The Acute Effects of Volume Infusion on Mechanisms and Severity of Exercise Induced Arterial...
Transcript of The Acute Effects of Volume Infusion on Mechanisms and Severity of Exercise Induced Arterial...
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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
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
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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