non-

infusion and infusion conditions at minute airee of exercise (P = 0.13 to 0.25)-

Pulmonary blood volume was higher (+A31 mL) in the acute volume expansion

condition (P = 0.01 5; Table 4).

22 Table 1: Subject characteristics and resting pulmonary function (n = 12).

Mean i S.D. Range Percentage predicted BSA (mZ) 1.93 i 0.12 1 -76 - 2.07 Age (years) Height (cm) Wight (kg)

(ml.kg'-min") (L . min-')

i(E (L-min*') HRm, (beatsmin-') Peak power output Hct (%) Hb (g . L") Blood volume (ml) Blood volume (mL . kg-') WC (LI FWl (L) FEVllFVC (%) PEF (L-S-') DLCO (ml .min-'.mm~g") 40.2 I 5.5 - - 113.8 i 11.3% 'Predicted value significantly different than obtained value (P < 0.05). Pulmonary function values in males as a percentage of normal values predicted for men of same height and age. Prediction equations are: spirometery (42)§. DLCO (1 7.40) W. V02mBX values in males as a percentage of values predicted for men of same age, weight, and peak power output at maximum exercise (193)k Wood volume in males as a percentage of values predicted for healthy young men of same weight (1 78)

Table 2: Classification of subjects with excessive AaD02 (> 25 mm Hg) and/or low Pa02 (c 90 mm Hg) dwing the 6.5 minutes, constant-load, severe cycling exercise in - the no-n-infusion &sion.

lndividuals with ElAH Subject Minimal Average PlT

Pa02 AaD02 (sec) over last 2.5 minutes

MV 79.4 30.7 2.405

Mean 79.1 27.9 2.400 SD 7.3 6.2 0.200 PaOz = arterial PO2 (mm Hg); AaD02 = i

lndividuals without ElAH Subject Minimal Average PTT

Pa02 A~DO; (sec) over last 2.5 minutes

AC 94.5 17.8 2.500

93.0" 18.2* 2.530 1.3 1.3 0.160

/eolar-arterial partial pressure difbrence (mm Hg); ElAH = exercise-inducd arterial hypoxemia; MD = missing data; significantly different from individuals with ElAH (P < 0.01)

Table 3: Cornparison of method and condition on assessrnent of red cell pulmonary transit times during minute 3 of the 6.5 minutes constantlload, severe cycling exercise. [n = 91; P = 0.002 compared to non-infusion condition.

Non-inhision Infusion

Subject Centroid Deconvolution Centroicl Deconvolution AC 2.40 2-60 2.72 2.91

Combined Mean I SD 2.45 iO.21 2.75 I 0.32" r = 0.96 between methods (P < 0.01); coefficient of variation between methods is 1.9%. Day-to-day intraobserver measurement error in assessing PTT was analyzed by a one- way ANOVA (20) over three trials and varied by 0.28 sec or 11% variation. The Intradass correlation coefficient for test-retest reliability (20) in assessing PTT was found to be fairlmoderate (ri = -0.50).

Table 4: Mean metabolic, arterial blood-gas (ABG), blood volume, and cardiac output data at minute 3 of intense cycling exercise (n = 12 except for PTf and PBV where n = 9). P < 0.05.

Variable Non-infusion Condition Infusion Condition P value (mean t SD) (mean t SD)

327 k 29 watts 340 t 29 watts 0.09 Blood volume (mL) 5949 t 894 6409 t 1 065 0.003*

(ml kg-' min-') 61.1 +. 5.6 61.2 t 6.0 0.88 \jE (L . min-') 138.3 I 34.2 146.9 t 23.3 0.64 EF (%) 74 14 7 2 t 6 0.25 PTT (sec) 2.45 t 0.21 2.75 t 0.32* 0.002 Q index (L . m2 min-') 15.8 I 2.0 15.6 k 1.8 0.67 SV index (ml . m2) 85.2 I 1 1.2 85.4 t 10.4 0.35 EDV index (ml m2) 115+15 119 + 13 0.1 3 ESV index (ml m2) 29.5 i 7.1 33.4 I 9.2 0.14 PBV index (L + m2) 0.63 t 0.05 0.70 i 0.09* 0.02 Cao2 (ml L-') 172.4 19.1 162.1 I 1 5.0* 0.002 Pa02 (mm Hg) 89.5 * 9.0 90.7 I 7.7 0.46 AaD02 (mm Hg) 21.8 +, 6.1 22.7 -t 6.8 0.50 %Saoz 93.5 I 2.6 93.3 I 1.6 0.78 Q index = cardiac index; SV index = stroke volume index ; EDV index = end diastolic volume index ; ESV index = end systolic volume index ; EF = ejection fraction; Pm = rnean right-to-left pulmonary transit time; PBV index = pulrnonary blood volume index; Caoz = arterial oxygen content; PaOz = arterial PO2; AaOQ = Alveolar-arterial partial pressure diirence; %Sa02 = artenal oxyhemoglobin saturation; PaC02 = artenal PC02; \Io2 = oxygen consumption; vE= minute ventilation.

Table 5: Mean metabolic, arterial blood-gas (ABG), blood volume, and cardiac output data at minute 3 of intense cycling exercise in athletes with ElAH (minimal Pa02< 90 mm Hg). [n = 7 except for P T and PBV where n = 61. * P < 0.05.

Variable Non-infusion Condition Infusion Condition P value (mean + SD) (mean I SD) 3-36 + 18 watts 345 i 20 watts 0.34

Blood volume (mL) 6275 t 878 6775 I 1249* 0.02 Y02 (ml . kg' min-') \jE (L . min-') EF (%) PTT (sec) Q index (L . m2 min") SV index (ml - m2) EDV index (ml m2) €SV index (ml . m2) PBV index (L mZ) Ca02 (ml + L-') Pa02 (mm Hg) AaD02 (mm Hg) %Sa02 92.7 e 2.5 92.9 I 1.6 0.70 Q index = cardiac index; SV index = stroke volume index ; EDV index = end diastolic volume index ; ESV index = end systolic volume index ; EF = ejection fraction; PTT = mean right-to-left pulmonary transit time; PBV index = pulmonary blood volume index; Cao2 = arterial oxygen content; PaOz = arterial PO2; &DO2 = Alveolar-arterial partial pressure difference; %SaO2 = arterial oxyhemoglobin saturation; PaC02 = arterial PC02; \j02 = oxygen consumption; \jE = minute ventilation.

Table 6: Cornparison of mean pulmonary transit times during exercise. Also mesponding Q, HR. VO-, PBV, and Vc values h m the literature. N = non-infusion condition; I = Infusion condition; BT = before training; AT = after training.

Present study Hopkins Iskandrian Warren et Rerych et al. (165) et al. (9û) et al, (101) al. (213)

N 1 BT AT Sample slze 12 - ~ e i d I k d

w PTT (sec) Rest Exercise PCTT (sec) t t Rest Exercise Q ~ L - min-') - Rest Exercise VOAL - min") - Rest Exercise HR ~beats-min-') Rest Exercise PBV (L) Rest Exercise Predicted Vc (mL) Exercise Predicted Vc (mL) a Rest Exmise Predicted Vc (rnL1m Rest Predicted Vc ( m l t Rest Exercise 236.3 286.5 252.5 179.3 229.1 205.7 244.7

Some variables could not be I were not measured. Therefore, regression equations were used to predict values. 5 = Gehr et al. (59); 99 = Johnson et al. (106); 9g9 = Young et al. 1963 (225); t = Hsia et al. (1 00); = Wiebe et al. (221); PBV = 6 (Us) x PTT (s); tt PCTT= Vc (ml) estimated from Hsia et al. (100) + Q (ml); PClT = pulmonary capillary transit tirne; PCTT and Vc from Warren's study were not predicted but were estimated h m rneasurements of DLCO by using the melhod h m Roughton and Forester (172); The underlined-bolded-italics nurnbers (269.5, 303, 283.5 ml) represents theoretical Vc h m the augmented PBV Johnson et al. (106), that is Vc = 40% of PBV or 52 ml increase in Vc added on to the predicted Vc h m respected regression equations.

Flgure 1: Mean transport functions created by deconvolution analysis cornparhg distribution of PTT between non-infusion (N) and infusion (1) conditions. Mean PTT increased by 0.30 seconds (P = 0.002) between the two conditions.

- N transport function -- I transport function

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0

Tirne (seconds)

Figure 2: Distribution of red cell pulmonary transit times during minute 3 of intense, constant-load exercise with (1) or wiaiout (N) volume infusion (n = 9). P = 0.02 between N and I within a given time interval.

% cells N E % cells I

4 1-1.8 2-2.8 3-3.8 4-4.8 >5

Time intewals (seconds)

Figure 3: Artenal PO2 (PaO2) and alveolaraygen differenœ (AaD02) during the 6.5 minutes severe, constant-load exercise test for non-infusion (N) and infusion (1) conditions. * different from minute O (corrected values only); " different from minute 1 (corrected values only; " difierent from minute 1 (corrected values only) [n = 121. Pa02 and AaD02 were temperature corrected at each time point by using esophageal temperature at each time point.

-e- N corrected to esophageal temperature -0- I corrected to esophageal temperature -+- N at 37 celcius -P I at 37 celcius

ïîme (minutes)

Figure 4: Arterial oxyhemoglobin saturation (%Saon), arterial PC02 (PaCO*), and esophageal temperature during the 6.5 minutes severe, constant-load exercise test for non-infusion (N) and infusion (1) conditions. a = different from minute O; b = dihrent from minute O to 1; c = diierent From minute O to 2; d = different from minute O to 3; e = different frorn minute O to 4 [values which are corrected to to temperature changes only; P < 0.05). ## = main effect present between conditions. (n = 12).

-t N adual + i adual + N mlnilated Io 37 cekius and pH of 7.4

+ N coneded to esphageal temparalum + 1 comded to esophawal temperetum + N at 37 cekius

I at 37 œldus

a

8 36.0

g 35.5

8 35.0 W

O 1 2 3 4 5 6 7

Time (minutes)

Figure 6: lndidual responses for Pa02 and AaDO2 during the 6.5 minutes severe, constant-load exercise test collapsed across condition (n = 12). All values corrected to esophageal temperature.

Subjects

. .O-- JE

NC

Time (minutes)

Figure 6: Minute ventilation, minutes severe, constant-load

oxygen consumption, and heart rate during the 6.5 exercise test for non-infusion (N) and infusion (1)

mdiions. a = difkrent fmn minute 0; b = different from minute O to 1; c = different Rom minute O to 2; d = different h m minute O to 3; [values which are wrrected to temperature changes only; P c 0.051. ## = main effect present behween conditions. (n =

I 1 I t

O 1 2 3 4 5 6 7 fime (minutes)

Figure 7: Artenal pH, bicarbonate (HCOj). and standard base excess (SBE) during the 6.5 minutes severe. constant-load exercise test for non-infusion (N) and infusion (1) conditions. a = different from minute 0; b = different from minute O to 1; c = different from minute O ta 2; d = diiferent from minute O ta 3; e = different from minute O to 4 [values which are corrected to temperature changes only; P < 0,051, ## = main effect present between conditions. (n = 12).

t 1 6 1 1 I 1

O 1 2 3 4 5 6 7 Time (minutes)

Figun, 8: Correlation be-n the change in AaD02 and the change in PTT wiai infusion at minute 3 of exercise in subjects with minimal PaOp < 85 mm Hg and excessive gas exchange impairment (AaD02 > 25mm Hg; n = 6)

r=032;?=0.52;~=0.10;n=6 Change in PTT = 0.37 - (O.W*change in AaDOp) SEE = 0.19

Change in AaDO2 (mm Hg)

36 2.4 DISCUSSION

Effects of volume expansion on EIAH: Acute volume infusion (using 500 mL of

10% pentastarch) prior to exercise did not change any measure (Pa02, AaDOz, %Saoz)

of EIAH. In contrast, acute volume infusion prior to exercise lengthened mean PTT.

Taken together, these results suggest first, that shortened PTT is not a major

mechanism of EIAH, and second, that there is not a maximal Vc during severe exercise

because Vc likely increased after acute volume expansion for the reasons described

below.

Eficts of acute volume infusion on PTT: The main result of this study is that

acute volume infusion before exercise increased PTT during severe exercise. To Our

knowledge, this is the first study to measure mean PTT in exercising elite humans

before and after acute hypervolemia. Since transit time is volume divided by flow, and

since there was no significant change in flow (Q), this suggests that PBV increased by

131 mL. This indirectly provides evidence against reaching a maximal Vc during

exercise because of the increase in PBV with volume infusion (59, 100, 106). If Vc

were maximal during severe exercise, PTT would have shortened due to the inability of

pulmonary capillaries to further dilate andlor be recniited, but this was not the case.

The assumption that Vc is not maximal during severe exercise is true if the

increase in PBV observed here (+131 ml) reflect changes in Vc. Indeed, it has been

shown that the arterial and venous tree can distend significantly (83), but there is also

evidence that recruitment in the pulmonary circulation occurs exclusively in capillaries

(77). About 40% of PBV resides in the pulmonary capillaries (106), and although we did

not measure Vc, several predictive equations in Table 6 (59, 100, 106) suggest that

Vc-at minute 3 of exercise-may have increased from 216.9 - 236 mL (control

condition) to 269.5 - 303 mL with acute hypervolemia.

37 Despite lengthening PTT by 0.30 i 0.20 seconds with acute volume infusion,

there was no improvement in indices of pulmonary gas exchange (Pa02, AaD02,

%Sa02, PaC02). Also, there was no significant relationship between P m and either

PaOz, AaD02, or %Sa02, suggesting that limited PTT may not be an important

mechanism of EIAH. Our results are in agreement with Warren et al. (213) who also

found no relationship between pulmonary capillary transit time (measured via single

breath hoid technique) and AaDO2. Conversely, Hopkins et al. (go), found that PTT and

AaD02 were correlated (r = -0.59; P ~0.05).

Other evidenœ against limited PTT (and therefore perhaps limited pulmonary

capillary transit time) as being a mechanism of EIAH, was that regardless of condition,

PaOz rapidly dropped from 105.2 i 8.2 to 90.6 + 10.0 mm Hg within the first minute of

constant-load severe exercise, and then did not change throughout the rest of the test

(Pa02 at end of exercise was 88.7 + 7.6 mm Hg; P > 0.05). Since at minute 1 was

only -76% of maximum (52.7 i 5.6 ml kg-' . min"), this would indicate that cardiac

output, and thus pulmonary blood flow was substantially less than at minute 3 (i/02 was

61.2 r 5.7 ml kg" min"), the point at which PTT was assessed. Hence, since

pulmonary blood flow from the m2 data was greater at minute 3 than at minute 1, and

yet Pa02 was no different between minute 1 and minute 3, it can be concluded that PTT

is not a main mechanism of EIAH. If PTT was a main mechanism of EIAH, then one

would expect to see a continued significant decline in Pa02 because of increasing

puhonary blood flow and ~ 0 2 . This was not the case. The rapid decrease in Pa02,

and rapid increase in AaD02 that we observed within the first minute of heavy cycling

exercise are consistent with other studies in which Pa02 decreased to -90.5 mm Hg

38 while AaD02 increased to -16.9 mm Hg rapidly in high aerobic capacity cyclists (47,

91,92, 167, lm) .

If it is assumed that changes in PTT reflect changes in pulmonary capillary transit

time, then mean pulmonary capillary transit time in the current study may have slowed

from 0.43 - 0.49 (N condition) to 0.53 - 0.60 seconds with acute hypervolemia (59, 100,

106,225). It has been suggested that maximal Vc is 2.87 mL kg" (59), and Hopkins et

al. (90) proposed PTT is 6 to 7 times greater than pulmonary capillary transit times. The

current is in agreement as mean calculated PTT was 4.6 - 5.8 times greater than mean

pulmonary capillary transit time estimated from several predicted Vc equations from (59,

100, 106,225).

Our results for the mean RBC PTT during severe exercise 2.45 and 2.75

seconds) are similar to previous reports (90, 101, 112, 165). Whole lung red blood cell

pulmonary transit times (PTT) can decrease from 7.3 I 0.3 seconds at rest to 2.6 I 0.3

seconds during severe exercise [pooled data from (90, 101, 165)). The effect of acute

volume expansion on PTT is similar to the effects of chronic endurance training on

blood volume and PTT. Our study is the first to show that acute volume expansion

lengthens PTT. Similarly, Rerych et al. (165) found that training-induced hypervolemia

also lengthened PTT. Maximal cardiac output increased from 25.5 L . min-' to 32.0 L .

min" after six months of swimming training, and PTT increased from 2.40 to 2.80

seconds post-training. These results are very similar to our study as we found that PTT

increased from 2.45 i 0.21 to 2.75 î 0.32 seconds before and after volume infusion,

respectively .

While it is important to know mean PTT through the lung, it is also necessary to

report distribution of PTT about a mean, as not al1 red blood cells have the same transit

times. As such, the distribution of PTT by deconvolution analysis pennitted calculation

39 and preseritstions of distributions of PTT (Figures 1 and 2). There was no change in

the relative dispersion (RD) of transit times during exercise (RD non-infusion = 0.29 * 0.07; RD infusion = 0.28 s 0.07), indicating that the shape of the transport functions

(heterogeneity of transit times) were not altered between non-infusion and infusion

conditions.

The Gaussian distribution of PTT (Figure 1 ) indicated that 22.5 k 13.2% of RBC1s

had PTT of less than 2 seconds in the non-infusion condition. This PTT distribution is

less than Hopkins and colleagues (90) in which 40% of red blood cells had transit times

c 2 seconds in exercising athletes (Q = 33.3 i 3.7 L . min-') (90). The proprtion of red

blood cells having very rapid transit times is important because rapid pulmonary

capillary transit times (< 0.25 sec) may be too short for complete oxygenation of RBC's.

Hopkins suggested that red blood cell transit times less than 2 seconds may represent

pulmonary capillary transit times of 0.28 (90) ta 0.33 (present study) seconds, which is

very dose to the theoretical limit of 0.25 seconds for complete oxygenation of RBC's in

the pulmonary capillary (202). With acute volume infusion, the RBC PTT distribution

was shifted to the right (Figure 1) such that only 13.2 I 12-6Oh of red cells had transit

times of c 2 seconds (P = 0.08) (Figure 2). Therefore, even though the mean PTT was

lengthened during severe exercise by acute volume infusion before exercise, PTT may

have b e n lengthened in only -9% of rd ceIIs that had the limitation of oxygen uptake

(i.e. red blood cells with PTT was less than 2 seconds). Red blood cells that have PTT

greater than 2 seconds gains no additional oxygen (go), and thus increasing their PTT

cannot compensate for red blood celfs whose PTT is less than 2 seconds.

Another mode1 that incorporates mixed m o u s PO2 considerations is relevant to

the understanding how acute volume infusion before exercise increased PTT but did not

40 reduœ EIAH. Wagner's mode1 (203) suggests that the time requimd for complete

equilibration of alveolar and capillary oxygen tension depends on the slope between

alveolar gas and of mixed venous blood. According to Wagner, the required partial

pressure equilibrium time in the pulmonary capillary is not 0.25 s e c o n d ~ s we

expected when mixed venous PO2 is 40 mm Hg (e.g. at rest)-but it is -0.50 seconds

during severe exercise because of decreased mixed venous POz (203). An

equilibration time of 0.5 seconds in the pulmonary capillary would then represent P T

less than 3 seconds. About 75 + 9% of red blood cells in Our curent study had PTT of

less than 3 seconds in the non-infusion condition, while acute volume infusion shifted

the distribution to the right such that only 63 + 15% of red blood cells had PTT of less

than 3 seconds (P = 0.01). Thus, it is suggested that acute volume expansion

tengthened PTT in 12 i 11% of red blood cells that had limited partial pressure tirne (i.e.

red blood cells < 3 seconds). Therefore, the mean lengthening of PTT in only 12% of

r d cells that had limited partial pressure equilibration time by acute volume expansion

may not have k e n enough to improve pulmonary gas exchange for oxygen.

Temperature Correction of Artenal-blood gas Measurements: Temperature

correction of ABG's during exercise is controversial. Several previous studies have

made blood-gas measurements at 3f°C (23, 64, 72, 87, 92, 145, 149, 158, 198).

However, it is critical to correct for the increases in body core temperature throughout

exercise to avoid overestimating the decrease in Pa02 and PaC02, and overestimating

the increase in AaOOz (48). However, other studies have not corrected for changes in

core temperature because short-duration, high-intensity exercise produœs about a

0.5% increase in core temperature (16, 176). Our data suggest this assumption may

not be accurate because we found that 6.5 minutes of intense exercise (including 10

minute warm-up) increases core temperature (as reflected by esophageal temperature)

41 from 36.3 k 0.6 O C at rest (before warm-up) ta 39.3 .t 0.3OC at minute 6.5 of severe

cycling exercise (P < 0.01; Figure 4). Our results are consistent with other studies and

curent review !48), which found that esophageal temperature increases by about 2*C in

a twelve minutes progressive maximal exercise test to exhaustion (78, 79). Because of

the wntroversy regarding temperature correction of ABGtsl we reported PaOsl &DO2,

and PaC02 at 37% as well as temperature corrected (Figures 3 and 4). Our data show

that with a 3OC increase in esophageal temperature, the decrease in Pa02 and PaCOz

after 6.5 minutes of constant, severe level exercise can be overestimated by 14% (12

mm Hg) and 10% (3.7 mm Hg), respectively if temperature correction is not done. This

is in agreement with a as our data represents a 4.7% change in Pa02 per celcius, and a

3.3% change in PaC02 per celcius increase in core temperature. Furthemore, by not

adequately wrrecting for both water vapor pressure changes and increasing core

temperature, AaD02 can be overestimated by as much as 41°h (17 mm Hg) after 6.5

minutes of severe cycling exercise (13.7Oh increase in AaDO2 per t°C increase in core

temperature). Thus, our approach has been to measure esophageal temperature

before and during exercise ta temperature correct ABG's, and to show both uncorrected

and temperature corrected ABG's.

Another significant finding was that arterial pH was lower with volume infusion (P

= 0.02). One reason for the change in pH was that the average exercising power output

was about 13 watts higher with volume infusion (P = 0.09). Even though statistical

significance was not reached, this may have resulted in the slightly lower pH values in

the infusion condition. Another reason why pH was lower with volume infusion was that

there was significantiy lower hemoglobin values with acute hypervolemia (infusion = 129

I 10 g - CI; non-infusion = 138 I 5 g . L-'. P = 0.002). Since hemoglobin acts as a

42 bMer for H' ions, acute hypervolemia may have resulted in the increased arterial Maod

acidity (lower pH) due to lower hemoglobin concentration.

Limitations: Limitations were experienced during the data collection process. For

example, a linear regression equation {(Temp = 37.74 + (0.238Time)) was developed

to temperature correct 33% of arterial blood gas measurements (56 out of 168 samples)

from minute 1 to minute 6.5 because the esophageal probe was not inserted far enough

down the esophagus. As such, during those instances, a reduction in esophageal

temperature was observed throughout exercise, as the probe may have been in the

region of one of the h o cold spots in the esophagus, located 10 and 13 cm below the

corniculate cartilage (47). Nevertheless, the esophageal probe insertion length was

determined during subsequent data collection from the formula of Mekjavic and Rempel

(47), and core temperature was recordeci properly for the remaining 16 trials. The

standard error of the estirnate used in the regression equation was 0.32OC (using 112

properiy temperature corrected ABG samples) showing that this population of subjects

had similar core temperature increases (2 SD = + 064°C). A second limitation was

variance in plasma volume (SD was + 422 ml) from pre to post-infusion. Indeed, this

was principally caused by two subjects having a -357 and 4 1 mL differenœ in plasma

volume compared to the non-infusion condition. Because the negative plasma volumes

would suggest that these two subjeets were hypovolemic on the infusion day, and

because previous studies found that trained subjects maintain stable plasma volume

and RBC mass over a 4 to 12 week period (63,66), we suspect rneasurement error is a

more likely explanation in these two subjects. In hindsight, we believe that RBC mass

and plasma volume should have b e n measured on both days. As such, measurernent

error may have been reduced. A third limitation was that only 58% of the subjects had

ElAH (Table 2). Thus, we did not expect acute volume expansion to have an effkct on

43 gas exchange in subjects without EIAH. However, the data was re-analyzed on 7

subjects who had EIAH and the results were identical to the data analyzed with the

original 12 subjects-fhat is, PTT and PBV increased with volume expansion despite

unaltered Q (Table 5). Nevertheless, we also looked at that comlation between that

change in AaD02 with infusion and the change in PTT with infusion in those with EIAH,

and found that 52% of the variance in the change in AaDOz explained the variance in

the change in P m (P = 0.10; Figure 8). Indeed, while this relationship was statistically

insignifiant, a trend does exist for possible Mure research. A fourth limitation was that

differences in the total counts of white blood cells (WBC) between individuals may have

influenœd PïT. White blood cells have shown to travel much more slowly through the

pulmonary capillaries than RBC's, and so increased concentration of WBC's in the

pulmonary vasculature may have slowed RBC transit time. However, a negative

correlation was observed between the pre-exercising circulating pool of WBC's and PTT

from both non-infusion and infusion days (r = -0.56; P = 0.009), suggesting that those

with higher circulating WBC's have faster PTT's, even with volume expansion. Further

study is needed to explain whether this relationship is due increased shunting of RBC's

to the branchial circulation or whether the WBC's in the lungs are relocated to the

circulating pool because some subjects may have had high catecholamine levels p re

exercise.

In conclusion, acute volume infusion does not prevent EIAH but does lengthen

PTT in elite endurance athletes. The increase in PTT suggests that pulmonary capilIary

blood volume increased and argues against a maximal Vc during severe exercise.

Furthemore, because pulmonary gas exchange was not improved and because there

was no correlation between PTT and pulmonary gas exchange, this suggests that rapid

pulmonary capillary transit time is not a significant mechanism of EIAH.

44

CHAPTER 3. GENERAL SUMMARY AND CONCLUSIONS 3.1 GENERAL SUMMARY

Exercise is an important component of lifestyle adjustrnent to decrease risk of

heart disease because it increases the arnount of highdensity Iipoproteins in the blood,

and conditions the heart to recover from acute myocardial infarction. Exercise in

healthy endurance athletes is a useful human model to understand mechanisms of

cardio-respiratory limitation of strenuous activity. Exercise performance can be limited

not only by cardiovascular performance but also by EIAH. The pathophysiology of EIAH

remains an interesting topic of discussion among exercise physiologists. Some elite

endurance athletes achieve arterial-btood gas profiles similar to those in a critically il1

patient in the intensive care unit This study sought to determine whether one potential

mechanism of EIAH, diffusion limitation consequent to rapid red cell transit times,

affects pulmonary gas exchange, and, whether Vc reaches maximal dimensions during

severe exercise.

Acute Hypervolemia and Pulmonary Gas Exchange. Twelve highly-trained

endurance athletes (V02ma = 69.6 i 7.4 ml . kg" . min"; weight = 74.8 I 6.0 kg; height

= 181.6 I 7.0 cm) performed repeated 6.5 minutes, constant, near-maximal cycling

exercise (-92% ~ 0 ~ ~ ~ ) tests on different days. Seven subjeds had exercise-inâuced

atterial hypoxemia [EIAH; minimal arterial PO2 (Paon) c 90 mm Hg]. Plasma volume

expansion (+460 * 422 mL; P c 0.05) was double-blinded and randomized. No

signifiant dmerences in %Sa02, Pa02, or AaD02 were observed throughout exercise

between non-infusion (N) and infusion conditions (1), even when analyzing the data on

just the subjects with EIAH.

Ac& Hypervolemia and Red C M Pulmonary Tiansit Time. Twelve highly-

trained endurance athletes (vo~, = 69.6 k 7.4 ml kg" min"; weight = 74.8 r 6.0 kg;

45 height = 181.6 k 7.0 cm) performed repeated 6.5 minutes, constant, near-maximal

cycling exercise (-92% V O ~ ~ ) tests on difrent days. Seven subjects had exercise-

induced arterial hypoxemia [EIAH; minimal arterial P02(Pa02) < 90 mm Hg]. PTT was

assessed during the ttiird minute of exercise via first-pass radionuclide cardiography

using centroid and deconvolution analysis, h i l e h was assessed via a caunt-based

ratio method from multigated acquisition technique, Mean red cet1 pulmonary transit

times and pulmonary blood volume at minute three of exercise significantly increased

between non-infusion and infusion sessions, respectively, even when analyzing the data

just on subjects with EIAH. No correlation between PTT and pulmonary gas exchange

at minute three of exercise was found. As well, cardiorespiratory variables and power

output were unaffected by acute hypervolemia, and yet arterial pH was lower with

volume infusion.

3.2 GEMERAL CONCLUSIONS

Based on aie current data it c m be concluded that acute hypervolemia lengthens

mean right-to-left ventricular red cell PTT in elite endurance athletes with already

expanded blood volumes, which provides evidence against a maximal Vc occuning

during severe exercise. Furthemore, the realization that pulmonary gas exchange was

not improved, nor was there any carrelation between PTT and various indices of

pulmonary gas exchange, leads to the contention that in an elite human model, PTT,

and therefore pulmonary capillary transit time, is not a significant mechanism of EIAH.

If diffusion limitation due to PTT is not a significant factor to EIAH, then diffusion

limitation due to pulmonary edema andlor capillary stress faiIure may be responsible for

EIAH. Nevertheless, we did not measure total lung water nor did we obtain

radiographie chest images of subjects postemise on both test days, sa no definite

conclusions can be made. However, since no worsening of pulrnonary gas exchange

46 was noticed aftw acute volume expansion, we can conclude that there was no

wonening of pulmonary edema andlor stress failure between non-infusion and infusion

conditions. We can also condude that since pulmonary edemdcapillary stress failure is

caused by high pulmonary artery pressures, the changes in pulmonary artery pressures

during severe exercise between non-infusion and infusion conditions-although not

measured-were probably minimal since pulmonary gas exchange did not differ

between both conditions. Also, since the drop in PaOp occurred within the first minute

of exercise, and did not worsen throughout exercise, pulmonary edema may not have

been a factor early on during the 6.5 minutes exercise bouts. However, pulmonary

edema may have played a minor role in diffusion limitation later on during exercise

because AaD02 slowly but significantly increased throughout the exercise bout.

Relative hypoventilation could be a possible mechanism for ElAH since there

were significant relationships between PAO2 and Pa02 (Figure 27), and between PaC02

and Paon (Figure 28) at minute 3 of exercise in both conditions. As well, 41% of the

variance in the change in PaOz was explained by the variance in the change in PaC02

between minute O and minute 1 of exercise (Figure 29). Taken together,

hypoventilation was a likely significant mechanism of ElAH in this cohort, not only in the

initial stages of exercise, but also in the midst of the exercise protocol. Besides,

Dempsey and Wagner have suggested that a PaC02greater than 35 mm Hg indicates

inadequate compensatory hyperventilation (48). Mean PaC02 in ouf subjects were -40

mm Hg at minute 1 of exercise that decreased to -37 mm Hg by the end of exercisa

Therefore, according to Dempsey and Wagner, hypoventilation was a mechanism of

ElAH in these athletes.

47

V ~ Q inequality ir the next alternative explanation as to the mechanism of ElAH

in these athletes. However, rince V ~ Q inequality was not measured, we are left to

speculate as to the contribution of Wh inequality as a mechanism of EIAH. So, while

we can rule out diffusion limitation due to PTT, and we can probably rule diffusion

limitation due to pulmonary edema, we are left with relative hypoventilation and a h

inequality as the main probable mechanisms for ElAH in this cohort.

APPENDIX A. REVIEW OF THE LITERATURE-EIAH INTRODUCTION

The human lung is a spectacular organ. It has about 300 million alveoli that are 1

interconnecteci to aiways to ensure proper ventilation (215). Their walls are covered

with blood capillaries about 15 pm in length, 7.5 pm in diameter (85), occupying an

alveolar surface area of about 143 m2 (59). The tissue sheet separating the blood from

the alveolar air is less than 1 pm thick-50 times thinner than a sheet of aimiail paper

(216). In fact, despite the effective mean thickness of alveolar-capillary membrane

being very thin (0.62 pm) (59), oxygen has to travel further through a plasma barrier,

which has been found to be about 0.15 pm thick (59). Alveolar oxygen has to diffuse

through a combined total of eight barriers before attaching to a hemoglobin molewle in

a red blood cell in a pulmonary capillary. These bamers are: (A) alveolar surfactant; (0)

alveolar epithelium; (C) alveolar epithelial basement membrane; (D) interstitial fiuid; (E)

capillary basement membrane; (F) capillary endothelium; (G) plasma; (H) red blood cell

membrane. As such, the ultrastructure of the alveolar-capillary membrane provides

minimum distance and mass of tissue between alveolar air and red blood cells in the

pulmonary circulation so exchange of oxygen and carbon dioxide in and out of the

pulmonary capillaries can occur at rest and dunng exercise.

During sea level exercise in normal, healthy males, the lung is able to meet

oxygen demands of the body, as pulmonary gas exchange is maintained such that

arterial PO2 (PaOa) remains within 10 mm Hg and arterial oxyhemoglobin saturation

(%Sa02) is maintained within 3% from resting levels (8, 52, 118, 220, 222). However,

over aie past two decades, evidence has ammulated to which suggest that in

appmxirnately 50 - 60% of endurance trained males with high aerobic capacities (23,

49

153) ( ~ 0 2 ~ - 2 65 mL kg-' - min-' or 5 L . min-'), the lung is a limiting factor dunng

strenuous aerobic work (45, 46, 217)- Several studies have shown that the lung is

unable to fully oxygenate venous blood at heavy (-75 - 80%~0maJ (76, 150), near-

maximal (-88 - 9 5 % ~ 0 2 4 (47, 128, 167, 188, 195) and maximal exercise (87, 145,

173, 188, 222), while prolonged (>55 minutes), submaximal exercise (65 - 70% \iOlmaw)

is not detrimental to pulmonary oxygenation (76, 91, 194). Therefore, during short-terni

heavy to severe exercise levels, Paon can drop to -75 mm Hg, and %Sa02 can drop to

< 92% by the end of exercise. Furthemore, it has been shown that arterial blood-gas

values are drastically altered within the first minute of constant-load, severe exercise

(47, 92, 145, 167, 184) (Table 7). This phenomenon has been termed exercise-induœd

hypoxemia (EIH), or exercise-induced arterial hypoxemia (EIAH). lndividuals with EIAH

also have widened alveolar-arterial partial pressure difference (AaD02), which can

increase to 40 - 50 mm Hg during severe exercise (47,92).

Between 1980 and 2000, there have been several published reviews on the

mechanisms of EIAH (45, 48, 93, 156, 185). These mechanisms are (1)

hypoventilation, (2) venoarterial shunt, (3) ventilation-perfusion (VAIQ) inequality. and

(4) pulmonary diffusion limitation. Of the four mechanisms, VAIQ inequality and

diffusion limitation seem to be the main contributors of EIAH (70, 91, 94, 156), since

each mechanism may account for about 50-60% of the increased alveolar-arterial

oxygen pressure difference (AaD02) during heavy exercise. Despite the previous

published reviews on EIAH, the purpose of the following review is to cover several

pertinent topics related to EIAH, namely summarixing the cnteria that have been used to

define EIAH, summarizing the previous reviews of the mechanisms of EIAH focusing

50 speutïcally on diffusion limitation, and, finally discussing gender and age Mects on

Table 7: Published snrdies that record changes in Pa02, AaOOz, and %Sa02 within the first minute of constant-lad, moderate ta severe sea level exercise (65 - 97% 904. P < 0.05 mmpared to cyding: A = change.

S ~ Y N Modeof %VO- A P a 4 during PaQ at AaûOzat %Saqat Combcted ii.i ex*. (L. min ) rom me fimt min& of minute 1 of mlnute 1 of m h m 1 of for A in t 2.5 minutes exmisa exerdse exerdse exerdse M Y

nf e~ercirpe mpared t" (mm Hg) (mm Hg) Wmp. -. ----.--- rest (mm Ha)

Present studv 12 Cyde 5.18 i 0.6 92.0 15.9 92.2 I 9.9 18.0 1 9.2 95.4 1 2.0 Yes Infusion sesdon Ptessnt study non- 12 Cyde 5.18 * 0.6 92.0 13.1 89.1 4 10.1 21.2 I 8.5 95.3 I 2.2 Yes Infusion session Shed (184) 7 Cyde 4.88 I0.4 =,O 10.6 93.2 I 4.7 16.5 k 8.1 97.4 I 0.4 Yes Rlce et al, (167) 6 Cycie 5.15 I 0.1 88.0 16.4 87.6 I 2.4 11.712.0 96.210.2 yes

Cycling M u n 9 - 6.12 96.5 14.0 90.5 16.9 gS.0 - Cyclln~ Sb 3 - 0.2 .B 2.7 2.6 4.0 0.8 - Dempsey et al. (47) 9 6 b n 4.97 i 0.2 93.0 16.0 72.5 i 8.8 40.1 i: 6.8 - Ye8 Hopklns and 12 Run 4.64 f 0.2 W.0 48.0 89.0 I 8 19.0 I 9.0 ge.g I 0.9 No McKenrie (02) Rice et al. (167) 7 Run 4.72 i 0.2 96.0 13.5 86.5 I 1.9 15.3 i 1 .O 96.2 I 0.2 Yes

Running Msrn 0 - 4-76. 95.0 15.9 82.7 24.8 98.6 - Runnlng $0 3 - 02 1.7 2.2 8.9 13.4 0.5 - Nielsen et al. (145) 7 1 Row 5.0 03.0 17.0 -88.0 30.0 -96.0 No

Where were actually 16 subjects in #is study. However, the required data &ed for this table could be dnly acquired fm 6 subjects (data from figure 3 of this paper (47)); t = males

52 DEFlNlNG ElAH

ElAH has had several definitions Fable 8). Some authors have defined ElAH

using Pa02 (3, 7, 47, 81), whiîe others have used %Sa02 (33, 48, 130, 153, 154).

Arterial oxyhemoglobin saturation follows the drop in Pa02 (48) but may also be

modified by the oxyhemoglobin dissociation curve shifts caused by changes in pH,

arterial PC02 (PaC02), and core (blood) temperature. The criteria to define ElAH are:

mild (i.e. Pa02 > 5 mm Hg (3)) to strict (%Sa02 < 90% (33); Pa02 75 mm Hg (47)).

As such, these definitions remain debatable. Several authors have not justified their

decision to use a specified cutoff value as their definition of EIAH. However, Powers et

al. (153) did explain why they used %Saoz s 91% as the cutoff point in his study.

Power's cutoff values are based on data from another study (222), which suggest that

untrained or moderately trained subjects maintain %Sa02 of -95% during maximal

exercise. Therefore, Powers suggested that "an exercise %Saop of -91% would be 4%

below the normal values for healthy untrained or moderately trained subjects during

intense exercise and [would bel below the 95% confidence limits (1 SD = 1.7%) of the

resolution of the ear oximeter to estimate %SaOs (153). Most recently, the definition

of ElAH has been updated by Dempsey and Wagner (48) to include three categories,

mild, moderate, and severe EIAH (Table 8). They purport that at the typical arterial

temperature and pH achieved at maximal exercise, the suggested guideline of a

minimal 3% decrease in %Saon from resting would be equivalent to a 10 mm Hg

decrease in resting Paon. As such, this drop would be "a cleariy measurable quantity

that signifies a failure of lung function to maintain arterial oxygenation (48)."

53 Table 8: Past definitions of EIAH.

Authors Pa02 (mm Hg) %Sa02 Masse-Biron et al. (1 30) 2 4%* Powers et al. (1 54) Powers et al. (153) Chapman et al. (33) Dempsey and Wagner (48)

s 92% 191% c 90% Mild 93 - 95% Moderate 88 - 93% Severe < 88%

Anguilaniu et al. (3) > 5" Anselme et al. (7) 2 8' Dempsey et al. (47) s 75 Hams et al. (79) Mild 10 > 20* . .

Severe > 20* indicates from rest

MECHANISMS OF ElAH

H y poventilation

During exercise, minute ventilation (VE) is elevated by increasing both respiratory

rate and tidal volume (146). However, hypoventilation occurs when alveolar ventilation

(v*) decreases below the rate required to maintain arterial blood gases (O2, COn) at

normal values (156). Therefore, the result of hypoventilation is decreased PAO2 and

PaOz, and excess levels of alveolar and arterial CO2 tensions (hypercapnia) in the

blood, while AaDO2 remains unaffected. A recent review of EIAH has suggested that a

PaC02 > 35 mm Hg during exercise indicates a lack of compensatory hyperventilation

while a PaC02 > 38 mm Hg suggests absence of compensatory hyperventilation (48).

lncreasing minute ventilation during exercise is important to maintain normal

%Sa02. Clinically, hypoventilation is recognized as PaC02 > 40 mm Hg (1 85) and may

account for 50% of the variability in %Sa02 during exercise in highly fit athletes (80,

141, 168). Several studies report that hypoventilation is an important mechanism in

ElAH (27, 47, 50, 57, 141, 166, 168) while others disagree (24, 34, 92, 142, 155). The

54 reasons for inadequate hyperventilatory response of highly trained athletes are many,

including a blunted chemoreflexive response (39, 80, 127, 143); aimow limitations due

to mechanical constraints (45, 49, 105, 132), and respiratory muscle fatigue (9, 10, 103,

An inadequate drive to breath during exercise in some athletes may be due to

blunted chernosensitivity. It has been shown that exercise i/~ is positively associated

with ventilatory chemoresponsiveness (127), and that some athletes have a blunted

hypoxic and hypercapnic responsiveness cornpared to mountain climbers and

sedentary controls (26, 127, 180). As such, exercising %Saoz and \jE may be

compromised in athletes with blunted drives to breath. Harms and Stager (80) tested

the hypothesis that low chemoresponsiveness contributes to EIAH. They analyzed

resting hypoxic (HVR) and hypercapnic ventilatory (HCVR) responsiveness, and found

that HVR and HCVR were lower in individuals with EIAH (P < 0.05). Furtherrnore,

exercising HVR was related to both ventilatory equivalent of oxygen (V~IVO~) and

carbon dioxide (\jEl\jCO2) (P < 0.05) suggesting that ElAH relates to the drive to

breath. This agrees with Cooper et al. (39) who found that HCVR was also lower in

athletes with ElAH compared to athletes without ElAH at rest, and at several

submaximal intensities (P < 0.05). Linear ngression analysis by Derchak et al. (49)

showed that HVR during exercise is also related to %Sa02, but that flow-limited athletes

had a lower HVR than non flow-limited athletes. Gavin et al. (57) showed that subjects

who dernonstrated reduced hyperventilatory responses to maximal exercise exhibited a

greater reduction in %Sa02 than those who did not exhibit reduced hyperventilatory

responses. However, Hopkins and McKenzie (92) also tested HVR response during

heavy exercise and found that there was no association between HVR and either

55 %Sa& or V ~ V O ~ (P > 0.05). implying mat hypoxk ventilatory drives are not related to

either vE or EIAH. Thenfore, the discrepancy in the data describing the relationship

between chernosensitiviiy and ElAH is still far from understood.

During hypoxia, athletes without a flow limitation can increase exercising \jE

signifïcantiy (wmpared to nomoxia) (34). On the other hand, flow-limited athletes

cannot increase \&. Most highly trained endurance athletes have little reserve to

increase &during exercise in hypoxia, and some even achieve a mechanical limitation

to increase ventilatory fiow at vOzmax (34,45,49, 105, 132); however, a flow limitation in

elite cyclists has been disputeci (142). In fact, ttiere seems to be a decreased drive to

breath in individuals who have a flow limitation (49, 132), due to feedback inhibition of

respiratory motor output (132). Breathing a helium-oxygen mixture prevents flow

limitations (47, 132) because the respiratory system becomes 'unioaded," tidal volume

and \jE increase (47), and end-expiratory fiow limitations are reduced (132). The extent

to which expiratory fiow limitation influences the increase in maximal exercise & was

recently studied (34). A flow limitation was characterized by having -56% of an

athtete's tidal-flow volume loop during maximal exercise meet the boundary set by their

maximal resting flow-volume Ioop (34). Athletes without a flow limitation have usually <

5% of their tidal-flow volume loop during maximal exercise meet the boundary set by

their maximal resting flow-volume loop. Chapman and colleagues demanstrated that the

mechanical limitation irnposed on these flow-limited athletes did not prevent the decline

in %Sa02 as non-flow-limited athletes experienced the same decrement in %Sa02 (34).

Thus, athletes who hypoventilate due to a flow limitation should not be too concerneci

with performance as ElAH can occur to the same extent in athletes without a flow

limitation.

56 Respiratory musde fatigue, resulting from the increased oxygen mst of breathing

with progressive exercise intensity, rnight also cause hypoventilation during severe

exercise in endurance athletes (9, 10, 103, 104). Therefore, ElAH may develop (47) and

performance can decrease (1, 47). Respiratory muscle fatigue has been previously

evaluated by using several different indices of fatigue, namely: maximum pleural or

transdiaphram pressure development (35, 36, 122, 147, 214), frequency spectrum shifts

of integrated electromyographic activity (IEMG) (25, Se), bilateral phrenic nerve

stimulation (BPNS) (9, 10, 15, la), or unloading of the respiratory muscles via (A)

pressure-assist deviee (82, 11 1) or (B), inspiring a less dense gas (e.g. helium) (47).

The results of these several studies are difficult to interpret, as many different indices of

fatigue were used, and there were wide ranges in age and athletic caliber of the

subjects. Moreover, interpretation remains difficult as respiratory muscle fatigue has

been shown to limit performance in some studies (56, 82, 104), but not in others (2,

111,125).

Although one ElAH review suggests that hypoventilation-from reduced

chernosensitivity, an airflow limitation, or via respiratory muscle fatigue-is nat an

important mechanism of ElAH (AS), curent data suggest that hypoventilation is

important in the development of EIAH (166, 168). Hence, the resuîts of these later

research papers confirms that further study is needed to elucidate the role of

hypoventilation as a mechanism of ElAH (185).

Venoarterial shunts

A second W a n i s m to explain ElAH in athletes is right-to-left shunt or venous-

to-artenal (venoarterial) shunts. Venoarterial shunts can be post-pulmonary or

intrapulmonary (48). Post-pulrnonary shunts occur when blood passes from the arteries

57 directly to the veins without going thrwgh the pulmonary system for gas exchange.

True anatomic shunts anse either from the m o u s blood draining from the bronchi or

from venous drainage via thebesian veins into the left ventride. On the other hand,

intrapulmonary shunts occur between the atria or ventrides (e.g. teratology of fallot) or

within the lungs (e.g. anastarnosis). Thus b t h types of shunts preclude oxygenation

by the lungs. The result is normal PA02 and PaC02, but low PaO2. In the healthy

individual at rest, there is a normal right-to-left shunt of 0.5 - 1.5% of the cardiac output

that bypasses oxygenation in the lungs (1 1,70), and accounts for approximately 49% of

the resting alveolar-arterial oxygen pressure differenœ of 8 - 10 mm Hg (61). If EIAH

does result from shunting during intense exercise, then breathing hyperoxic oxygen

mixtures would have a limited effect on Paon. However, it has been demonstrated that

breathing a gas mixture of 24 - 29% oxygen restores Pa02 and %Sa02 to normal in

runners who desaturate during heavy exercise (47, 150, 155). Thus, a venoarterial

(right-to-left) shunt is not a major mechanisrn of EIAH in elite athletes.

Ventilation-perfusion mismatch

Ventilation-perfusion (WQ) mismatch is the third mechanism to explain EIAH.

Ventilation-perfusion mismatch is a condition in which ventilation of alveoli is not

matched to perfusion of capillaries (175). Ventilation-perfusion mismatch, as

determineci by Multiple lnert Gas Elimination Technique (MIGET), results in decreased

Pa02, and widened AaD02, Mi le PAOZ. alveolar PC02 (PACO~), and PaCO2 remain

unaffaded. A low VJQ ratio causes hypoxemia, while high VJQ regions increase

dead space (175).

Normally, at rest VA is about 4 - 6 L min-' and Q (which is equal to pulmonary

blood flow) has a similar range. Thus. the ratio of WQ of the whole lung is 0.8 to 1.2.

58

However, the V ~ Q ratio must be matched at the alveolar-capillary level and \ i A l ~ for

the Mole lung is only an approximation of VAIQ in a l alveolar-capillary units (1 19). In

fact, the gravity dependent regions of the lung (the bases) are better perfused but less

ventilated than the independent regions (the apices) which are better ventilated but less

perfused (1 19). While gravity plays an important role in determining regional pulmonary

blood flow, it plays second fiddle to the anatomic structure of the arterial tree

(pulmonary vascular structure), which determines -75% of distribution of pulmonary

blood flow (62, 84).

Abnormalities of VAIQ are seen in hypoxemic athletes during prolonged (91) and

severe exercise (70, 94, 179, 197, 207). Furthemore, it is documented that V,JQ

inequality worsens with exercise intensity (70, 91). This is in contrast to horses (208)

which show no wotsening of V*/Q ratio's, pmbably due to the large splenic release of

red blood cells into the circulation.

It has been suggested that increases VA~Q mismatching during prolonged

exercise (-65% ~ 0 ~ ~ ) may be due to pulmonary edema (70, 91)) since the npid

transcapillary fluid flux may be in excess of the lymphatic drainage capacity of the lung.

Other possibilities of ~ / A / Q inequality are hypoxic non-uniform pulmonary

vasoconstriction at altitude (70), reduction of gas rnixing in large airways (179, 198), or

ventilation time constant inequality (207).

Pulmonary edema is an attractive mechanism of VJQ inequality in exercising

humans (91). Studies have shown that \IJb inequality is exaggerated in extrema

hypobaric hypoxia (210), and impraves with 100% oxygen breathing at altitude (70),

which would decrease pulmonary artery pressure and driving pressure for fluid flux.

Coates et al. (38) showed in sheep and goats that normoxic and hypoxic exercise is

59 associated with a two to threefold increase in lung lymph flow, which is compatible with

the hypothesis of exercise-induced pulmonary edema. Furthemiore, there is no

evidence of bronchownstriction (91) despite moderate VAIQ inequality. Also, ~plh

inequality persists up to twenty minutes post-exercise, even after ventilation and h

have returned to normal (179). These latter reasons suggest that pulmonary edema is

a potentiai cause of VAIQ inequality.

Non-uniforrn hypoxic pulmonary vasoconstriction may be another cause of V ~ Q

inequality during exercise (207). Pulmonary capillaries downstream of less wnstricted

small arteries would experience the high pressure, and edema could result, Therefore,

Wagner suggests that non-uniform vasoconstriction of certain capillaries may lead to

redistribution of blood flow (207).

A reduction of gas mixing in large aiways [decreased dead space ventilation] is

another cause of Wh inequality during exercise (179, 198). A study performed on

dogs shwed that WQ inequality worsened as dead space was reduced (198). They

hypothesized that the reduced dead space of exercise produced less gas mixing in

large airways, leading to a less homogeneous ~ / A / Q distribution in the lung. Howewr,

this mechanism of VJQ inequality seems unlikely in humans as dead space ventilation

was identical between a group of athletes who had VAIQ inequality cornpared to

another group of athletes who did not have V~IQ inequality (179). Another study

demonstrated that a reduction of gas mixing in large airways is not the cause for VJQ

inequality dunng exercise because no correlation was found between i/E normalized for

lung size or PaC02 and the resting log SD of the perfusion distribution (91). As such,

this mechanism of VAIQ inequality is unlikely.

Ventilation time constant inquaMy is the last reason why VJQ mismatching can o m r

during exercise. VAIQ inequality has been show to correlate with & (207). Therefore,

Wagner suggests that a mechanism dependent on a level of VE may contribute to the

mismatching of \iJQ during exercise. lncreased mucus secretion caused by the shear

stresses of high airflow rates during exercise or from minor changes in regional airway

tone associated with vagal reflexes (207) can worsen VJQ inequality. On the other

hand, no correlation was observed between VE at any level of exercise and resting log

SD of the perfusion distribution (961, suggesting that a ventilation tirne constant

ineguality may not be a major cause for VA/Q mismatch at any level of exercise

intensity. Therefore, the cause of VA/Q inequality remains speculative, but the favored

hypothesis is the formation of pulrnonary edema (5, 91).

Diffusion limitation

The fourth mechanism of EIAH is diffusion limitation, whereby decreases in PaOt

and increases AaD02 are observed. MlGET analysis has shown that -40 - 60% of the

AaD02 is due to diffusion limitation, while the remaining amount is due to V~IQ

inequality (70, 94). Diffusion limitation is not only evident in humans exercising at sea

level (94, 207), but it becomes more pronounced at simulated and actual aititude (69,

71, 207). As with VA/Q mismatching, diffusion limitation becomes worse with

increasing workload (69-71, 91, 94, 207), but rarely is a difision limitation in males

seen below \>OZ values of 2.5 - 3 1 min-' (-65% of V O ~ ~ ) (70, 91, 94). Aocording to

some authors (107) diffusion equilibrium depends simply on the ratio of the diffusional

conductance [diffusion capacity of the lung for oxygen (DL)] of the blood gas-bamer for

6 1

oxygen to the perfusional conductance (89) of the pulmonary vasculature for oxygen

Diisional conductance or DL, depends on two distinct processes, membrane

resistance [also known as the diffusion capacity of the membrane (DM)], and red cell

resistance [atso known the time taken for oxygen to react with Hb (WC)] (172). Red

cell resistance depends on the specific rate of oxygen uptake by red cells at d i r e n t

oxygen tensions, otherwise known as reaction rate of O2 to Hb (O), multiplied by

pulmonary capillary blwd volume (Vc) (172). Perfusional conductance of the pulmonary

vasculature for oxygen is dependent on the linear slope (p) between mixed venous and

arterial oxyhemogtoéin saturation taken from a standardized oxyhemoglobin

dissociation curve, and pulmonary blood flow (otherwise known as cardiac output or Q).

As exercise intensity increases, DL Iinearly increases, likely due to increased DM and Vc

from recruitrnent and distention (199, 224). However, P also increases because mixed

venous PO2 fais dramatically (107, 207). Therefore, the lowered mixed venous PO2

lengthens the time necessary for oxygen pressure equilibrium in the pulmonary capillary

(203), and p rises from about 2 mL . L" of blood. mm ~ g - ' at rest to 5 mL . L' of blood -

mm ~ g ' at heavy exercise (107. 207). Concomitantiy, Q also increases lineatly with

exercise intensity, and as a result, the D JPQ ratio can fall preupitously, especially in

athletes where maximal Q can be twice as great as matched, sedentary controls. When

diffusion equilibration is 99% mplete, the D ~ I ~ Q ratio is about 4.6; when DL/PQ ratio

is 3.0, there is 95% diffusion equilibration; and during maximal sea-ievel exercise in elite

athletes, D ~ P Q ratio can fall to 1.0, which represents 63% equilibration (48). The

decrease in the D ~ I ~ h ratio is even more pmnounced during aaite hypoxia, as Q and p

62 are higher at given submaximal exercise workloads (107, 204). Thus, a diffusion

limitation is evident during exercise, espeeially in highly trained athletes.

There are several reasons to explain ElAH caused by diffusion limitation due to

the fall in the D ~ I ~ Q ratio during exeruse. As with \iA/Q inequality, one possible reason

for diffusion limitation is pulmonary edema due to either increased thickening or stress

failure [rupture] of the alveolar-capillary membrane (5, 28). A second possibility for

diffusion limitation was discussed previously-a reduction in mixed venous PO2 (44,

156, 203), which reduces the rate of equilibration (44). A third possibility is very rapid

pulmonary capillary transit times (45, 46). Finally, non-uniformity of red blood ce11

distribution along a single capillary can atso alter DL and cause diffusion limitation. A

discussion of these possible reasons follows.

Pulmonary edema can decrease diffusing capacity of oxygen due to thickening of

alveolar-capillary membrane. During severe or long-term exercise, increased

hydrostatic pressures in the pulmonary artery can increase transcapillary fluid flux into

the interstitial space (206) and a low-grade pulmonary edema can occur (5, 27,28, 133,

179). Also, during extreme leveis of exercise, it has been shown that ultrastructural

mechanical stresses may result, causing leakage of plasma, protein, and red blood

cells, into the interstitial space (95, 218). Capillary wall stress depends on the

transmural pressure, which is the difference between the inside and outside of the

capillary. The greater the pressure differential between pressure inside and outside of

the capillary, the greater the stress. Evidence suggests that mean pulmonary capillary

pressures (PCP) in excess of 30 mm Hg are probably required to rupture the thin side of

the human pulmonary capillary wall (218), and cause pulmonary capillary stress failure

(PCSF). These pressures cause stress on the thin side the capillary wall of >50 kPa

which approaches the breaking strength of type IV collagen (218). However, recent

63 data has show that ElAH occurred in highly trained athletes despite maintenance of

the alveolar epithelium (51), suggesting that PCSF may not o m r in humans with high

oxygen uptakes. As such, pulmonary edema via a thickened alveolar-capillary

membrane without complete rupture of the blood-gas bamer is a more probable cause

of hypoxemia that occurs in athletes during severe exercise. On the other hand, studies

have shown that one to two hours of prolonged, sustained, moderate exercise (-75 to

77% v O ~ ~ ) did not alter lung density (1 24) or concentrations of red blood cells. or total

protein and leukotriene B4 (96) compareci to pre-exercise. This suggests that edema

occurs only during exercise of severe-intensity.

Dunng maximal exercise, thoroughbred race horses frequently show PCSF since

very high pulmonary arterial pressures of about 120 mm Hg, (and therefore PCP of

about 100 mm Hg), occur during intense exercise (> 80% i(Ozmax (219)). PCSF in

thoroughbred horses is calculated to occur at about 80 kPa, (218). More reœntiy,

PCSF was shown to occur at a pulmonary capiilary transmural pressure >75 mm Hg in

racehorses (18). Thus, pulmonary edema from PCSF is very possible cause of EtAH in

horses.

A second condition which inhibits diffusion of oxygen across the alveolar-capillary

barrier is the reduction of mixed venous POz (44, 156, 203). As the intensity of exercise

progresses towards maximum, the enhanced oxygen extraction in the skeletal muscles

reduces mixed venous PO2, and in elite athletes, the reduction in mixed venous PO2 is

greater than in sedentary wntrols. As such, the slope of the oxyhemoglobin

dissociation curve between mixed venous and arterial blood will increase (203), which

lowers the D~I~Q ratio. The skpe, P, and not the drMng pressure gradient be(ween

PAOZ and mixed venous POz is fundamentally responsible for the rate of equilibration

64 (44, 203). The reason why the slope is fat more important than the driving gradient

between PAO2 and mixed venous PO2 is explained mathematically by Wagner (203).

Wagner shows that for an inert gas, the rate of difision equilibrium is independent of

PAo2 and mixed venous PO2 but that the principle determinant of this rate is p.

Consequently, mixed venous POz can be an important factor in the development of

EIAH because it affects p. Take for example, a trained athlete who is performing

maximal exercise and has an exercising Q of 28 L . min*'. According to Dempsey (44,

the estimated available mean pulmonary capillary transit time is 0.45 seconds (Vc = 210

mL). However, since this athlete has PA02 of about 100 to 110 mm Hg and a mixed

venous PO2 of 10 to 15 mm Hg, then according to Wagner's mode1 (203), the time

requimd for complete equilibration of mixed venous blood with alveolar gas by the

pulmonary capillary is not 0.25 seconds as we would expect when mixed venous PO2 is

40 mm Hg (e.g. at rest), but is now -0.50 seconds at this exercise intensity. As such,

this exercising athlete now has a diffusion limitation due to the differences between the

required and available time for pressure equilibration, and this is due to the very low

mixed venous PO2 and consequently, high p.

Diffusion limitation consequent to rapid pulmonary capillary transit times (45, 46,

205) may also be responsible for EIAH. The average time a red blood cell and its

attendant plasma spend in the pulmonary capillaries during rest is about 0.75 seconds

(106, 171,202) at a mixed venous POz of 40 mm Hg (203). This is more than adequate

for oxygen to diffuse through the alveolar-capillary membrane, as pressure equilibnum

occurs about one third the distance down a pulmonary capillary (191). However, during

severe exercise, with cardiac outputs sometimes in excess of 40 L - min-', the blood

may only stay in the capillary 0.25 seconds or less, which is about the minimum time

65 available for pressure equilibrium at a PO2 of 40 mm Hg (202, 203). Dempsey's

theoretical scheme to explain ElAH (45, 46) suggests that Q and Vc increase linearly

up to about 25 L . min-' and 210 mL, thereby maintaining sulficient time of red blwd

cells to achieve pressure equilibrium. lncreasing flow, however, elevates capillary

transmural pressure, which recruits capillaries that were not prefused at rest and

distends capillaries that were already perfused. The resulting increase in capillary blood

volume has the important effect of reducing the rate of fall in capillary transit time (159,

160). As Q increases furlher in the trained individual, Vc reaches maximum dimensions

and mean pulmonary capillary transit time drops below the theoretical limit for partial

pressure equilibrium. Dempsey and Fregosi (46) also suggest that distribution of transit

times around the mean probably results in much faster transit times in some parts of the

lung, and these transit times may be reduced even further, as capillary flow is not

unifom but pulsatile (93,202). In fact, there is a vertical gradient of pulmonary capillary

transit tirnes with the shortest times at the bottom of the lung (86); hence, these

dependent regions may experience the highest capillary hydrostatic pressure gradient

for creating very rapid transit times.

Arterial desaturation is more likely to occur if the distribution of capillary transit

times about the mean is large. Capen et al. (31) tripled Q in dogs h m 2.9 to 9.9 L

min'' and founb-using videomicroscopy-that capillary transit times in the dependent

regions decreased from 2.0 to 0.8 seconds while capillary recruitment increased by

25%. However, further increases in Q caused no further change in transit time,

suggesting that the variation in red cell number and arrangement pattern among

different lung regions (also called relative dispersion = SD of transit timelmean transit

time) were the same at both lower and high cardiac outputs. This irnplies that full

66 recruitment of the pulmonary capillaries occurs in the dependent regions of the lung with

only modest increments in flow. This is in agreement with another study (160) in which

Q increased fmm 1.6 to 3.2 mC . min" in dogs whiie pulmonary capillary transit time

and relative dispersion decreased. Doubling blood flow again decreased transit time

further, but did not change either capillary recruitment or the relative dispersion. Later,

Presson et al. (159) showed that a threefoid increase in Q in dogs (from 4 to 12 ~mmin")

resulted in a decreased mean pulmonary capillary transit time to one-fourth of control

values, while relative dispersion decreased by 20%. The decreased transit times with

increased Q were made less severe by bath capillary recruitmenWhich ocairred

most in the top three cm of the lungsand by a narrowing of the transit time distribution

(159). Presson and colleagues proposed that the design feature of the pulrnonary

capillary bed in dogs keeps the shortest times from falling below the theoretical

minimum time for complete oxygenation (159). A later study by the same authors

showed that the rat lung is not as recruitable as the dog lung because the pulrnonary

capillaries of rats were nearly cornpletely perfused a lower than basal fiow rates (Q=

-69 mL kg-' min")(l61). These authors suggest that the nearly fully recruited Vc at

near resting flow rates in the rat (Q= -250 mL kg-' min") is one explanation for the

inability of smaller species with high resting metabolic rates (i.e. rodents) to increase

VOP above basal values.

Research has demonstrated aiat pulmonary capillary transit times obtained from

direct measurements in dog lungs using in vivo microscopy were the same as capillary

transit times measured indirectly in the entire dog lung using DLCO methods (32).

Nevertheless, despite research done on capillary transit times in dogs and rats, there is

no data examining pulmonary capillary transit times directly in exercising humans,

67 because methodological limitations make this impossible at present However, with

traditional DLCO measurements (either by single-breath method or rebreathing

technique), pulmonary capillary transit times during exercise can be calculated indirectly

(100, 213). It has been observed mean pulmonary capillary transit times during

exercise do not fall below 0.46 seconds (213), and that there is no relationship between

capillary transit time and AaD02 (213). As well, data exists which demonstrates that Vc

does not plateau in exercising humans (100, 163, 213, 224). However, this is in

opposition to several other studies demonstrating that Vc is maximally recruited during

various exercise intensities (1 1, 31 , 109, 160, 184). Indeed, the debate remains.

Inasmuch as capillary transit times cannot be directly measured in humans

during exercise, radionuclide cardiography has been used for direct right-to-left

ventncular or right ventricular-to-left atrial pulmonary transit times (i.e whole lung or

pulmonary transit time) at rest and during exercise in normal, healthy (14, 30, 60, 75,

90, 101, 102, 112, 113, 115, 123, 126, 164, 165) and diseased (29, 114) subjects.

Some have used technitium 99-m labelled human serurn albumin (99m~c HSA) (29, 30,

1 13, 115) instead of technitium 99-m labelled red blood cells (99m~c RBC) as a tracer for

PTT, but the differences in PTT curves (and thus PTT) are minimal (Jyrki Kuikka:

personal communication). Furthemore, if using the left ventricle instead of the left

atrium as the output curve, exercising PTT times increase by less than 0.4 seconds

(Jyrki Kuikka: personal communication). Assuming that pulmonary vessels have

negligible capacitance, then pulmonary capillary transit times refiect PTT, and, changes

in pulmonary capillary transit times reflect changes in PTT (Connie Hsia: personal

communication). Hence, first pass radionuclide cardiography may be sufficient to track

mean changes in red cell velocity through a pulmonary capillary. Indeed, one study has

demonstrated that most of the transit time variation in the pulmonary vasculature occurs

88 within the pulmonary capillary bed than in amducting arteries and veins (37). Clough

and coworkers (37) demonstrated that the artenal and venous trees contributed to less

than 20% of total lobar mean transit time in isolated dog lung lobe preparation. This

data suggests that changes in whole lung PTT should also affect capillary transit times.

The theoretical curve of pulrnonary capillary transit time vs Q put forth by

Dempsey and Fregosi in 1985 (46) and then in 1986 (45) resembles capillary transit

times of Warren's (213)- The theoretical cuwe also closely resembles an exponential

decay regression curve plotted f ' m several mean PTT's and cardiac outputs across

thirteen different studies (Figure 30), and the curve plotted from individual data points

from 72 hsalthy subjects across 5 different studies, including the present study (Figure

31) (30, 88, 1 12, 164). As such, this added evidence strengthens the concept that PTT

and pulmonary capillary transit times reflect each other. An interesting study from

Hopkins et al., (90) has shown that about 45% of red blood cells have mean right-to-left

ventricular pulmonary transit times of less than two seconds, and this was estimated

from morphometric data (59) to be six to seven times longer than capillary transit times.

Therefore, Hopkins estimated that in her highly trained subjects, 45% of red blood cells

had mean pulmonary capillary transit times of less than 0.3 seconds, very close to the

theoretical limit for partial pressure equilibrium. However, Hopkins et al. (90) did not

account for changes in mixed venous PO2 such that the 0.25 - 0.30 second theoretical

limit for partial pressure equilibrium is valid only if mixed venous PO2 = 40 mm Hg and

PAOZ = 100 mm Hg (203). Given the fact that during severe exercise PA02 is -1 00 mm

Hg and mixed venous POz is 15 to 20 mm Hg in endurance trained individuals (195,

200), the time required for pressure equilibrium is about 0.50 seconds (203). Therefore,

again assuming that PTT is six to seven times greater than capillary transit times, then

-70% and not 45% of the ceils in Hopkins paper (90) could have been below the

69 theoretical time required for complete partial pressure equilibflum (Le. those œlls with a

PTT < 3.0 seconds). Hopkins et al. (90) also obsenred significant relationships between

Pa02, AaDOn, versus PTT (r = 0.65 between PTT and Pa02; r = -0.59 between PiT

and AaD02) (88, go), thus supporting a rde for pulmonary diffusion limitation

consequent to rapid red cell vetocity through the lung. Other studies have show that

P T t decreases from about 5.4 - 9.3 seconds at rest to 2.3 - 2.8 seconds during

exercise at Q'S of 18 - 32 t min" in healthy normal humans (14, 101, 102, 1 12, 1 13,

115, 164, 165), but no arterial blood-gas measurernents were reported in these studies.

Clearly, the controversy in the literature and the potential importance of short

PTT as a cause of EIAH indicates that the relationship between pulmonary gas

exchange and PTT needs to be studied further. Nevertheless, despite the available

theory and data (e.g. Figures 30 and 31), decreased PTT cannot be the only cause for

EIAH. Due to the linear relationship between Q and ~ 0 2 , athletes who have high

maximal aerobic capacities (*ma 2 65 mL kg-' . min'' or 5 L min-') would have

similar maximal Q'S during exercise. Yet, only -50 - 60% of these individuals

experience ElAH (23, 153). Again, this may be due to variations in mixed venous PO2.

More research needs to be done on diffusion limitation consequent to rapid capillary

transit times in aailetes and on the effects of mixed venous POz.

A fourth, recently discovered condition that inhibits pulmonary diffusing capacity

is non-unifomity of RBC distribution along a single capillary. This phenomenon has

been explained by Forester (54). He explains that a single red blood cell sufficiently

distant [but not too distant] from its nearest neighbors bkes up oxygen most rapidly

since the plasma diffusion path is not encroached on. Forester states that "as the

num ber of cells in the capillary increases, the distance between the cells decreases,

70 and thus the path through the plasma becornes restricted, so that the rate of oxygen

uptake of the cell decreases; but of course, there are many more cells, so the total

uptake in the capillary rises, but less than proportionally." However, if spacing between

red blood cells increases too much (as with reduced Hct; (54)), diffusion capacity for the

whole lung (DLCO) decreases due to a reduœd membrane diffusion capacity (53). This

creates a non-unifonn spacing that can become large and inhibit membrane and thus

whole lung diffusion capacity. Employing a theoretical geometric model, Hsia et al., (99)

concluded that the greatest DLCû- 50% improvement in DLCû-was obsenred when

cells were evenly spaced (i.e. when there are 3 - 7 red blood cells per capillary segment

corresponding to a Hct of 18 - 43%). A more uniform distribution of red blood cells in a

capillary segment may explain part of the increase in DLCO during exercise (54,

independent of the number of capitlaries recruited or the Hct (99). lncreases in Hct

should further enhance a uniforrn distribution of red blood cells within a capillary

segment (Connie Hsia: personal communication). In an earlier study (224), red blood

cells that were released by dogs spleens' increased Hct from 40 to 55 % during

exercise, and this accounted for the enhanced DLCO of dogs compared to humans.

Humans have the capacity to release only -180 rnL of red blood cells from the spleen

dunng exercise (223), resulting in Hct increasing fiom 39 to about 42% (223, 224). This

is quite small compared to the twelve liters of blood released from the spleen of a 500

kg exercising horse (1 07). Thus, it is likely that uniformity of red blood cell spacing

improves during exercise, due to either augmented Hct or increased blood flow.

Diffision capacity of the whole lung for oxygen is usually measured as DLCO, or

diffusion capacity of the lung for carbon monoxide. When either membrane diffusing

capacity (DM) or pulmonary capillary blood volume (Vc) is reduced, then DLCO will also

be reduced. Dunng exercise up to maximum, DLCO increases by -66% (199), likely

71 due to inueased perfusion of pulmonary capillaries. However, DLCO is decreased

post-exercise compared to pre-exercise (72, 134, 183). Thus, could repeated exercise

bouts alter %Saoz and promote ElAH in athletes? Normally, onehalf of the 6% -14%

(73, 74) redudion of pst-exercise pulmonary di ision capacity has been shown to be

due to a 7% reduction in central blood volume as redistribution of blood to the more

distal regions occurs (74). Theoretically, an altered body position (from upright to

supine) can improve Vc and thus DLCO since gravity enhances venous retum and total

pulmonary blood flow. But, maintained diffusion impairment is shown to exist

independent of body position, indicating that passive relocation of blood into the

periphery due to gravity is unlikely. Rather, active vasoconstriction of pulmonary

vasculature andlor peripheral vasodilatation occurs post-exercise (192). However,

impaired DLCO postexercise has no effect on continuecl performance as VO-,

%Saoz, pH, and Paon were found to be similar between repeated bouts of exercise (72,

116, 134). In addition, since post-exercise DLCO is not related to aerobic capacity

(183), it seems unlikely that DLCO post-exercise correlates with EIAH in athletes.

GENDER

The incidence of ElAH has been traditionally assessed in mates. Recent

research has shown that about 76% of women with widely varying fitness levels (\iOmax

= 57 I 6 mL . kg" - min'; range = 31 to 70 mL . kg'' min") have ElAH (> 10 mm Hg

dmp in PaOI) (79). Almost half of the women with significant ElAH have VO- scores

within 15% of predicted normal values (79). This is interesting because males with

scores within 15% of predicted normal values (40 - 50 mL . kg*' min") do not

develop EIAH, Furthermore, inasmuch as a reduction in %Sa02 from 98% at rest to

93% during severe exercise in male athletes is sufficient to cause a measurable change

72 in maxiSmal aembic pomr (~0ha) that applodmates a 1% decrement in VO- for

each 1% decrement in %Sa% (154), women experience almost the same relaüonship

(78). In fact, a 3% reduction in %Sa02 from rest can have a signifiant detrimental effect

on women (78).

So why do a greater proportion of women develop ElAH compared to men, and

why do they develop it at a lower absolute V O ~ ~ ? Compared to adult men, adult

women have smaller lung volumes and lower maximal expiratory flow rates even when

correctecl for standing height (4, 131). It has been determined that women have smaller

Vc, reduœd airway diameter, smaller diffusion surface, and lower hemoglobin levels

relative to males at comparable statures, height and body mass (79). Consequentiy,

those factors can account for the greater proportion of women who develop ElAH

compared to men, and can also partly explain why women develop ElAH at a lower

absolute VO2m(u. Sinœ women have smaller Vc, reduœd airway diameter, smaller

diffusion surface, and lower hemoglobin levels relative to males at comparable statures,

height, and body mass, this also accounts for the differences in DLCO and

DLCOlalveolar volume between genders. DLCO and DLCOIalveolar volume is 12 and

10% lower in women, respectivety, than predicted in males (79). In a similar paper that

used the same whort of women, there was more expiratory flow limitation during heavy

exercise in highly fit versus less fit women, which caused higher end-expiratory and

end-inspiratory lung volumes and greater usage of their mam'mum available ventilatory

resewes (131). As such, the mechanisms for ElAH in women and men may be

difkrent. One paper has determined that ElAH in women was lessened and not

enhanced by prior maximal exercise (within 2 hours) (189). This implies that ElAH is not

caused by a mechanism that persists after the initial exercise period. This shows that

73 pulmonary oxygenation may improve with subsequent exercise (within 2 hours) in

wornen (and maybe men) with EIAH. The findings demonstrate that ElAH in women, as

in men, is an acute transient pathology that is present only during the exercise period.

Nevertheless, Pa02 responses to ninning and cycling exercise protocols are similar

from those previously observed in men (89). Further research is still needed comparing

EIAH and gender.

AG€

ElAH has been shown to also occur in older athletes (> 62 yrs old) (130, 143,

157). The incidence of ElAH (%Sa02 < 4% from rest) may occur in 50 (130), to 100%

(Pa02 < 10 mm Hg from rest) (130) of older athletes. For the same absolute workload,

the drop in Pa02 is greater in older than in younger athletes and the drop is significant

at 40°h w2- (157). Hypoventilation seems to be a major cause (157) due to

diminished chemosensitivity in this population (143), but the paucity of research on

ElAH and older athletes allows only for a cautious interpretation of the mechanism(s)

involved.

When interpreting arterial blood gases for the determination of ElAH in older

athletes, it is essential to know the range of normal values in this population. Sorbini

and colleagues (187) developed a regression equation between age and Pa02 based

on 152 subjects ranging from 14 - 84 years old. They noted a significant inverse

correlation (r = - 0.91; P c 0.01) between age and resting Pa02. Their regression

equation relating sea level Pa02 to age is: Paon = 109 - 0.43 (age) i 4.1 (1 SD).

Similarly, a recent paper has published reference values on arterial blood gases based

on 96 subjects ranging from 18 to 79 years old (41). They also reported at significant

inverse correlation (r = - 0.88; P c 0.01) between age and Pa02. Their regression

equation relating resting sea level Pa02 to age is: Pa02 = 0.1 8 (PB) - 0.25 (age) - 31.5

74 i 5.5, where PB is the baromdnc pressure. The demase in resüng Pa02 with age is

due to the increased AaDQ and has been show ta be associated mth increased VIJQ

inequality (209). As such, determination of ElAH should be based on changes in Paon

h m rest and not the absolute Pa@ value. For example, resting sea level Pa& in

individuals 62 years old is 80 - 82 mm Hg (157, t87), but it can be also -90 mm Hg

(41). For camparison, resting sea level Pa02 in young males 18 - 34 pars old is 100 i

5 mm Hg (41). Therefore, by not knowing the normal ranges in Pa02 in vanous

populations, the resting Pa02 values in older athletes could be misconstrued as

hypoxemia, since these low Pa02 values are representative of EIAH in young exercising

endurance athletes.

SUMMARY

The effect of ElAH on QOh, has been doeumented in highly fit male and fmale

athletes. The mechanisms of EtAH were presented and hypoventilation, di ision

limitation and VJQ inequality are the most probable medianisms of EIAH, but no

conclusive answers can be made at bis stage. Age and gender alsa play a role in

EIAH. The vast amount of data present in the literature reveals that ElAH is an acute,

transient, pathology because ElAH only occurs during exereise that is not aaitely

worsened by prior exercise. As quoteci h m a present review on EIAH: "significant

advances have beeil made, especially over the past decade.. . . . . .[yet] several

fundamental problems remain unresolved, in many cases because we are unable to

apply definitive measurements to the cornplex in vivo conditions present during

maximum exereise (48)." For these reasons, EIAH will continue to be an interesthg

pathology that will be studied among exercise physiologists for the ne& several years.

APPENDIX B. BACKGROUND INFORMATION OF PENTASTARCH AS A PLASMA VOLUME EXPANDER

Acute plasma volume expansion can be typically achieved via intravenous

infusion of crystalloid or colloid fluids. Crystalloids (e.g. Saline, Ringers Lactate,

Plasmalyte) are advantageous in that they are far less expensive than colloid therapy, it

promotes urine output, and the agents of crystalloids are chemically simple. However,

one problem associated with crystalloid therapy is that expansion is more difficult

because crystalloids leak into interstitium quite rapidly. As such, crystalloids may

promote extravascular lung water accumulation, and therefore, intravascular volume

expansion is below the volume infused. However, the advantages of using colloid

expanders (e.g. Albumin, Dextrans, Gelatins, Hydroxythyl starches) are that they have

the ability to hold water in the intravascular compartment since the aggregates of

submicroscopic molecules resists filtration and diffusion (170). Thus, the advantages of

colloids are that they produce less edema, and that they expand plasma volume

effectively with a lower volume (170). Furthermore, artificial colloids are free from the

risk of transmitting diseases (136). One disadvantage of colloids however, is that they

are more expensive than crystalloids. Another disadvantage of colloids is that

occasional severe anaphylactoid reactions (grade III and IV) can occur. However, that

has b e n shown to be only 0.006% of the time when using hydroxyethyl starch (e.g.

entasp pan? (169). Furthermore, dextran colloids have the same incidence of severe

aiaphyiactoid reactions, at about 0.008%@) (169). Later research has indicated that

grade 1, II or III anaphylactic shock occurs once in every 14169 infusions of hydroxyethl

starch, and that incidence is reduced greatly when only calculaüng the occurrence of

grade III shock (1 in 188918) (139). Thus, these colloids appear to be quite safe since

76 other natural substances such as blood, and oiher drugs have higher incidenees of

seven reactions than artifidal colloids (136). Of al1 colloids, expansion is greatest with

pentaspanQ such that Pentastarch > Dextran Hetastarch > Albumin (162). A single

does of 500 mL of pentaspanQ results in the elimination of approximately 70% of the

dose in 24 hrs (via urinary excretion) and approximately 80% of the dose within one

week (151). 24 hrs post-infusion, only about 7% of the dose remains in the bloodstream

and 33% remain in the extravascular space (139). The initial plasma half-Me of this

product is about 2.5 hrs (170), the intrinsic viswsity of pentaspanQ is 0.16 dltgr (139),

and time to maximum expansion is within the initial minutes of complete infusion (162).

entasp pan^ has a colloid osmotic pressure of 40 mm Hg, pulling the water from the

interstitium, providing an increase in intravascular volume in a ratio of 1.2 - 1.6:l .O of

the volume infused (170). A 500 mL bag of pantaspan@ (2640.45) indicates that the

average molecular weight is 264000 daltons and that the degree of substitution is 0.45

(140). This means that for every 100 glucose residues, there are about 45 hydroxyethyl

groups. So, while 1 gram of hydroxyethyl statch theoretically binds with 30 mL of water,

(140), Pentaspan" with its degree of substitution of 0.45, holds -13.5 mL of water.

Therefore, in a 500 mL bag of 10% pentaspanQ, there are 50 grams of hydroxyathyl

starch and thus since each gram of pentaspanm infused causes the passage of -13.5

mL of water into the intravascular space, the infusion of 500 mL of 10% pentaspanQ

expands BV by about 675 mL (1 70).

APPENDlX C. STATISTICAL ANALYSES Table 9: General subject characteristics and resting pulmonary fundion for each subject.

AC BW ME MV NC Li! PC JB SP SS AF PG Mean&SD Range 34 23 27 24 27 35 30 26 25 24 29 44 29.0 * 6.1 23 - 44

HR,,,.,, (beatsmin")

Peak Wattage (W)

H d (W Hb (g * L'l)

Methemogiobin (micrainits) Blood wlume (ml)

B W wlume (mi . kgm1) W C (L) FEV1 (Q FEV,m/C (%)

PEF (i.8-')

DLCO

(rnL min" mm Hg)

78

Table 10: Plasma volume changes between non-infusion and infusion sessions.

Subject Non-infusion day Infusion day Li PV (mL) Days between (mu (mL) non-infusion and

infusion sessions AC 3005 3505 +500 14

Range 3442to5911 2917to4799 -357to+1112 7 to 66 P = 0.003 change in PV (Paired t-test)

Table 11: Ratings of perceived exertion for the V O ~ ~ test, and both 6.5 minutes exercise tests (non-infusion and infusion sessions).

Subject ~0~~~ 6.5 minutes test non- 6.5 minutes test W..-

infusion session infusion session AC 17 18 18

Mean i SD 17.8 i 0.8 18.1 i 1.1 18.3 i 0.6

Range 17-19 15 - 19 17-19

Table 12: Repeated measures ANOVA for ~ 0 2

Source of Variance DF SS MS F P

Condition 1 4.54 4.54 0.041 0.38

Time 7 561 22.54 801 7.51 668.41 ~0.01

Condition x Time 7 18.57 2.65 0.52 0.82

Residual 70 357.79 5.tl

Tabie 13: Paiwise multiple comparison proœdures for VO* (Bonferroni's method).

Time comparison Difference of rneans t P < 0.05

O vs 6.5 -55.55 -53.20 Yes Ovs6 -56.24 -53.86 Yes Ovs5 -55.82 -53.46 Yes Ovs4 -54.78 -52.46 Yes O s 3 -52.80 -50.57 Yes O vs 2 -49.94 -47.84 Yes Ovsl -44.08 -42.21 Yes 1 vs 6.5 -1 1.47 -1 0.98 Yes 1 vs 6.0 -12.16 -1 1.65 Yes 1 vs 5 -1 1.74 -1 1.24 Yes 1 vs4 -10.70 -1 0.25 Yes 1 vs3 -8.72 -8.35 Yes 1 vs 2 -5.86 -5.61 Yes 2 vs 6.5 -5.61 -5.37 Yes 2 vs 6 4.30 -6.03 Yes 2 vs 5 -5.89 -5.63 Yes 2 vs 4 -4.84 -4.36 Yes 2-3 -2.86 -2.74 NO 3 vs 6.5 -2.75 -2.63 NO 3-6 -3.44 -3.29 Yes 3 vs 5 -3.02 -2.89 NO 3 ~ 4 -1.98 -1.90 NO 4 vs 6.5 -0.77 -0.73 NO 4 vs 6 -1.46 -1 -40 NO 4 ~ ~ 5 -1 .O4 -1 .O0 NO 5 vs 6.5 0.27 0.26 No 5 ~ ~ 6 -0.42 -0.42 NO 6 vs 6.5 0.69 0.66 No

Table 14: Repeated measures ANOVA for VE.

Source of Variance DF SS MS F P

Condition 1 486.80 486.80 0.27 0.61

Time 7 327839.90 46834.30 178.70 <0.01

Condition x Time 7 310.20 44.30 0.68 0.69

Residual 70 4552.0 65.00

Table 15: Pairwise multiple comparison procedures for & (Bonferroni's method).

Time cornparison Difference of means t P c 0.05

O vs 6.5 -1 39.02 -27.93 Yes O vs 6 -1 36.67 -27.46 Yes O vs 5 -1 32.42 -26.60 Yes O vs 4 -126.58 -25.43 Yes Ovs3 -1 19.14 -23.93 Yes Ovs2 -1 08.64 -21.42 Yes Ovsl -87.71 -1 7.29 Yes 1 vs 6.5 -51.31 -10.31 Yes 1 vs 6.0 -48.95 -9.83 Yes 1vs5 -44.70 -8.98 Yes 1 vs4 -38.86 -7.81 Yes 1 vs 3 -31.43 -6.31 Yes 1 vs2 -20.92 -4.12 Yes 2 vs 6.5 -30.39 -6.1 O Yes 2vs6 -28.03 -5.63 Yes 2vs5 -23.78 -4.78 Yes 2 ~ 4 -1 7.94 -3.60 YS 2vs3 -1 0.50 -2.1 1 No 3 vs 6-5 -1 9.88 -4.07 Yes 3 vs 6 -1 7-53 -3.59 Yes 3-5 -1 3.28 -2.72 NO 3 -4 -7.44 -1 -52 NO 4 vs 6.5 -1 2.45 -2.55 NO 4 vs 6 -1 0.09 -2.07 NO 4 ~ s 5 -5.84 -1 -20 NO 5 vs 6.5 -6.60 -1 -35 NO 5 ~ 6 -4.25 -0.87 NO 6 vs 6.5 -2.35 -0.48 NO

Table 16: Repeated measures ANOVA for heart rate.

Source of Variance DF SS MS F P

Condition 1 245.30 245.26 5.34 0.04

Time 7 181 331.3 25904.47 666.57 ~0.01

Condition x Time 7 33.70 4.81 0.56 0.77

Residual 77 663.20 8.61

Table 17: Pairwise multiple comparison procedures for heart rate (Bonferroni's method).

Time comparison Difference of means t P < 0.05

O vs 6.5 -98.17 -54.55 Yes O vs 6 -97.25 -54.04 Yes Ovs5 -94.88 -52.72 Yes Ovs4 -92.79 -51 .56 Yes Ovs3 -90.25 -50.1 5 Yes O vs 2 -85.92 47.74 Yes Ovsl -78.04 -43.37 Yes 1 vs 6.5 -20.1 3 -1 1 .18 Yes 1 vs 6.0 -1 9.21 -10.67 Yes 1 vs5 -16.83 -9.35 Yes 1 vs4 -1 4.75 -8.20 Yes 1 vs 3 -12.21 -6.78 Yes l m 2 -7.88 -4.38 Yes 2 vs 6.5 -1 2-25 -6.81 Yes 2 vs 6 -1 1.33 -6.30 Yes 2 vs 5 -8.96 -4.99 Yes 2 vs 4 -6.88 -3.82 Yes 2 ~ ~ 3 -4.33 -2.41 NO 3 vs 6.5 -7.92 -4.40 Yes 3vs6 -7.00 -3.89 Yes 3vs5 -4.63 2.57 No 3 ~ ~ 4 -2.54 -1.41 NO 4 vs 6.5 -5.38 -2-90 NO 4 vs 6 -4.46 -2.48 NO 4 vs 5 -2.08 -1.16 NO 5 vs 6.5 -3.29 -1 -83 NO 5 vs 6 -2.38 -1 -32 NO 6 vs 6.5 -0.92 -0.51 NO

Table 18: Repeated measures ANOVA for %Sa02.

Source of Variance DF SS MS F P

Condition 1 7.90 7.90 1.89 0.20

Time 7 889.85 127.12 47.32 e0.01

Condition x Time 7 9.16 1.31 1.18 0.33

Residual 76 84.46 1.11

Table 19: Pairwise multiple camparison procedures for %Saoz (Bonferroni's method).

Time cornparison Difference of means t P < 0.05

O vs 6.5 6.94 14.46 Yes O vs 6 6.36 13.39 Yes Ovs5 5.70 12.00 Yes Ovs4 4.45 9.38 Yes O vs 3 3.75 7.89 Yes O vs 2 2.82 5.93 Yes O vs 1 2.23 4.69 Yes 1 vs 6.5 4.71 9.82 Yes 1 vs 6.0 4.13 8.71 Yes 1 vs 5 3.47 7.31 Yes 1 vs4 2.23 4.69 Yes 1 vs3 1 .52 3.20 No 1vs2 0.59 1.25 No 2 vs 6.5 4.12 8.59 Yes 2vs6 3.54 7.46 Yes 2 -5 2.88 6.06 Yes 2vs4 1 -64 3.45 Yes 2vs3 0.93 1.96 No 3 vs 6.5 3.19 6.65 Yes 3 vs 6 2.61 5.50 Yes 3 vs 5 1.95 4.1 1 Yes 3-4 0.71 1 -49 No 4 vs 6.5 2.48 5.18 Yes 4-6 1.90 4.01 Yes 4vs5 1.24 2.62 No 5 vs 6.5 1.24 2.59 No 5 - 6 0.66 1.40 No 6 vs 6.5 0.60 1.21 No

Table 20: Repeated measures ANOVA for PaOa corrected to esophageal temperature.

Source of Variance DF SS MS F P

Condition 1 123.90 123.90 1.58 0.23

Time 7 5385.80 769.40 17.38 <0.01

Condition x Time 7 182.50 26.10 1.61 0.14

Residual 76 1 228.30 16.20

Table 21: Pairwise multiple comparison procedures for Pa02 corrected to esophageal temperature (Bonferroni's method).

Time comparison Difference of means T P < 0.05

O vs 6.5 16.83 8.65 Yes Ovs6 16.57 8.59 Yes O n 5 17.46 9.06 Yes O vs 4 15.33 7.95 Yes O vs 3 15.04 7.80 Yes Ovs2 13.00 6.74 Yes O vs 1 14.53 7.54 Yes 1 vs 6.5 2.30 1.18 No 1 vs 6.0 2-04 1 .O6 No 1 vs5 2.93 1.52 No 1 vs4 0.80 0.42 No 1 vs 3 0.51 0.27 No 1 vs 2 -1.53 -0.79 NO 2 vs 6.5 3.83 1.97 No 2-6 3.57 1.85 No 2vsS 4.64 2.32 No 2 vs 4 2.330 1.21 No 2vs3 2.042 1 .O6 No 3 vs 6.5 1.79 0.92 No 3vs6 1.53 0.79 No 3 vs 5 2.42 1.26 No . 3-4 0.29 0.1 5 No 4 vs 6.5 1.50 0.77 No 4vs6 1 -24 0.65 No 4vs5 2-13 1.11 No 5 vs 6.5 -0.63 -0.33 No 5 ~ ~ 6 -0.90 -0.47 NO 6 vs 6.5 0.26 0.14 No

Table 22: Repeated measures ANOVA for AaOOz correeted to esophageal temperature.

Source of Variance DF SS MS F P

Condition 1 6.23 6.23 0.1 1 0.74

Time 7 6596.1 3 942.30 37.00 ~0.01

Condition x Time 7 172.29 24.61 1.55 0.16

Residual 76 1204.64 15.85

Table 23: Pairwise multiple comparison proœdures for AaD02 corrected to esophageal temperature (Bonferroni's method).

Time comparison Difference of means t P < 0.05

O vs 6.5 -18.71 -1 2.61 Yes O vs 6 -1 8.49 -1 2.66 Y ~ s Ovs5 -19.15 -1 3.1 1 Yes Ovs4 -1 7.09 -1 1.70 Yes Ovs3 -1 6.33 -1 1 .18 Yes O vs 2 -1 3.92 -9.53 Yes Ovs l -1 3.65 -9.35 Yes 1 vs 6.5 -5.07 -3.45 Yes 1 vs 6.0 -4.85 -3.42 Yes 1 vs 5 -5.50 -3.32 Yes 1 vs4 -3.44 -3.77 Yes 1 V S ~ -2.68 -2.36 NO 1 V S ~ -0.28 -1 -84 NO 2 vs 6.5 -4.79 -0.19 NO 2 ~ 6 -4.57 -3.23 NO 2 ~ ~ 5 -5.23 -3.13 NO 2 -4 -3.17 -3.58 Y ~ s 2-3 -2.41 -2.1 7 NO 3 vs 6.5 -2.38 -1.61 NO 3 ~ ~ 6 -2.1 6 -1.48 NO 3 ~ 5 -2.82 -1.93 NO 3 - 4 -0.76 -0.52 NO 4 vs 6.5 -1 -63 -1 -10 NO 4 vs 6 -1 -40 -0.96 NO 4 ~ ~ 5 -2.06 -1 .14 NO 5 vs 6.5 0.43 0.29 No 5vs6 0.65 0.45 No 6 vs 6.5 -0.22 -0.14 NO

86 fable 24. Repeated tneasures ANOVA for PaC02 corrected to esophageaf temperature.

Source of Variance DF SS MS F P

Condition 1 2.48 2.48 0.15 0.71

f?me 7 337.42 48.20 6.82 ~0.01

Condition x Time 7 14.37 2.05 0.88 0.53

Residual 76 178.29 2.35

Table 25: Painivise multiple comparison procedures for PaC02 corrected to esophageal temperature (Bonferroni's method).

Time cornparison Dierence of means t P c 0.05

O vs 6.5 -0.45 -0.58 NO 0 - 6 -0.12 -0.1 6 NO O V S ~ -0.66 -0.85 NO O V S ~ -1 29 -1.68 NO O vs 3 -2.25 -2.92 NO Ovs2 -3.42 -4.44 Yes Ovsl -3.48 -4.52 Yes 1 us 6.5 3.03 3.89 Yes 1 vs 6.0 3.36 4.36 Yes 1 vs5 2.82 3.66 Yes 1 vs4 2.19 2.84 No 1vs3 1.23 1 -60 No 1 vs2 0.06 0.08 No 2 vs 6.5 2.97 3.82 Yes 2vs6 3.30 4.28 Yes 2vs5 2.76 3.59 Yes 2vs4 2.1 3 2.76 No 2vs3 1.17 1.52 No 3 vs 6.5 1.80 2.31 No 3vs6 2.22 2.76 No 3vs5 1.59 2.06 No 3vs4 0.96 1.24 No 4 vs 6.5 0.84 1 .O8 No 4vs6 1.g7 1.52 No 4vs5 0.63 0.82 No 5 vs 6.5 0.21 0.26 No 5vs6 0.54 0.70 No 6 vs 6.5 -0.33 4-43 NO

Table 26: Repeated rneasures ANOVA for pH correeted to esophageal temperature.

Source of Variance DF SS MS F P

Condition 1 0.01 0.01 7.38 0.02

Time 7 1.13 0.16 131.19 <0.01

Condition x Time 7 0.01 0.00 1.68 0.13

Residual 76 0.03 0.00

Table 27: Pairwise multiple comparison procedures for pH corrected to esophageal temperature (Bonferroni's method).

Time cornparison Oifference of means t P < 0.05

O vs 6.5 0.24 23.08 Yes O vs 6 0.23 22.76 Yes Ovs5 0.21 20.14 Yes Ovs4 0.18 17.64 Yes O vs 3 0.15 14.82 Yes 0 -2 0.12 1 1.46 Yes 0 -1 0.07 7-00 Yes 1 vs 6.5 0.17 16.14 Yes 1 vs 6.0 0.16 15.76 Yes 1 vs 5 0.1 3 13.14 Yes 1 vs4 0.1 1 10.64 Yes l m 3 0.08 7.82 Yes l m 2 0.05 4.46 Yes 2 vs 6.5 0.12 1 1.72 Yes 2vs6 0.12 1 1 -30 Yes 2vs5 0.08 8.67 Yes 2vs4 0.06 6.18 Yes 2vs3 0.03 3.36 Yes 3 vs 6.5 0.09 8.39 Yes 3vs6 0.08 7.94 Yes 3 -5 0.05 5.32 Yes 3 vs 4 0.03 2.28 No 4 vs 6.5 0.06 5.59 Yes 4vs6 0.05 5.12 Yes 4vs5 0.03 2.50 No 5 vs 6.5 0.03 3.12 No 5vs6 0.03 2.62 No 6 vs 6.5 0.04 0.52 No

Table 28: Repeated measures ANOVA for standard base excess (SBE) correded to esophageal temperature.

Source of Variance DF SS MS F P

Condition 1 1 1.20 11 .19 2.21 0.17

Time 7 3394.40 484.91 127.52 cO.01

Condition x Time 7 10.80 1.55 0.92 0.50

Residual 76 127.90 1.68

Table 29: Pairwise multiple comparison procedures for standard base excess (SBE) wrrected to esophageal temperature (Bonferroni's method).

Time cornparison Difference of means t P c 0.05

O vs 6.5 1 2.42 21.74 Yes O vs 6 12.25 21.69 Yes O vs 5 10.98 19.45 Yes Ovs4 9.69 17.15 Yes O v s 3 7.89 13.97 Yes Ovs2 5.75 10.19 Yes O vs 1 2.93 5.19 Yes 1 vs 6.5 9.49 16.61 Yes 1 vs 6.0 9.32 16.50 Yes 1 vs 5 8.05 14.25 Yes 1 vs4 6.75 1 1.96 Yes 1 vs 3 4-95 8.77 Yes 1 vs 2 2.82 4.99 Yes 2 vs 6.5 6.M 1 1.67 Yes 2 vs 6 6.50 1 1.50 Yes 2 vs 5 5.23 9.26 Yes 2 -4 3.93 6.97 Yes 2vs3 2.1 3 3.78 Yes 3 vs 6.5 4.53 7.93 Yes 3 vs 6 4.36 7.72 Yes 3vs5 3.10 5.48 Yes 3 vs 4 1.80 3.19 No 4 vs 6.5 2.73 4.78 Yes 4 -6 2.56 4.54 Yes 4vs5 1.30 2.29 No 5 vs 6.5 1 A4 2.51 No 5-6 1 -27 2.24 No 6 vs 6.5 0.17 0.30 No

89 Table 30: Repeated measures ANOVA for bicarbonate (HCOj) correctecl to esophageal temperature.

Source of Variance DF SS MS F P

Condition 1 22.46 22.46 9.22 0.01

Time 7 21 83.85 31 1.98 179.99 <0.01

Condition x Time 7 4-54 0.65 0.73 0.65

Residual 76 67.64 0.89

Table 31: Pairwise multiple comparison procedures for bicarbonate (HCOi) corrected to esophageal temperature (Bonferroni's method).

Time comparison Difference of means t P < 0.05

O vs 6.5 9.81 25.41 Yes Ovs6 9.71 25.47 Yes OvsS 8.67 22.74 Yes Ovs4 7.69 20.18 Yes Ovs 3 6.19 16.24 Yes 0 -2 4.29 11.26 Yes O vs 1 2.1 1 5.53 Yes 1 vs 6.5 7.71 19.95 Yes 1 vs 6.0 6.70 19.94 Yes l m 5 6.56 17.21 Yes 1 vs4 5.58 14.65 Yes 4 vs 3 4.08 10.71 Yes 1 -2 2.18 5.73 Yes 2 vs 6.5 5.52 14.30 Yes 2vs6 5.42 14.21 Yes 2vs5 4.38 1 1 -48 Yes 2vs4 3.40 8.92 Yes 2-3 1.90 4.99 Yes 3 vs 6.5 3.62 9.38 Yes 3vs6 3.52 9.23 Yes 3vs5 2.48 6.49 Yes 3vs4 1.50 3.94 Yes 4 vs 6.5 2.12 5.49 Yes 4vs6 2.02 5.29 Yes 4-5 0.98 2.56 No 5 vs 6.5 1.1 5 2.97 No 5 vs 6 1.04 2.73 No

Table 32: Repeated measures ANOVA for esophageal temperature.

Source of Variance DF SS MS F P

Condition 1 0.083 0.08 0.33 0.58

Time 7 150.94 21 .56 257.54 ~0.01

Condition x Time 7 0.1 3 0.02 0.40 0.90

Residual 77 3.50 0.05

Table 33: Pairwise multiple comparison procedures for esophageal temperature (Bonferroni's method).

Time comparison Difference of means t P c 0.05

O vs 6.5 -2.97 -35.57 Yes Ovs6 -2.83 -33.87 Yes Ovs5 -2.55 -30.58 Yes Ovs4 -2.35 -28.08 Yes Ovs3 -2.14 -25.59 Yes Ovs2 -1.86 -22.30 Yes O vs 1 -1.55 -1 8.56 Yes 1 vs 6.5 -1.42 -1 7.01 Yes 1 vs 6.0 -1.28 15.31 Yes 1 -5 -1 .O0 - 1 2.02 Yes 1 vs4 -0.80 -9.53 Yes 1 V S ~ -0.59 -7.03 Y ~ s 1 vs2 -0.31 -3.74 Yes 2 vs 6.5 -1.1 1 -1 3.27 Yes 2vs6 -0.97 -1 1.57 Yes 2 vs 5 -0.69 -8.28 Y ~ s 2vs4 -0.48 05.79 Yes 2vs3 -0.28 -3.29 Yes 3 vs 6.5 -0.83 -9.98 Yes 3 vs 6 -0.69 -8.28 Yes 3 -5 -0.42 -4.99 Yes 3 ~ ~ 4 -0.21 -2.49 NO 4 vs 6.5 -0.63 -7.48 Yes 4 vs 6 -0.21 -5.79 Yes 4 vs 5 -0.63 -2.49 NO 5 vs 6.5 -0.48 -4.99 Yes 5 -6 -0.21 -3.29 ' Y ~ s 6 vs 6.5 -0.14 -1 .?O NO

91 Tabfe 34: Repeated measures ANOVA for Alveotar PO2.

Source of Variance DF SS MS F P

Condition 1 74.8 74.82 3.51 0.09

Time 7 173.4 24.76 2.43 0.03

Condition x Time 7 20.8 2.97 0.79 0.59

Residual 76 284.0 3.74

Table 35: Pairwise multiple companson procedures for alveotar PO2 (Bonferroni's method).

Tirne cornparison Difference of means t P < 0.05

O vs 6.5 -1 -90 -2.04 NO O vs 6 -1 3 2 -2.08 NO 0 - 5 -1 -69 -1.83 NO O vs 4 -1 .n -1 -91 NO 0 -3 -1.30 -1 -40 NO O V S ~ -0.92 -1 .O0 NO Ovsl 0.88 0.95 No 1 vs 6.5 -2.78 -2.98 NO 1 vs 6.0 -2.80 -3.02 NO 1 vs 5 -2.57 -2.78 NO l m 4 -2.64 -2.86 NO 1-3 -2.17 -2.35 NO 1 V S ~ -1.80 -1.95 NO 2 vs 6.5 -0.97 -1 .O4 NO 2 vs 6 -0.99 -1 .O7 NO 2 ~ ~ 5 -0.76 -0.82 NO 2-4 -0.84 -0.91 NO 2-3 -0.37 -0.40 NO 3 vs 6.5 -0.61 -0.65 NO 3-6 -0.63 -0.68 NO 3-5 -0.40 -0.43 NO 3 ~ ~ 4 -0.47 -0.51 NO 4 vs 6.5 -011 4 -0.15 NO 4vs6 -0.1 5 -0.17 No 4 vs 5 0.08 0.08 No 5 vs 6.5 -0.21 -0.23 NO 5-6 -0.23 -0.25 NO 6 vs 6.5 0.0 1 0.9 9 No

Table 36: Repeated measures ANOVA for PS0.

Source of Variance DF SS MS F P

Condition 1 16.85 16.85 6.87 0.02

Time 7 1 343.45 191.92 108.56 <0.01

Condition x Time 7 7.06 1-01 1.78 0.10

Residual 76 42.98 0.57

Table 37: Pairwise multiple wmparison procedures for PS0 (Bonferroni's method).

Time comparison Difference of means t P c 0.05

O vs 6.5 -8.13 -20.91 Yes Ovs6 -7.90 -20.50 Yes 0 - 5 -6.82 -1 7.72 Yes 0 - 4 -5.96 -1 5.47 Yes O vs 3 -4.89 -1 2.70 Yes 0 - 2 -3.67 -9.52 Yes Ovs 1 -2.22 -5.76 Yes 1 vs 6.5 -5.91 -1 5.20 Yes 1 vs 6.0 -5.68 -14.74 Yes 1 vs5 -4.61 -1 1.96 Yes 1 vs4 -3.74 -9.71 Yes 1 vs3 -2.67 -6.94 Yes 1 us2 -1.45 -3.76 Yes 2 vs 6.5 -4.46 -1 1.47 Yes 2vs6 -4.23 -1 0.98 Yes 2 vs 5 -3.16 -8.21 Yes 2 vs 4 -2.30 -5.96 Yes 2 vs 3 -1.23 -3.18 NO 3 vs 6.5 -3.23 -8.31 Yes 3vs6 -3.00 -7.80 Yes 3-5 -1.94 -5.02 Yes 3-4 -1 .O7 -2.77 NO 4 vs 6.5 -2.16 -5.56 Yes 4vs6 -1.94 -5.02 Yes 4 ~ ~ 5 -0.87 -2.25 NO 5 vs 6.5 -1 -30 -3.33 Yes 5-6 -1 .O7 -2.78 NO 6 vs 6.5 -0.23 -0.58 NO

Tabk 3û: Repeated masures ANOVA for mean pulmonary transit times at 3rd minute of exefcise during the 6.5 minute exercise tests.

Source of Variance DF SS MS F P

Condition 1 0.83 0.83 0.85 <0.01

Meaiod 1 0.00 0.00 65.60 0.43

Condition x Methcd 1 0.00 0.00 2.17 0.16

Residual 8 0.01 0.00

Table 39: Repeated measures ANOVA for distribution of pulmonary transit times at 3rd minute of exercise during the 6.5 minutes exercise tests.

Source of Variance DF SS MS F P

Condition 1 0.048 0,048 0.85 0.38

Tîme 8 33356.40 6671 .28 65.60 ~0.01

Condition x Time 5 692.1 1 138.42 2.17 0.08

Residual 40 2553.38 63.83

Table 40: Pairwise multiple cornparison procedures for distribution of pulmonary transit times at 3rd minute of exercise during the 6.5 minute exercise tests.

Time interval Difference of means t P < 0.05 camparison

c l vs 1-1.8 -16.93 -5.21 Yes Yes Yes No No Yes No Yes Yes Yes Yes Yes Yes Yes

Table 41: One way ANOVA for day-to-day variability [intraobsewer error] in assessing mean pulmonary transit times at 3rd minute of exercise during the 6.5 minutes exercise tests.

Source of Variance DF SS MS F P

Between treatments 2 0.007 0.00 0.04 0.95

Residual 51 3.94 0.077

Total 53 3.95

Table 42: One way ANOVA for day-today variability [intraobserver error] in assessing ejection fraction at 3rd minute of exercise during the 6.5 minutes exercise tests.

Source of Variance DF SS MS F P

Between treatrnents 1 3.56 3.56 0.134 0.72

Residual 32 847.06 26.47

Total 33 850.62

Table 43: One way ANOVA for day-to-day variability (intraobserver error] in assessing mean end diastolic volume at 3rd minute of exercise during the 6.5 minutes exercise tests.

Source of Variance DF SS MS F P

Between treatments 1 2.38 2.38 0.002 0.97

Residual 32 40860.35 1276.89

Total 33 40822.74

Table rM: One way ANOVA for ratings of perceived exertion (RPE) between al1 three exercise sessions.

Source of Variance DF SS MS F P

Between treatments 2 1.56 1.30 1.88 0.18

Residual 22 9.1 1 0.78 0.41

Total 35 24.97

Table 45: Summary of F values from the repeated measures ANOVA tables.

F Values Variables Condition Time Condition x Time

Heart rate

Mean PTT at 3' minute

Distribution of PTT at 3' minute

Esophageal temperature

min- I INFUSION

Table 48: ME raw data for both 6.5 minutes exercise tests. Pa02, PaC02, pH correctecl to esophageal temperature.

SBE

\jo2= mL kg-' min-'; P a , P A , AaMh, PEP2 = mm Hg; \jE = L min"; HC0< (bicarbonate), SBE (standard base excess) = rnmol .CI;

MD = missing deta; RER = resplratory exdiange ratio; = used linear tegression formula to calailate esophageal temperature because temperature probe was not inserted properly (y = 37.74 + 0.238Yime). SE€ -0.32.

Table 49. NC raw data for both 6.5 minutes exercise tests. PaOz, PaC02, pH corrected to esophageal temperature.

HCa- SBE w

= mL kg*' m ~ ' ; Pa02, PA&, &DO2, P& = mm Hg; vE = L . min-'; HCO; (bicarbonate). SBE (standard base exœss) = mmol .CI; MD = rnissing da@ RER = respiratory exchange ratio; = used linear regression formula to cakuïate esophageal temperature because temperature probe was not inserted properiy (y = 37.74 + 0.238Yime). SEE r0.32.

Table 6k PC raw data for both 6.5 minutes exercise tests. Pa02, PaC02, pH correctecl to esophageal temperature.

h = mL . kg" mln-'; PaO,, PAOZ, AaD4, P A = mm Hg; ' = L . min-'; H C 0 i (bicarbonate), SBE (standard base 8x0855) = mmoi .L-l; RER respiratory endiange ratio; = used linear regression formula to calculate esophageal temperature because temperature probe was not inserted proper (y = 37.74 + 0.238Yime), SEE -0.32.

Table 62: BW raw data for both 6.5 minutes exercise tests. PaO2, PaC02, pH correctecl to esophageal temperature,

V O ~ = mL . kg-' - min-'; Pa%, P~02, ASID%. P* =mm ~ g ; VE = L - min-'; H C O ~ (bicarbonate), SBE (standard base excess) = mmoi .L-'; RER = respiratory exchange ratio.

Table 63: AC raw data for both 6.5 minutes exeruse tests. Pa02, PaC02, pH wrrected to esophageal temperature.

V O ~ = m l ? kg-' min-'; PA0z, AaW2, P d 2 = mm Hg; i/E = L - min-'; HCO; (bicarbonate). SBE (standard base excess) = mrnol .CI; RER = respiratory exchange ratio.

Table 6k SP raw data for both 6.5 minutes exercise tests. Pa02, PaC02, pH correcteci to esophageal temperature,

TEMP Pa% =qJ- Ph02 hWz %Sa02 PaC02 RER P d 2 HR PAO2 pH i(E HCW SBE -

Table 6& SS raw data for both 6.5 minutes exercise tests. Pa02, PaC02, pH correcteci to esophageal temperature.

i/02= mL kgv' min-'; PaOz, PAOZ, AaD02, P A = mm Hg; VE = L . min-'; HCOi (bicarbonate), SBE (standard base excess) = mmol .L"; RER = respiratory exchange ratio.

Table 56: AF raw data for both 6.5 minutes exercise tests. Pa02, PaC02, pH correcteci ta esophageal temperature,

--

~ O Z = mL kg-' min-'; Pa% P A ~ ~ , AaD4, P&Î = mm Hg; i /E = L . min-'; HCa- (bicarbonate), SB€ (standard base * ~ c e s ~ ) = m m .rl; RER = respiraîory exchange ratio.

6.1 MD Aven- MD of lu t 2.5

38.6 38.6

86.4 65.7

80.8 87.4

116.0 114.9

28.2 27.5

94.4 91.2

33.7 34.5

l.W 1.01

119.1 117.2

182 180

-3.1 -2.28

7.22 7

151.0 141.0

12.8 13.6

-13.4 -12.4

Table 57: PG raw data for boai 6.5 minutes exercise tests. PaOz, PaC02, pH conected to esophageal temperature.

TlME \jo2 TEMP Pi& PAOZ h D O I %&O2 P i C a RER P d HR PA% PH QE HCW SBE (min) OUTPUT cc) -

P A NON-INFUSION

SESSION .

mL kg" min-'; PaOz, PA@, Aa-, P A = mm Hg; VE = L min-'; HCOi (bicarbonate), SBE (standard base ewœss) = mmol .rl; RER = respiratory exchange d o .

APPENDIX E. INDIVIDUAL RAW DATA TABLES: CARDIAC FUNCTION AND RED CELL PULMONARY TRANSIT TlME

Table 58: Cardiac fundion data obtained at minute 3 of severe exercise. Non-infusion session.

indiCates missing data due to technical dicutties; HR = heait rate (bats . min"); index (L - m2 - min-'); SV, ESV and EDV index (mL . m2); PBV

index (mL . L-'); Q = carrilac output (L . min-'); 00, (calculated O2 transport) and h 2 (L . min-'); BSA or body su- area (m2); Hb (g . L"); Ca02 or calculated arterial oxygen content (mL . L-'); CvOz or calwtated mixed venous content (mL L").

Table 69: Cardiac fundion data obtained at minute 3 of severe exercise. Infusion session.

Indicales missing data due to technical d i i îües; HR = heart rate (beats . min-'); Q index (L . m2 . min-'); SV, ESV and EDV index (mL . mz); PBV index (mL . c'); Q = cardiac output (L . min-'); DO2 (ePlalated O2 transport) and V O ~ (L , min-'); BSA or body surface area (m2); Hb (g . L-'); C a or calculated artevial oxygen content (mL . L"); Cv02 or calwlated mbced venous content (mL . c').

Table 61: Distribution descriptors of each wbject's PTT transport fundion during minute 3 of constant-load, severe exercise.

I I PTT I I I I I

. ~-~~ IP valwsl 0.10 1 O. 003 0.004 1 0.67 1 0.67 O. 78 1 0.54 *-• WIcates tedinical probkms with first-pass data and thus unable to fit airues; N = non-infusion session; I = infusion session; HR =

I heart rate (beats min"); PTT = red cell pulmonary transiî time (seconds); relative dispersion = dispersion/PTT; PTT/RR describes the pulmonary blood volume in number of stroke Wumes and is defineci as PTT x HRIBO; skewness is an index of wnm asymmetry; Kurtosis Is an index of curw iiatness. This table was created from the meîhods of Capderou et al. (29)

APPENDIX F. FlRST PASS RAW DATA AND GAMMA VARIATE FIT FOR CALCULATION OF RED CELL PULMONARY

TRANSIT TlME Figure 9: Raw data and gamma variate fit for subject AC at minute 3 of constant-load, severe exercise.

- RV gamma vanate fit -+ LV gamma variate fit

O RV raw data L V n w data

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Time (seconds)

Infusion session 175 'O0 1 O 0 .

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Time (seconds)

113 Figure IO: Raw data and gamma variate fit for subject JE at minute 3 of constant-load, severe exercise.

Non-infusion session

300 1 O - RV gamma variate Fi -- LV gamma variate fit

O RV raw data 0 LV raw data

Time (seconds)

Tirne (seconds)

114 Figum 11: Raw data and gamma variate fit for subject UI at minute 3 of eonstant-load, severe exereise.

250 1 Noninfusion sessiwn RV gamma variate fit LV gamma variate f i

A O RVrawdaîa

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4

Time (seconds) Infusion session

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 i 3 1 4

Time (seconds)

Figure 12: Raw data and gamma variate fit for subject AC at minute 3 of constant-load, severe exetcise.

4m , Non-infusion session m e - RV gamma variate fit

-- LV gamma variate tït O RV rawdata

LV raw data

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Time (seconds)

800 infusion session 1 O ee

O 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (seconds)

Figure 13: Raw data and gamma variate fit for subject MV at minute 3 of constant-load, severe exercise.

Non-infusion session

400

- RV gamma variate fil -- LV gamma variale M O RVrawdata

LVrawâata

O 1 2 3 4 5 6 7 8 9 1 0 1 t 1 2 1 3 1 4 Tirne (seconds)

11 W 1 Infusion session

O 1 2 3 4 S 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Time (seconds)

I l 7 Figure 14: Raw data and gamma variate fit for subject NC at minute 3 of constant-load, severe exercise.

450 - O

400 - LV gamma variate fit O RV raw data

LV raw data

a Y 6 250

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Time (seconds)

Infusion session

250 O

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Tirne (seconds)

Figure 15: Raw data and gamma variate fh for subject PC at minute 3 of constant-load, severe exercise.

1 Non-infusion session RV gamma variate fit LV gamma variate fit

O RVraw data

500

s a 400 C3

300

s 200

100

O O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4

Time (seconds) Infusion session

O 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (seconds)

119 Figure 16: Raw data and gamma variate ffi for subject PG at minute 3 of constant-load, severe exercise.

Non-infusion session 700

600 1 h o - RV gamma variate fit -- LV gamma vanale fit O RVrawdafa O LV favu data

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 lime (seconds)

1 Infusion session 0

f

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 rune (seconds)

120 Figure 17: Raw data and gamma variate fit for subject SS at minute 3 of constant-load, severe exercise.

1800 1 Non-infusion session - UV gamma variale lit -- LV gamma variale lit

O Rvrawdata LV rawdala

O 1 2 3 4 5 6 7 8 4 1 0 1 1 1 2 1 3 1 4 Time (seconds)

2700 1 Infusion session

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 t 4 Time (seconds)

Figun 18: Raw data and gamma variate fit fw subject BW at minute 3 of constant-load. severe exercise.

Non-infusion session (unable to fit air&)

1 O

- -- LV gamma variate fit O RVrawdata a LV raw data

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Tirne (seconds)

"1 Infusion sessiw O

O 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Tirne (seconds)

122 Figure 18: Raw data and gamma variate fit for subject SP at minute 3 of constant-ioad, severe exercise.

Non-infusion session O

250 1 8 - RV gamma variate fit -- LV gamma variate fit O RVrawdaîa

LVrawdata

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Tirne (seconds)

Infusion session 2m 1 (unable to fit RV gamma v)

150 -

8 C 3

~ 1 0 0 - E

13 P '

0 1 \.

O \ I E \ 8 a. f

50 -

8

1 1 T I I I I 1

O 1 2 3 4 5 6 7 8 9 1 0 1 1 t 2 1 3 1 4 Tirne (seconds)

Figure 20: Raw data and gamma variate fit for subject AF at minute 3 of constant-load, severe exercise.

700 Non-infusion session

1 O

- RV gamma variate fit -- LV gamma variate fit O Wrawdata O LV raw data

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Infusion session Time (seconds)

700 (unable to fit curves) 0

600 1

O 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 Thne (seconds)

APPENDIX G. ANALYSIS OF DATA Figure 21: Best-fit Iinear regression line utilized for temperature correcting fifty-six blood gas samples during the 6.5 minutes, constant-load, severe cycling exercise sessions.

r = 0.82; ? =0.68; Temp = 37.7 + ( 0.238 ' Time) SE€ = 0.32; n = 112 blood samples

37.0 0 O 1 2 3 4 5 6 7

Time (minutes)

125 Figure 22: Correlation between changes in blood volume versus changes in pulmonary transit tirne at minute 3 of constant-load, severe exercise in both infusion and non- infusion conditions.

-0.4 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Change in pulmonary transit time betwean infusion and non-infusion conditions (sec)

1 26 Fjgun 23: Correlation between cardiac index and blood volume venus pulmonary transit time at minute 3 of constant-load, severe exercise in both infusion and non- infusion conditions.

r = 0.41; ? = 0.22; P = 0.03 cardiac index = 23.1 - ( 2.97 PTT) SEE = 1.7

a

r = 0.39; ? = 0.15; P = 0.08 BV = 116.5 - ( 13.2 ' PTT) SEE = 9.4

110 120 1 A

60 1 , I , , ,

2.0 2.2 2.4 2.6 2.8 3.0 3.2 Pulmonary transit time (sec)

127 Figure W. Correlation between Pa02, AaD02. and %Sa02 venus pulmonary transit time in both infusion and non-infusion conditions.

2.0 2.2 2.4 2.6 2.8 3.0 3.2 Pulmonary transit time (seconds)

Figum 25: Correlation between %SaO2 and AaDO;! versus Paon, and %SaO2 versus AaOOz during minute 3 of constant-load, severe exercise in both non-infusion and inkision conditions.

r = 0.85; ? = 0.72; P < 0.01 %Sa02 = 75.1 + ( 0.208 ' Pa02) SEE = 1.07 I

86 1 r = - 0.85; ? = 0.72; P c 0.01

40 1 h m 2 = 81.8 - ( 0.620 Paq) ÇEE = 3.45

65 70 75 80 85 90 95 100 105 Pa02 (mm Hg)

r = - 0.60; r2 = 0.36; P < 0.01 w

%Sa02 = 98.0 - (0.188 'ABDOZ) SEE = 1.64

10 15 20 25 30 35 AaDO2 (mm Hg)

Figure 26: Correlation between PaO2, PaCQ verws VE 1 ~ 0 2 during minute 3 of constant-load, severe exercise in both non-infusion and infision conditions.

PaO, r = 0.45; P = 0.20: P = 0.03 PaO, = 626 + (0.923 VWOJ SEE = 7.57

a

i3Q Figure 27: Correlation between alveolar POp (ho2) versus artenai PO2 (Paoz), and bshnreen pulmonary blood volume versus oxygen uptake and between during minute 3 of mnstantlload, severe exercise in both non-infusion and infusion candiions.

a r = 0.64; r' = 0.40; P * 0.01 a PaO, = 43.5 + (1.19 ' PAOJ SEE = 6.45

PAO, (mm Hg)

r = 0.5f; ? = 0.32; P = 0.01 VO, = 2.38 + (1.76 PBV) SEE = 0.49

0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8

Pulmonary blood volume (Lii is)

Figure 28: Correlation between arterial PO2 (PaOz) and arterial PC02 (PaCOz) during minute 3 of constant-load, severe exercise in both non-infusion and infusion conditions.

r = -0.57; ? = 0.33; P < 0.01

105 1 PaO,= 136.48 -(1 .Z*PaCO,) SEE = 6.86

65 1 1 1 I 1 1 1 t 1 1 1 I

32 34 36 38 40 42 44 46 48 50 52 54

PaCO,(mm Hg)

132 Figure 28: (A) Correlation between the change in arterial PC02 (APaC02) and the change in arterial POa (APa02) between minute O and minute 1 of constant-load, severe exercise in both non-infusion and infusion conditions; (B) Correlation between r d ce11 pulmonary transit time and pre-exercising circulating pool of white blood cells (WBC) in both infusion and non-infusion conditions.

Change in PaCO, = 0.72- (0.19'Change in Pa$) SEE = 3.22

-50 -40 -30 -20 -10 O 10 Change in PaO, (mm Hg)

r = - 0.56; P = 0.31; P = 0.009

3 3.5 PTT = 3.19 - (0.12WBC) SEE = 0.25

-

133 Figure 30: Relationship between pulmonary transit time (PTT) and cardiac index ftom the literature (means based on 152 different subjects from 13 di irent studies). The relationship abeys a single, 3 parameter exponential decay fundion. Shape of curve resembles that of Dempsey and Fregosi (46) and Warren et al. (213). No plateau in Vc is obsetved as PTT fails to decrease in the face of increasing Q index.

r = 0.97, ? = 0.94, SEE = 0.51

PTT = 257+ 46.72e4"m

10.0 1

Present siudpNon-infusion condition [exeruse] Present siudy-lnfusion condioon (exercise] Hopkins et al. (f 99B)-exercise Hopkins et al. (1996)-nst lskandrian et ai. (1982)-sxerase lskandrian at ai. (1982)-rmt Rerych et al. (1980)-before training [exercise] Rerych et al. (t980)-afkr training [exercise] Rsyrch et al. (f980)-befare training @est] Reryth et al. (?98O)-after training [rest] Capderou et al. (1 997)+est Hannon et al. (1981)-reat Matkwiz and Hemmer (1 491)-rest Mark- and Hemmer (1 991)-exercise Behr et ai. (1981)-rest Behr et al. (198l)-exercise Guintini et al. (1963)-rest MacNee et al. (1 W9)-rest Kuikka and Lansimies (1999)-rest Kuikka et al. (1 979)-rest Kuikka et al. (1979)-moderate exerck Kuikka et ai. (1979)-heavy exercise Kuikka and Lansimies (1999)-exercise Rerych et al. (1978)-rest Rerych et al. (1978)-emrciae

0.0 : L 1 1 4 1 I I b I 1 1 I I 1 1 1

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Cardiac in de^ (L -in2 . min")

134 Figure 31: Pooled data on the relationship between pulmonary transit time (Pm, pulmonaty b l d volume (PBV), and cardiac output (Q) from 5 different studies, induding the present study.

Data f m 72 difkrent healthy subjects from 5 different studies at various h 'S. Mean age = 31 years old. Pooled data from studies (30, 88, 112, 164) and the wrrent study. The relationship obeys a single, 3 parameter exponential decay function. ïhe relationship between PTT vs Q dosely resernbles that of capillary transl tirne (PCm vs Q h m Dempsey and Fregosi (46) and Warren et al. (213). Howwer. after Q reaches -20 - 25 L min", no further deaease in PTT is observed, whereas Dempsey's theoretical curve shows drastic decreases PCTT a Q 's greater than -25 L min*'. The present curve shows PBV increases to cornpensate for the incxeasing Q such that PTT remains unchanged (predided PTT at 25 L min" = 2.45 sec; PTT at 40 L - min-' = 2.25 s). Notice how PBV fails to reach rnorphological lirnit. The systernatic increase in PBV with increasing Q displays an adaptive response of the cardiopulrnonary system to prevent capillary transit tirnes from falling below the -0.52 seconds aieoretical Iimit for partial pressure equilibriurn at these high &S.

Pm vs cardiac output PBV vs cardiac output r = 0.83; ? = 0.60; SEE = 1.31 r = 0.82; P = 0.67; SEE = 0.20 PTT = 2.23 +11 Ale .O.IS~X PBV = 0.746 -0.0188~ + 0.00122

l4 i

Cardiac output (L -min4)

135

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