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The acute effects of volume infusion on mechanisms and severity of exercise-induced arterial hypoxemia Zavorsky, Gerald Stanley 2001

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THE ACUTE EFFECTS OF VOLUME INFUSION ON MECHANISMS AND SEVERITY OF EXERCISE-INDUCED ARTERIAL HYPOXEMIA  by  Gerald Stanley Zavorsky B.Ed., McGill University, 1995 M.A., McGill University, 1997  A T H E S I S SUBMITTED IN PARTIAL FULFILMENT O F T H E R E Q U I R M E N T S F O R T H E D E G R E E OF DOCTOR OF PHILOSOPHY IN T H E F A C U L T Y O F G R A D U A T E STUDIES EXPERIMENTAL  MEDICINE  PROGRAM  W e accept this thesis as conformirj^c^tJie required standard  UNIVERSITY O F BRITISH C O L U M B I A April 2001 © Gerald Stanley Zavorsky, 2001  In presenting  this  degree at the  thesis  in  University of  freely available for reference copying  of  department  this or  publication of  partial  British Columbia, and study.  of  by  his  or  her  the  The University of British Columbia Vancouver, Canada  that the  I further agree  representatives.  may be It  this thesis for financial gain shall not  Department of  requirements  I agree  thesis for scholarly purposes  permission.  DE-6 (2/88)  fulfilment  is  that  an  advanced  Library shall make it  permission for extensive  granted  by the  understood be  for  that  allowed without  head  of  my  copying  or  my written  II  ABSTRACT Incomplete  recruitment  of  pulmonary  capillaries  could  shorten  right-to-left  ventricular red cell pulmonary transit time ( P T T ) a n d explain e x e r c i s e - i n d u c e d arterial h y p o x e m i a (EIAH). V o l u m e e x p a n s i o n could dilate a n d / o r recruit pulmonary capillaries, lengthen P T T a n d improve g a s e x c h a n g e (reduce E I A H ) .  T h e p u r p o s e of this study  w a s to determine whether acute v o l u m e e x p a n s i o n using pentastarch c h a n g e d E I A H a n d P T T during s e v e r e e x e r c i s e . T w e l v e m a l e e n d u r a n c e athletes ( V 0  2 m a x  = 69.6 + 7.4  ml • kg" • min" ; weight = 74.8 ± 6.0 kg; height = 180.6 + 7.0 cm) performed 6.5 minutes 1  1  constant, n e a r - m a x i m a l cycling e x e r c i s e (~92% V 0  2 m a x  ) o n two different d a y s . S e v e n  subjects w e r e classified a s having E I A H [minimal arterial P 0 ( P a 0 ) during e x e r c i s e < 2  2  90 m m H g a n d / o r alveolar-arterial o x y g e n p r e s s u r e difference ( A a D 0 ) during the last 2  2.5 minutes of e x e r c i s e > 2 5 m m Hg]. P e n t a s t a r c h [(500 m L , 10%), Infusion condition, I] or p l a c e b o [(60 m L normal saline), non-infusion condition, N] w e r e infused prior to e x e r c i s e in a r a n d o m i z e d , double-blind f a s h i o n . Arterial blood g a s e s , pulmonary transit time, multigated acquisition technique ( M U G A ) - d e r i v e d c a r d i a c output ( Q ) , a n d o x y g e n c o n s u m p t i o n ( V 0 ) w e r e m e a s u r e d during e x e r c i s e . P e n t a s t a r c h i n c r e a s e d p l a s m a 2  v o l u m e significantly (+460 ± 4 2 2 ml; P = 0.002; n = 12). P T T w a s m e a s u r e d during the third minute of e x e r c i s e by first-pass radionuclide cardiography using centroid a n d deconvolution a n a l y s i s , while c a r d i a c output ( Q ) w a s m e a s u r e d via a c o u n t - b a s e d ratio method from M U G A technique. P a 0  2  (N = 89.5 ± 9.0; I = 90.7 ± 7.7 m m Hg), A a D 0  2  (N  = 21.8 ± 6 . 1 ; I = 22.7 ± 6.8 m m Hg), a n d arterial o x y h e m o g l o b i n saturation [ ( % S a 0 ) , N 2  = 93.9 ± 2.4; I = 93.8 ± 1.6%] conditions (P > 0.05; n = 12).  at minute three of e x e r c i s e did not differ between  P T T minute three of e x e r c i s e w a s significantly greater in  the infusion than non-infusion conditions [I = 2.75 ± 0.32 s e c o n d s ; N = 2.45 ± 0.21  s e c o n d s (P = 0.002)].  P u l m o n a r y blood v o l u m e w a s a l s o greater in the infusion than  non-infusion conditions [I = 1.35 ± 0 . 2 1 ; N = 1.22 ± 0 . 1 3 liters ( P = 0.015)].  V0  (N =  2  4 . 5 6 ± 0.54; I = 4 . 5 7 ± 0.56 L • m i n ) a n d Q (N = 3 0 . 6 + 4 . 2 ; I = 30.2 + 3.9 L • min" ) did 1  not differ b e t w e e n conditions. Pa0 , AaD0 , 2  2  1  P T T at minute three of e x e r c i s e w a s not correlated with  or %SaC>2 in subjects with or without  correlated with c a r d i a c index (r  2  EIAH.  However, P T T was  = 0.22, P = 0.03) a n d p r e - e x e r c i s i n g white blood cell  count in the circulating pool (r = 0 . 3 1 ; P = 0.009) w h e n c o m b i n i n g d a t a from both n o n 2  infusion a n d infusion conditions. W e c o n c l u d e that v o l u m e e x p a n s i o n d o e s not c h a n g e E I A H despite i n c r e a s i n g P T T , a n d s u g g e s t that P T T (and thus p e r h a p s pulmonary capillary transit time) is not a significant m e c h a n i s m of E I A H . T h e s e results a l s o provide e v i d e n c e against a morphological limit in pulmonary capillary blood v o l u m e capacity during s e v e r e e x e r c i s e .  iv  TABLE OF CONTENTS ABSTRACT  ii  TABLE OF CONTENTS  JV  LIST OF TABLES  VI  LIST OF FIGURES  X  ACKNOWLEDGEMENTS  xiif  CHAPTER 1. GENERAL INTRODUCTION 1.1 1.2 1.3 1.4 1.5 1.6  EXERCISE-INDUCED ARTERIAL HYPOXEMIA R E D U C T I O N IN R E D C E L L T R A N S I T T I M E S STATEMENT OF THE PROBLEM HYPOTHESES SPECIFIC AIMS STATISTICS  CHAPTER 2. EIAH AND ACUTE HYPERVOLEMIA 2.1 I N T R O D U C T I O N 2.2 M E T H O D S 2.3 R E S U L T S  1 3 4 5 5 6  7 7 8 16  CHAPTER 3. GENERAL SUMMARY AND CONCLUSIONS 3.1 G E N E R A L S U M M A R Y 3.2 G E N E R A L C O N C L U S I O N S  44 44 45  APPENDIX A. REVIEW OF THE LITERATURE—EIAH INTRODUCTION DEFINING EIAH M E C H A N I S M S O F EIAH HYPOVENTILATION VENOARTERIAL SHUNTS VENTILA TION-PERFUSION DIFFUSION LIMITATION GENDER AGE SUMMARY  1  MISMATCH  48 48 52 53 53 56 57 60 71 73 74  APPENDIX B. BACKGROUND INFORMATION OF PENTASTARCH AS A PLASMA VOLUME EXPANDER 75 APPENDIX C. STATISTICAL ANALYSES APPENDIX D. BLOOD GASES  INDIVIDUAL RAW  77  DATA TABLES: METABOLIC / ARTERIAL96  APPENDIX E. INDIVIDUAL RAW DATA TABLES: CARDIAC FUNCTION AND RED CELL PULMONARY TRANSIT TIME 108  V  APPENDIX F. FIRST PASS RAW DATA AND GAMMA VARIATE FIT CALCULATION OF RED CELL PULMONARY TRANSIT TIME  FOR 112  APPENDIX G. ANALYSIS OF DATA  124  APPENDIX H. REFERENCES  135  vi  LIST OF TABLES T a b l e 1: Subject characteristics a n d resting pulmonary function (n = 12)  22  T a b l e 2: C l a s s i f i c a t i o n of subjects with e x c e s s i v e A a D 0 (> 2 5 m m Hg) and/or low P a 0 (< 90 m m Hg) during the 6.5 minutes, constant-load, s e v e r e cycling e x e r c i s e in the non-infusion s e s s i o n 23 2  2  T a b l e 3: C o m p a r i s o n of method a n d condition on a s s e s s m e n t of red cell pulmonary transit times during minute 3 of the 6.5 minutes constant-load, s e v e r e cycling e x e r c i s e , [n = 9]; * P = 0.002 c o m p a r e d to non-infusion condition 24 T a b l e 4: M e a n metabolic, arterial b l o o d - g a s ( A B G ) , blood v o l u m e , a n d c a r d i a c output data at minute 3 of intense cycling e x e r c i s e (n = 12 e x c e p t for P T T a n d P B V w h e r e n = 9). * P < 0.05 25 T a b l e 5: M e a n metabolic, arterial b l o o d - g a s ( A B G ) , blood v o l u m e , a n d c a r d i a c output data at minute 3 of intense cycling e x e r c i s e in athletes with E I A H (minimal P a 0 < 90 m m Hg). [n = 7 except for P T T a n d P B V w h e r e n = 6]. * P < 0.05 26 2  Table  6:  Comparison  of  mean  pulmonary  transit  times  during  exercise. Also  corresponding Q , HR, V 0 , P B V , a n d V c v a l u e s from the literature. N = n o n infusion condition; I = Infusion condition; B T = before training; A T = after training. 27 2 m a x  T a b l e 7: P u b l i s h e d studies that record c h a n g e s in P a 0 , A a D 0 , a n d % S a 0 within the first minute of constant-load, moderate to s e v e r e s e a level e x e r c i s e (65 - 9 7 % 2  V0  2 m a x  2  2  ) . * P < 0.05 c o m p a r e d to cycling; A = c h a n g e  51  T a b l e 8: P a s t definitions of E I A H  53  T a b l e 9: G e n e r a l subject characteristics a n d resting pulmonary function for e a c h subject 77 T a b l e 10: P l a s m a v o l u m e c h a n g e s b e t w e e n non-infusion a n d infusion s e s s i o n s T a b l e 11: R a t i n g s of p e r c e i v e d exertion for the V 0 e x e r c i s e tests (non-infusion a n d infusion s e s s i o n s )  test, a n d both 6.5 minutes 79  2 m a x  T a b l e 12: R e p e a t e d m e a s u r e s A N O V A for V 0  80  2  T a b l e 13: P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for V 0 T a b l e 14: R e p e a t e d m e a s u r e s A N O V A for V  2  (Bonferroni's method)... 80 81  E  T a b l e 15: P a i r w i s e multiple c o m p a r i s o n procedures for V  78  E  (Bonferroni's method)  81  Vll  T a b l e 16: R e p e a t e d m e a s u r e s A N O V A for heart rate  82  T a b l e 17: P a i r w i s e multiple c o m p a r i s o n procedures for heart rate (Bonferroni's  T a b l e 18: R e p e a t e d m e a s u r e s A N O V A for % S a 0  83  2  T a b l e 19: P a i r w i s e multiple c o m p a r i s o n procedures for % S a 0 T a b l e 20: R e p e a t e d m e a s u r e s A N O V A for P a 0  2  measures  ANOVA  for  measures  ANOVA  for  method).83  AaD0  2  PaC0  corrected to e s o p h a g e a l 84  2  corrected  T a b l e 2 3 : Pairwise multiple c o m p a r i s o n procedures for A a D 0 temperature (Bonferroni's method) T a b l e 24: R e p e a t e d temperature  (Bonferroni's  2  corrected to e s o p h a g e a l temperature. 84  T a b l e 2 1 : P a i r w i s e multiple c o m p a r i s o n procedures for P a 0 temperature (Bonferroni's method) Table 22: Repeated temperature  method). 82  2  T a b l e 2 5 : Pairwise multiple c o m p a r i s o n procedures for P a C 0 temperature (Bonferroni's method)  2  esophageal 85  corrected to e s o p h a g e a l 85  corrected  2  to  to  esophageal 86  corrected to e s o p h a g e a l 86  T a b l e 26: R e p e a t e d m e a s u r e s A N O V A for pH corrected to e s o p h a g e a l temperature.. 87 T a b l e 27: Pairwise multiple c o m p a r i s o n procedures for p H corrected to e s o p h a g e a l temperature (Bonferroni's method) 87 T a b l e 28: R e p e a t e d m e a s u r e s A N O V A for standard b a s e e x c e s s ( S B E ) corrected to e s o p h a g e a l temperature 88 T a b l e 29: P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for standard b a s e e x c e s s ( S B E ) corrected to e s o p h a g e a l temperature (Bonferroni's method) 88 T a b l e 30: R e p e a t e d m e a s u r e s A N O V A for bicarbonate ( H C 0 " ) corrected to e s o p h a g e a l temperature 89 3  T a b l e 3 1 : Pairwise multiple c o m p a r i s o n procedures for bicarbonate ( H C 0 " ) corrected to e s o p h a g e a l temperature (Bonferroni's method) 89 3  T a b l e 32: R e p e a t e d m e a s u r e s A N O V A for e s o p h a g e a l temperature T a b l e 33: P a i r w i s e multiple (Bonferroni's method)  comparison  procedures  for  esophageal  90 temperature 90  VIII  T a b l e 34: R e p e a t e d m e a s u r e s A N O V A for A l v e o l a r P 0  91  2  T a b l e 3 5 : P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for alveolar P 0 method) T a b l e 36: R e p e a t e d m e a s u r e s A N O V A for P  2  (Bonferroni's 91 92  5 0  T a b l e 37: P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for P  5 0  (Bonferroni's method)  92  T a b l e 38: R e p e a t e d m e a s u r e s A N O V A for m e a n pulmonary transit times at 3rd minute of e x e r c i s e during the 6.5 minute e x e r c i s e tests 93 T a b l e 39: R e p e a t e d m e a s u r e s A N O V A for distribution of pulmonary transit times at 3rd minute of e x e r c i s e during the 6.5 minutes e x e r c i s e tests 93 T a b l e 4 0 : P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for distribution of pulmonary transit times at 3rd minute of e x e r c i s e during the 6.5 minute e x e r c i s e tests 93 T a b l e 4 1 : O n e w a y A N O V A for day-to-day variability [intraobserver error] in a s s e s s i n g m e a n pulmonary transit times at 3rd minute of e x e r c i s e during the 6.5 minutes e x e r c i s e tests 94 T a b l e 4 2 : O n e w a y A N O V A for day-to-day variability [intraobserver error] in a s s e s s i n g ejection fraction at 3rd minute of e x e r c i s e during the 6.5 minutes e x e r c i s e tests... 9 4 T a b l e 4 3 : O n e w a y A N O V A for day-to-day variability [intraobserver error] in a s s e s s i n g m e a n e n d diastolic v o l u m e at 3rd minute of e x e r c i s e during the 6.5 minutes e x e r c i s e tests 94 T a b l e 4 4 : O n e w a y A N O V A for ratings of perceived exertion ( R P E ) b e t w e e n all three exercise sessions 94 T a b l e 4 5 : S u m m a r y of F v a l u e s from the repeated m e a s u r e s A N O V A tables  95  T a b l e 4 6 : M V raw d a t a for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 96 2  2  T a b l e 4 7 : J B raw d a t a for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 97 2  2  T a b l e 4 8 : M E raw data for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 98 2  2  T a b l e 4 9 : N C raw data for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 99 2  2  T a b l e 50: P C raw data for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 100 2  2  ix T a b l e 5 1 : L Z raw d a t a for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected 2  2  to e s o p h a g e a l temperature.  101  T a b l e 52: B W raw d a t a for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 102 2  2  T a b l e 5 3 : A C raw data for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 103 2  2  T a b l e 54: S P raw d a t a for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 104 2  2  T a b l e 5 5 : S S raw d a t a for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 105 2  2  T a b l e 56: A F raw d a t a for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 106 2  2  T a b l e 57: P G raw data for both 6.5 minutes e x e r c i s e tests. P a 0 , P a C 0 , p H corrected to e s o p h a g e a l temperature 107 2  2  T a b l e 58: C a r d i a c function data obtained at minute 3 of s e v e r e e x e r c i s e . Non-infusion session 108 T a b l e 59: C a r d i a c function data obtained at minute 3 of s e v e r e e x e r c i s e . session  Infusion 109  T a b l e 60: R e d cell pulmonary transit times during minute 3 of constant-load, s e v e r e e x e r c i s e : C o m p a r i n g method a n d condition 110 T a b l e 6 1 : Distribution descriptors of e a c h subject's P T T transport function during minute 3 of constant-load, s e v e r e e x e r c i s e 111  X  LIST O F  FIGURES  Figure 1: M e a n transport functions created by d e c o n v o l u t i o n a n a l y s i s c o m p a r i n g distribution of P T T b e t w e e n non-infusion (N) a n d infusion (I) conditions. M e a n P T T i n c r e a s e d by 0.30 s e c o n d s (P = 0.002) b e t w e e n the two conditions 28 Figure 2: Distribution of red cell pulmonary transit times during minute 3 of intense, c o n s t a n t - l o a d e x e r c i s e with (I) or without (N) v o l u m e infusion (n = 9). * P = 0.02 b e t w e e n N a n d I within a given time interval 29 Figure 3: Arterial P 0 ( P a 0 ) a n d a l v e o l a r - o x y g e n difference ( A a D 0 ) during the 6.5 minutes s e v e r e , constant-load e x e r c i s e test for non-infusion (N) a n d infusion (I) conditions. * different from minute 0 (corrected v a l u e s only); ** different from minute 1 (corrected v a l u e s only; ** different from minute 1 (corrected v a l u e s only) [n = 12]. P a 0 a n d A a D 0 w e r e temperature corrected at e a c h time point by using e s o p h a g e a l temperature at e a c h time point 30 2  2  2  2  2  Figure 4: Arterial o x y h e m o g l o b i n saturation ( % S a 0 ) , arterial P C 0 ( P a C 0 ) , and e s o p h a g e a l temperature during the 6.5 minutes s e v e r e , constant-load e x e r c i s e test for non-infusion (N) a n d infusion (I) conditions, a = different from minute 0; b = different from minute 0 to 1; c = different from minute 0 to 2; d = different from minute 0 to 3; e = different from minute 0 to 4 [values w h i c h are corrected to to temperature c h a n g e s only; P < 0.05]. ## = main effect present b e t w e e n conditions. (n = 12) 31 2  2  2  Figure 5: Individual r e s p o n s e s for P a 0 a n d A a D 0 during the 6.5 minutes s e v e r e , constant-load e x e r c i s e test c o l l a p s e d a c r o s s condition (n = 12). A l l v a l u e s corrected to e s o p h a g e a l temperature 32 2  2  Figure 6: Minute ventilation, o x y g e n c o n s u m p t i o n , a n d heart rate during the 6.5 minutes s e v e r e , c o n s t a n t - l o a d e x e r c i s e test for non-infusion (N) a n d infusion (I) conditions, a = different from minute 0; b = different from minute 0 to 1; c = different from minute 0 to 2; d = different from minute 0 to 3; [values w h i c h are corrected to temperature c h a n g e s only; P < 0.05]. ## = main effect present b e t w e e n conditions, (n = 12) 33 Figure 7: Arterial p H , b i c a r b o n a t e ( H C 0 ~ ) , a n d standard b a s e e x c e s s ( S B E ) during the 6.5 minutes s e v e r e , constant-load e x e r c i s e test for non-infusion (N) a n d infusion (I) conditions, a = different from minute 0; b = different from minute 0 to 1; c = different from minute 0 to 2; d = different from minute 0 to 3; e = different from minute 0 to 4 [values w h i c h are corrected to temperature c h a n g e s only; P < 0.05]. ## = main effect present b e t w e e n conditions, (n = 12) 34 3  Figure 8: C o r r e l a t i o n b e t w e e n the c h a n g e in A a D 0 a n d the c h a n g e in P T T with infusion at minute 3 of e x e r c i s e in subjects with minimal P a 0 < 8 5 m m H g a n d e x c e s s i v e g a s e x c h a n g e impairment ( A a D 0 > 2 5 m m H g ; n = 6) 35 2  2  2  XI  Figure 9: R a w data a n d g a m m a variate fit for subject A C at minute 3 of constant-load, severe exercise 112 Figure 10: R a w d a t a a n d g a m m a variate fit for subject J B at minute 3 of constant-load, severe exercise 113 Figure 11: R a w d a t a a n d g a m m a variate fit for subject L Z at minute 3 of constant-load, severe exercise 114 Figure 12: R a w d a t a a n d g a m m a variate fit for subject A C at minute 3 of constant-load, severe exercise 115 Figure 13: R a w d a t a a n d g a m m a variate fit for subject M V at minute 3 of constant-load, severe exercise 116 Figure 14: R a w data a n d g a m m a variate fit for subject N C at minute 3 of constant-load, severe exercise 117 Figure 15: R a w d a t a a n d g a m m a variate fit for subject P C at minute 3 of constant-load, severe exercise 118 Figure 16: R a w data a n d g a m m a variate fit for subject P G at minute 3 of constant-load, severe exercise 119 Figure 17: R a w data a n d g a m m a variate fit for subject S S at minute 3 of constant-load, severe exercise 120 Figure 18: R a w data a n d g a m m a variate fit for subject B W at minute 3 of constant-load, severe exercise 121 Figure 19: R a w d a t a a n d g a m m a variate fit for subject S P at minute 3 of constant-load, severe exercise 122 Figure 2 0 : R a w data a n d g a m m a variate fit for subject A F at minute 3 of constant-load, severe exercise 123 Figure 2 1 : Best-fit linear regression line utilized for temperature correcting fifty-six blood g a s s a m p l e s during the 6.5 minutes, constant-load, s e v e r e cycling e x e r c i s e sessions 124 Figure 22: Correlation b e t w e e n c h a n g e s in blood v o l u m e v e r s u s c h a n g e s in pulmonary transit time at minute 3 of constant-load, s e v e r e e x e r c i s e in both infusion a n d n o n infusion conditions 125 Figure 2 3 : Correlation b e t w e e n c a r d i a c index a n d blood v o l u m e v e r s u s pulmonary transit time at minute 3 of constant-load, s e v e r e e x e r c i s e in both infusion a n d n o n infusion conditions 126  xii Figure 2 4 : C o r r e l a t i o n b e t w e e n PaC>2, A a D 0 , a n d % S a 0 time in both infusion a n d non-infusion conditions 2  2  v e r s u s pulmonary transit 127  Figure 2 5 : Correlation b e t w e e n % S a 0 a n d A a D 0 v e r s u s P a 0 and % S a 0 versus A a D 0 during minute 3 of constant-load, s e v e r e e x e r c i s e in both non-infusion a n d infusion conditions 128 2  2  2 l  2  2  Figure 2 6 : Correlation b e t w e e n P a 0 , P a C 0 v e r s u s V / V 0 during minute 3 of c o n s t a n t - l o a d , s e v e r e e x e r c i s e in both non-infusion a n d infusion conditions 129 2  2  E  2  Figure 2 7 : Correlation b e t w e e n alveolar P 0 ( P A 0 ) v e r s u s arterial P 0 ( P a 0 ) , a n d b e t w e e n pulmonary blood v o l u m e v e r s u s o x y g e n uptake a n d b e t w e e n during minute 3 of constant-load, s e v e r e e x e r c i s e in both non-infusion a n d infusion conditions 130 2  2  2  2  Figure 2 8 : Correlation b e t w e e n arterial P 0 ( P a 0 ) a n d arterial P C 0 ( P a C 0 ) during minute 3 of constant-load, s e v e r e e x e r c i s e in both non-infusion a n d infusion conditions 131 2  2  2  2  Figure 2 9 : (A) Correlation b e t w e e n the c h a n g e in arterial P C 0 ( A P a C 0 ) a n d the c h a n g e in arterial P 0 ( A P a 0 ) b e t w e e n minute 0 a n d minute 1 of constant-load, s e v e r e e x e r c i s e in both non-infusion a n d infusion conditions; (B) Correlation b e t w e e n red cell pulmonary transit time a n d pre-exercising circulating pool of white blood cells ( W B C ) in both infusion a n d non-infusion conditions 132 2  2  2  2  Figure 3 0 : R e l a t i o n s h i p b e t w e e n pulmonary transit time ( P T T ) a n d c a r d i a c index from the literature ( m e a n s b a s e d on 152 different subjects from 13 different studies). T h e relationship o b e y s a single, 3 p a r a m e t e r exponential d e c a y function. S h a p e of curve r e s e m b l e s that of D e m p s e y a n d F r e g o s i (46) a n d W a r r e n et al. (213). N o plateau in V c is o b s e r v e d a s P T T fails to d e c r e a s e in the f a c e of increasing Q index. 133 Figure 3 1 : P o o l e d data o n the relationship b e t w e e n p u l m o n a r y transit time ( P T T ) , p u l m o n a r y blood v o l u m e ( P B V ) , a n d c a r d i a c output ( Q ) including the present study  from 5 different studies, 134  Xlll  A C K N O W L E D G E M E N T S S i n c e arriving at University of British C o l u m b i a in 1 9 9 7 , I p u r s u e d the idea of doing m y thesis r e s e a r c h on E I A H a n d red cell pulmonary transit time v i a acute v o l u m e expansion.  H o w e v e r , I did not k n o w h o w m u c h preparation, collaboration, a n d funding  w a s n e e d e d to p u r s u e this topic.  N e v e r t h e l e s s , in the past fifteen months, good luck  sprung u p o n m e a n d I m a n a g e d to d o this r e s e a r c h . I would like to take this opportunity to thank e v e r y o n e w h o helped in the data collection, preparation, a n d editing of this thesis.  First, a n d foremost, I a m deeply indebted to Dr. J a m e s R u s s e l l , m y P h . D .  supervisor, w h o d e c i d e d to take m e o n a s his student w h e n I w a s in a difficult situation. T h i s project could not h a v e b e e n c o m p l e t e d without his support, e n t h u s i a s m , a n d valued suggestions.  S e c o n d , I would like to thank Dr. G e o r g e S e x s m i t h , (Nuclear  Medicine) w h o g a v e enthusiastic help in evaluating M U G A a n d first-pass cardiography data of m y subjects, a n d for reviewing my work. appreciation  to Dr. Keith W a l l e y  (Critical  c o u n t l e s s proofreading a n d s u g g e s t i o n s .  Care  I a l s o w o u l d like to s h o w m y  M e d i c i n e ) w h o provided  m e with  Furthermore, I would like to thank Dr. D o n  M c K e n z i e (Family P r a c t i c e a n d H u m a n Kinetics) w h o g a v e helpful a d v i c e o n several o c c a s i o n s , reviewing a n d critiquing s e v e r a l p i e c e s of m y work.  A s well, I must give  s i n c e r e gratitude to the I C U r e s e a r c h n u r s e s V i n c e Dunlop a n d T a r a L e h m a n , w h o w e r e by m y side at almost every instance collecting the blood s a m p l e s , a n d arranging the r a n d o m i z e d double-blind procedure for this r e s e a r c h .  I would a l s o like to thank Dr.  Garth Hunte, w h o helped m e with arterial catheterization, proofreading s e v e r a l p i e c e s of my work, a n d just being m y friend.  M o r e o v e r , I would like to thank Dr. N o r m a n W o n g ,  Director of E x p e r i m e n t a l M e d i c i n e , w h o allowed m e to transfer into the department.  I  would a l s o like to thank all the staff of the N u c l e a r M e d i c i n e Department at St. P a u l ' s  xiv Hospital, w h o h e l p e d m e with the c a r d i a c imaging a n d b l o o d / p l a s m a v o l u m e a n a l y s i s . Indeed, I a m very grateful to C l i v e G l o v e r , Niklas R o e b e r , Dr. S o r e l B o s a n , a n d Dr. A n n a C e l l e r w h o helped m e with the mathematical software for calculating transit times via centroid a n d deconvolution a n a l y s i s , a n d calculating c a r d i a c output via the m a n u a l c o u n t - b a s e d ratio method.  I would a l s o like to thank Erin Digitale for believing in me,  a n d Darren W a r b u r t o n for helping m e m a n a g e my r e f e r e n c e s using Endnote® software. Last, but certainly not least, I would like to thank my father w h o h a s supported my d e c i s i o n to continue through the ranks of a c a d e m i a .  1 C H A P T E R  1. G E N E R A L  INTRODUCTION  In the past twenty y e a r s , e v i d e n c e h a s b e e n a c c u m u l a t i n g to s u g g e s t that the lung c a n limit m a x i m a l o x y g e n c o n s u m p t i o n ( V 0 a x ) a n d e x e r c i s e p e r f o r m a n c e (45, 4 6 , 2 m  215).  Respiratory limitations to e x e r c i s e in healthy individuals, therefore, are of interest  to e x e r c i s e physiologists. limitations  of the  P u b l i s h e d reviews that d i s c u s s the m e c h a n i s m s of the  respiratory  s y s t e m to maintain a d e q u a t e oxygenation  (93,  156)  s u g g e s t that rapid red cell velocity through the pulmonary capillary b e d during e x e r c i s e m a y contribute to this limitation. T h i s relationship h a s recently b e e n given attention in a featured review (185).  T h i s doctoral dissertation e x a m i n e s the relationship between  m e a n w h o l e lung red cell transit times (as a reflection of m e a n pulmonary capillary transit times) a n d respiratory limitations to e x e r c i s e a s reflected by pulmonary g a s exchange variables.  First, t h e s e topics are briefly introduced along with the general  h y p o t h e s e s a n d s p e c i f i c a i m s of this intricate r e s e a r c h experiment. T h e n , the details of the experiment are d e s c r i b e d in the following chapter, followed by a general s u m m a r y and c o n c l u d i n g chapter. A p p e n d i c e s are attached at the e n d of this dissertation.  1.1 EXERCISE-INDUCED ARTERIAL HYPOXEMIA S e a level arterial o x y h e m o g l o b i n saturation ( % S a 0 ) a n d arterial partial p r e s s u r e 2  of o x y g e n ( P a 0 ) are maintained during intense e x e r c i s e in untrained a n d moderately 2  trained m a l e s (8, 5 2 , 118, 2 2 0 , 222). a e r o b i c c a p a c i t y athletes ( V 0  H o w e v e r , in approximately 5 0 - 6 0 % of high  > 6 5 m L • kg" • min" or 5 L • min" ) (23, 153), the lung 1  2 m a x  1  1  is unable to fully o x y g e n a t e returning v e n o u s blood during e x e r c i s e at near m a x i m a l (47, 118,  128) a n d m a x i m a l intensities (87, 145, 173, 222).  s h o w n that % S a 0  2  (166) a n d P a 0  2  R e c e n t l y , it h a s a l s o b e e n  (91) c a n drop significantly in s o m e individuals at  s u b m a x i m a l intensities (40 - 6 5 % V 0  2 m a x  ) , a n d e x e r c i s e - i n d u c e d arterial h y p o x e m i a  2 (EIAH), defined by % S a 0 155).  < 9 1 % and/or P a 0  2  2  < 7 5 m m H g , e n s u e s (47, 118, 153,  T h u s , w h e n E I A H o c c u r s , o x y g e n delivery ( D 0 ) is d i m i n i s h e d d u e to r e d u c e d 2  arterial o x y g e n content ( C a 0 ) , a n d V 0 2  2 m a x  theoretically d e c r e a s e s .  Independent of  the e x e r c i s e protocol (116), but not the m o d e of e x e r c i s e (58, 167), arterial o x y g e n saturation h a s b e e n inversely related to V 0  2 m a x  (r = -0.49, - 0.71, and -0.77) (79, 143,  222). T h e s e correlative data demonstrate that individuals with higher V 0 have lower % S a 0  2  during intense e x e r c i s e . In fact, a reduction in % S a 0  2 m a x  values  from 9 8 % at  2  rest to 9 3 % during s e v e r e e x e r c i s e is sufficient to c a u s e a m e a s u r a b l e c h a n g e in m a x i m a l a e r o b i c power a n d approximates a 1-2% d e c r e m e n t in V 0 d e c r e m e n t in % S a 0  2  (78, 154).  2 m a x  T h u s , not only c a n E I A H affect V 0  for e a c h 1%  2 m a x  , but it c a n  impair e x e r c i s e performance (as evaluated by total work output in kilojoules) linearly with % S a 0  2  reductions of > 6 % from rest (110).  M o r e o v e r , it h a s b e e n s h o w n that  athletes w h o h a v e d i s p l a y e d E I A H in normoxia h a v e greater d e c r e a s e s in V 0  2 m a x  in  hypoxia c o m p a r e d to n o r m o x e m i c athletes (33). M e c h a n i s m s explaining E I A H include relative hypoventilation, venoarterial shunt, ventilation-perfusion ( V / Q ) inequality, a n d pulmonary diffusion limitation. Of the four A  m e c h a n i s m s , venoarterial shunts (47, 155) a n d relative hypoventilation (155, 156) have b e e n s h o w n to play minor roles in the d e v e l o p m e n t of E I A H , while V / Q inequality a n d A  diffusion limitation are m a i n contributors of E I A H in elite m a l e athletes (70, 9 1 , 94, 156) s i n c e e a c h m a y a c c o u n t for about 50 - 6 0 % of the i n c r e a s e d alveolar-arterial o x y g e n p r e s s u r e difference ( A a D 0 ) during h e a v y e x e r c i s e . 2  In fact, a mathematical analysis  revealed that a combination of V / Q inequality a n d diffusion limitation m a y lead to A  greater d e c r e a s e s in P a 0  2  than the simple addition of their individual influences (201).  3 Hence,  individuals  who  exhibit  both  mechanisms  of  EIAH  could  be  seriously  performance limited. R a p i d pulmonary capillary transit times m a y also c a u s e diffusion limitation in very fit individuals (45, 46). High c a r d i a c outputs a c h i e v e d by elite e n d u r a n c e athletes during strenuous e x e r c i s e preclude red blood cells from reaching c o m p l e t e o x y g e n partial p r e s s u r e equilibrium, which then p r e d i s p o s e s the athlete to E I A H .  T h i s is d i s c u s s e d  below in more detail.  1.2 REDUCTION IN RED CELL TRANSIT TIMES T h e a v e r a g e transit time of red cells in h u m a n pulmonary capillaries is obtained by the ratio of pulmonary capillary blood v o l u m e (Vc) to c a r d i a c output ( Q ) a n d is about 0.75 s e c o n d s at rest (75 m L / 1 0 0 m L - s e c " ) (106). 1  venous P 0  2  U n d e r normal conditions [e.g. mixed  = 4 0 m m Hg], partial pressure equilibrium of o x y g e n in a pulmonary  capillary is r e a c h e d after about 0.25 s e c o n d s (171, 202), or one-third along a n a v e r a g e capillary d i s t a n c e .  If the complete 0.75 s e c o n d s normally available at rest were  required for partial p r e s s u r e equilibrium, a large A a D 0  2  during m o d e r a t e e x e r c i s e would  a p p e a r a n d , d e p e n d i n g particularly on the Q , V c , a n d V 0 , E I A H could d e v e l o p (202). 2  Of the vast body of literature developing in the a r e a of E I A H , the a s p e c t of diffusion  limitation  c o n s e q u e n t to  i n c r e a s e d red  blood  cell velocity  through  the  pulmonary capillaries is a p o s s i b l e , yet unstudied m e c h a n i s m of E I A H in h u m a n s . T h e theoretical s c h e m e of rapid red blood cell velocity through the pulmonary capillaries a s a m e c h a n i s m of E I A H is d i s c u s s e d eloquently by D e m p s e y a n d F r e g o s i (46) a n d a g a i n in a later p a p e r (45). T h e y report that Q a n d V c i n c r e a s e linearly up to 2 5 L • min" a n d 1  2 1 0 m L , respectively, thereby maintaining a sufficiently long transit time to e n s u r e alveolar-end capillary equilibrium.  As  Q  increases above - 2 5  L • min"  1  in  the  4 endurance-trained individual, V c a c h i e v e s m a x i m u m d i m e n s i o n s a n d transit times fall abruptly. T h e y a l s o s u g g e s t that the distribution of transit times around the m e a n m a y result in e v e n m o r e r e d u c e d times in s o m e parts of the lung [i.e. the more d e p e n d e n t regions], a n d t h e s e transit times m a y be r e d u c e d e v e n further, a s capillary flow is not uniform but pulsatile (93, 202). H o w e v e r , there h a s b e e n controversy over whether diffusing capacity of the lung (D ), L  a n d therefore  w o r k l o a d s (107).  V c , reaches an  upper  limit at s u b m a x i m a l  or  near-maximal  It e v e n h a s b e e n p r o p o s e d that h u m a n pulmonary capillaries are  already 8 0 % perfused at rest (121), s o e v e n minimal e x e r c i s e would fully recruit them. Since D  L  is m a d e up of two c o m p o n e n t s arranged in s e r i e s , that d u e to the diffusion  p r o c e s s itself [ M e m b r a n e resistance (D )], a n d that attributable to the time taken for M  o x y g e n to react with hemoglobin [red cell resistance (©Vc)] (172), a morphological limit in V c r e a c h e d during e x e r c i s e will shorten transit times a n d r e d u c e D L .  W h i l e there is  microscopic,  Dempsey  morphometric,  and  physiological e v i d e n c e to  support  and  F r e g o s i ' s theory that V c is maximally recruited during various e x e r c i s e intensities (12, 109, 160, 184), other data on d o g s (foxhounds) (97, 98, 107, 224), a n d h u m a n s (100, 163, 2 1 3 , 224), s h o w D  L  (and therefore, V c ) d o e s not plateau at s e v e r e e x e r c i s e  intensities. A s s u c h , controversy r e m a i n s on this topic.  1.3 STATEMENT OF THE PROBLEM W h i l e red cell pulmonary capillary transit times cannot be m e a s u r e d directly in healthy  exercising  humans,  first-pass  radionuclide  cardiography  can  allow  direct  m e a s u r e m e n t of right-to-left ventricular red cell pulmonary transit times ( P T T ) during exercise.  P r e v i o u s r e s e a r c h d o n e in our lab s h o w s that P T T c a n be a s s o c i a t e d with  g a s e x c h a n g e impairment  during s e v e r e e x e r c i s e , a s significant correlations  were  o b s e r v e d b e t w e e n P a 0 , A a D 0 , a n d P T T (r = 0.65, P a 0 ; r = -0.59, A a D 0 ; P < 2  2  2  2  5 0. 05.(88, 90). A s s u c h , v o l u m e loading m a y alter pulmonary g a s e x c h a n g e by c h a n g i n g PTT.  A n i n c r e a s e in blood v o l u m e by elevation in v e n o u s p r e s s u r e (constant flow or  pressure) m a y i n c r e a s e transit time in the entire vasculature a n d p e r h a p s in the capillaries (67), w h e r e a s an i n c r e a s e in flow rate greater than a n a s s o c i a t e d i n c r e a s e in pulmonary blood v o l u m e d i m i n i s h e s transit time (67).  If V c is not at a morphological  limit during s e v e r e e x e r c i s e , then p l a s m a v o l u m e e x p a n s i o n s h o u l d lengthen P T T d u e to i n c r e a s e d pulmonary capillary dilatation/recruitment. A s s u c h , a prolonged P T T m a y r e d u c e the g a s e x c h a n g e impairment in elite exercising athletes with E I A H .  O n the  other h a n d , If V c is at morphological limit during s e v e r e e x e r c i s e , p l a s m a volume e x p a n s i o n s h o u l d then reduce (shorten) P T T , a n d w o r s e n pulmonary g a s e x c h a n g e in athletes with E I A H .  T h i s thesis intends to further e x a m i n e the relationship between  pulmonary g a s e x c h a n g e a n d P T T , a n d e x a m i n e s the i s s u e of whether V c r e a c h e s m a x i m a l d i m e n s i o n s during s e v e r e e x e r c i s e in endurance-trained athletes with high a e r o b i c capabilities.  1.4 HYPOTHESES T h e p u r p o s e of this study w a s to determine the relationship b e t w e e n red cell P T T a n d E I A H . Specifically, the h y p o t h e s e s tested were: 1. V o l u m e infusion improves g a s e x c h a n g e a n d prevents E I A H during s e v e r e e x e r c i s e in elite e n d u r a n c e athletes. 2. V o l u m e infusion lengthens right-to-left ventricular red cell pulmonary transit time during s e v e r e e x e r c i s e in elite e n d u r a n c e athletes. 3.  P u l m o n a r y blood v o l u m e d o e s not reach a limit at n e a r - m a x i m a l e x e r c i s e s o that in  this setting, v o l u m e infusion i n c r e a s e s pulmonary blood v o l u m e .  1.5 SPECIFIC AIMS T h e h y p o t h e s e s were tested by a d d r e s s i n g t h e s e specific a i m s :  6 1. T o determine whether v o l u m e infusion alters pulmonary g a s e x c h a n g e during s e v e r e e x e r c i s e a n d whether v o l u m e infusion attenuates E I A H in elite e n d u r a n c e s athletes. 2. T o determine whether v o l u m e infusion lengthens right-to-left ventricular red cell pulmonary transit time during s e v e r e e x e r c i s e in elite e n d u r a n c e athletes. 3.  T o determine whether v o l u m e infusion i n c r e a s e s pulmonary blood v o l u m e at near-  maximal exercise.  1.6 STATISTICS In order to a s s e s s our h y p o t h e s e s , S i g m a s t a t 1.0 statistical software (Jandel Scientific, C A ) w a s u s e d to estimate required s a m p l e size.  In order to a d d r e s s the first  hypothesis, it w a s calculated that 12 subjects would be required for statistical A N O V A power to be at 0.8 a n d a l p h a = 0.05. G r o u p m e a n c h a n g e s in arterial P 0 alveolar-arterial  oxygen  difference  (AaD0 ) 2  between  non-infusion  2  ( P a 0 ) and  and  2  infusion  conditions w a s estimated to be - 5 m m H g (standard deviation of residuals = 4 m m Hg). For the s e c o n d hypothesis, it w a s calculated that 12 subjects w o u l d be required for statistical paired t-test power to be 0.8 a n d a l p h a = 0.05. G r o u p m e a n c h a n g e s in rightto-left red cell ventricular pulmonary transit time ( P T T ) w a s estimated at - 0 . 3 3 s e c o n d s between non-infusion a n d infusion conditions with a n e x p e c t e d standard deviation of c h a n g e of 0.35 s e c o n d s .  F o r the third hypothesis, it w a s calculated that 11 subjects  would be required for statistical paired t-test power to be 0.8 a n d a l p h a = 0.05.  Group  m e a n c h a n g e s in pulmonary blood v o l u m e w a s estimated at ~ 1 6 5 m L between n o n infusion a n d infusion conditions with a n e x p e c t e d standard deviation of c h a n g e of 175 mL. N o n e t h e l e s s , 12 subjects were u s e d to a d d r e s s all three h y p o t h e s e s .  7 C H A P T E R 2. 2.1  EIAH AND  A C U T E  H Y P E R V O L E M I A  INTRODUCTION During h e a v y e x e r c i s e , ventilation-perfusion  (V /Q) A  inequality  and  diffusion  limitation are the main m e c h a n i s m s of e x e r c i s e - i n d u c e d arterial h y p o x e m i a [(EIAH) arterial o x y h e m o g l o b i n saturation (%Sa02) < 9 1 % and/or arterial PO2 (Pa02) < 9 0 m m Hg] in e n d u r a n c e athletes with high a e r o b i c c a p a c i t i e s ( V 0 a x > 6 5 ml • kg" • min" or 5 1  1  2m  L • min" ) (70, 9 1 , 94, 156). 1  Both V / Q inequality a n d diffusion limitation m a y a c c o u n t A  for about 5 0 - 6 0 % of the i n c r e a s e d alveolar-arterial o x y g e n p r e s s u r e  difference  ( A a D 0 ) in s e v e r e e x e r c i s e . Diffusion limitation c a u s e d by rapid red cell velocity though 2  the lung m a y a l s o partially explain E I A H (45, 46). Incomplete dilation and/or recruitment of pulmonary capillaries could shorten red cell pulmonary transit time ( P T T ) a n d this could partially explain E I A H .  P r e v i o u s studies of acute v o l u m e e x p a n s i o n prior to  e x e r c i s e in elite athletes h a v e found that V 0 a x r e m a i n s unaltered despite a u g m e n t e d 2m  c a r d i a c output ( Q ) a n d stroke v o l u m e ( S V ) (108, 138, 211).  H o w e v e r , n o n e of t h e s e  previous studies h a v e determined the effect of acute v o l u m e e x p a n s i o n on P T T a n d EIAH.  Therefore, the first hypothesis w a s that acute v o l u m e e x p a n s i o n dilates and/or  recruits more pulmonary capillaries, lengthens P T T a n d prevents E I A H . During e x e r c i s e , if a morphological limit in pulmonary capillary blood v o l u m e (Vc) is r e a c h e d prior to r e a c h i n g m a x i m u m c a r d i a c output, pulmonary capillary transit times could fall b e l o w the 0.25 s e c o n d s n e c e s s a r y for diffusion of o x y g e n , thereby limiting oxygenation (93, 156, 185, 202). Transit time is e q u a l to v o l u m e (ml) divided by flow (ml • s e c " ) , a n d thus any i n c r e a s e in flow without a concomitant i n c r e a s e in v o l u m e will 1  shorten transit times (sec). W h i l e V c d o e s not plateau at s e v e r e e x e r c i s e in s o m e studies (100, 213), V c m a y plateau in athletes with c a r d i a c outputs of > 2 5 L • min" (45, 1  8 46).  H o w e v e r , if V c is not yet at a morphological limit during s e v e r e e x e r c i s e , acute  h y p e r v o l e m i a m a y lengthen P T T b e c a u s e of i n c r e a s e d distention/recruitment  of V c .  T h u s , determining the effects of acute v o l u m e e x p a n s i o n prior to e x e r c i s e on P T T at n e a r - m a x i m a l e x e r c i s e in elite athletes provides insights into the morphological limit in V c during s e v e r e e x e r c i s e . Therefore, the specific a i m s of this study w e r e to determine whether acute v o l u m e infusion prior to e x e r c i s e : (1) prevents E I A H a n d (2), lengthens P T T in athletes with high a e r o b i c capacities. 2.2 M E T H O D S T w e l v e healthy m a l e e n d u r a n c e athletes ( V 0 min" ) with no 1  history  participate in the study.  of  respiratory  > 6 5 ml • kg" • min" or 5 L • 1  2 m a x  1  or c a r d i o v a s c u l a r d i s e a s e w e r e  selected  to  T h i s study w a s a p p r o v e d by the St. P a u l ' s Hospital/University  of British C o l u m b i a Ethics C o m m i t t e e .  S u b j e c t s g a v e informed written consent, and  completed a P h y s i c a l Activity R e a d i n e s s Questionnaire ( P A R - Q ) . S u b j e c t s performed resting pulmonary lung function testing ( J a e g e r M a s t e r S c r e e n B o d y P l e t h y s m o g r a p h ) , to a s s e s s b a s e l i n e pulmonary function a n d then performed a n incremental cycling protocol to determine e a c h subject's V 0 Preliminary  Incremental  2 m a x  .  Cycling Exercise  Protocol  to Determine  V0  2 m a  x.'  Prior  to all testing, subjects w e r e a s k e d not to partake in exhaustive e x e r c i s e for 24 hr, restrict t h e m s e l v e s from caffeine a n d alcohol c o n s u m p t i o n for c o n s u m e food or fluid other than water for 2 hours. computer-aided  electronically-braked  load  simulator  V0  2 m a x  12 hours, and  not  w a s a s s e s s e d using a  (Computrainer™  PRO  8001,  R a c e r M a t e , Seattle, W A ) . Metabolic variables were a s s e s s e d with a S e n s o r m e d i c s V M A X 2 9 C metabolic cart ( S e n s o r m e d i c s , Y o r b a Linda, C A ) using the breath-by-breath  9 system.  Heart rate (HR) w a s recorded using a Marquette  12SL™ E C G monitor  (Marquette Electronics, M i l w a u k e e , WI). V0  w a s c o n s i d e r e d to h a v e b e e n obtained w h e n at least three of the four  2 m a x  following criteria w e r e met: (1) a plateau in V 0 with increasing w o r k l o a d , (2) respiratory 2  e x c h a n g e ratio ( R E R ) > 1.10, (3) attainment of 9 0 % age-predicted m a x i m a l H R ( H R  m a x  ),  a n d or (4), volitional fatigue. T h e highest three c o n s e c u t i v e a v e r a g e d 2 0 s interval's w a s defined a s V 0  2 m a x  .  Rating of p e r c e i v e d exertion ( R P E ) (21) w a s recorded immediately  post-exercise. Experimental  Design:  T h e r e s e a r c h d e s i g n w a s a r a n d o m i z e d , double-blinded,  c r o s s o v e r d e s i g n , with subjects serving a s their own control.  Acute plasma volume  e x p a n s i o n w a s the intervention. A repeated m e a s u r e s A N O V A w a s u s e d for m e a s u r i n g the primary d e p e n d e n t variable, P T T : C  2  x M , that is, condition (C; non-infusion, 2  infusion) c r o s s e d with method ( M ; centroid, deconvolution). A 2 x 8 repeated m e a s u r e s A N O V A w a s u s e d in the statistical a n a l y s i s for the s e c o n d a r y d e p e n d e n t variables: C  2  x  T , that is, condition (C; non-infusion, infusion) c r o s s e d with time (T; minute 0, 1-6, 6.5) 8  for arterial P 0  2  ( P a 0 ) , alveolar to arterial o x y g e n difference ( A a D 0 ) , a n d % S a 0 . 2  2  2  P a i r e d T-tests w e r e u s e d to c o m p a r e c a r d i a c output, a n d pulmonary blood v o l u m e ( P B V ) b e t w e e n conditions at minute 3 of the constant-load e x e r c i s e task. Protocol:  S u b j e c t s were r a n d o m i z e d to receive 5 0 0 m l of 1 0 % Pentaspan® (Du  Pont P h a r m a , Kirkland, P Q ) or - 6 0 m L of intravenous normal saline infusion to k e e p the vein o p e n ( T K V O ) before s e s s i o n s 1 a n d 2.  During e a c h of s e s s i o n s 1 and 2, all  r e s e a r c h p e r s o n n e l a n d r e s e a r c h subjects (except o n e r e s e a r c h nurse a n d two medical technicians) w e r e blinded a s to whether subjects received Pentaspan® or saline.  Each  of s e s s i o n s 1 a n d 2 w a s identical in s e q u e n c e , duration, a n d protocol of m e a s u r e m e n t s .  10 After a peripheral intravenous catheter w a s inserted, o n e r e s e a r c h nurse infused either 5 0 0 m l of Pentaspan® [infusion s e s s i o n (I)] or ~ 6 0 m L saline [non-infusion s e s s i o n (N)] (0.9% s o d i u m chloride injection; Baxter C o r p o r a t i o n , Toronto, O n t ) .  T h e following line  d i a g r a m s h o w s the protocol for s e s s i o n s 1 a n d 2:  Arterial cannulation, blood volume or plasma volume measurement, esophageal probe insertion E x e r c i s e at - 9 2 % V 0 a x (min)  -90min  -60min  Baseline measurements Hb, Hct  2 m  A  -15min  0  3  3.5  First pass radionuclide cardiography  Randomized, doubleblind crossover infusion of 500 mL Pentaspan or 60 mL saline TKVO  • 6.5  MUGA acquisition  V0 , V , HR, RER, averaged every 20 s; ABG's, and esophageal temperature taken every minute and at 6.5 minutes 2  Sessions  4  1 and 2—6.5 minute Constant-load  Severe  E  Cycling  Exercise:  Sessions  1 a n d 2 c o n s i s t e d of repeated 6.5 minute, constant, n e a r - m a x i m a l cycling e x e r c i s e tests (-92% V 0  2 m a  Blood stretcher  x ) on s e p a r a t e d a y s , with a minimum of 6 d a y s b e t w e e n s e s s i o n s 1 a n d 2. and Plasma  and  rested for  volume. -1.5  Prior to arterial catheterization, subjects laid on a hours  prior  to  exercise. A n  18 g a u g e  peripheral  intravenous catheter w a s inserted into a n antecubital vein on both d a y s , 1.5 hours prior to e x e r c i s e . During this time, hematocrit (Hct), h e m o g l o b i n (Hb), blood v o l u m e and/or plasma volume were measured.  B l o o d v o l u m e w a s m e a s u r e d using 2.7 M B q of  5 1  Cr  m e a s u r e red blood cell ( R B C ) m a s s a n d p l a s m a v o l u m e w a s m e a s u r e d using 0.17 M B q 1 2 5  l  h u m a n s e r u m by standard methodology  (6). T h e quantity of p l a s m a v o l u m e  11 e x p a n s i o n w a s determined by c o m p a r i n g p l a s m a v o l u m e post-infusion during the I s e s s i o n to the p l a s m a v o l u m e from the blood v o l u m e m e a s u r e m e n t of the N s e s s i o n b e c a u s e trained individuals have stable p l a s m a v o l u m e (66) a n d R B C m a s s (63) over a 4 - 1 2 w e e k period.  Therefore, blood v o l u m e w a s only m e a s u r e d o n c e (N s e s s i o n ) ,  while p l a s m a v o l u m e w a s only m e a s u r e d post-infusion (I s e s s i o n ) . Arterial Catheterization, Gas Sampling:  Esophageal  Temperature  Probe Insertion, Arterial  Blood-  Within 10 minutes of having p l a s m a v o l u m e or blood v o l u m e m e a s u r e d ,  the subjects r e m a i n e d s u p i n e while a 20 g a u g e arterial catheter (Arrow  International,  Erding, G e r m a n y ) w a s inserted into the left radial artery under local a n a e s t h e s i a (2% lidocaine hydrochloride). An  e s o p h a g e a l temperature  probe  was  inserted  to  measure  temperature  continuously during e x e r c i s e s o that arterial blood g a s e s ( A B G ' s ) could be corrected for the i n c r e a s e in temperature that o c c u r s during e x e r c i s e (48). In a sitting  position,  subjects had a general p u r p o s e temperature probe (Sheridan Corporation, Argyle, N Y ) inserted though a preferred nostril into the e s o p h a g u s at a specified depth (135). temperature  probe w a s then c o n n e c t e d to a Y e l l o w S p r i n g s 4 0 0  The  tele-thermometer  (Yellow S p r i n g s Instrument C o m p a n y , O H ) . Pa0 , 2  PaC0 , 2  a n d pH w e r e m e a s u r e d directly via a n A B L 3 0 A c i d -  A n a l y z e r (Radiometer, C o p e n h a g e n , D K ) . % S a 0  2  w a s calculated from m e a s u r e m e n t s  of p H , P 0 , a n d body temperature using a normal 0 2  Base  2  dissociation curve (186).  ABG's  were s a m p l e d at rest (prior to warm-up), every minute during e x e r c i s e , a n d at 6.5 minutes of the e x e r c i s e test. (182).  All A B G ' s s a m p l e s w e r e corrected for core temperature  T h e ideal alveolar g a s equation w a s u s e d to calculate alveolar partial pressure  ( P A 0 ) a n d A a D 0 , a n d the P C 0 2  (V ). A  2  2  equation w a s u s e d to calculate alveolar ventilation  12 Determination RadioNuclide  of  Cardiography:  Right-to-Left  Pulmonary  Transit  Times  by  First  Pass  A b o u t 1 hr prior to the 6.5 minute e x e r c i s e test, 10 ml of  v e n o u s blood w e r e withdrawn into a 20ml_ heparinised luer-lock tip syringe ( S h e r w o o d M e d i c a l , St. Louis, Mo). T h e R B C ' s w e r e labeled with 1110 M B q  9 9 m  T c (TechneLite®  M o l y b d e n u m 99 - T e c h n e t i u m 9 9 m G e n e r a t o r ; D u Pont P h a r m a , M i s s i s s a u g a , Ontario) by a s t a n d a r d i z e d in vitro labeling procedure (13). d o s e for  9 9 m  T h e estimated radiation a b s o r b e d  T c labeled - 3 6 0 m R (180 m R per s e s s i o n ) (68), w h i c h is equivalent to - 3 . 6  m S v of effective radiation e x p o s u r e (68).  Prior to e x e r c i s e , the r e s e a r c h e r s positioned  the bicycle ( s e c u r e d to the Computrainer™) in front of a S i e m e n s Orbiter G a m m a C a m e r a (wide field of view, low e n e r g y high resolution parallel hole collimator, 64 x 6 4 matrix, 0.65 c m per pixel). S u b j e c t s l e a n e d forward placing their c h e s t s directly in contact with the c a m e r a a n d grasping the c a m e r a with the left h a n d while the g a m m a c a m e r a acquired i m a g e s at a n approximate 30° left anterior oblique position.  They  maintained this position for both 6.5 minute e x e r c i s e tests. P T T a n d distribution of P T T were a s s e s s e d during a 30 s e c o n d period (beginning at the third minute of s e v e r e exercise) by first-pass radionuclide cardiography using previously validated centroid a n d deconvolution m e t h o d s (90, 123).  Minute 3 w a s s e l e c t e d a s the time-point to a s s e s s  P T T b e c a u s e first-pass radionuclide cardiography must p r e c e d e the m e a s u r e m e n t of c a r d i a c output.  S i n c e c a r d i a c output m e a s u r e m e n t with nuclear m e d i c i n e technology  takes about 2.5 minutes, a n d s i n c e athletes could only perform c l o s e to m a x i m u m intensity for about 6 minutes, m e a s u r e m e n t P T T (which t a k e s 30 s e c o n d s ) occurred at minute 3. F o r the a s s e s s m e n t of P T T , one picture w a s taken every 0.2 s e c o n d s for a total of 150 f r a m e s . of  9 9 m  Radioactivity w a s m e a s u r e d during first-pass of the injected bolus  T c labeled R B C ' s through the central circulation via a n antecubital vein.  Time-  activity c u r v e s for the right ventricle (RV) a n d left ventricle (LV) w e r e g e n e r a t e d allowing  13 calculation  of  mean  right-to-left ventricular  red  cell  P T T (centroid  method)  and  distribution of P T T (deconvolution method). Calculation  of Mean PTT—Centroid  Method.  E a c h time-activity curve ( R V a n d  L V raw data) w a s fitted by a g a m m a function of the form t-t,  C(t) = ka(t-t )e  '  a  [ 1 ]  w h e r e , k, a, p are arbitrary parameters, t = first a p p e a r a n c e time, t = time in s e c o n d s , a  a n d C(t) = indicator concentration at time t (190). T h i s function h a s b e e n s h o w n to yield g o o d fits to u n i m o d a l c u r v e s (43, 5 5 , 65). P a r a m e t e r s w e r e e s t i m a t e d through m a n u a l fitting of equation [1] to R V a n d L V raw data. M e a n P T T w a s determined by subtracting the first m o m e n t of the L V curve (the center of m a s s of the L V curve) from the first moment of the R V curve, w h e r e the first m o m e n t of equation [1] is given by  %= ^ a Distribution  of PTT—Deconvolution  +t  [2]  a  Method.  Deconvolution is a mathematical  p r o c e s s by which a distribution of P T T (called a transport function) c a n be derived from the input ( R V ) a n d output (LV) time-activity c u r v e s .  T h e Fourier d o m a i n transport  function m a p p i n g R V to L V is the transport function that provided the frequency distribution of P T T . T h e theory follows: G i v e n that both input a n d output c u r v e s c a n be d e s c r i b e d by a g a m m a function, then the transport function is also a g a m m a function. Mathematically: 0(t) = h(t)*i(t)  [ 3 ]  where l(t) = input function, o(t) = output function, h(t) is the transport function or distribution of P T T , a n d * is the convolution operator.  S i n c e input a n d output functions  are obtained from the s m o o t h e d g a m m a - v a r i a t e fitted R V a n d L V time-activity c u r v e s ,  14 h(t) is the remaining function to be s o l v e d . using  GLANSE  computer  software  (22),  physiological transport modeling (174).  T h i s mathematical p r o c e s s w a s performed developed  by  Vanderbilt  University  Briefly, the software s e t s the a r e a underneath  both R V input a n d L V output c u r v e s equal to one.  G L A N S E then actually directly  c o m p u t e s the transport function using a numerical deconvolution algorithm. deconvolution  is  very  for  noise-dependent,  in  can  be  a  difficult  process  Because to  do.  C o n s e q u e n t l y , all R V a n d L V raw data time-activity c u r v e s w e r e s m o o t h e d by using a three point s m o o t h i n g technique a n d g a m m a variate fit (43) from the g a m m a - c a m e r a computer software. Theoretically, m e a n P T T obtained from the deconvolution of the g a m m a variated fitted input a n d output c u r v e s , is the s a m e a s the m e a n P T T obtained via the centroid method (123).  Therefore, the c l o s e approximation of m e a n P T T obtained by both  m e t h o d s s h o u l d validate the application of both mathematical p r o c e s s e s a n d strengthen evaluation of both e s t i m a t e s of P T T . Ejection  Fraction  and Cardiac  Output Measurement:  Ejection fraction ( E F ) w a s  determined from Multigated Acquisition ( M U G A ) T e c h n i q u e (also called equilibrium radionuclide ventriculography), obtained during the last 2.5 minutes of both 6.5 minute tests.  T h e M U G A technique w a s c h o s e n for its relatively n o n - i n v a s i v e procedure, a n d  for its compatibility of m e a s u r i n g P T T sequentially. D a t a from e a c h c a r d i a c c y c l e of the final 2.5 minutes of the test w a s divided up into 16 f r a m e s of equal length, a n d data from e a c h portion of the c a r d i a c cycle w a s put into the appropriate f r a m e s .  The end  result w a s a final 16 i m a g e s e a c h of which s h o w e d a portion of the c a r d i a c cycle. B e c a u s e of the inherent reliance of gated methodology on E C G input, the s u c c e s s of M U G A t e c h n i q u e to determine E F (and thus c a r d i a c output) is related to the c o n s i s t e n c y of c a r d i a c rate a n d rhythm in a given subject (137).  S e v e r e d i s t u r b a n c e s in E C G  15 w a v e f o r m length c a u s e distortion  of the data obtained.  Therefore, commercially  available software ( S I E M E N S I C O N ) w a s u s e d 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 e a s y recognition of aberrant c a r d i a c beats. In all subjects, the validity of the data w a s p r e s e r v e d by arrhythmia filtering.  T h i s p r o c e s s allowed for the  rejection of c a r d i a c c y c l e s that did not conform to the a v e r a g e length of the c a r d i a c cycle during the last 2.5 minutes of the e x e r c i s e test.  W h e r e the R - R interval w a s  outside the a c c e p t e d limits (± 1 0 % variation), beats w e r e rejected a n d thus did not contribute to the final i m a g e set (137).  Ejection fraction ( E F ) w a s calculated from the  M U G A s c a n w h e r e the L V region of interest (ROI) with the highest n u m b e r of counts w a s a s s i g n e d a s the e n d diastolic counts ( E D C ) , the L V ROI with the lowest n u m b e r of counts w a s the e n d systolic counts ( E S C ) , a n d " b a c k g r o u n d " w a s the correction factor applied for the e x c e s s radioactive counts from overlaying t i s s u e s d u e to recirculation:  EF =  ~ EDC - background E  D  C  E  S  [4]  C  Left ventricular v o l u m e s w e r e then calculated using a validated m a n u a l c o u n t - b a s e d ratio method originally derived by M a s s a r d o et al. (129) a n d modified by L e v y et al. (120).  T h e c o u n t - b a s e d method of calculating left-ventricular v o l u m e s relies on the  theory that if radioactivity is completely mixed in a c h a m b e r , the n u m b e r of counts recorded in a c h a m b e r is directly proportional to its volume.  T h e count distribution is  directly related to the three-dimensional activity distribution in front of a g a m m a c a m e r a (144).  Of c o u r s e , the i m a g e itself is only p s e u d o - t h r e e - d i m e n s i o n a l b e c a u s e radiation  depths are s u p e r i m p o s e d (144). N o n e t h e l e s s , a g o o d v o l u m e estimate c a n be obtained from  the  count-density  distribution  of  the  left  ventricle  that  has  radioactivity  h o m o g e n e o u s l y m i x e d , with a s h a p e that is not too irregular (144). T h e m a n u a l count-  16 b a s e d method by L e v y a n d c o l l e a g u e s (120) a l s o a s s u m e s that the left-ventricle is a prolate ellipsoid with the major axis 1.8 times the length of the minor axis (D), a n d u s e s b a c k g r o u n d correction. In fact, the left ventricle h a s b e e n s h o w n to represent a prolate ellipsoid for left-ventricular v o l u m e s of less than 3 0 0 ml (117, 177) [the v o l u m e of a prolate ellipsoid = 0.37tD ]. 3  Therefore, left ventricular E D V w a s obtained by manually  drawing a R O I of the left ventricle in the E D V image from M U G A s c a n , a n d then calculating v o l u m e (V ) from the formula: t  V = 2.02M C R 3  3,2  312  [ 5 ]  t  where M is the pixel width in c m ; R is the ratio of the total counts in the ROI (minus the total b a c k g r o u n d correction in that ROI), divided by the a v e r a g e of the four highest count pixels (minus the a v e r a g e b a c k g r o u n d count rate per pixel); a n d C is the t r a n s m i s s i o n factor of the highest count pixel ( T ) , to the t r a n s m i s s i o n factor of the m  whole ROI (Tf). T h e absolute t r a n s m i s s i o n factor d e c r e a s e s with distance, but d o e s not vary over depths of 5 - 15 c m (120). of T  m  In this study, it w a s a s s u m e d that the attenuation  a n d T w e r e the s a m e , a n d thus C w a s equal to 1. In addition, w e determined the f  pixel width from the S i e m e n s Orbiter to be 0.65 c m per pixel. T h u s , the final formula u s e d to calculate E D V w a s : V = 0.55/? ' 3  [6]  2  t  S V w a s then calculated by multiplying E D V by the E F obtained from the M U G A s c a n , a n d w a s then calculated by multiplying H R by S V . 2.3  RESULTS Subject  Characteristics  and resting  pulmonary  function:  Subject characteristics  a n d resting pulmonary function data are s h o w n in T a b l e 1. All subjects w e r e very fit a s m e a n V 0 a x w a s 69.6 + 7.4 ml • kg" • min" . T h e s e elite endurance-trained subjects 1  2 m  1  17 had predicted or s o m e w h a t better than predicted resting pulmonary function. function abnormalities w e r e present.  N o lung  F r o m the 6.5 minutes, constant-load s e v e r e  e x e r c i s e tests, s e v e n subjects (58%) w e r e classified a s having E I A H (minimal P a 0 < 90 m m H g and/or e x c e s s i v e A a D 0 Effects  of infusion  on PTT:  2  2  of  > 2 5 m m H g ; T a b l e 2).  P e n t a s t a r c h (500 m L of 10%) infusion significantly  i n c r e a s e d blood v o l u m e (460 ± 4 2 2 m L ) c o m p a r e d to normal s a l i n e (P = 0.002).  The  primary results of this study s h o w that v o l u m e e x p a n s i o n lengthened right-to-left P T T by 0.30 + 0.20 s e c o n d s during s e v e r e e x e r c i s e (range = +0.11 to +0.66 s e c o n d s ; T a b l e 3; P = 0.002; n = 9). P a i r e d m e a s u r e m e n t s on three subjects P T T data w e r e omitted from the overall P T T a n a l y s i s b e c a u s e of technical p r o b l e m s .  N e v e r t h l e s s , deconvolution  and centroid m e t h o d s g a v e the s a m e results (r = 0.96 b e t w e e n both methods).  Day-to-  day intraobserver error in determining P T T ( a s s e s s e d by a o n e - w a y A N O V A (20) over three blinded r a n d o m i z e d trials) varied by 1 1 % or 0.28 s e c o n d s . Test-retest reliability of manually fitting right a n d left time-activity c u r v e s h a d a n intraclass correlation coefficient of-0.50. A c u t e v o l u m e e x p a n s i o n by pentastarch (500 m L of 10%) shifted the distribution of P T T to the right during s e v e r e e x e r c i s e (Figures 1 a n d 2).  In the non-infusion  condition, 2 2 . 5 ± 1 3 . 2 % of R B C ' s had P T T of l e s s than 2 s e c o n d s , while volume infusion shifted the distribution to the right a s only 13.2 ± 1 2 . 6 % of R B C ' s h a d P T T l e s s than 2 s e c o n d s (P = 0.08).  Furthermore, 75.0 ± 8 . 7 % of R B C ' s h a d P T T of l e s s than 3  s e c o n d s , while 62.8 ± 1 5 . 4 % of red cells h a d P T T l e s s than 3 s e c o n d s during the infusion condition  (P = 0.01).  A c u t e hypervolemia a l s o altered the distribution of P T T  within a time interval b e c a u s e there w a s significantly greater p e r c e n t a g e of R B C ' s within the 3 - 3.8 s e c o n d s time interval after acute v o l u m e infusion than in the non-infusion  18 condition (Figure 1; P = 0.02).  R e d blood cell d i s p e r s i o n of the m e a n P T T ' s during  e x e r c i s e (defined a s S D of m e a n P T T + m e a n P T T ) w a s a l s o slightly altered between conditions.  T h e lengthened P T T during v o l u m e infusion i n c r e a s e d m e a n red cell P T T  dispersion to 0.12 c o m p a r e d to 0.09 in the N condition. Therefore, the data s h o w s that acutely i n c r e a s e d blood v o l u m e lengthened P T T c a u s i n g red cell distribution to b e c o m e more h e t e r o g e n e o u s c o m p a r e d to the non-infusion condition. In addition, there w a s a strong trend for the blood v o l u m e (per kg of body weight) to be a s s o c i a t e d with P T T (r = 0.39; P = 0.08). Moreover, c a r d i a c index w a s negatively a s s o c i a t e d with P T T (r = 0.22; 2  P = 0.03). Arterial Blood Gases and Esophageal PaC0  2  and % S a 0  2  Temperature:  P a 0 and A a D 0 2  2  (Figure 3),  (Figure 4), w e r e not altered b e t w e e n infusion (I) a n d non-infusion  (N) conditions (P > 0.05). P a 0  2  (corrected to e s o p h a g e a l temperature) d e c r e a s e d from  105.2 ± 6.8 to 90.6 + 9.2 m m Hg (range = 69.7 - 102.3 m m H g ; Figure 5) within the first minute of s e v e r e cycling e x e r c i s e (P < 0.05) a n d did not significantly c h a n g e throughout the rest of e x e r c i s e , irrespective of condition ( P a 0 Hg).  AaD0  2  2  at e n d of test w a s 88.2 ± 7.4 m m  (corrected to e s o p h a g e a l temperature) i n c r e a s e d from 5.9 + 7.8 m m Hg at  minute 0 to 19.6 ± 7.8 m m H g (range = 9.8 - 34.4 m m H g ; Figure 5) at minute 1 of s e v e r e cycling e x e r c i s e (P < 0.05).  Thereafter, w a s a significant i n c r e a s e of A a D 0  throughout the rest of the 6.5 minute test s u c h that at the e n d of e x e r c i s e , A a D 0  2  2  was  24.8 + 6.0 m m H g (range = 16.2 - 35.2 m m Hg) (P < 0.05; Figure 3). T h e r e w a s no significant relationship between P T T a n d pulmonary oxygenation s i n c e P T T w a s not a s s o c i a t e d with P a 0 0.30) or % S a 0  2  2  (r = 0.19; P  (r = 0.15; P = 0.53). C a l c u l a t e d % S a 0  = 0.43), A a D 0 2  2  (r = -0.24; P =  d e c r e a s e d from 97.9 ± 0 . 5 % at  minute 0 to 90.6 + 2 . 4 % (range = 86.0 - 93.5%) at minute 6.5, irrespective of v o l u m e  19 infusion (P < 0.01; Figure 4). In order to determine what part of the m e a n 7 . 3 % drop in %Sa0  2  during the 6.5 minute cycling e x e r c i s e w a s d u e to the B o h r effect ( c h a n g e s p H  a n d body c o r e temperature) v e r s u s other factors (i.e. T A a D 0 , ^ P a 0 , T P a C 0 , V 0 ) , 2  2  s t a n d a r d i z e d formulas (181) w e r e implemented to correct % S a 0  2  2  2  to a p H of 7.4 a n d  37°C (Figure 4). It w a s found that at the e n d of the cycling e x e r c i s e , 4 1 % of the total drop in % S a 0  2  from minute 0 to minute 6.5 w a s d u e to the i n c r e a s e d core temperature  (as reflected by e s o p h a g e a l temperature, T ) a n d d e c r e a s e d p H , while 5 9 % of the e s  remaining 7 . 3 % drop w a s d u e to other factors (i.e t A a D 0 , ^ P a 0 ) . 2  2  Esophageal  temperature i n c r e a s e d significantly during e x e r c i s e but there w a s no difference in the i n c r e a s e in temperature b e t w e e n non-infusion a n d infusion conditions (Figure 4; P = 0.58).  Arterial P C 0  2  corrected for temperature did not c h a n g e during e x e r c i s e in either  the non-infusion nor infusion group (Figure 3; P = 0.71). Metabolic  variables,  heart rate and ratings of perceived  Infusion did not affect V 0 , V 2  E  exertion:  Acute volume  (Figure 5) or R P E between s e s s i o n s 1 a n d 2 (P > 0.05).  O x y g e n c o n s u m p t i o n i n c r e a s e d from 8.5 ± 2.0 at rest to 63.6 ± 6.6 ml • kg" • min" at 1  1  minute 6.5 of s e v e r e cycling e x e r c i s e , irrespective of v o l u m e infusion (p < 0.05). T h i s represented a n intensity of about - 9 2 % of m a x i m u m w h e n a v e r a g i n g the last 2.5 minutes of e x e r c i s e . Minute ventilation i n c r e a s e d from 18.6 ± 2.8 at rest to 158.6 ± 27.4 L • min" at minute 6.5 of e x e r c i s e (P < 0.05). 1  u n c h a n g e d b e t w e e n the preliminary V 0  2 m a x  R a t i n g s of p e r c e i v e d exertion (21) w e r e  s e s s i o n ( R P E = 17.8 ± 0.8) a n d both 6.5  minutes cycling e x e r c i s e s e s s i o n s (N = 18.1 ± 1.1; I = 18.3 + 0.6) (P > 0.05), s u g g e s t i n g that the s a m e effort w a s maintained during e a c h e x e r c i s e s e s s i o n . H o w e v e r , there w a s a main effect of condition on H R , a s H R w a s about 2 beats • min" lower at all time 1  intervals with v o l u m e infusion (Figure 6; P = 0.04).  20 Arterial pH, Standard  Base Excess,  and Bicarbonate  concentration:  Arterial p H ,  bicarbonate a n d standard b a s e e x c e s s d e c r e a s e d steadily a n d significantly  during  s e v e r e e x e r c i s e (Figure 7). A c u t e v o l u m e e x p a n s i o n d e c r e a s e d p H (P = 0.02) and bicarbonate concentration (P = 0.01) during the 6.5 minute cycling e x e r c i s e test by about 4 - 5 % (Figure 7), while calculated standard b a s e e x c e s s w a s not affected by infusion (Figure 7; P = 0.16). B e c a u s e there w a s no difference b e t w e e n non-infusion a n d infusion condition in P a C 0 , a n d b e c a u s e arterial p H is negatively a s s o c i a t e d with 2  blood lactate levels (148), it is p o s s i b l e that p e a k blood lactate levels in this study rose from - 1 4 . 5 m m o l • L" in the non-infusion s e s s i o n to - 1 5 . 5 m m o l • L" in the v o l u m e 1  1  infusion s e s s i o n (148) (P <0.05). Cardiac  function data:  C a r d i a c index w a s u n c h a n g e d despite v o l u m e infusion in  all 12 athletes (P = 0.73; T a b l e 4) a n d in the s u b s e t of athletes with E I A H (P = 0.48; T a b l e 5).  C a r d i a c index at minute 3 of constant-load s e v e r e e x e r c i s e ( - 8 8 %  w a s 15.8 ± 2.0 a n d 15.6 ± 1.8 L • m  2  V0  2 m a x  )  • min" in the non-infusion a n d infusion conditions, 1  respectively (n = 12). T h e r e w a s a significant a s s o c i a t i o n b e t w e e n V 0 a n d Q (r = 0.81; 2  P < 0.01), confirming the linear relationship between V 0 a n d Q during e x e r c i s e . 2  In addition, predicted Q from V 0  m e a s u r e m e n t s (221) demonstrated similar  2  v a l u e s to Q m e a s u r e d using radionuclide t e c h n i q u e s (r = 0.68; P < 0.01). T h e a v e r a g e Q w a s predicted to be 32.1 ± 3.5 L • min" (221) while the a v e r a g e calculated Q from 1  the c o m b i n e d E D V estimation using the c o u n t - b a s e d ratio method (120) a n d the E F from the M U G A s c a n , w a s 30.4 ± 4 . 1  L • min"  1  (P > 0.05 b e t w e e n predicted a n d  calculated Q ) . T h e 2 L • min" underestimation of Q u s i n g radionuclide m e t h o d s is in 1  a g r e e m e n t with a current  review (212), which indicates underestimation of Q  radionuclide m e t h o d s during e x e r c i s e .  by  21 EDV reproducibility  assessed  by  [day-to-day  the  count-based  intraobserver  error  ratio  method  (19)  by  (120)  G S Z was  showed 36  mL  good (15%)].  R e p e a t e d a n a l y s i s of the s a m e raw data indicated excellent correlation between E D V m e a s u r e d o n all twelve subjects m e a s u r e d on two o c c a s i o n s by G S Z (r = 0.91; P < 0.01).  Furthermore, calculating ejection fraction from the M U G A s c a n s h o w e d g o o d  reproducibility a s day-to-day intraobserver error (19) w a s 5 % .  Repeated measurement  of E F on two o c c a s i o n s s h o w e d g o o d correlation (r = 0.92; P < 0.01). Stroke v o l u m e , ejection fraction, E D V , and E S V w e r e unaltered between n o n infusion a n d infusion conditions at minute three of e x e r c i s e (P = 0.13 to P u l m o n a r y blood v o l u m e w a s higher (+131 condition (P = 0.015; T a b l e 4).  0.25).  mL) in the acute v o l u m e e x p a n s i o n  22 T a b l e 1:  Subject characteristics a n d resting pulmonary function (n = 12).  B S A (m ) A g e (years) Height (cm) W e i g h t (kg) 2  V0 ax ( m l k g " m i n " ) 1  1  2m  V0 ax (L • min" ) 1  2m  V  (Lmin" ) 1  E  HRmax (beatsmin" ) 1  P e a k power output (W) Hct (%) Hb (g • L" ) B l o o d v o l u m e (mL) 1  Mean ± S.D.  Range  1.93 + 0.12 29.0 + 6.1 180.6 ±7.0 74.8 ± 6 . 0 69.6 ± 7 . 4 5.18 ±0.59 176.9 ±29.0 192 ± 1 0 427 ± 54 41.1 ± 1.7 138.0 ±5.2 5949 ± 8 9 4 79.3 ±7.7 6.2 ±0.9 5.2 ±0.7 83.0 ±6.0 11.2 ± 1.4 40.2 ±5.5  1.76-2.07 23-44 172-192 65.0-87.1 62.0-83.3 4.33-6.33 132.7-214.3 178-209 350-515 38-43 131 - 145 4677 - 7428 78.2-96.2 4.9-7.8 3.9-6.6 71.3-92.7 8.0-12.9 31.9-47.8  P e r c e n t a g e predicted —  — —  —  100.6 ± 9 . 8 * 100.4 ± 9 . 3 * —  — —  ~  118 ± 13* B l o o d v o l u m e (mL • kg" ) 117.7 ± 13.2* FVC (L) 111.4± 11.6* FEVi (L) 112.5 ± 10.3* FEWFVC (%) 101.0±6.8 P E F (Ls" ) 112.8 ± 13.9* D L C O (ml m i n " m m H g " ) 113.8 ±11.3*** * P r e d i c t e d v a l u e significantly different than obtained v a l u e ( P < 0.05). P u l m o n a r y 1  1  1  1  §§  §§  §  §  §  §  function v a l u e s in m a l e s a s a p e r c e n t a g e of normal v a l u e s predicted for m e n of s a m e height a n d a g e . Prediction equations are: spirometery (42) . D L C O (17, 40) **. V 0 2 m a x v a l u e s in m a l e s a s a p e r c e n t a g e of v a l u e s predicted for m e n of s a m e a g e , weight, a n d peak power output at m a x i m u m e x e r c i s e (193)*. B l o o d v o l u m e in m a l e s a s a p e r c e n t a g e of v a l u e s predicted for healthy y o u n g m e n of s a m e weight (178) §  §§  23 T a b l e 2: C l a s s i f i c a t i o n of subjects with e x c e s s i v e AaDC»2 (> 2 5 m m Hg) and/or low PaC>2 (< 90 m m Hg) during the 6.5 minutes, constant-load, s e v e r e cycling e x e r c i s e in the non-infusion s e s s i o n .  Subject  Individuals with E I A H Minimal A v e r a g e Pa0 AaD0 over last 2.5 minutes 79.4 30.7 2  MV  2  PTT (sec)  Subject  2.405  AC  Individuals without E I A H PTT Minimal A v e r a g e (sec) Pa0 AaD0 over last 2.5 minutes 94.5 17.8 2.500 2  2  JB  76.4  33.4  2.255  BW  91.7  17.4  MD  ME  77  32.5  2.200  AF  92.7  20.3  2.445  LZ  83.3  24.6  2.775  PG  94.3  18.6  2.400  SS  65.8  27.6  2.255  PC  91.7  17  2.755  SP  89.2 .  15.5  2.430  NC  82.4  30.9  2.485  18.2* 2.530 0.160 1.3 P a 0 = arterial P 0 (mm Hg); A a D 0 = a veolar-arterial partial p r e s s u r e difference (mr Hg); E I A H = e x e r c i s e - i n d u c e d arterial h y p o x e m i a ; M D = m i s s i n g data; * significantly different from individuals with E I A H (P < 0.01) Mean SD 2  27.9 6.2  79.1 7.3  2  2.400 0.200 2  93.0* 1.3  24 T a b l e 3 : C o m p a r i s o n of method a n d condition o n a s s e s s m e n t of red cell pulmonary transit times during minute 3 of the 6.5 minutes constant4oad, s e v e r e cycling e x e r c i s e , [n = 9]; * P = 0.002 c o m p a r e d to non-infusion condition.  Non-infusion Subject AC  Centroid 2.40  Infusion  Deconvolution 2.60  Centroid 2.72  Deconvolution 2.91  NC  2.48  2.49  2.61  2.58  SS  2.20  2.31  2.75  2.74  LZ  2.76  2.79  3.12  3.02  MV  2.40  2.41  3.04  3.08  PC  2.75  2.76  3.20  3.22  JB  2.20  2.31  2.52  2.46  PG  2.40  2.40  2.61  2.56  ME  2.25  2.15  2.20  2.19  Mean ± S D Combined Mean + S D  2.43 + 0.21 2.47 + 0.21 2.45 +0.21  2.75 + 0.32 2.75 + 0.33 2 . 7 5 + 0.32*  r = 0.96 b e t w e e n m e t h o d s (P < 0.01); coefficient of variation b e t w e e n m e t h o d s is 1.9%. Day-to-day intraobserver m e a s u r e m e n t error in a s s e s s i n g P T T w a s a n a l y z e d by a o n e w a y A N O V A (20) over three trials a n d varied by 0.28 s e c or 1 1 % variation. T h e Intraclass correlation coefficient for test-retest reliability (20) in a s s e s s i n g P T T w a s found to be fair/moderate (n = -0.50).  25 Table 4: M e a n metabolic, arterial b l o o d - g a s ( A B G ) , blood v o l u m e , a n d c a r d i a c output data at minute 3 of intense cycling e x e r c i s e (n = 12 e x c e p t for P T T a n d P B V w h e r e n = 9). * P < 0.05. Variable  B l o o d v o l u m e (mL) V0  (ml • kg" • m i n ) 1  2  1  V (L • min" ) E F (%) P T T (sec) 1  E  Q index (L • m • min" ) S V index (ml • m ) E D V index (ml • m ) E S V index (ml • m ) P B V index (L • m ) 2  1  Non-infusion Condition (mean + S D ) 327 + 2 9 watts  Infusion Condition (mean ± S D ) 340 ± 2 9 watts  P value  5949 ± 8 9 4  6409±1065  0.003*  61.1 ± 5 . 6  61.2±6.0  0.88  138.3 ± 3 4 . 2  146.9 ± 2 3 . 3  0.64  74 ± 4 2.45 ± 0 . 2 1 15.8 ± 2 . 0  72 ± 6  0.25  2.75 ± 0.32*  0.002  15.6±  0.09  0.67  1.8  0.35 85.2 ± 11.2 85.4 ± 10.4 0.13 115 + 15 119 + 13 0.14 29.5 ± 7 . 1 33.4 ± 9 . 2 0.02 0.63 ± 0 . 0 5 0.70 ± 0 . 0 9 * 0.002 172.4 ± 9 . 1 162.1 ± 15.0* C a 0 (ml • L" ) P a 0 (mm Hg) 0.46 89.5 ± 9 . 0 90.7 ± 7.7 A a D 0 (mm Hg) 0.50 21.8 ± 6.1 22.7 ± 6 . 8 %Sa0 0.78 93.5 ± 2 . 6 93.3 ± 1.6 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; C a 0 = arterial oxygen content; P a 0 = arterial P 0 ; A a D 0 = Alveolar-arterial partial pressure difference; % S a 0 = arterial oxyhemoglobin saturation; P a C 0 = arterial P C 0 ; V 0 = oxygen consumption; V = minute ventilation. 2  2  2  2  1  2  2  2  2  2  2  2  2  2  E  2  2  2  26 Table 5: M e a n metabolic, arterial b l o o d - g a s ( A B G ) , blood v o l u m e , a n d c a r d i a c output data at minute 3 of intense cycling e x e r c i s e in athletes with E I A H (minimal P a 0 < 9 0 m m Hg). [n = 7 e x c e p t for P T T a n d P B V w h e r e n = 6]. * P < 0.05. 2  Variable  B l o o d v o l u m e (mL) V0  (ml • kg" • min" ) 1  2  1  V (L • min" ) E F (%) P T T (sec) 1  E  Q index (L • m • min" ) S V index (ml • m ) E D V index (ml • m ) E S V index (ml • m ) P B V index (L • m ) 2  1  Non-infusion Condition (mean ± S D ) 336 ± 18 watts  Infusion Condition (mean ± S D ) 3 4 5 ± 2 0 watts  P value  6275 ± 878  6775±1249*  0.02  61.8 + 7.5  61.4±6.1  0.80  136.7 + 3 9 . 3  143.8 ± 18.6  0.69  74 + 4 2.40 ± 0.20 15.8 ± 2 . 0  73 ± 6  0.60  2.69 ± 0.34*  0.03  16.0±  0.34  0.48  1.9  0.26 86.1 ± 12.8 87.9 ± 1 1 . 1 0.16 120.4 ± 16.2 116.5 ± 19.0 0.38 32.5 ± 9 . 3 30.4 ± 8 . 5 0.066 0.63 ± 0 . 0 5 0.71 ± 0 . 1 1 0.006 171.0±9.3 158.5 ± 13.7* C a 0 (ml • L" ) P a 0 (mm Hg) 0.22 84.0 ± 7 . 8 86.5 ± 5 . 7 A a D 0 (mm Hg) 0.68 26.0 ± 4 . 5 26.5 ± 4 . 9 0.70 %Sa0 92.7 ± 2 . 5 92.9 ± 1.6 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; C a 0 = arterial oxygen content; P a 0 = arterial P 0 ; A a D 0 = Alveolar-arterial partial pressure difference; % S a 0 = arterial oxyhemoglobin saturation; P a C 0 = arterial P C 0 ; V 0 = oxygen consumption; V = minute ventilation. 2  2  2  2  1  2  2  2  2  2  2  2  2  2  E  2  2  2  27 Table  6: Comparison  of m e a n  pulmonary  transit times  during  exercise.  Also  c o r r e s p o n d i n g Q , H R , V 0 a x , P B V , a n d V c v a l u e s from the literature. N = non-infusion condition; I = Infusion condition; B T = before training; A T = after training. 2 m  Present study  Hopkins et al. (90)  Iskandrian etal. (101)  Warren et al. (213)  Rerych etal. (165)  N I BT AT — — Sample size 12 10 12 16 18 — 78.2 — — Weiaht (ka) 74.8 73.0 ~ — — Height (cm) 180.6 185.5 182.0 — BSA (m*) 1.93 2.56 1.97 2.01 1.94 1.96 PTT (sec) ~ — Rest 9.32 5.40 6.70 7.60 — Exercise 2.45 2.75 2.91 2.30 2.40 2.80 PCTT (sec) t t 0.77 Rest 0.76 0.74 0.71 1.05 0.74 0.75 0.52 0.57 Exercise 0.45 0.51 0.46 0.48 0.46 Q(L • min" ) 7.9* 7.7* 7.7 Rest 6.9 6.1 6.9 6.7 Exercise 30.6 30.2 33.3 21.1 29.4 32 25.5 VO,(L • min" ) 0.61 0.67 0.41 0.61 0.42 0.44 Rest 0.48 4.57 Exercise 4.56 5.13 2.84 4.32 3.58 4.66 HR (beatsmin ) Rest 91 86 70 80 62 74 61 183 181 166 163 184 185 181 Exercise PBV (L) — — — 1.08 0.67 0.77 0.85 Rest — 1.02 1.49 Exercise 1.22 1.35 1.61 0.73 Predicted Vc (mL) § 216.9 269.5 224.4 215.3 215.0 215.3 212.4 Exercise Predicted Vc (mL) §§ 92.2 90.9 79.7 Rest 90.9 85.3 85.3 83.9 251.2 303 270.1 184.7 242.8 261.0 Exercise 215.5 Predicted Vc (mL) §§§ 93.3 89.5 87.1 89.5 88.3 Rest 90.5 90.5 Predicted Vc (mL) t 94.1 94.1 98.9 89.3 92.9 100.0 98.9 Rest 229.1 205.7 244.7 236.3 286.5 252.5 179.3 Exercise Some variables could not be / were not measured. Therefore, regression equations were used to predict values. § = Gehr et al. (59); §§ = Johnson et al. (106); §§§ = Young et al. 1963 (225); t = Hsia et al. (100); * = Wiebe et al. (221); PBV = Q (l/s) x PTT (s); t t PCTT= Vc (ml) estimated from Hsia et al. (100) + Q (ml); PCTT = pulmonary capillary transit time; PCTT and Vc from Warren's study were not predicted but were estimated from measurements of DLCO by using the method from Roughton and Forester (172); The underlined-bolded-italics numbers (269.5, 303, 283.5 ml) represents theoretical Vc from 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 from respected regression equations. 1  1  1  28  Figure 1: M e a n transport functions created by deconvolution a n a l y s i s c o m p a r i n g distribution of P T T between non-infusion (N) a n d infusion (I) conditions. M e a n P T T i n c r e a s e d by 0.30 s e c o n d s (P = 0.002) between the two conditions.  13 -,  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  Time (seconds)  7.0  29  F i g u r e 2: Distribution of red cell pulmonary transit times during minute 3 of intense, constant-load e x e r c i s e with (I) or without (N) v o l u m e infusion (n = 9). * P = 0.02 b e t w e e n N a n d I within a given time interval.  T i m e intervals ( s e c o n d s )  30 3: Arterial P 0 ( P a 0 ) and alveolar-oxygen difference ( A a D 0 ) during the 6.5 minutes severe, constant-load exercise test for non-infusion (N) and infusion (I) conditions. * different from minute 0 (corrected values only); ** different from minute 1 (corrected values only; ** different from minute 1 (corrected values only) [n = 12]. P a 0 and A a D 0 were temperature corrected at each time point by using esophageal temperature at each time point. Figure  2  2  2  2  2  Time (minutes)  31  F i g u r e 4: Arterial o x y h e m o g l o b i n saturation (%SaC>2), arterial PCO2 (PaC02), a n d e s o p h a g e a l temperature during the 6.5 minutes s e v e r e , constant-load e x e r c i s e test for non-infusion (N) a n d infusion (I) conditions, a = different from minute 0; b = different from minute 0 to 1; c = different from minute 0 to 2; d = different from minute 0 to 3; e = different from minute 0 to 4 [values which a r e corrected to to temperature c h a n g e s only; P < 0.05]. ## = m a i n effect present between conditions, (n = 12).  50.0 -i 47.5 45.0 42.5 40.0 37.5 H 35.0 32.5 30.0 27.5 25.0  N corrected to esphageal temperature I corrected to esophageal temperature N at 37 celcius I at 37 celcius  40.0 39.5 39.0 38.5 38.0 37.5 37.0 36.5 36.0 35.5 H 35.0 2  3  Time (minutes)  4  32  F i g u r e 5: Individual r e s p o n s e s for P a 0 and A a D 0 during the 6.5 minutes s e v e r e , constant-load e x e r c i s e test c o l l a p s e d a c r o s s condition (n = 12). All v a l u e s corrected to e s o p h a g e a l temperature. 2  2  33  F i g u r e 6: Minute ventilation, o x y g e n c o n s u m p t i o n , a n d heart rate during the 6.5 minutes s e v e r e , constant-load e x e r c i s e test for non-infusion (N) a n d infusion (I) conditions, a = different from minute 0; b = different from minute 0 to 1; c = different from minute 0 to 2; d = different from minute 0 to 3; [values which are corrected to temperature c h a n g e s only; P < 0.05]. ## = main effect present b e t w e e n conditions, (n = 12).  0  1  2  3  Time (minutes)  4  5  6  7  34  F i g u r e 7: Arterial p H , bicarbonate ( H C O 3 ) , a n d standard b a s e e x c e s s ( S B E ) during the 6.5 minutes s e v e r e , constant-load e x e r c i s e test for non-infusion (N) a n d infusion (I) conditions, a = different from minute 0; b = different from minute 0 to 1; c = different from minute 0 to 2; d = different from minute 0 to 3; e = different from minute 0 to 4 [values w h i c h are corrected to temperature c h a n g e s only; P < 0.05]. ## = main effect present b e t w e e n conditions, (n = 12).  1  0  1  2  1  1  1  1  1  3  4  5  6  7  Time (minutes)  35 F i g u r e 8: Correlation b e t w e e n the c h a n g e in A a D 0 a n d the c h a n g e in P T T with infusion at minute 3 of e x e r c i s e in subjects with minimal P a 0 < 8 5 m m H g a n d e x c e s s i v e g a s e x c h a n g e impairment ( A a D 0 > 2 5 m m H g ; n = 6) 2  2  2  36 2.4  DISCUSSION Effects  of volume  expansion  on EIAH:  A c u t e v o l u m e infusion (using 500 m L of  1 0 % pentastarch) prior to e x e r c i s e did not c h a n g e any m e a s u r e ( P a 0 , A a D 0 , % S a 0 ) 2  of E I A H .  2  2  In contrast, a c u t e v o l u m e infusion prior to e x e r c i s e lengthened m e a n P T T .  T a k e n together,  these  results s u g g e s t first, that shortened  P T T is not  a  major  m e c h a n i s m of E I A H , a n d s e c o n d , that there is not a m a x i m a l V c during s e v e r e e x e r c i s e b e c a u s e V c likely i n c r e a s e d after acute v o l u m e e x p a n s i o n for the r e a s o n s d e s c r i b e d below. Effects  of acute  volume  infusion  on PTT:  T h e main result of this study is that  acute v o l u m e infusion before e x e r c i s e i n c r e a s e d P T T during s e v e r e e x e r c i s e . T o our knowledge, this is the first study to m e a s u r e m e a n P T T in e x e r c i s i n g elite h u m a n s before a n d after acute hypervolemia. S i n c e transit time is v o l u m e divided by flow, a n d s i n c e there w a s no significant c h a n g e in flow ( Q ) , this s u g g e s t s that P B V i n c r e a s e d by 131 m L .  T h i s indirectly provides e v i d e n c e against reaching a m a x i m a l V c during  e x e r c i s e b e c a u s e of the i n c r e a s e in P B V with v o l u m e infusion (59, 100, 106).  If V c  were m a x i m a l during s e v e r e e x e r c i s e , P T T would have shortened d u e to the inability of pulmonary capillaries to further dilate and/or be recruited, but this w a s not the c a s e . T h e a s s u m p t i o n that V c is not m a x i m a l during s e v e r e e x e r c i s e is true if the i n c r e a s e in P B V o b s e r v e d here (+131 mL) reflect c h a n g e s in V c . Indeed, it has b e e n s h o w n that the arterial a n d v e n o u s tree c a n distend significantly (83), but there is a l s o e v i d e n c e that recruitment in the pulmonary circulation o c c u r s exclusively in capillaries (77). A b o u t 4 0 % of P B V resides in the pulmonary capillaries (106), a n d although w e did not m e a s u r e V c , s e v e r a l predictive equations in T a b l e 6 (59, 100, 106) s u g g e s t that V c — a t minute 3 of e x e r c i s e — m a y h a v e i n c r e a s e d from 2 1 6 . 9 condition) to 2 6 9 . 5 - 3 0 3 m L with acute hypervolemia.  236 mL  (control  37 Despite lengthening P T T by 0.30 + 0.20 s e c o n d s with acute v o l u m e infusion, there w a s no improvement in indices of pulmonary g a s e x c h a n g e ( P a 0 , 2  %Sa0 , PaC0 ). 2  Pa0 ,  2  AaD0 ,  2  2  AaD0 , 2  A l s o , there w a s no significant relationship b e t w e e n P T T and either  or % S a 0 ,  s u g g e s t i n g that limited  2  m e c h a n i s m of E I A H .  P T T m a y not be a n  important  O u r results are in a g r e e m e n t with W a r r e n et al. (213) w h o a l s o  found no relationship b e t w e e n pulmonary capillary transit time ( m e a s u r e d via singlebreath hold technique) a n d A a D 0 . C o n v e r s e l y , H o p k i n s et al. (90), found that P T T a n d 2  AaD0  2  w e r e correlated (r = - 0 . 5 9 ; P <0.05). Other e v i d e n c e against limited P T T (and therefore p e r h a p s limited pulmonary  capillary transit time) a s being a m e c h a n i s m of E I A H , w a s that r e g a r d l e s s of condition, Pa0  rapidly d r o p p e d from 105.2 ± 8.2 to 90.6 ± 10.0 m m H g within the first minute of  2  constant-load s e v e r e e x e r c i s e , a n d then did not c h a n g e throughout the rest of the test (Pa0  2  at e n d of e x e r c i s e w a s 88.7 ± 7.6 m m H g ; P > 0.05). S i n c e V 0 a t minute 1 w a s 2  only ~ 7 6 % of m a x i m u m (52.7 + 5.6 ml • kg" • min" ), this w o u l d indicate that c a r d i a c 1  1  output, a n d thus pulmonary blood flow w a s substantially less than at minute 3 ( V 0 w a s 2  61.2 ± 5.7 ml • kg"  1  • min" ), the point at which P T T w a s a s s e s s e d . 1  pulmonary blood flow from the V 0 yet P a 0  2  2  Hence, since  data w a s greater at minute 3 than at minute 1, a n d  w a s no different b e t w e e n minute 1 a n d minute 3, it c a n be c o n c l u d e d that P T T  is not a main m e c h a n i s m of E I A H .  If P T T w a s a main m e c h a n i s m of E I A H , then o n e  would expect to s e e a continued significant decline in P a 0 pulmonary blood flow a n d V 0 . T h i s w a s not the c a s e . 2  b e c a u s e of increasing  T h e rapid d e c r e a s e in P a 0 ,  2  a n d rapid i n c r e a s e in A a D 0  2  2  that w e o b s e r v e d within the first minute of h e a v y cycling  e x e r c i s e are consistent with other studies in which P a 0  2  d e c r e a s e d to ~ 9 0 . 5 m m Hg  38 while A a D 0  2  i n c r e a s e d to  - 1 6 . 9 m m H g rapidly in high a e r o b i c capacity cyclists (47,  9 1 , 9 2 , 167, 184). If it is a s s u m e d that c h a n g e s in P T T reflect c h a n g e s in pulmonary capillary transit time, then m e a n pulmonary capillary transit time in the current study m a y have s l o w e d from 0.43 - 0.49 (N condition) to 0.53 - 0.60 s e c o n d s with acute h y p e r v o l e m i a (59, 100, 106, 225). It h a s b e e n s u g g e s t e d that m a x i m a l V c is 2.87 m L • kg" (59), a n d H o p k i n s et 1  al. (90) p r o p o s e d P T T is 6 to 7 times greater than pulmonary capillary transit times. T h e current is in a g r e e m e n t a s m e a n calculated P T T w a s 4.6 - 5.8 times greater than m e a n pulmonary capillary transit time estimated from several predicted V c equations from (59, 100, 106, 225). O u r results for the m e a n R B C P T T during s e v e r e e x e r c i s e 2.45 a n d 2.75 s e c o n d s ) are similar to previous reports (90, 1 0 1 , 112, 165). W h o l e lung red blood cell pulmonary transit times ( P T T ) c a n d e c r e a s e from 7.3 ± 0.3 s e c o n d s at rest to 2.6 ± 0.3 s e c o n d s during s e v e r e e x e r c i s e [pooled data from (90, 1 0 1 , 165)]. T h e effect of acute v o l u m e e x p a n s i o n o n P T T is similar to the effects of chronic e n d u r a n c e training on blood v o l u m e a n d P T T .  O u r study is the first to s h o w that a c u t e v o l u m e e x p a n s i o n  lengthens P T T . Similarly, R e r y c h et al. (165) found that training-induced hypervolemia also lengthened P T T . M a x i m a l c a r d i a c output i n c r e a s e d from 2 5 . 5 L • min" to 32.0 L • 1  min"  1  after six months of s w i m m i n g training, a n d P T T i n c r e a s e d from 2.40 to 2.80  s e c o n d s post-training. T h e s e results are very similar to our study a s w e found that P T T i n c r e a s e d from 2.45 ± 0.21 to 2.75  ± 0.32 s e c o n d s before a n d after v o l u m e infusion,  respectively. W h i l e it is important to k n o w m e a n P T T through the lung, it is a l s o n e c e s s a r y to report distribution of P T T about a m e a n , a s not all red blood cells h a v e the s a m e transit times. A s s u c h , the distribution of P T T by deconvolution a n a l y s i s permitted calculation  39 and presentations of distributions of P T T (Figures 1 a n d 2).  T h e r e w a s no c h a n g e in  the relative d i s p e r s i o n (RD) of transit times during e x e r c i s e ( R D non-infusion = 0.29 ± 0.07;  R D infusion = 0.28 + 0.07), indicating that the s h a p e of the transport functions  (heterogeneity of transit times) were not altered b e t w e e n non-infusion a n d infusion conditions. T h e G a u s s i a n distribution of P T T (Figure 1) indicated that 2 2 . 5 + 1 3 . 2 % of R B C ' s had P T T of l e s s than 2 s e c o n d s in the non-infusion condition. T h i s P T T distribution is less than H o p k i n s a n d c o l l e a g u e s (90) in which 4 0 % of red blood cells had transit times < 2 s e c o n d s in e x e r c i s i n g athletes ( Q = 3 3 . 3 + 3.7 L • min" ) (90). T h e proportion of red 1  blood cells having very rapid transit times is important  b e c a u s e rapid  pulmonary  capillary transit times (< 0.25 sec) m a y be too short for c o m p l e t e o x y g e n a t i o n of R B C ' s . H o p k i n s s u g g e s t e d that red blood cell transit times l e s s than 2 s e c o n d s m a y represent pulmonary capillary transit times of 0.28 (90) to 0.33 (present study) s e c o n d s , which is very c l o s e to the theoretical limit of 0.25 s e c o n d s for complete oxygenation of R B C ' s in the pulmonary capillary (202).  With acute v o l u m e infusion, the R B C P T T distribution  w a s shifted to the right (Figure 1) s u c h that only 13.2 ± 1 2 . 6 % of red cells had transit times of < 2 s e c o n d s (P = 0.08) (Figure 2). Therefore, e v e n though the m e a n P T T w a s lengthened during s e v e r e e x e r c i s e by acute v o l u m e infusion before e x e r c i s e , P T T m a y h a v e b e e n lengthened in only ~ 9 % of red cells that h a d the limitation of o x y g e n uptake (i.e. red blood cells with P T T w a s l e s s than 2 s e c o n d s ) . R e d blood cells that have P T T greater than 2 s e c o n d s gains no additional o x y g e n (90), a n d thus increasing their P T T cannot c o m p e n s a t e for red blood cells w h o s e P T T is l e s s than 2 s e c o n d s . A n o t h e r m o d e l that incorporates mixed v e n o u s P 0  2  considerations is relevant to  the understanding h o w acute v o l u m e infusion before e x e r c i s e i n c r e a s e d P T T but did not  40 reduce EIAH.  W a g n e r ' s model (203) s u g g e s t s that the time required  for complete  equilibration of alveolar a n d capillary o x y g e n tension d e p e n d s on the s l o p e between alveolar g a s a n d of mixed v e n o u s blood.  A c c o r d i n g to W a g n e r , the required partial  p r e s s u r e equilibrium time in the pulmonary capillary is not 0.25 s e c o n d s — a s w e e x p e c t e d w h e n mixed v e n o u s P 0 during  severe  exercise  2  is 4 0 m m Hg (e.g. at rest)—but it is - 0 . 5 0 s e c o n d s  b e c a u s e of  d e c r e a s e d mixed  venous  P0  2  (203).  An  equilibration time of 0.5 s e c o n d s in the pulmonary capillary would then represent P T T less than 3 s e c o n d s . A b o u t 7 5 ± 9 % of red blood cells in our current study h a d P T T of less than 3 s e c o n d s in the non-infusion condition, while a c u t e v o l u m e infusion shifted the distribution to the right s u c h that'only 6 3 ± 1 5 % of red blood cells h a d P T T of less than 3 s e c o n d s (P = 0.01).  T h u s , it is s u g g e s t e d that acute v o l u m e e x p a n s i o n  lengthened P T T in 12 ± 1 1 % of red blood cells that had limited partial p r e s s u r e time (i.e. red blood cells < 3 s e c o n d s ) . Therefore, the m e a n lengthening of P T T in only 1 2 % of red cells that h a d limited partial p r e s s u r e equilibration time by acute v o l u m e e x p a n s i o n m a y not h a v e b e e n e n o u g h to improve pulmonary g a s e x c h a n g e for o x y g e n . Temperature  Correction  of  Arterial-blood  gas  correction of A B G ' s during e x e r c i s e is controversial.  Measurements:  Temperature  S e v e r a l previous studies have  m a d e b l o o d - g a s m e a s u r e m e n t s at 37°C (23, 64, 72, 87, 9 2 , 145, 149, 158, 196). However, it is critical to correct for the i n c r e a s e s in body core temperature e x e r c i s e to avoid overestimating the d e c r e a s e in P a 0 the i n c r e a s e in A a D 0 core temperature  2  (48).  2  throughout  a n d P a C 0 , a n d overestimating 2  H o w e v e r , other studies have not corrected for c h a n g e s in  b e c a u s e short-duration, high-intensity e x e r c i s e p r o d u c e s about a  0.5°C i n c r e a s e in core temperature (16, 176).  O u r data s u g g e s t this a s s u m p t i o n m a y  not be a c c u r a t e b e c a u s e w e found that 6.5 minutes of intense e x e r c i s e (including 10 minute warm-up) i n c r e a s e s core temperature (as reflected by e s o p h a g e a l temperature)  41 from 3 6 . 3 + 0.6 °C at rest (before warm-up) to 39.3 ± 0.3°C at minute 6.5 of s e v e r e cycling e x e r c i s e (P < 0.01; Figure 4). O u r results are consistent with other studies a n d current review (48), w h i c h found that e s o p h a g e a l temperature i n c r e a s e s by about 2°C in a twelve minutes progressive m a x i m a l e x e r c i s e test to e x h a u s t i o n (78, 79). B e c a u s e of the controversy regarding temperature correction of A B G ' s , w e reported P a 0 , A a D 0 , 2  and P a C 0  2  at 37°C a s well a s temperature corrected (Figures 3 a n d 4). O u r data s h o w  2  that with a 3°C i n c r e a s e in e s o p h a g e a l temperature, the d e c r e a s e in P a 0  2  and P a C 0  2  after 6.5 minutes of constant, s e v e r e level e x e r c i s e c a n be overestimated by 1 4 % (12 m m Hg) a n d 1 0 % (3.7 m m Hg), respectively if temperature correction is not d o n e . T h i s is in a g r e e m e n t with a a s our data represents a 4 . 7 % c h a n g e in P a 0 3 . 3 % c h a n g e in P a C 0  2  2  per c e l c i u s , and a  per c e l c i u s i n c r e a s e in core temperature. Furthermore, by not  adequately correcting for both water v a p o r p r e s s u r e c h a n g e s a n d increasing core temperature, A a D 0  2  c a n be overestimated by a s m u c h a s 4 1 % (17 m m Hg) after 6.5  minutes of s e v e r e cycling e x e r c i s e (13.7% i n c r e a s e in A a D 0 temperature).  2  per 1°C i n c r e a s e in core  T h u s , our a p p r o a c h h a s b e e n to m e a s u r e e s o p h a g e a l temperature  before a n d during e x e r c i s e to temperature correct A B G ' s , a n d to s h o w both uncorrected and temperature corrected A B G ' s . A n o t h e r significant finding w a s that arterial pH w a s lower with v o l u m e infusion (P = 0.02). O n e r e a s o n for the c h a n g e in p H w a s that the a v e r a g e e x e r c i s i n g power output w a s about 13 watts higher with v o l u m e infusion (P = 0.09). E v e n though statistical significance w a s not r e a c h e d , this m a y have resulted in the slightly lower p H v a l u e s in the infusion condition. A n o t h e r r e a s o n why p H w a s lower with v o l u m e infusion w a s that there w a s significantly lower h e m o g l o b i n v a l u e s with acute h y p e r v o l e m i a (infusion = 129 ± 10 g • L" ; non-infusion = 138 ± 5 g • L " , P = 0.002). 1  1  S i n c e h e m o g l o b i n acts a s a  42 buffer for H ions, acute hypervolemia m a y h a v e resulted in the i n c r e a s e d arterial blood +  acidity (lower pH) d u e to lower h e m o g l o b i n concentration. Limitations:  Limitations w e r e e x p e r i e n c e d during the data collection p r o c e s s . For  e x a m p l e , a linear regression equation {(Temp = 37.74 + (0.238*Time)} w a s d e v e l o p e d to temperature correct 3 3 % of arterial blood g a s m e a s u r e m e n t s (56 out of 168 s a m p l e s ) from minute 1 to minute 6.5 b e c a u s e the e s o p h a g e a l probe w a s not inserted far e n o u g h d o w n the e s o p h a g u s .  A s s u c h , during those i n s t a n c e s , a reduction in e s o p h a g e a l  temperature w a s o b s e r v e d throughout e x e r c i s e , a s the probe may h a v e b e e n in the region of o n e of the two cold spots in the e s o p h a g u s , located 10 a n d 13 c m below the corniculate cartilage (47).  N e v e r t h e l e s s , the e s o p h a g e a l probe insertion length w a s  determined during s u b s e q u e n t data collection from the formula of Mekjavic a n d R e m p e l (47), a n d core temperature w a s recorded properly for the remaining 16 trials.  The  standard error of the estimate u s e d in the regression equation w a s 0.32°C (using 112 properly temperature corrected A B G s a m p l e s ) s h o w i n g that this population of subjects h a d similar core temperature i n c r e a s e s (2 S D = + 0.64°C).  A s e c o n d limitation w a s  v a r i a n c e in p l a s m a v o l u m e ( S D w a s ± 4 2 2 ml) from pre to post-infusion. Indeed, this w a s principally c a u s e d by two subjects having a - 3 5 7 a n d - 8 1 m L difference in p l a s m a v o l u m e c o m p a r e d to the non-infusion condition. B e c a u s e the negative p l a s m a v o l u m e s would s u g g e s t that t h e s e two subjects w e r e h y p o v o l e m i c on the infusion day, a n d b e c a u s e previous studies found that trained subjects maintain stable p l a s m a volume a n d R B C m a s s over a 4 to 12 w e e k period (63, 66), w e s u s p e c t m e a s u r e m e n t error is a more likely explanation in t h e s e two subjects.  In hindsight, w e believe that R B C m a s s  a n d p l a s m a v o l u m e s h o u l d h a v e b e e n m e a s u r e d on both d a y s . A s s u c h , m e a s u r e m e n t error m a y h a v e b e e n r e d u c e d . A third limitation w a s that only 5 8 % of the subjects had E I A H (Table 2). T h u s , w e did not expect acute v o l u m e e x p a n s i o n to h a v e a n effect on  43 g a s e x c h a n g e in subjects without E I A H .  H o w e v e r , the data w a s r e - a n a l y z e d on 7  subjects w h o h a d E I A H a n d the results w e r e identical to the data a n a l y z e d with the original 12 subjects—that is, P T T a n d P B V i n c r e a s e d with v o l u m e e x p a n s i o n despite unaltered Q (Table 5). c h a n g e in A a D 0  2  N e v e r t h e l e s s , w e also looked at that correlation between that  with infusion a n d the c h a n g e in P T T with infusion in t h o s e with E I A H ,  a n d found that 5 2 % of the v a r i a n c e in the c h a n g e in A a D 0  2  e x p l a i n e d the v a r i a n c e in  the c h a n g e in P T T (P = 0.10; Figure 8). Indeed, while this relationship w a s statistically insignificant, a trend d o e s exist for p o s s i b l e future r e s e a r c h . A fourth limitation w a s that differences in the total counts of white blood cells ( W B C ) b e t w e e n individuals m a y h a v e influenced P T T . White blood cells h a v e s h o w n to travel m u c h more slowly through the pulmonary capillaries than R B C ' s , a n d s o i n c r e a s e d concentration of W B C ' s in the pulmonary v a s c u l a t u r e m a y h a v e s l o w e d R B C transit time.  However, a  negative  correlation w a s o b s e r v e d b e t w e e n the pre-exercising circulating pool of W B C ' s a n d P T T from both non-infusion a n d infusion d a y s (r = -0.56; P = 0.009), s u g g e s t i n g that those with higher circulating W B C ' s have faster P T T ' s , e v e n with v o l u m e e x p a n s i o n . Further study is n e e d e d to explain whether this relationship is d u e i n c r e a s e d shunting of R B C ' s to the bronchial circulation or whether the W B C ' s in the lungs are relocated to the circulating pool b e c a u s e s o m e subjects m a y have had high c a t e c h o l a m i n e levels preexercise. In c o n c l u s i o n , acute v o l u m e infusion d o e s not prevent E I A H but d o e s lengthen P T T in elite e n d u r a n c e athletes. T h e i n c r e a s e in P T T s u g g e s t s that pulmonary capillary blood v o l u m e i n c r e a s e d a n d a r g u e s against a m a x i m a l V c during s e v e r e e x e r c i s e . Furthermore, b e c a u s e pulmonary g a s e x c h a n g e w a s not improved a n d b e c a u s e there w a s no correlation between P T T a n d pulmonary g a s e x c h a n g e , this s u g g e s t s that rapid pulmonary capillary transit time is not a significant m e c h a n i s m of E I A H .  44  C H A P T E R 3. G E N E R A L S U M M A R Y A N D C O N C L U S I O N S 3.1 G E N E R A L S U M M A R Y E x e r c i s e is a n important c o m p o n e n t of lifestyle adjustment to d e c r e a s e risk of heart d i s e a s e b e c a u s e it i n c r e a s e s the amount of high-density lipoproteins in the blood, a n d conditions the heart to recover from acute myocardial infarction.  E x e r c i s e in  healthy e n d u r a n c e athletes is a useful h u m a n model to understand m e c h a n i s m s of cardio-respiratory limitation of strenuous activity.  E x e r c i s e p e r f o r m a n c e c a n be limited  not only by c a r d i o v a s c u l a r performance but also by E I A H . T h e pathophysiology of E I A H r e m a i n s a n interesting topic of d i s c u s s i o n a m o n g e x e r c i s e physiologists.  S o m e elite  e n d u r a n c e athletes a c h i e v e arterial-blood g a s profiles similar to t h o s e in a critically ill patient in the intensive c a r e unit. T h i s study sought to determine whether o n e potential m e c h a n i s m of E I A H , diffusion limitation c o n s e q u e n t to rapid red cell transit times, affects pulmonary g a s e x c h a n g e , a n d , whether V c r e a c h e s m a x i m a l d i m e n s i o n s during severe exercise. Acute Hypervolemia  and Pulmonary  Gas Exchange.  T w e l v e highly-trained  e n d u r a n c e athletes ( V 0 a x = 69.6 ± 7.4 ml • kg" • min" ; weight = 74.8 ± 6.0 kg; height 1  1  2m  = 181.6 ± 7.0 cm) performed repeated 6.5 minutes, constant, n e a r - m a x i m a l cycling e x e r c i s e (~92% V 0  2 m a x  ) tests on different d a y s . S e v e n subjects h a d e x e r c i s e - i n d u c e d  arterial h y p o x e m i a [ E I A H ; minimal arterial P 0 ( P a 0 ) < 90 m m Hg]. 2  2  P l a s m a volume  e x p a n s i o n (+460 + 4 2 2 m L ; P < 0.05) w a s double-blinded a n d r a n d o m i z e d . significant differences in % S a 0 , P a 0 , or A a D 0 2  2  2  No  w e r e o b s e r v e d throughout e x e r c i s e  between non-infusion (N) a n d infusion conditions (I), e v e n w h e n a n a l y z i n g the data o n just the subjects with E I A H . Acute Hypervolemia  and Red Cell Pulmonary  trained e n d u r a n c e athletes ( V 0  Transit Time.  = 69.6 ± 7.4 ml • kg" • min" ; weight = 74.8 ± 6.0 kg; 1  2 m a x  T w e l v e highly-  1  45 height = 181.6 + 7.0 cm) performed repeated 6.5 minutes, constant, near-maximal cycling e x e r c i s e ( - 9 2 % V 0  2 m a x  ) tests o n different d a y s . S e v e n subjects h a d e x e r c i s e -  induced arterial h y p o x e m i a [ E I A H ; minimal arterial P 0 ( P a 0 ) < 90 m m Hg]. 2  2  PTT was  a s s e s s e d during the third minute of e x e r c i s e via first-pass radionuclide cardiography using centroid a n d deconvolution a n a l y s i s , while Q w a s a s s e s s e d via a c o u n t - b a s e d ratio method from multigated acquisition technique.  M e a n red cell pulmonary transit  times a n d pulmonary blood v o l u m e at minute three of e x e r c i s e significantly i n c r e a s e d b e t w e e n non-infusion a n d infusion s e s s i o n s , respectively, e v e n w h e n a n a l y z i n g the data just on subjects with E I A H .  N o correlation between P T T a n d pulmonary g a s e x c h a n g e  at minute three of e x e r c i s e w a s found.  A s well, cardiorespiratory variables a n d power  output w e r e unaffected by acute h y p e r v o l e m i a , a n d yet arterial p H w a s lower with v o l u m e infusion. 3.2 G E N E R A L C O N C L U S I O N S B a s e d on the current data it c a n be c o n c l u d e d that acute h y p e r v o l e m i a lengthens m e a n right-to-left ventricular red cell P T T in elite e n d u r a n c e athletes with already e x p a n d e d blood v o l u m e s , which provides e v i d e n c e against a m a x i m a l V c occurring during s e v e r e e x e r c i s e . Furthermore, the realization that pulmonary g a s e x c h a n g e w a s not improved, nor w a s there any correlation b e t w e e n P T T a n d various indices of pulmonary g a s e x c h a n g e , l e a d s to the contention that in a n elite h u m a n m o d e l , P T T , a n d therefore pulmonary capillary transit time, is not a significant m e c h a n i s m of E I A H . If diffusion limitation d u e to P T T is not a significant factor to E I A H , then diffusion limitation d u e to pulmonary e d e m a and/or capillary stress failure m a y be responsible for EIAH.  Nevertheless, we  did  not  m e a s u r e total  lung water  nor did w e  obtain  radiographic c h e s t i m a g e s of subjects post-exercise on both test d a y s , s o no definite c o n c l u s i o n s c a n be m a d e . However, s i n c e no w o r s e n i n g of pulmonary g a s e x c h a n g e  46 was  noticed after  acute v o l u m e e x p a n s i o n , w e c a n c o n c l u d e that there w a s  no  w o r s e n i n g of pulmonary e d e m a and/or stress failure b e t w e e n non-infusion a n d infusion conditions. W e c a n a l s o c o n c l u d e that s i n c e pulmonary e d e m a / c a p i l l a r y stress failure is c a u s e d by high pulmonary artery p r e s s u r e s , the c h a n g e s in pulmonary artery p r e s s u r e s during s e v e r e e x e r c i s e b e t w e e n non-infusion a n d infusion conditions—although measured—were  probably  b e t w e e n both conditions.  minimal  s i n c e pulmonary  A l s o , s i n c e the drop in P a 0  g a s e x c h a n g e did not 2  not differ  o c c u r r e d within the first minute  of e x e r c i s e , a n d did not w o r s e n throughout e x e r c i s e , pulmonary e d e m a m a y not have b e e n a factor early on during the 6.5 minutes e x e r c i s e bouts.  H o w e v e r , pulmonary  e d e m a m a y h a v e played a minor role in diffusion limitation later o n during e x e r c i s e because A a D 0  2  slowly but significantly i n c r e a s e d throughout the e x e r c i s e bout.  Relative hypoventilation could be a possible m e c h a n i s m for E I A H s i n c e there w e r e significant relationships b e t w e e n P 0 a n d P a 0 A  and P a 0  2  2  (Figure 27), a n d b e t w e e n P a C 0  2  (Figure 28) at minute 3 of e x e r c i s e in both conditions. A s well, 4 1 % of the  v a r i a n c e in the c h a n g e in P a 0 between  2  minute  0  and  2  w a s e x p l a i n e d by the v a r i a n c e in the c h a n g e in P a C 0  minute  1  of  exercise  (Figure  29).  Taken  2  together,  hypoventilation w a s a likely significant m e c h a n i s m of E I A H in this cohort, not only in the initial s t a g e s of e x e r c i s e , but a l s o in the midst of the e x e r c i s e protocol.  Besides,  D e m p s e y a n d W a g n e r h a v e s u g g e s t e d that a P a C 0 greater than 3 5 m m H g indicates 2  inadequate c o m p e n s a t o r y hyperventilation (48). M e a n P a C 0  2  in our subjects were - 4 0  m m Hg at minute 1 of e x e r c i s e that d e c r e a s e d to ~ 3 7 m m H g by the e n d of e x e r c i s e . Therefore, a c c o r d i n g to D e m p s e y a n d W a g n e r , hypoventilation w a s a m e c h a n i s m of E I A H in t h e s e athletes.  47 V / Q inequality is the next alternative explanation a s to the m e c h a n i s m of E I A H A  in t h e s e athletes.  H o w e v e r , s i n c e V / Q inequality w a s not m e a s u r e d , w e are left to A  s p e c u l a t e a s to the contribution of V / Q inequality a s a m e c h a n i s m of E I A H . A  S o , while  w e c a n rule out diffusion limitation d u e to P T T , a n d w e c a n probably rule diffusion limitation d u e to pulmonary e d e m a , w e are left with relative hypoventilation a n d V / Q A  inequality a s the main probable m e c h a n i s m s for E I A H in this cohort.  48  APPENDIX A. REVIEW OF THE LITERATURE—EIAH INTRODUCTION T h e h u m a n lung is a s p e c t a c u l a r organ. It h a s about 3 0 0 million alveoli that are I interconnected to airways to e n s u r e proper ventilation (215). Their walls are c o v e r e d with blood capillaries about 15 ^im in length, 7.5 um in diameter (85), o c c u p y i n g an alveolar s u r f a c e a r e a of about 143 m  2  (59). T h e tissue sheet separating the blood from  the alveolar air is l e s s than 1 um t h i c k — 5 0 times thinner than a sheet of airmail paper (216).  In fact, despite the effective m e a n t h i c k n e s s of alveolar-capillary m e m b r a n e  being very thin (0.62 um) (59), o x y g e n h a s to travel further through a p l a s m a barrier, which h a s b e e n found to be about 0.15 um thick (59).  A l v e o l a r o x y g e n h a s to diffuse  through a c o m b i n e d total of eight barriers before attaching to a hemoglobin molecule in a red blood cell in a pulmonary capillary. T h e s e barriers are: (A) alveolar surfactant; (B) alveolar epithelium; (C) alveolar epithelial b a s e m e n t m e m b r a n e ; (D) interstitial fluid; (E) capillary b a s e m e n t m e m b r a n e ; (F) capillary endothelium; (G) p l a s m a ; (H) red blood cell membrane.  A s s u c h , the ultrastructure of the alveolar-capillary m e m b r a n e provides  minimum d i s t a n c e a n d m a s s of tissue b e t w e e n alveolar air a n d red blood cells in the pulmonary circulation s o e x c h a n g e of o x y g e n a n d c a r b o n dioxide in a n d out of the pulmonary capillaries c a n o c c u r at rest a n d during e x e r c i s e . During s e a level e x e r c i s e in normal, healthy m a l e s , the lung is able to meet o x y g e n d e m a n d s of the body, a s pulmonary g a s e x c h a n g e is maintained s u c h that arterial P 0  ( P a 0 ) remains within 10 m m H g a n d arterial o x y h e m o g l o b i n  saturation  ( % S a 0 ) is maintained within 3 % from resting levels (8, 52, 118, 2 2 0 , 222).  However,  2  2  2  over the past two d e c a d e s , e v i d e n c e has a c c u m u l a t e d to w h i c h s u g g e s t that in approximately 50 - 6 0 % of e n d u r a n c e trained m a l e s with high a e r o b i c capacities (23,  49 153) (V02max ^ 65 m L • k g " • m i n " or 5 L • min" ), the lung is a limiting factor during 1  1  1  strenuous a e r o b i c work (45, 46, 217).  S e v e r a l studies h a v e s h o w n that the lung is  unable to fully o x y g e n a t e v e n o u s blood at h e a v y (-75 - 80%VO2max) (76, 150), nearm a x i m a l (-88 - 95%V0 ax) (47, 128, 167, 188, 195) a n d m a x i m a l e x e r c i s e (87, 145, 2m  173, 188, 222), while prolonged (>55 minutes), s u b m a x i m a l e x e r c i s e (65 - 70% V0 ax) 2m  is not detrimental to pulmonary oxygenation (76, 91, 194). Therefore, during short-term h e a v y to s e v e r e e x e r c i s e levels, P a 0 < 92% by the e n d of e x e r c i s e .  2  c a n drop to -75 m m H g , a n d %SaC>2 c a n drop to  Furthermore, it h a s b e e n s h o w n that arterial b l o o d - g a s  v a l u e s a r e drastically altered within the first minute of c o n s t a n t - l o a d , s e v e r e e x e r c i s e (47, 92, 145, 167, 184) (Table 7). T h i s p h e n o m e n o n h a s b e e n termed e x e r c i s e - i n d u c e d h y p o x e m i a (EIH), o r e x e r c i s e - i n d u c e d arterial h y p o x e m i a (EIAH). Individuals with E I A H a l s o h a v e w i d e n e d alveolar-arterial  partial p r e s s u r e difference  ( A a D 0 ) , which c a n 2  i n c r e a s e to 40 - 50 m m H g during s e v e r e e x e r c i s e (47, 92). B e t w e e n 1980 a n d 2000, there h a v e b e e n s e v e r a l p u b l i s h e d reviews o n the mechanisms  of  EIAH  (45,  48,  93,  156,  185).  These  mechanisms  a r e (1)  hypoventilation, (2) venoarterial shunt, (3) ventilation-perfusion ( V / Q ) inequality, a n d A  (4) pulmonary  diffusion  limitation.  O f the four m e c h a n i s m s , V / Q inequality a n d A  diffusion limitation s e e m to b e the main contributors of E I A H (70, 91, 94, 156), s i n c e e a c h m e c h a n i s m m a y a c c o u n t for about 50-60% of the i n c r e a s e d o x y g e n p r e s s u r e difference ( A a D 0 ) during h e a v y e x e r c i s e . 2  alveolar-arterial  D e s p i t e the previous  published reviews o n E I A H , the p u r p o s e of the following review is to c o v e r s e v e r a l pertinent topics related to E I A H , n a m e l y s u m m a r i z i n g the criteria that h a v e b e e n u s e d to define E I A H , s u m m a r i z i n g the previous reviews of the m e c h a n i s m s of E I A H focusing  50 specifically o n diffusion limitation, a n d , finally d i s c u s s i n g g e n d e r a n d a g e effects EIAH.  51 CD E o  CD  -*—*  •— >< Q. <"§ E  CD  CO  o  >-  >-  5- >-  o  CN  Tt  c\i +1 co  o d +1 +1  +1  Tt  to cn  LO  cn  -*—<  o z  TD  Z3  Tt  CC  CO  cu cu  CD  CN  O 0 co -g  c  (/)  cu  •a CO  CO  Ye  i_ <u o E  Ye  CO  CN  CN  cn  CN CO CO  oo  i  d  d  cn  CN CO  +i  +i  d  cn cn  cn  o  CO CO  ro °  -55  cri  LO CO  +1 o  CN  CM  O a) E£ c Q 3 0) E  * f 3 £  T O CO CN  +1  CO ~  +1 +1 h-  LO  cn  cn  cn  oo o CO cri  +i  CO  T -  (6 r-  T—  T—  ^—•  +i  +1 o  co  3g CO Tf TT CO CM T -  LO  M-  T—  o co  c .c o  cu  9 ••  -E  CO  CO  ^  T3 C  CO  CM  o Q  CO  < CM  o  o  ra ° S °5  «2f 3  +i  CM  +i +i  +1  CN CN  E  cn  O  oi  <^ CD O  CM CD CO h-'  cn co  cn  o_  +1 o ^ d 0 3  in o  +i  + l  cn  LO CD  CM CO  cn oo  CM  cn CO  co co i  T3  CD  T3  co  CD CD  c c? o 'E .ffi co  °o3  el  51  CO  ro  X  E o .E t: co c:  ~* T3  o  CD T t O CD  co  CD  o 00  CD CO  cn: LO  CN  o  T3 T3  CD  cr  CD CO Q.  CD — i  E o o  CD  SZ  x w SP. a) x  U)  J  O  9°  _CD  CO  cn  P  CM  o o ro  O)  CO  c o CD  LO  d cn  1  CN  T  CO  o  a)  CO  LO  CO  c o o o 0 c  cr o  ro aj w  o)  O -<=  c ~  c  v  £  ^  o  o  CN  CD  cn  CN  o o d cd  cn  cn CO  in  O  cd cn  O  co d  CD  cn cn  cn  10 •  cn  CO  cn  CD CN  CD  CO  § E o II  x  o  CO  <D  CD C CO  J=  ra  E  O  E .!=  O  E  ° > •> J. 0 £  1 i tf) CD  5 CD  x: XCO J Q.  1^ O A CO  CD  O  CD  Tt  CM CN  CN  d  d  d d  2 CN  d d +1 +1  d +1  CO  CO  CO LO  LO <=>  LO  LO  Tt  0)  03  +i  +i  +i +i  co  Tt  CN N-  Tt  Tt  c  C  cn CO  LO  * in  CM  o LO  £ 9-  ,_ co .E a.  CD  o  o O  o  CN  CM  c  O O . > . >»  3  3  3  Ddcr:  o o  3 o OH  ct:  CO  N- CD  CD  CD  CD L— CD > CD CO  at  co  c  >  c  o  CD CO CD CO  g  - o ' t n -n  3  CO  o  co  to  s  CO  CO CO  -jg  S .2  00  § .2  CO CO CO <{> 3 CD 3 CD  o3 CD 2  CO CD  c ra  CD Q  £ cu  CO  co co  Q. . £ CL . £ CO 0i  S to  O) a>{  c c  o o,  o o  CO  CM CD  — T3 OJ CD >, CD  T -  C CO CU CO * N  to c  c CD  E 8 CD o o .2 Q  T -  LO  x 2 a:  c ra C4)  Tt  Q  S CO  ail c c E c c c O)  3  3  CO  U o co  CD CN  Tt,  c  CD  B TJ  Io S  CO w  o fc «£  CD  o co  2 3  2  <D  -2  CD  CD  O  co  CO  cu c  0  JO  cu  52 DEFINING EIAH E I A H h a s h a d s e v e r a l definitions (Table 8). using P a 0  S o m e authors h a v e defined E I A H  (3, 7, 4 7 , 81), while others have u s e d % S a 0  2  (33, 4 8 , 130, 153, 154).  2  Arterial o x y h e m o g l o b i n saturation follows the drop in P a 0  (48) but m a y a l s o be  2  modified by the o x y h e m o g l o b i n dissociation curve shifts c a u s e d by c h a n g e s in p H , arterial P C 0  2  mild (i.e. P a 0  ( P a C 0 ) , a n d core (blood) temperature. 2  2  T h e criteria to define E I A H are:  > 5 m m H g (3)) to strict ( % S a 0 < 9 0 % (33); P a 0 2  A s s u c h , t h e s e definitions remain debatable.  2  < 75 m m Hg (47)).  S e v e r a l authors h a v e not justified their  d e c i s i o n to u s e a s p e c i f i e d cutoff v a l u e a s their definition of E I A H . al. (153) did explain w h y they u s e d % S a 0  2  H o w e v e r , P o w e r s et  < 9 1 % a s the cutoff point in his study.  P o w e r ' s cutoff v a l u e s are b a s e d on data from another study (222), which s u g g e s t that untrained or moderately trained subjects maintain % S a 0  2  of - 9 5 % during m a x i m a l  e x e r c i s e . Therefore, P o w e r s s u g g e s t e d that "an e x e r c i s e % S a 0  2  o f - 9 1 % would be 4 %  below the normal v a l u e s for healthy untrained or moderately trained subjects during intense e x e r c i s e a n d [would be] below the 9 5 % c o n f i d e n c e limits (1 S D = 1.7%) of the resolution of the e a r oximeter to estimate % S a 0 " (153). 2  M o s t recently, the definition  of E I A H h a s b e e n updated by D e m p s e y a n d W a g n e r (48) to include three categories, mild, moderate, a n d s e v e r e E I A H (Table 8).  T h e y purport that at the typical arterial  temperature a n d p H a c h i e v e d at m a x i m a l e x e r c i s e , the s u g g e s t e d guideline of a minimal 3 % d e c r e a s e in % S a 0 d e c r e a s e in resting P a 0 . 2  2  from resting would be equivalent to a 10 m m H g  A s s u c h , this drop would be "a clearly m e a s u r a b l e quantity  that signifies a failure of lung function to maintain arterial oxygenation (48)."  53 T a b l e 8: P a s t definitions of E I A H . Authors M a s s e - B i r o n et al. (130) P o w e r s et al. (154) P o w e r s et al. (153) C h a p m a n et al. (33) D e m p s e y a n d W a g n e r (48)  Pa0  A n g u i l a n i u et al. (3) A n s e l m e et al. (7) D e m p s e y et al. (47) H a r m s et al. (79)  > 5* > 8* <75 Mild 10 > 2 0 * Severe > 20*  2  (mm Hg)  %Sa0 > 4%* < 92% <91% < 90% Mild 9 3 - 9 5 % M o d e r a t e 88 - 9 3 % Severe < 88% 2  * indicates from rest M E C H A N I S M S O F EIAH  Hypoventilation During e x e r c i s e , minute ventilation ( V ) is e l e v a t e d by increasing both respiratory E  rate a n d tidal v o l u m e (146).  H o w e v e r , hypoventilation o c c u r s w h e n alveolar ventilation  ( V ) d e c r e a s e s below the rate required to maintain arterial blood g a s e s ( 0 , C 0 ) at A  2  2  normal v a l u e s (156). Therefore, the result of hypoventilation is d e c r e a s e d P 0 A  P a 0 , a n d e x c e s s levels of alveolar a n d arterial C 0 2  blood, while A a D 0 PaC0  2  2  2  and  t e n s i o n s (hypercapnia) in the  remains unaffected. A recent review of E I A H h a s s u g g e s t e d that a  > 3 5 m m H g during e x e r c i s e indicates a lack of c o m p e n s a t o r y hyperventilation  2  while a P a C 0  2  > 38 m m H g s u g g e s t s a b s e n c e of c o m p e n s a t o r y hyperventilation (48).  Increasing minute ventilation during e x e r c i s e is important to maintain normal %Sa0 . 2  Clinically, hypoventilation is r e c o g n i z e d a s P a C 0  a c c o u n t for 5 0 % of the variability in % S a 0 141, 168).  2  2  > 4 0 m m H g (185) a n d m a y  during e x e r c i s e in highly fit athletes (80,  S e v e r a l studies report that hypoventilation is a n important m e c h a n i s m in  E I A H (27, 4 7 , 50, 57, 1 4 1 , 166, 168) while others d i s a g r e e (24, 34, 9 2 , 142, 155). T h e  54 r e a s o n s for inadequate hyperventilatory r e s p o n s e of highly trained athletes are many, including a blunted chemoreflexive r e s p o n s e (39, 80, 127, 143); airflow limitations d u e to m e c h a n i c a l constraints (45, 4 9 , 105, 132), a n d respiratory m u s c l e fatigue (9, 10, 103, 104). A n i n a d e q u a t e drive to breath during e x e r c i s e in s o m e athletes m a y be d u e to blunted chemosensitivity.  It h a s b e e n s h o w n that e x e r c i s e V  E  is positively a s s o c i a t e d  with ventilatory c h e m o r e s p o n s i v e n e s s (127), a n d that s o m e athletes have a blunted hypoxic  and  hypercapnic  responsiveness compared  sedentary controls (26, 127, 180).  to  mountain  A s s u c h , exercising % S a 0  c o m p r o m i s e d in athletes with blunted drives to breath.  2  climbers  and V  E  and  m a y be  H a r m s a n d S t a g e r (80) tested  the hypothesis that low c h e m o r e s p o n s i v e n e s s contributes to E I A H .  They analyzed  resting hypoxic ( H V R ) a n d h y p e r c a p n i c ventilatory ( H C V R ) r e s p o n s i v e n e s s , a n d found that H V R a n d H C V R w e r e lower in individuals with E I A H (P < 0.05). Furthermore, exercising H V R w a s related to both ventilatory equivalent of o x y g e n ( V / V 0 ) a n d E  2  c a r b o n dioxide ( V / V C 0 ) (P < 0.05) s u g g e s t i n g that E I A H relates to the drive to E  breath. athletes  2  T h i s a g r e e s with C o o p e r et al. (39) w h o found that H C V R w a s a l s o lower in with  E I A H c o m p a r e d to  s u b m a x i m a l intensities (P < 0.05).  athletes without  E I A H at  rest,  and  at several  Linear regression a n a l y s i s by D e r c h a k et al. (49)  s h o w e d that H V R during e x e r c i s e is a l s o related to % S a 0 , but that flow-limited athletes 2  h a d a lower H V R than non flow-limited athletes. G a v i n et al. (57) s h o w e d that subjects w h o d e m o n s t r a t e d r e d u c e d hyperventilatory r e s p o n s e s to m a x i m a l e x e r c i s e exhibited a greater reduction in % S a 0 responses.  2  than those w h o did not exhibit r e d u c e d hyperventilatory  H o w e v e r , H o p k i n s a n d M c K e n z i e (92) a l s o tested H V R r e s p o n s e during  heavy e x e r c i s e a n d found that there w a s no a s s o c i a t i o n b e t w e e n H V R a n d either  55 %Sa0  or V / V 0  2  E  either V  2  (P > 0.05), implying that hypoxic ventilatory drives are not related to  or E I A H .  E  Therefore, the d i s c r e p a n c y in the data describing the relationship  b e t w e e n chemosensitivity a n d E I A H is still far from understood. During hypoxia, athletes without a flow limitation c a n i n c r e a s e exercising V significantly ( c o m p a r e d to normoxia) (34). O n the other h a n d , flow-limited cannot i n c r e a s e V . E  E  athletes  M o s t highly trained e n d u r a n c e athletes h a v e little reserve to  i n c r e a s e V during e x e r c i s e in hypoxia, a n d s o m e e v e n a c h i e v e a m e c h a n i c a l limitation E  to i n c r e a s e ventilatory flow at V 0  2 m a x  ( 3 4 , 4 5 , 4 9 , 105, 132); however, a flow limitation in  elite cyclists h a s b e e n disputed (142).  In fact, there s e e m s to be a d e c r e a s e d drive to  breath in individuals w h o have a flow limitation (49, 132), d u e to f e e d b a c k inhibition of respiratory motor output  (132).  Breathing a helium-oxygen mixture prevents  flow  limitations (47, 132) b e c a u s e the respiratory s y s t e m b e c o m e s " u n l o a d e d , " tidal v o l u m e and V  E  i n c r e a s e (47), a n d end-expiratory flow limitations are r e d u c e d (132). T h e extent  to which expiratory flow limitation influences the i n c r e a s e in m a x i m a l e x e r c i s e V recently studied (34).  E  was  A flow limitation w a s characterized by having ~ 5 6 % of a n  athlete's tidal-flow v o l u m e loop during m a x i m a l e x e r c i s e meet the boundary set by their m a x i m a l resting flow-volume loop (34). Athletes without a flow limitation have usually < 5 % of their tidal-flow v o l u m e loop during maximal e x e r c i s e meet the boundary set by their m a x i m a l resting flow-volume loop. C h a p m a n a n d c o l l e a g u e s d e m o n s t r a t e d that the m e c h a n i c a l limitation i m p o s e d on t h e s e flow-limited athletes did not prevent the decline in % S a 0  2  a s non-flow-limited athletes e x p e r i e n c e d the s a m e d e c r e m e n t in % S a 0  2  (34).  T h u s , athletes w h o hypoventilate d u e to a flow limitation s h o u l d not be too c o n c e r n e d with p e r f o r m a n c e a s E I A H c a n o c c u r to the s a m e extent in athletes without a flow limitation.  56 Respiratory m u s c l e fatigue, resulting from the i n c r e a s e d o x y g e n cost of breathing with p r o g r e s s i v e e x e r c i s e intensity, might a l s o c a u s e hypoventilation during s e v e r e e x e r c i s e in e n d u r a n c e athletes (9, 10, 103, 104). Therefore, E I A H m a y d e v e l o p (47) a n d performance c a n d e c r e a s e (1, 47). Respiratory m u s c l e fatigue h a s b e e n previously e v a l u a t e d by using s e v e r a l different indices of fatigue, namely: m a x i m u m pleural or transdiaphram p r e s s u r e d e v e l o p m e n t (35, 36, 122, 147, 214), frequency s p e c t r u m shifts of  integrated  electromyographic  activity  (IEMG)  (25,  56),  bilateral  phrenic  nerve  stimulation ( B P N S ) (9, 10, 15, 104), or unloading of the respiratory m u s c l e s via (A) p r e s s u r e - a s s i s t d e v i c e (82, 111) or (B), inspiring a less d e n s e g a s (e.g. helium) (47). T h e results of t h e s e s e v e r a l studies are difficult to interpret, a s m a n y different indices of fatigue w e r e u s e d , a n d there w e r e wide r a n g e s in a g e a n d athletic caliber of the subjects.  M o r e o v e r , interpretation remains difficult a s respiratory m u s c l e fatigue has  b e e n s h o w n to limit performance in s o m e studies (56, 8 2 , 104), but not in others (2, 111, 125). Although  one  EIAH  review  suggests  that  hypoventilation—from  reduced  chemosensitivity, a n airflow limitation, or via respiratory m u s c l e fatigue—is not a n important  m e c h a n i s m of E I A H (156), current data s u g g e s t that hypoventilation  important in the d e v e l o p m e n t of E I A H (166, 168). research  p a p e r s confirms  that further study  is  H e n c e , the results of these later  is n e e d e d to  elucidate the  role  of  hypoventilation a s a m e c h a n i s m of E I A H (185).  Venoarterial shunts A s e c o n d m e c h a n i s m to explain E I A H in athletes is right-to-left shunt or v e n o u s to-arterial  (venoarterial)  shunts.  Venoarterial  shunts  can  be  post-pulmonary  or  intrapulmonary (48). P o s t - p u l m o n a r y shunts o c c u r w h e n blood p a s s e s from the arteries  57 directly to the v e i n s without going through the pulmonary s y s t e m for g a s e x c h a n g e . T r u e a n a t o m i c shunts arise either from the v e n o u s blood draining from the bronchi or from v e n o u s d r a i n a g e via t h e b e s i a n v e i n s into the left ventricle. O n the other hand, intrapulmonary shunts o c c u r b e t w e e n the atria or ventricles (e.g. teratology of fallot) or within the lungs (e.g. a n a s t a m o s i s ) . by the lungs.  T h u s both types of shunts preclude oxygenation  T h e result is normal P 0 A  2  a n d P a C 0 , but low P a 0 . 2  2  In the healthy  individual at rest, there is a normal right-to-left shunt of 0.5 - 1.5% of the c a r d i a c output that b y p a s s e s oxygenation in the lungs (11, 70), a n d a c c o u n t s for approximately 4 9 % of the resting alveolar-arterial o x y g e n p r e s s u r e difference of 8 - 10 m m H g (61).  If E I A H  d o e s result from shunting during intense e x e r c i s e , then breathing hyperoxic o x y g e n mixtures would h a v e a limited effect o n P a 0 . 2  H o w e v e r , it h a s b e e n demonstrated that  breathing a g a s mixture of 2 4 - 2 9 % o x y g e n restores P a 0  2  and % S a 0  runners w h o desaturate during h e a v y e x e r c i s e (47, 150, 155).  2  to normal in  T h u s , a venoarterial  (right-to-left) shunt is not a major m e c h a n i s m of E I A H in elite athletes.  Ventilation-perfusion mismatch Ventilation-perfusion ( V / Q ) m i s m a t c h is the third m e c h a n i s m to explain E I A H . A  Ventilation-perfusion m i s m a t c h is a condition in which ventilation of alveoli is not matched  to  perfusion  of  capillaries  (175).  Ventilation-perfusion  mismatch,  as  determined by Multiple Inert G a s Elimination T e c h n i q u e ( M I G E T ) , results in d e c r e a s e d P a 0 , a n d w i d e n e d A a D 0 , while P 0 , alveolar P C 0 2  2  A  2  2  ( P C 0 ) , and P a C 0 A  2  2  remain  unaffected. A low V / Q ratio c a u s e s h y p o x e m i a , while high V / Q regions i n c r e a s e A  A  d e a d s p a c e (175). Normally, at rest V  is about 4 - 6 L • min" a n d Q (which is e q u a l to pulmonary 1  A  blood flow) h a s a similar range. T h u s , the ratio of V / Q of the w h o l e lung is 0.8 to 1.2. A  58 However, the V / Q ratio must be m a t c h e d at the alveolar-capillary level a n d V / Q for A  A  the w h o l e lung is only a n approximation of V / Q in all alveolar-capillary units (119).  In  A  fact, the gravity d e p e n d e n t regions of the lung (the b a s e s ) are better perfused but less ventilated than the independent regions (the apices) which are better ventilated but less perfused (119). W h i l e gravity plays a n important role in determining regional pulmonary blood flow,  it plays s e c o n d fiddle  to the  a n a t o m i c structure  of the  arterial  tree  (pulmonary v a s c u l a r structure), which determines - 7 5 % of distribution of pulmonary blood flow (62, 84). A b n o r m a l i t i e s of V / Q are s e e n in h y p o x e m i c athletes during prolonged (91) a n d A  s e v e r e e x e r c i s e (70, 94, 179, 197, 207). Furthermore, it is d o c u m e n t e d that V / Q A  inequality w o r s e n s with e x e r c i s e intensity (70, 91).  This is in contrast to h o r s e s (208)  which s h o w no w o r s e n i n g of V / Q ratio's, probably d u e to the large s p l e n i c release of A  red blood cells into the circulation. It has b e e n s u g g e s t e d that i n c r e a s e s V / Q A  exercise (-65%  mismatching  during  prolonged  VC>2max) m a y be d u e to pulmonary e d e m a (70, 91), s i n c e the rapid  transcapillary fluid flux m a y be in e x c e s s of the lymphatic drainage capacity of the lung. Other  possibilities  of  V /Q A  inequality  are  hypoxic  non-uniform  pulmonary  vasoconstriction at altitude (70), reduction of g a s mixing in large airways (179, 198), or ventilation time constant inequality (207). P u l m o n a r y e d e m a is a n attractive m e c h a n i s m of V / Q inequality in exercising A  h u m a n s (91).  S t u d i e s have s h o w n that V / Q inequality is e x a g g e r a t e d in extreme A  hypobaric hypoxia (210), a n d improves with 1 0 0 % o x y g e n breathing at altitude (70), which would d e c r e a s e pulmonary artery p r e s s u r e a n d driving p r e s s u r e for fluid flux. C o a t e s et al. (38) s h o w e d in s h e e p a n d goats that normoxic a n d hypoxic e x e r c i s e is  59 a s s o c i a t e d with a two to threefold i n c r e a s e in lung lymph flow, w h i c h is compatible with the hypothesis of e x e r c i s e - i n d u c e d pulmonary e d e m a .  Furthermore, there is no  e v i d e n c e of bronchoconstriction (91), despite moderate V / Q inequality. A  Also, V / Q A  inequality persists up to twenty minutes post-exercise, e v e n after ventilation a n d Q h a v e returned to normal (179). T h e s e latter r e a s o n s s u g g e s t that pulmonary e d e m a is a potential c a u s e of V / Q inequality. A  Non-uniform hypoxic pulmonary vasoconstriction m a y be another c a u s e of V / Q A  inequality during e x e r c i s e (207).  P u l m o n a r y capillaries d o w n s t r e a m of l e s s constricted  small arteries w o u l d e x p e r i e n c e the high p r e s s u r e , a n d e d e m a could result. Therefore, W a g n e r s u g g e s t s that non-uniform vasoconstriction of certain capillaries m a y lead to redistribution of blood flow (207). A reduction of g a s mixing in large airways [ d e c r e a s e d d e a d s p a c e ventilation] is another c a u s e of V / Q inequality during e x e r c i s e (179, 198). A  A study performed on  d o g s s h o w e d that V / Q inequality w o r s e n e d a s d e a d s p a c e w a s r e d u c e d (198). T h e y A  h y p o t h e s i z e d that the r e d u c e d d e a d s p a c e of e x e r c i s e p r o d u c e d l e s s g a s mixing in large airways, leading to a l e s s h o m o g e n e o u s V / Q distribution in the lung. A  However,  this m e c h a n i s m of V / Q inequality s e e m s unlikely in h u m a n s a s d e a d s p a c e ventilation A  w a s identical b e t w e e n a group of athletes w h o h a d V / Q inequality c o m p a r e d to A  another group of athletes w h o did not have V / Q inequality (179).  A n o t h e r study  A  d e m o n s t r a t e d that a reduction of g a s mixing in large airways is not the c a u s e for V / Q A  inequality during e x e r c i s e b e c a u s e no correlation w a s found b e t w e e n V lung size or P a C 0  2  E  normalized for  a n d the resting log S D of the perfusion distribution (91). A s s u c h ,  this m e c h a n i s m of V / Q inequality is unlikely. A  60 Ventilation time constant inequality is the last r e a s o n why V / Q m i s m a t c h i n g c a n o c c u r A  during e x e r c i s e . V / Q inequality h a s b e e n s h o w n to correlate with V (207). Therefore, A  E  W a g n e r s u g g e s t s that a m e c h a n i s m d e p e n d e n t o n a level of V m a y contribute to the E  m i s m a t c h i n g of V / Q during e x e r c i s e . Increased m u c u s secretion c a u s e d by the s h e a r A  s t r e s s e s of high airflow rates during e x e r c i s e or from minor c h a n g e s in regional airway tone a s s o c i a t e d with vagal reflexes (207) c a n w o r s e n V / Q inequality. O n the other A  h a n d , no correlation w a s o b s e r v e d between V at any level of e x e r c i s e a n d resting log E  S D of the perfusion distribution  (96), suggesting that a ventilation  time  constant  inequality m a y not b e a major c a u s e for V / Q m i s m a t c h at a n y level of e x e r c i s e A  intensity.  Therefore, the c a u s e of V / Q inequality r e m a i n s speculative, but the favored A  hypothesis is the formation of pulmonary e d e m a (5, 91).  Diffusion limitation T h e fourth m e c h a n i s m of E I A H is diffusion limitation, w h e r e b y d e c r e a s e s in P a 0 2 a n d i n c r e a s e s A a D 0 2 are o b s e r v e d . M I G E T analysis h a s s h o w n that -40 - 60% of the A a D 0 2 is d u e to diffusion limitation, while the remaining amount is d u e to V / Q A  inequality (70, 94). Diffusion limitation is not only evident in h u m a n s exercising at s e a level (94, 207), but it b e c o m e s more p r o n o u n c e d at simulated a n d actual altitude (69, 71,  207).  A s with  V / Q m i s m a t c h i n g , diffusion A  limitation  becomes worse  with  increasing w o r k l o a d (69-71, 91, 94, 207), but rarely is a diffusion limitation in m a l e s s e e n below V 0 v a l u e s of 2.5 - 3 L • min" (-65% of V 0 a x ) (70, 91, 94). A c c o r d i n g to 1  2  2m  s o m e authors (107) diffusion equilibrium d e p e n d s simply o n the ratio of the diffusional c o n d u c t a n c e [diffusion capacity of the lung for o x y g e n (DL)] of the blood gas-barrier for  61 o x y g e n to the perfusional c o n d u c t a n c e ( p Q ) of the pulmonary vasculature for o x y g e n (152). Diffusional c o n d u c t a n c e or D , d e p e n d s on two distinct p r o c e s s e s , m e m b r a n e L  resistance [also k n o w n a s the diffusion capacity of the m e m b r a n e (DM)], a n d red cell resistance  [also known the time taken for o x y g e n to react with H b (8Vc)] (172).  Red  cell resistance d e p e n d s on the specific rate of o x y g e n uptake by red cells at different o x y g e n t e n s i o n s , otherwise known a s reaction rate of 0  2  to Hb (0),  multiplied  by  pulmonary capillary blood v o l u m e (Vc) (172). Perfusional c o n d u c t a n c e of the pulmonary vasculature for o x y g e n is d e p e n d e n t on the linear slope (P) b e t w e e n mixed v e n o u s a n d arterial  oxyhemoglobin  saturation  taken  from  a  standardized  oxyhemoglobin  dissociation curve, a n d pulmonary blood flow (otherwise known a s c a r d i a c output or Q ) . A s e x e r c i s e intensity i n c r e a s e s , D linearly i n c r e a s e s , likely d u e to i n c r e a s e d D L  M  and V c  from recruitment a n d distention (199, 224). However, p a l s o i n c r e a s e s b e c a u s e mixed venous P 0  2  falls dramatically (107, 207). Therefore, the lowered mixed v e n o u s P 0  2  lengthens the time n e c e s s a r y for o x y g e n p r e s s u r e equilibrium in the pulmonary capillary (203), a n d p rises from about 2 m L • L" of blood- m m H g " at rest to 5 m L • L" of blood • 1  m m H g " at h e a v y e x e r c i s e (107, 207). 1  1  1  Concomitantly, Q a l s o i n c r e a s e s linearly with  e x e r c i s e intensity, a n d a s a result, the D / p Q ratio c a n fall precipitously, e s p e c i a l l y in L  athletes w h e r e m a x i m a l Q c a n be twice a s great a s m a t c h e d , sedentary controls. W h e n diffusion equilibration is 9 9 % complete, the D / p Q ratio is about 4.6; w h e n D / p Q ratio L  L  is 3.0, there is 9 5 % diffusion equilibration; and during maximal s e a - l e v e l e x e r c i s e in elite athletes, D / p Q ratio c a n fall to 1.0, which represents 6 3 % equilibration (48). T h e L  d e c r e a s e in the D / p Q ratio is e v e n more p r o n o u n c e d during acute hypoxia, a s Q a n d p L  62 are higher at given s u b m a x i m a l e x e r c i s e w o r k l o a d s (107, 204).  T h u s , a diffusion  limitation is evident during e x e r c i s e , e s p e c i a l l y in highly trained athletes. T h e r e are s e v e r a l r e a s o n s to explain E I A H c a u s e d by diffusion limitation d u e to the fall in the D /(3Q ratio during e x e r c i s e . A s with V / Q inequality, o n e p o s s i b l e r e a s o n L  A  for diffusion limitation is pulmonary e d e m a d u e to either i n c r e a s e d thickening or stress failure [rupture] of the alveolar-capillary m e m b r a n e (5, 28). A s e c o n d possibility for diffusion limitation w a s d i s c u s s e d p r e v i o u s l y — a reduction in mixed v e n o u s PO2 (44, 156, 203), which r e d u c e s the rate of equilibration (44).  A third possibility is very rapid  pulmonary capillary transit times (45, 46). Finally, non-uniformity distribution along a single capillary c a n a l s o alter D  L  of red blood cell  a n d c a u s e diffusion limitation.  A  d i s c u s s i o n of t h e s e p o s s i b l e r e a s o n s follows. P u l m o n a r y e d e m a c a n d e c r e a s e diffusing capacity of o x y g e n d u e to thickening of alveolar-capillary  membrane.  During  severe  or  long-term  exercise,  increased  hydrostatic p r e s s u r e s in the pulmonary artery c a n i n c r e a s e transcapillary fluid flux into the interstitial s p a c e (206) a n d a low-grade pulmonary e d e m a c a n o c c u r (5, 2 7 , 28, 133, 179).  A l s o , during extreme levels of e x e r c i s e , it h a s b e e n s h o w n that ultrastructural  m e c h a n i c a l s t r e s s e s m a y result, c a u s i n g l e a k a g e of p l a s m a , protein, a n d red blood cells, into the interstitial  s p a c e (95, 218).  Capillary wall s t r e s s d e p e n d s on the  transmural p r e s s u r e , which is the difference b e t w e e n the inside a n d outside of the capillary. T h e greater the p r e s s u r e differential b e t w e e n p r e s s u r e inside a n d outside of the capillary, the greater the stress. E v i d e n c e s u g g e s t s that m e a n pulmonary capillary p r e s s u r e s ( P C P ) in e x c e s s of 30 m m H g are probably required to rupture the thin side of the h u m a n pulmonary capillary wall (218), a n d c a u s e pulmonary capillary stress failure (PCSF).  T h e s e p r e s s u r e s c a u s e stress on the thin side the capillary wall of >50 k P a  which a p p r o a c h e s the breaking strength of type IV c o l l a g e n (218).  H o w e v e r , recent  63 d a t a h a s s h o w n that E I A H o c c u r r e d in highly trained athletes despite m a i n t e n a n c e of the alveolar epithelium (51), suggesting that P C S F m a y not o c c u r in h u m a n s with high oxygen  uptakes.  As  such,  pulmonary  edema  via  a  thickened  alveolar-capillary  m e m b r a n e without c o m p l e t e rupture of the b l o o d - g a s barrier is a more probable c a u s e of h y p o x e m i a that o c c u r s in athletes during s e v e r e e x e r c i s e . O n the other h a n d , studies h a v e s h o w n that o n e to two hours of prolonged, s u s t a i n e d , moderate e x e r c i s e (-75 to 7 7 % V0 max) did not alter lung density (124) or concentrations of red blood cells, or total 2  protein a n d leukotriene B  (96) c o m p a r e d to pre-exercise. T h i s s u g g e s t s that e d e m a  4  o c c u r s only during e x e r c i s e of severe-intensity. During m a x i m a l e x e r c i s e , thoroughbred race h o r s e s frequently s h o w P C S F s i n c e very high pulmonary arterial p r e s s u r e s of about 120 m m H g , (and therefore P C P of about 100 m m Hg), o c c u r during intense e x e r c i s e (> 8 0 % V0 max (219)). 2  thoroughbred h o r s e s is calculated to o c c u r at about 80 k P a , (218).  P C S F in  M o r e recently,  P C S F w a s s h o w n to o c c u r at a pulmonary capillary transmural p r e s s u r e >75 m m H g in r a c e h o r s e s (18). T h u s , pulmonary e d e m a from P C S F is very p o s s i b l e c a u s e of E I A H in horses. A s e c o n d condition which inhibits diffusion of o x y g e n a c r o s s the alveolar-capillary barrier is the reduction of mixed v e n o u s P 0 (44, 156, 203). A s the intensity of e x e r c i s e 2  p r o g r e s s e s towards m a x i m u m , the e n h a n c e d o x y g e n extraction in the skeletal m u s c l e s r e d u c e s mixed v e n o u s P 0 , a n d in elite athletes, the reduction in mixed v e n o u s P 0 2  greater  than  in s e d e n t a r y  controls.  A s such,  the  s l o p e of the  2  is  oxyhemoglobin  dissociation curve b e t w e e n mixed v e n o u s a n d arterial blood will i n c r e a s e (203), which lowers the D / p Q ratio. L  P 0 A  2  T h e s l o p e , (3, a n d not the driving p r e s s u r e gradient between  a n d mixed v e n o u s P 0  2  is fundamentally r e s p o n s i b l e for the rate of equilibration  64 (44, 203).  T h e r e a s o n why the s l o p e is far more important than the driving gradient  between P A 0  2  a n d mixed v e n o u s P 0  2  is e x p l a i n e d mathematically by W a g n e r (203).  W a g n e r s h o w s that for a n inert g a s , the rate of diffusion equilibrium is independent of P 0 A  2  and mixed venous P 0  2  but that the principle determinant  Consequently, mixed venous P 0 E I A H b e c a u s e it affects p.  2  of this rate is p.  c a n be a n important factor in the d e v e l o p m e n t of  T a k e for e x a m p l e , a trained athlete w h o is performing  m a x i m a l e x e r c i s e a n d h a s a n exercising Q of 28 L • min" . A c c o r d i n g to D e m p s e y (44), 1  the estimated available mL).  m e a n pulmonary capillary transit time is 0.45 s e c o n d s (Vc = 2 1 0  H o w e v e r , s i n c e this athlete h a s P 0 A  venous P 0 required  2  2  of about 100 to 110 m m H g a n d a mixed  of 10 to 15 m m H g , then a c c o r d i n g to W a g n e r ' s m o d e l (203), the time  for c o m p l e t e equilibration of mixed v e n o u s blood with alveolar g a s by the  pulmonary capillary is not 0.25 s e c o n d s a s w e would e x p e c t w h e n m i x e d v e n o u s P 0 4 0 m m Hg (e.g. at rest), but is now - 0 . 5 0 s e c o n d s at this e x e r c i s e intensity.  2  is  A s such,  this e x e r c i s i n g athlete now h a s a diffusion limitation d u e to the differences between the required  a n d available  time for p r e s s u r e equilibration, a n d this is d u e to the very low  m i x e d v e n o u s P 0 a n d c o n s e q u e n t l y , high p. 2  Diffusion limitation c o n s e q u e n t to rapid pulmonary capillary transit times (45, 4 6 , 205) m a y a l s o be r e s p o n s i b l e for E I A H . T h e a v e r a g e time a red blood cell a n d its attendant p l a s m a s p e n d in the pulmonary capillaries during rest is about 0.75 s e c o n d s (106, 171, 202) at a mixed v e n o u s P 0 of 4 0 m m H g (203). T h i s is more than a d e q u a t e 2  for o x y g e n to diffuse through the alveolar-capillary m e m b r a n e , a s p r e s s u r e equilibrium o c c u r s about o n e third the d i s t a n c e d o w n a pulmonary capillary (191).  H o w e v e r , during  s e v e r e e x e r c i s e , with c a r d i a c outputs s o m e t i m e s in e x c e s s of 4 0 L • min" , the blood 1  m a y only stay in the capillary 0.25 s e c o n d s or less, which is about the m i n i m u m time  65 available for p r e s s u r e equilibrium at a PO2 of 4 0 m m H g (202, 203).  Dempsey's  theoretical s c h e m e to explain E I A H (45, 46) s u g g e s t s that Q a n d V c i n c r e a s e linearly up to about 2 5 L • min" a n d 2 1 0 m L , thereby maintaining sufficient time of red blood 1  cells to a c h i e v e p r e s s u r e equilibrium. Increasing flow, however, e l e v a t e s capillary transmural p r e s s u r e , w h i c h recruits capillaries that w e r e not prefused at rest a n d distends capillaries that w e r e already perfused. T h e resulting i n c r e a s e in capillary blood v o l u m e h a s the important effect of reducing the rate of fall in capillary transit time (159, 160). A s Q i n c r e a s e s further in the trained individual, V c r e a c h e s m a x i m u m d i m e n s i o n s a n d m e a n pulmonary capillary transit time drops below the theoretical limit for partial p r e s s u r e equilibrium. D e m p s e y a n d F r e g o s i (46) a l s o s u g g e s t that distribution of transit times around the m e a n probably results in m u c h faster transit times in s o m e parts of the lung, a n d t h e s e transit times m a y be r e d u c e d e v e n further, a s capillary flow is not uniform but pulsatile (93, 202). In fact, there is a vertical gradient of pulmonary capillary transit times with the shortest times at the bottom of the lung (86); h e n c e , t h e s e d e p e n d e n t regions m a y e x p e r i e n c e the highest capillary hydrostatic p r e s s u r e gradient for creating very rapid transit times. Arterial desaturation is more likely to o c c u r if the distribution of capillary transit times about the m e a n is large.  C a p e n et al. (31) tripled Q in d o g s from 2.9 to 9.9 L •  min" a n d f o u n d — u s i n g v i d e o m i c r o s c o p y — t h a t capillary transit times in the d e p e n d e n t 1  regions d e c r e a s e d from 2.0 to 0.8 s e c o n d s while capillary recruitment i n c r e a s e d by 25%.  H o w e v e r , further i n c r e a s e s in Q c a u s e d no further c h a n g e in transit  suggesting that the variation in red cell number a n d a r r a n g e m e n t pattern  time,  among  different lung regions (also called relative d i s p e r s i o n = S D of transit t i m e / m e a n transit time) w e r e the s a m e at both lower a n d high c a r d i a c outputs. This implies that full  66 recruitment of the pulmonary capillaries o c c u r s in the d e p e n d e n t regions of the lung with only m o d e s t increments in flow. T h i s is in a g r e e m e n t with another study (160) in which Q i n c r e a s e d from 1.6 to 3.2 m L • min" in d o g s while pulmonary capillary transit time 1  a n d relative d i s p e r s i o n d e c r e a s e d .  Doubling blood flow a g a i n d e c r e a s e d transit time  further, but did not c h a n g e either capillary recruitment or the relative d i s p e r s i o n .  Later,  P r e s s o n et al. (159) s h o w e d that a threefold i n c r e a s e in Q in d o g s (from 4 to 12 L-min" ) 1  resulted in a d e c r e a s e d m e a n pulmonary capillary transit time to one-fourth of control v a l u e s , while relative d i s p e r s i o n d e c r e a s e d by 2 0 % . T h e d e c r e a s e d transit times with i n c r e a s e d Q w e r e m a d e less s e v e r e by both capillary recruitment—which  occurred  most in the top three c m of the l u n g s — a n d by a narrowing of the transit time distribution (159).  P r e s s o n a n d c o l l e a g u e s p r o p o s e d that the d e s i g n feature of the pulmonary  capillary b e d in d o g s k e e p s the shortest times from falling b e l o w the minimum time for c o m p l e t e oxygenation (159).  theoretical  A later study by the s a m e authors  s h o w e d that the rat lung is not a s recruitable a s the d o g lung b e c a u s e the pulmonary capillaries of rats w e r e nearly completely perfused at lower than b a s a l flow rates ( Q = - 6 9 m L • kg" • min" )(161). 1  1  T h e s e authors s u g g e s t that the nearly fully recruited V c at  near resting flow rates in the rat ( Q = - 2 5 0 m L • kg" • min" ) is o n e explanation for the 1  1  inability of s m a l l e r s p e c i e s with high resting metabolic rates (i.e. rodents) to i n c r e a s e VO2 above basal values. R e s e a r c h h a s d e m o n s t r a t e d that pulmonary capillary transit times obtained from direct m e a s u r e m e n t s in d o g lungs using in vivo m i c r o s c o p y w e r e the s a m e a s capillary transit times m e a s u r e d indirectly in the entire d o g lung using D L C O m e t h o d s (32). N e v e r t h e l e s s , despite r e s e a r c h d o n e o n capillary transit times in d o g s a n d rats, there is no data e x a m i n i n g pulmonary capillary transit times directly in exercising h u m a n s ,  67 b e c a u s e methodological limitations m a k e this i m p o s s i b l e at present. traditional  DLCO  measurements  (either  by  single-breath  method  However, with or  rebreathing  technique), pulmonary capillary transit times during e x e r c i s e c a n b e calculated indirectly (100, 213).  It h a s b e e n o b s e r v e d m e a n pulmonary capillary transit times  during  e x e r c i s e d o not fall b e l o w 0.46 s e c o n d s (213), a n d that there is no relationship between capillary transit time a n d AaDC>2 (213). A s well, data exists w h i c h d e m o n s t r a t e s that V c d o e s not plateau in exercising h u m a n s (100, 163, 2 1 3 , 224).  H o w e v e r , this is in  opposition to s e v e r a l other studies demonstrating that V c is maximally recruited during various e x e r c i s e intensities (11, 3 1 , 109, 160, 184). Indeed, the d e b a t e remains. I n a s m u c h a s capillary transit times cannot be directly m e a s u r e d in h u m a n s during  e x e r c i s e , radionuclide  cardiography  ventricular or right ventricular-to-left  has  been  u s e d for  direct  right-to-left  atrial pulmonary transit times (i.e w h o l e lung or  pulmonary transit time) at rest a n d during e x e r c i s e in normal, healthy (14, 3 0 , 6 0 , 7 5 , 90, 101, 102, 112, 113, 115, 123, 126, 164, 165) a n d d i s e a s e d (29, 114) subjects. S o m e h a v e u s e d technitium 9 9 - m labelled h u m a n s e r u m albumin ( 113, 115) instead of technitium 99-m labelled red blood cells (  9 9 m  9 9 m  T c H S A ) (29, 30,  T c R B C ) a s a tracer for  P T T , but the differences in P T T c u r v e s (and thus P T T ) are minimal (Jyrki K u i k k a : p e r s o n a l communication).  Furthermore, if using the left ventricle instead of the left  atrium a s the output curve, exercising P T T times i n c r e a s e by less than 0.4 s e c o n d s (Jyrki  Kuikka:  p e r s o n a l communication).  A s s u m i n g that pulmonary  vessels  have  negligible c a p a c i t a n c e , then pulmonary capillary transit times reflect P T T , a n d , c h a n g e s in pulmonary capillary transit times reflect c h a n g e s in P T T ( C o n n i e H s i a : p e r s o n a l communication).  H e n c e , first p a s s radionuclide cardiography m a y b e sufficient to track  m e a n c h a n g e s in red cell velocity through a pulmonary capillary. Indeed, o n e study h a s d e m o n s t r a t e d that most of the transit time variation in the pulmonary v a s c u l a t u r e o c c u r s  68 within the pulmonary capillary b e d than in conducting arteries a n d v e i n s (37). C l o u g h a n d c o w o r k e r s (37) d e m o n s t r a t e d that the arterial a n d v e n o u s trees contributed to less than 2 0 % of total lobar m e a n transit time in isolated d o g lung lobe preparation. T h i s d a t a s u g g e s t s that c h a n g e s in w h o l e lung P T T s h o u l d a l s o affect capillary transit times. T h e theoretical curve of pulmonary capillary transit time vs Q put forth by D e m p s e y a n d F r e g o s i in 1985 (46) a n d then in 1986 (45) r e s e m b l e s capillary transit times of W a r r e n ' s (213).  T h e theoretical curve a l s o closely r e s e m b l e s a n exponential  d e c a y r e g r e s s i o n curve plotted from s e v e r a l m e a n P T T ' s a n d c a r d i a c outputs a c r o s s thirteen different studies (Figure 30), a n d the curve plotted from individual data points from 72 healthy subjects a c r o s s 5 different studies, including the present study (Figure 31) (30, 88, 112, 164). A s s u c h , this a d d e d e v i d e n c e strengthens the c o n c e p t that P T T a n d pulmonary capillary transit times reflect e a c h other.  A n interesting study from  H o p k i n s et a l . , (90) h a s s h o w n that about 4 5 % of red blood cells have m e a n right-to-left ventricular pulmonary transit times of less than two s e c o n d s , a n d this w a s estimated from morphometric data (59) to be six to s e v e n times longer than capillary transit times. Therefore, H o p k i n s estimated that in her highly trained subjects, 4 5 % of red blood cells h a d m e a n pulmonary capillary transit times of less than 0.3 s e c o n d s , very c l o s e to the theoretical limit for partial p r e s s u r e equilibrium. a c c o u n t for c h a n g e s in mixed v e n o u s P 0  2  H o w e v e r , H o p k i n s et al. (90) did not  s u c h that the 0.25 - 0.30 s e c o n d theoretical  limit for partial p r e s s u r e equilibrium is valid only if mixed v e n o u s P 0 P 0 A  2  2  = 4 0 m m Hg a n d  = 100 m m H g (203). G i v e n the fact that during s e v e r e e x e r c i s e P 0  H g a n d mixed v e n o u s P 0  A  2  2  is - 1 0 0 m m  is 15 to 2 0 m m H g in e n d u r a n c e trained individuals (195,  200), the time required for p r e s s u r e equilibrium is about 0.50 s e c o n d s (203). Therefore, a g a i n a s s u m i n g that P T T is six to s e v e n times greater than capillary transit times, then - 7 0 % a n d not 4 5 % of the cells in H o p k i n s paper (90) could have b e e n below the  69 theoretical time required for complete partial p r e s s u r e equilibrium (i.e. those cells with a P T T < 3.0 s e c o n d s ) . H o p k i n s et al. (90) also o b s e r v e d significant relationships between P a 0 , A a D 0 , v e r s u s P T T (r = 0.65 b e t w e e n P T T a n d P a 0 ; r = -0.59 between P T T 2  and  2  AaD0 ) 2  2  (88,  90),  thus  supporting  a  role for  c o n s e q u e n t to rapid red cell velocity through the lung. P T T d e c r e a s e s from about 5.4 -  pulmonary  diffusion  limitation  Other studies h a v e s h o w n that  9.3 s e c o n d s at rest to 2.3 - 2.8 s e c o n d s during  e x e r c i s e at Q ' s of 18 - 3 2 L • min" in healthy normal h u m a n s (14, 101, 102, 112, 113, 1  115, 164, 165), but no arterial b l o o d - g a s m e a s u r e m e n t s w e r e reported in t h e s e studies. Clearly, the controversy in the literature a n d the potential importance of short P T T a s a c a u s e of E I A H indicates that the relationship b e t w e e n pulmonary g a s e x c h a n g e a n d P T T n e e d s to be studied further. N e v e r t h e l e s s , despite the available theory a n d data (e.g. F i g u r e s 30 a n d 31), d e c r e a s e d P T T cannot be the only c a u s e for EIAH.  D u e to the linear relationship between Q a n d V 0 , athletes w h o h a v e high 2  maximal aerobic capacities ( V 0 similar m a x i m a l  > 6 5 m L • kg" • min" or 5 L • min" ) would h a v e 1  2 m a x  Q ' s during e x e r c i s e . Y e t , only - 5 0 -  1  1  6 0 % of t h e s e  individuals  e x p e r i e n c e E I A H (23, 153). A g a i n , this m a y be d u e to variations in mixed v e n o u s P 0 . 2  M o r e r e s e a r c h n e e d s to be d o n e on diffusion limitation c o n s e q u e n t to rapid capillary transit times in athletes a n d on the effects of mixed v e n o u s P 0 . 2  A fourth, recently d i s c o v e r e d condition that inhibits pulmonary diffusing capacity is non-uniformity of R B C distribution along a single capillary. b e e n explained by F o r e s t e r (54).  T h i s p h e n o m e n o n has  H e explains that a single red blood cell sufficiently  distant [but not too distant] from its nearest neighbors t a k e s up o x y g e n most rapidly s i n c e the p l a s m a diffusion path is not e n c r o a c h e d on.  F o r e s t e r states that " a s the  n u m b e r of cells in the capillary i n c r e a s e s , the distance b e t w e e n the cells d e c r e a s e s ,  70 a n d thus the path through the p l a s m a b e c o m e s restricted, s o that the rate of o x y g e n uptake of the cell d e c r e a s e s ; but of c o u r s e , there are m a n y more cells, s o the total uptake in the capillary rises, but l e s s than proportionally."  H o w e v e r , if s p a c i n g between  red blood cells i n c r e a s e s too m u c h (as with r e d u c e d Hct; (54)), diffusion capacity for the whole lung ( D L C O ) d e c r e a s e s d u e to a r e d u c e d m e m b r a n e diffusion capacity (53). This c r e a t e s a non-uniform s p a c i n g that c a n b e c o m e large a n d inhibit m e m b r a n e a n d thus w h o l e lung diffusion capacity. E m p l o y i n g a theoretical geometric m o d e l , H s i a et al., (99) c o n c l u d e d that the greatest D L C O — 5 0 % improvement in D L C O — w a s o b s e r v e d w h e n cells w e r e e v e n l y s p a c e d (i.e. w h e n there are 3 - 7 red blood cells per capillary s e g m e n t c o r r e s p o n d i n g to a Hct of 18 - 4 3 % ) . A more uniform distribution of red blood cells in a capillary s e g m e n t m a y explain part of the i n c r e a s e in D L C O during e x e r c i s e (54), independent of the n u m b e r of capillaries recruited or the Hct (99). s h o u l d further e n h a n c e a uniform distribution  Increases in Hct  of red blood cells within a capillary  s e g m e n t ( C o n n i e H s i a : personal communication). In an earlier study (224), red blood cells that w e r e r e l e a s e d by d o g s s p l e e n s ' i n c r e a s e d Hct from 4 0 to 5 5 %  during  e x e r c i s e , a n d this a c c o u n t e d for the e n h a n c e d D L C O of d o g s c o m p a r e d to h u m a n s . H u m a n s h a v e the capacity to r e l e a s e only - 1 8 0 m L of red blood cells from the s p l e e n during e x e r c i s e (223), resulting in Hct increasing from 39 to about 4 2 % (223, 224). T h i s is quite s m a l l c o m p a r e d to the twelve liters of blood r e l e a s e d from the s p l e e n of a 5 0 0 kg exercising horse (107).  T h u s , it is likely that uniformity of red blood cell s p a c i n g  improves during e x e r c i s e , d u e to either a u g m e n t e d Hct or i n c r e a s e d blood flow. Diffusion capacity of the whole lung for o x y g e n is usually m e a s u r e d a s D L C O , or diffusion capacity of the lung for c a r b o n monoxide.  W h e n either m e m b r a n e diffusing  capacity (DM) or pulmonary capillary blood v o l u m e (Vc) is r e d u c e d , then D L C O will a l s o be r e d u c e d .  During e x e r c i s e up to m a x i m u m , D L C O i n c r e a s e s by - 6 6 % (199), likely  71 d u e to i n c r e a s e d perfusion of pulmonary capillaries.  H o w e v e r , D L C O is d e c r e a s e d  p o s t - e x e r c i s e c o m p a r e d to pre-exercise (72, 134, 183). T h u s , could repeated e x e r c i s e bouts alter % S a 0  a n d promote E I A H in athletes? Normally, one-half of the 6 % - 1 4 %  2  (73, 74) reduction of post-exercise pulmonary diffusion capacity h a s b e e n s h o w n to be d u e to a 7 % reduction in central blood v o l u m e a s redistribution of blood to the more distal regions o c c u r s (74).  Theoretically, a n altered body position (from upright to  supine) c a n improve V c a n d thus D L C O s i n c e gravity e n h a n c e s v e n o u s return a n d total pulmonary  blood  flow.  But, maintained  diffusion  impairment  is s h o w n  to  exist  independent of body position, indicating that p a s s i v e relocation of blood into the periphery d u e to gravity is unlikely.  Rather, active vasoconstriction of pulmonary  v a s c u l a t u r e and/or peripheral vasodilatation o c c u r s p o s t - e x e r c i s e (192).  However,  impaired D L C O p o s t - e x e r c i s e h a s no effect o n continued performance a s V02max, % S a 0 2 , p H , a n d P a 0 2 w e r e found to be similar b e t w e e n repeated bouts of e x e r c i s e (72, 116, 134). In addition, s i n c e p o s t - e x e r c i s e D L C O is not related to a e r o b i c capacity (183), it s e e m s unlikely that D L C O p o s t - e x e r c i s e correlates with E I A H in athletes. GENDER T h e i n c i d e n c e of E I A H h a s b e e n traditionally  a s s e s s e d in m a l e s .  Recent  r e s e a r c h h a s s h o w n that about 7 6 % of w o m e n with widely varying fitness levels (V02max = 57 ± 6 m L • kg" • min" ; range = 31 to 7 0 m L • kg" • min" ) h a v e E I A H (> 10 m m H g 1  1  1  1  drop in P a 0 2 ) (79). A l m o s t half of the w o m e n with significant E I A H h a v e V02max s c o r e s within 1 5 % of predicted normal v a l u e s (79). T h i s is interesting b e c a u s e m a l e s with V0 max s c o r e s within 1 5 % of predicted normal v a l u e s (40 - 5 0 m L • k g " • min" ) d o not 1  1  2  develop EIAH.  Furthermore, i n a s m u c h a s a reduction in % S a 0  2  from 9 8 % at rest to  9 3 % during s e v e r e e x e r c i s e in m a l e athletes is sufficient to c a u s e a m e a s u r a b l e c h a n g e  72 in m a x i m a l a e r o b i c power ( V 0 e a c h 1% d e c r e m e n t in % S a 0  2 m a x  2  ) that a p p r o x i m a t e s a 1% d e c r e m e n t in V 0  2 m a  x for  (154), w o m e n e x p e r i e n c e almost the s a m e relationship  (78). In fact, a 3 % reduction in % S a 0  2  from rest c a n h a v e a significant detrimental effect  o n w o m e n (78). S o w h y d o a greater proportion of w o m e n d e v e l o p E I A H c o m p a r e d to m e n , a n d w h y d o they d e v e l o p it at a lower absolute V 0  2 m a x  ?  C o m p a r e d to adult m e n , adult  w o m e n h a v e s m a l l e r lung v o l u m e s a n d lower m a x i m a l expiratory flow rates e v e n w h e n corrected for standing height (4, 131). It h a s b e e n determined that w o m e n have s m a l l e r V c , r e d u c e d airway diameter, s m a l l e r diffusion surface, a n d lower h e m o g l o b i n levels relative to m a l e s at c o m p a r a b l e statures, height a n d body m a s s (79).  Consequently,  those factors c a n a c c o u n t for the greater proportion of w o m e n w h o d e v e l o p E I A H c o m p a r e d to m e n , a n d c a n a l s o partly explain why w o m e n d e v e l o p E I A H at a lower absolute V 0 a x -  S i n c e w o m e n have smaller V c , r e d u c e d airway diameter, s m a l l e r  2 m  diffusion s u r f a c e , a n d lower h e m o g l o b i n levels relative to m a l e s at c o m p a r a b l e statures, height,  and  body  m a s s , this  also  a c c o u n t s for  the  differences  in  DLCO  and  D L C O / a l v e o l a r v o l u m e b e t w e e n g e n d e r s . D L C O a n d D L C O / a l v e o l a r v o l u m e is 12 a n d 1 0 % lower in w o m e n , respectively, than predicted in m a l e s (79). In a similar p a p e r that u s e d the s a m e cohort of w o m e n , there w a s more expiratory flow limitation during heavy e x e r c i s e in highly fit v e r s u s l e s s fit w o m e n , which c a u s e d higher end-expiratory a n d end-inspiratory lung v o l u m e s a n d greater u s a g e of their m a x i m u m available ventilatory r e s e r v e s (131). different.  A s s u c h , the m e c h a n i s m s for E I A H in w o m e n a n d m e n m a y be  O n e p a p e r h a s determined that E I A H in w o m e n w a s l e s s e n e d and not  e n h a n c e d by prior m a x i m a l e x e r c i s e (within 2 hours) (189). T h i s implies that E I A H is not c a u s e d by a m e c h a n i s m that persists after the initial e x e r c i s e period. T h i s s h o w s that  73 pulmonary o x y g e n a t i o n m a y improve with s u b s e q u e n t e x e r c i s e (within 2 hours) in w o m e n (and m a y b e men) with E I A H . T h e findings demonstrate that E I A H in w o m e n , a s in m e n , is a n a c u t e transient pathology that is present only during the e x e r c i s e period. Nevertheless, P a 0  2  r e s p o n s e s to running a n d cycling e x e r c i s e protocols are similar  from those previously o b s e r v e d in m e n (89). Further r e s e a r c h is still n e e d e d c o m p a r i n g E I A H a n d gender. AGE E I A H h a s b e e n s h o w n to a l s o o c c u r in older athletes (> 6 2 yrs old) (130, 143, 157). T h e i n c i d e n c e of E I A H ( % S a 0 < 4 % from rest) m a y o c c u r in 5 0 (130), to 1 0 0 % 2  (Pa0  2  < 10 m m H g from rest) (130) of older athletes. F o r the s a m e absolute w o r k l o a d ,  the drop in P a 0 at 4 0 % V 0  2  2 m a x  is greater in older than in y o u n g e r athletes a n d the drop is significant (157).  Hypoventilation s e e m s to be a major c a u s e (157) d u e to  diminished chemosensitivity in this population (143), but the paucity of r e s e a r c h on E I A H a n d older athletes allows only for a cautious interpretation of the m e c h a n i s m ( s ) involved. W h e n interpreting arterial blood g a s e s for the determination of E I A H in older athletes, it is e s s e n t i a l to k n o w the range of normal v a l u e s in this population. a n d c o l l e a g u e s (187) d e v e l o p e d a r e g r e s s i o n equation b e t w e e n a g e a n d P a 0 o n 152 subjects ranging from 14 - 8 4 y e a r s old. correlation (r = -  Sorbini 2  based  T h e y noted a significant inverse  0.91; P < 0.01) b e t w e e n a g e a n d resting P a 0 . Their regression  equation relating s e a level P a 0  2  2  to a g e is: P a 0  2  = 109 - 0.43 (age) ± 4 . 1 (1 S D ) .  Similarly, a recent paper h a s published reference v a l u e s on arterial blood g a s e s b a s e d on 9 6 subjects ranging from 18 to 79 y e a r s old (41).  T h e y a l s o reported at significant  inverse correlation (r = - 0.88; P < 0.01) between a g e a n d P a 0 . 2  equation relating resting s e a level P a 0  2  to a g e is: P a 0  2  Their regression  = 0.18 ( P ) - 0.25 (age) - 3 1 . 5 B  74 ± 5.5, w h e r e P  B  is the barometric p r e s s u r e . T h e d e c r e a s e in resting P a 0  d u e to the i n c r e a s e d A a D 0  with a g e is  2  a n d h a s b e e n s h o w n to be a s s o c i a t e d with i n c r e a s e d V / Q  2  A  inequality (209). A s s u c h , determination of E I A H s h o u l d be b a s e d on c h a n g e s in P a 0 from rest a n d not the absolute P a 0  2  value.  F o r e x a m p l e , resting s e a level P a 0  2  2  in  individuals 6 2 y e a r s old is 8 0 - 82 m m H g (157, 187), but it c a n be a l s o - 9 0 m m H g (41). F o r c o m p a r i s o n , resting s e a level P a 0 5 m m H g (41).  2  in y o u n g m a l e s 1 8 - 3 4 y e a r s old is 100 ±  Therefore, by not knowing the normal r a n g e s in P a 0  populations, the resting  Pa0  in various  v a l u e s in older athletes could be misconstrued  2  h y p o x e m i a , s i n c e t h e s e low P a 0  2  2  as  v a l u e s are representative of E I A H in y o u n g exercising  e n d u r a n c e athletes. SUMMARY T h e effect of E I A H on V 0  2 m a  x h a s b e e n d o c u m e n t e d in highly fit male a n d f e m a l e  athletes. T h e m e c h a n i s m s of E I A H w e r e presented a n d hypoventilation,  diffusion  limitation a n d V / Q inequality are the most probable m e c h a n i s m s of E I A H , but no A  c o n c l u s i v e a n s w e r s c a n be m a d e at this stage. EIAH.  A g e a n d g e n d e r a l s o play a role in  T h e vast a m o u n t of data present in the literature reveals that E I A H is a n acute,  transient, pathology b e c a u s e E I A H only o c c u r s during e x e r c i s e that is not acutely w o r s e n e d by prior e x e r c i s e . advances  have  been  made,  A s quoted from a present review o n E I A H : especially  over  the  past  decade  "significant  [yet]  several  fundamental p r o b l e m s remain u n r e s o l v e d , in m a n y c a s e s b e c a u s e w e are unable to apply definitive  m e a s u r e m e n t s to the  m a x i m u m e x e r c i s e (48)."  c o m p l e x in vivo  conditions  present  during  F o r t h e s e r e a s o n s , E I A H will continue to be a n interesting  pathology that will be studied a m o n g e x e r c i s e physiologists for the next s e v e r a l y e a r s .  75  APPENDIX B. BACKGROUND INFORMATION OF PENTASTARCH AS A PLASMA VOLUME EXPANDER A c u t e p l a s m a v o l u m e e x p a n s i o n c a n be typically a c h i e v e d via infusion of crystalloid or colloid fluids.  intravenous  Crystalloids (e.g. S a l i n e , R i n g e r s Lactate,  Plasmalyte) are a d v a n t a g e o u s in that they are far less e x p e n s i v e than colloid therapy, it promotes urine output, a n d the agents of crystalloids are chemically simple.  However,  o n e problem a s s o c i a t e d with crystalloid therapy is that e x p a n s i o n is more difficult b e c a u s e crystalloids leak into interstitium  quite rapidly. A s s u c h , crystalloids  may  promote e x t r a v a s c u l a r lung water a c c u m u l a t i o n , a n d therefore, intravascular v o l u m e e x p a n s i o n is b e l o w the v o l u m e infused.  However, the a d v a n t a g e s of using colloid  e x p a n d e r s (e.g. A l b u m i n , Dextrans, G e l a t i n s , Hydroxythyl starches) are that they h a v e the ability to hold water in the intravascular compartment  s i n c e the aggregates of  s u b m i c r o s c o p i c m o l e c u l e s resists filtration a n d diffusion (170). T h u s , the a d v a n t a g e s of colloids are that they produce less e d e m a , a n d that they e x p a n d p l a s m a v o l u m e effectively with a lower v o l u m e (170). risk of transmitting d i s e a s e s (136). are  more  e x p e n s i v e than  Furthermore, artificial colloids are free from the  O n e d i s a d v a n t a g e of colloids however, is that they  crystalloids.  Another  d i s a d v a n t a g e of colloids is that  o c c a s i o n a l s e v e r e anaphylactoid reactions (grade III a n d IV) c a n occur.  However, that  h a s b e e n s h o w n to be only 0 . 0 0 6 % of the time w h e n using hydroxyethyl starch (e.g. Pentaspan®) (169).  Furthermore, dextran colloids have the s a m e incidence of s e v e r e  anaphylactoid reactions, at about 0.008%®) (169). Later r e s e a r c h h a s indicated that grade I, II or III anaphylactic s h o c k o c c u r s o n c e in every 1 4 1 6 9 infusions of hydroxyethl starch, a n d that i n c i d e n c e is r e d u c e d greatly w h e n only calculating the o c c u r r e n c e of grade III s h o c k (1 in 188918) (139). T h u s , these colloids a p p e a r to be quite safe s i n c e  76 other natural s u b s t a n c e s s u c h a s blood, a n d other drugs have higher i n c i d e n c e s of s e v e r e reactions than artificial colloids (136). Of all colloids, e x p a n s i o n is greatest with Pentaspan® s u c h that P e n t a s t a r c h > Dextran > Hetastarch > A l b u m i n (162).  A single  d o e s of 5 0 0 m L of Pentaspan® results in the elimination of approximately 7 0 % of the d o s e in 24 hrs (via urinary excretion) a n d approximately 8 0 % of the d o s e within one w e e k (151). 24 hrs post-infusion, only about 7 % of the d o s e remains in the bloodstream a n d 3 3 % r e m a i n in the extravascular s p a c e (139). T h e initial p l a s m a half-life of this product is about 2.5 hrs (170), the intrinsic viscosity of Pentaspan® is 0.16 dl/gr (139), a n d time to m a x i m u m e x p a n s i o n is within the initial minutes of c o m p l e t e infusion (162). Pentaspan® h a s a colloid o s m o t i c p r e s s u r e of 4 0 m m H g , pulling the water from the interstitium, providing a n i n c r e a s e in intravascular v o l u m e in a ratio of 1.2 - 1.6:1.0 of the v o l u m e infused (170).  A 5 0 0 m L b a g of Pentaspan® (264/0.45) indicates that the  a v e r a g e m o l e c u l a r weight is 2 6 4 0 0 0 daltons a n d that the d e g r e e of substitution is 0.45 (140). T h i s m e a n s that for every 100 g l u c o s e r e s i d u e s , there are about 4 5 hydroxyethyl groups. S o , while 1 gram of hydroxyethyl starch theoretically binds with 30 m L of water, (140), Pentaspan® with its d e g r e e of substitution of 0.45, holds - 1 3 . 5 m L of water. Therefore, in a 5 0 0 m L b a g of 1 0 % Pentaspan®, there are 50 g r a m s of hydroxyethyl starch a n d thus s i n c e e a c h gram of Pentaspan® infused c a u s e s the p a s s a g e of - 1 3 . 5 m L of water into the intravascular s p a c e , the infusion of 5 0 0 m L of 1 0 % Pentaspan® e x p a n d s B V by about 6 7 5 m L (170).  co CJ)  CD  o>| c  CM  a:  I CO  p  +1  CO  c +1 CO co o ci o> CM  0_  •tf  tf CJ) CM  tf CM  o  •tf  hT _ CM  rT _  in  CO CO  co h-  CM  O  co  in  CO  T  oo ~ T  CD CO  CM  tf  CM  LU N-  CM  CO OQ CM  o tf < co  T  ~  +1  ai CO  CM  m  iri CD  oo  CJ) CO  in in  m CM CO  CO CO  tf'  co co  CD  CD  iri  o ci oo  o  CO  t _  r-  oo  1 |-N  tf  o  CM  CM  cd  • r\  in oo \  in  CD  CM  T—  T—  UJ  co  LO  tf  T—  CO CO  o  iri  in  CO  co oo  CD  o  o  CM  CJ) CO  CJ) CO  tf  CO  in  o  tf oo  O  h-  •  o m co  m co  tfi  oo co  tf T  —  co  T  CM  +1  +1 +i  O) CO  ° CM h~ CT) co T - CM  —•  ^—  1  .—.  CO  hCM •tf  CM  in  tf  +i  CM  +1 tf  co co  00  co T _  +1 tf  o  CM •tf  tf  CO  CO  00  oo •  O)  tf  CD CO i CJ) co  CM CJ) 1  co  h-  o o CM  O  o o  CD  o  CO  00 T—  •tf  co  CO  co  co  o  •tf  CO  co T _  •tf  CJ)  m  o  CJ) CM CO  co  in  oo  o co  r»  o o  CO  —  •tf  oo co  •tf •tf  CJ>  ~  co ci CM  •tf  CM O CM  o  CM  o  tf tf  T—  tf  CM  tf  oo  CJ)  '~ r  iri  r-  CD  CJ) T  ~  T  ~  tf tf o 1"-  tf  CM •tf  CM  tf  co CD r-  +1 +i +1  CM CO  h-  CD  CM  co T—  co co  CD  CM  tf  tf  oo  CD  in  m  T _  o •tf  oo  in o  !•»  CO  CD  o  in in co  tf  iri  CD  CD  tf  oo  ci oo  r-  CM  iri  tf  tf m  •tf  CD  T  o  CM OO  CM  CM CO CD  CD CO  iri  a>  o  T—  •tf  CO  co  T _  o co  T  O CM  r-  tf  CM  tf  tf~  CD  tf  ~  -  O  co T  O  co co  tf  T •>~  in  T-  co CD  •tf  co  CM  in "r-  m  tf  in o  co h-  T _  o  ci oo T—  o  o oo  m  o  CM  o ci  in  CJ)  ~  T  CO  m  CO  CO  tf  CM  tf  O)  co  m m  •tf  ~  T  CM  tf  o  oo tf  m  oo CD CO  CO oo  CO  T—  CM O  O  T—  CD ci  oo  00  oo  •tf  o  CO  iri 00  CM CM ~  co  in  CJ)  CO  CD  r-  iri oo  CD CD  CO o iri iri  tf  T  tf  CJ)  co CM co CO co  tf tf  00  tf m  CO  tf  CD  hci  oo  •tf  CJ) CM  CM CD  tf  CD ci  O CO  tf  co  tf tf tf  d oo  oo  T _  iri  co  tf m  CD  •tf  m  tf  co co co  csi CD  in iri  ci  in  o iri  in  CO  CJ) CO co  tf  CD  1  CD  CM  iri  iri  tf  CM  CD  o  oo  tf in iri +1 +i  CO  CD  CM CD CD  CD  o cd  iri 00  CM  1^  o  •  •tf  CO  CM  m  ci  co  tf  O  iri  CD ci  r*-  o iri  hCM CO  1^  +1 +1  CJ)  oo  CO  CJ)  CO tf  O) co  O  T—  CD  i h~  CM CO O) i CM  CM tf  q  tf  tf  CO  CO  m  tf in  o  T  CM  dt 00 r- f-  oo  m  •tf  CM CO  CJ)  co  in ci  00  r—  CO CO  CJ) O 1 CM CO i CM tf oo co CM  CJ>  in  oo  r-I--  CD  +1 CD +i  T—  CM  co  oo  co  CJ)  CO  CO  CM  CM  o z  CM CD  CO  co ~  D_  in  tf  T  CO CO OO  CM  oo ~  in  o  00  CD  +1  (3  CM  12.9  77  CM CD  CM  tf  •tf  o  CD co  CO  c 'E CO  m  CO CD  0  <  E o  ^—'  D)  E  —i  'E  § CD cj)  X  D)  I .a  O  g.  O  LU  X 0  !o  CO  UL  0)  X CL  O  X  X  E  CD  E  i l l o" >  -  x  s ro  CD  o ^  co CO <u JO  2  S m  TJ O O  OQ  o  > > LU LU  if)  ^ o LiLU QL  O  -J  Q  c 'E  J  78 T a b l e 1 0 : P l a s m a v o l u m e c h a n g e s between non-infusion a n d infusion s e s s i o n s . Subject  Non-infusion day (mL)  Infusion day (mL)  A P V (mL)  AC  3005  3505  +500  D a y s between non-infusion a n d infusion s e s s i o n s 14  BW  3575  4124  +549  8  MV  3297  3646  +349  60  ME  4555  5560  +1005  66  NC  3765  4358  +593  15  LZ  3304  3442  +138  8  PC  3779  3422  -357  14  JB  3906  3825  -81  12  SP  4138  4525  +387  20  SS  4799  5911  +1112  21  AF  2917  3727  +810  7  PG  3951  4460  +509  8  4210 ± 8 1 4  3 7 4 9 ± 576  460 ± 422*  21 ± 2 0  -357 to+1112  7 to 66  MEAN ± SD  Range 3 4 4 2 to 5911 2 9 1 7 to 4 7 9 9 * P = 0.003 c h a n g e in P V (Paired t-test)  79 T a b l e 1 1 : R a t i n g s of p e r c e i v e d exertion for the V 0 2 m a x test, a n d both 6.5 minutes e x e r c i s e tests (non-infusion a n d infusion s e s s i o n s ) . 6.5 minutes test infusion s e s s i o n 18  AC  17  6.5 minutes test n o n infusion s e s s i o n 18  BW  18  18  18  ME  19  18  18  MV  17  19  19  NC  17  18  18  LZ  18  19  19  PC  18  18  18  JB  17  18  19  SP  18  18  18  SS  19  19  18  AF  18  19  19  PG  17  15  17  17.8 + 0.8  18.1 + 1.1  18.3 + 0.6  17-19  15-19  17-19  Subject  Mean ± S D Range  VC>2nnax  80 T a b l e 1 2 : R e p e a t e d m e a s u r e s A N O V A for V 0  2  S o u r c e of V a r i a n c e  DF  SS  MS  F  P  Condition  1  4.54  4.54  0.041  0.38  Time  7  56122.54  8017.51  668.41  <0.01  Condition x T i m e  7  18.57  2.65  0.52  0.82  Residual  70  357.79  5.11  T a b l e 1 3 : P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for V 0 Time comparison 0 vs 6.5 0 vs 6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 vs 6.5 1 vs 6.0 1 vs 5 1 vs 4 1 vs 3 1 vs2 2 v s 6.5 2 vs 6 2vs5 2 vs 4 2vs3 3 vs 6.5 3 vs 6 3 vs 5 3 vs 4 4 v s 6.5 4 vs 6 4 vs 5 5 vs 6.5 5 vs 6 6 v s 6.5  2  (Bonferroni's method).  Difference of m e a n s  t  P < 0.05  -55.55 -56.24 -55.82 -54.78 -52.80 -49.94 -44.08 -11.47 -12.16 -11.74 -10.70 -8.72 -5.86 -5.61 -6.30 -5.89 -4.84 -2.86 -2.75 -3.44 -3.02 -1.98 -0.77 -1.46 -1.04 0.27 -0.42 0.69  -53.20 -53.86 -53.46 -52.46 -50.57 -47.84 -42.21 -10.98 -11.65 -11.24 -10.25 -8.35 -5.61 -5.37 -6.03 -5.63 -4.36 -2.74 -2.63 -3.29 -2.89 -1.90 -0.73 -1.40 -1.00 0.26 -0.42 0.66  Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes No No No No No No No No  81 T a b l e 14: R e p e a t e d m e a s u r e s A N O V A for V . E  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 T i m e  7  310.20  44.30  0.68  0.69  Residual  70  4552.0  65.00  S o u r c e of V a r i a n c e  T a b l e 1 5 : P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for V Time comparison 0 v s 6.5 0 vs 6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 vs 6.5 1 v s 6.0 1 vs 5 1 vs 4 1 vs 3 1 vs 2 2 v s 6.5 2 vs 6 2 vs 5 2 vs4 2 vs 3 3 v s 6.5 3 vs 6 3 vs 5 3 vs4 4 vs 6.5 4 vs 6 4 vs 5 5 v s 6.5 5 vs 6 6 vs 6.5  E  (Bonferroni's method).  Difference of m e a n s  t  P < 0.05  -139.02 -136.67 -132.42 -126.58 -119.14 -108.64 -87.71 -51.31 -48.95 -44.70 -38.86 -31.43 -20.92 -30.39 -28.03 -23.78 -17.94 -10.50 -19.88 -17.53 -13.28 -7.44 -12.45 -10.09 -5.84 -6.60 -4.25 -2.35  -27.93 -27.46 -26.60 -25.43 -23.93 -21.42 -17.29 -10.31 -9.83 -8.98 -7.81 -6.31 -4.12 -6.10 -5.63 -4.78 -3.60 -2.11 -4.07 -3.59 -2.72 -1.52 -2.55 -2.07 -1.20 -1.35 -0.87 -0.48  Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No No No No No No No No  82 T a b l e 1 6 : R e p e a t e d m e a s u r e s A N O V A for heart rate. S o u r c e of V a r i a n c e  DF  SS  MS  F  P  Condition  1  245.30  245.26  5.34  0.04  Time  7  181331.3  25904.47  666.57  <0.01  Condition x T i m e  7  33.70  4.81  0.56  0.77  Residual  77  663.20  8.61  T a b l e 17: method).  P a i r w i s e multiple  Time comparison 0 v s 6.5 0 vs 6 0 vs 5 0 vs4 0 vs 3 0 vs 2 0 vs 1 1 v s 6.5 1 v s 6.0 1 vs 5 1 vs 4 1 vs 3 1 vs2 2 vs 6.5 2 vs 6 2 vs 5 2 vs 4 2 vs 3 3 v s 6.5 3 vs 6 3 vs 5 3 vs 4 4 v s 6.5 4 vs 6 4 vs 5 5 v s 6.5 5 vs 6 6 v s 6.5  comparison procedures  for heart  rate  (Bonferroni's  Difference of m e a n s  t  P < 0.05  -98.17 -97.25 -94.88 -92.79 -90.25 -85.92 -78.04 -20.13 -19.21 -16.83 -14.75 -12.21 -7.88 -12.25 -11.33 -8.96 -6.88 -4.33 -7.92 -7.00 -4.63 -2.54 -5.38 -4.46 -2.08 -3.29 -2.38 -0.92  -54.55 -54.04 -52.72 -51.56 -50.15 -47.74 -43.37 -11.18 -10.67 -9.35 -8.20 -6.78 -4.38 -6.81 -6.30 -4.99 -3.82 -2.41 -4.40 -3.89 2.57 -1.41 -2.90 -2.48 -1.16 -1.83 -1.32 -0.51  Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No No No No No No No No  83 T a b l e 1 8 : R e p e a t e d m e a s u r e s A N O V A for % S a 0 . 2  S o u r c e of V a r i a n c e  DF  SS  MS  F  P  Condition  1  7.90  7.90  1.89  0.20  Time  7  889.85  127.12  47.32  <0.01  Condition x T i m e  7  9.16  1.31  1.18  0.33  Residual  76  84.46  1.11  T a b l e 19: P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for % S a 0 Time comparison 0 v s 6.5 0 vs 6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 vs 6.5 1 v s 6.0 1 vs 5 1 vs 4 1 vs3 1 vs 2 2 v s 6.5 2 vs6 2 vs 5 2 vs 4 2 vs 3 3 vs 6.5 3 vs 6 3 vs 5 3 vs 4 4 v s 6.5 4 vs 6 4 vs 5 5 v s 6.5 5 vs 6 6 v s 6.5  2  (Bonferroni's method).  Difference of m e a n s  t  P < 0.05  6.94 6.36 5.70 4.45 3.75 2.82 2.23 4.71 4.13 3.47 2.23 1.52 0.59 4.12 3.54 2.88 1.64 0.93 3.19 2.61 1.95 0.71 2.48 1.90 1.24 1.24 0.66 0.60  14.46 13.39 12.00 9.38 7.89 5.93 4.69 9.82 8.71 7.31 4.69 3.20 1.25 8.59 7.46 6.06 3.45 1.96 6.65 5.50 4.11 1.49 5.18 4.01 2.62 2.59 1.40 1.21  Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes Yes Yes No Yes Yes Yes No Yes Yes No No No No  84 Table 20: R e p e a t e d m e a s u r e s A N O V A for P a 0  2  corrected to e s o p h a g e a l temperature.  S o u r c e of V a r i a n c e  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 T i m e  7  182.50  26.10  1.61  0.14  Residual  76  1228.30  16.20  Table 21: P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for P a 0 temperature (Bonferroni's method). Time comparison 0 v s 6.5 0vs6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 v s 6.5 1 v s 6.0 1 vs 5 1 vs 4 1 vs 3 1vs2 2 v s 6.5 2 vs 6 2vs5 2 vs 4 2vs3 3 v s 6.5 3 vs 6 3 vs 5 3 vs 4 4 v s 6.5 4 vs 6 4 vs 5 5 v s 6.5 5 vs 6 6 v s 6.5  2  corrected to e s o p h a g e a l  Difference of m e a n s  T  P < 0.05  16.83 16.57 17.46 15.33 15.04 13.00 14.53 2.30 2.04 2.93 0.80 0.51 -1.53 3.83 3.57 4.64 2.330 2.042 1.79 1.53 2.42 0.29 1.50 1.24 2.13 -0.63 -0.90 0.26  8.65 8.59 9.06 7.95 7.80 6.74 7.54 1.18 1.06 1.52 0.42 0.27 -0.79 1.97 1.85 2.32 1.21 1.06 0.92 0.79 1.26 0.15 0.77 0.65 1.11 -0.33 -0.47 0.14  Yes Yes Yes Yes Yes Yes Yes No No No No No No No No No No No No No No No No No No No No No  85 ANOVA  corrected  to  esophageal  Table 22: Repeated temperature.  measures  S o u r c e of V a r i a n c e  DF  SS  MS  F  P  Condition  1  6.23  6.23  0.11  0.74  Time  7  6596.13  942.30  37.00  <0.01  Condition x T i m e  7  172.29  24.61  1.55  0.16  Residual  76  1204.64  15.85  for  AaD0  2  T a b l e 2 3 : P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for A a D 0 temperature (Bonferroni's method). Time comparison 0 v s 6.5 0 vs 6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 vs 6.5 1 vs 6.0 1 vs5 1 vs 4 1 vs 3 1 vs2 2 v s 6.5 2 vs 6 2 vs 5 2vs4 2vs3 3 v s 6.5 3 vs 6 3 vs 5 3 vs 4 4 vs 6.5 4vs6 4 vs 5 5 vs 6.5 5 vs 6 6 v s 6.5  2  corrected to e s o p h a g e a l  Difference of m e a n s  t  P < 0.05  -18.71 -18.49 -19.15 -17.09 -16.33 -13.92 -13.65 -5.07 -4.85 -5.50 -3.44 -2.68 -0.28 -4.79 -4.57 -5.23 -3.17 -2.41 -2.38 -2.16 -2.82 -0.76 -1.63 -1.40 -2.06 0.43 0.65 -0.22  -12.61 -12.66 -13.11 -11.70 -11.18 -9.53 -9.35 -3.45 -3.42 -3.32 -3.77 -2.36 -1.84 -0.19 -3.23 -3.13 -3.58 -2.17 -1.61 -1.48 -1.93 -0.52 -1.10 -0.96 -1.14 0.29 0.45 -0.14  Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No No No Yes No No No No No No No No No No No  86 ANOVA  corrected  to  esophageal  Table 24: Repeated temperature.  measures  S o u r c e of V a r i a n c e  DF  SS  MS  F  P  Condition  1  2.48  2.48  0.15  0.71  Time  7  337.42  48.20  6.82  <0.01  Condition x T i m e  7  14.37  2.05  0.88  0.53  Residual  76  178.29  2.35  for  PaC0  2  T a b l e 2 5 : Pairwise multiple c o m p a r i s o n p r o c e d u r e s for P a C 0 temperature (Bonferroni's method). Time comparison 0 v s 6.5 0 vs 6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 v s 6.5 1 v s 6.0 1 vs 5 1 vs 4 1 vs 3 1 vs2 2 v s 6.5 2 vs6 2 vs 5 2 vs4 2 vs 3 3 v s 6.5 3 vs 6 3 vs 5 3 vs 4 4 vs 6.5 4 vs 6 4 vs 5 5 vs 6.5 5 vs 6 6 vs 6.5  2  corrected to e s o p h a g e a l  Difference of m e a n s  t  P < 0.05  -0.45 -0.12 -0.66 -1.29 -2.25 -3.42 -3.48 3.03 3.36 2.82 2.19 1.23 0.06 2.97 3.30 2.76 2.13 1.17 1.80 2.22 1.59 0.96 0.84 1.17 0.63 0.21 0.54 -0.33  -0.58 -0.16 -0.85 -1.68 -2.92 -4.44 -4.52 3.89 4.36 3.66 2.84 1.60 0.08 3.82 4.28 3.59 2.76 1.52 2.31 2.76 2.06 1.24 1.08 1.52 0.82 0.26 0.70 -0.43  No No No No No Yes Yes Yes Yes Yes No No No Yes Yes Yes No No No No No No No No No No No No  87 T a b l e 2 6 : R e p e a t e d m e a s u r e s A N O V A for p H corrected to e s o p h a g e a l temperature. S o u r c e of V a r i a n c e  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 T i m e  7  0.01  0.00  1.68  0.13  Residual  76  0.03  0.00  T a b l e 2 7 : Pairwise multiple c o m p a r i s o n p r o c e d u r e s for p H corrected to e s o p h a g e a l temperature (Bonferroni's method). Time comparison 0 v s 6.5 0vs6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 vs 6.5 1 vs 6.0 1 vs5 1 vs 4 1 vs 3 1 vs2 2 vs 6.5 2 vs 6 2 vs 5 2 vs 4 2 vs3 3 v s 6.5 3vs6 3 vs 5 3 vs4 4 vs 6.5 4vs6 4 vs 5 5 v s 6.5 5 vs 6 6 v s 6.5  Difference of m e a n s  t  P < 0.05  0.24 0.23 0.21 0.18 0.15 0.12 0.07 0.17 0.16 0.13 0.11 0.08 0.05 0.12 0.12 0.08 0.06 0.03 0.09 0.08 0.05 0.03 0.06 0.05 0.03 0.03 0.03 0.04  23.08 22.76 20.14 17.64 14.82 11.46 7.00 16.14 15.76 13.14 10.64 7.82 4.46 11.72 11.30 8.67 6.18 3.36 8.39 7.94 5.32 2.28 5.59 5.12 2.50 3.12 2.62 0.52  Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No No No No  88 T a b l e 2 8 : R e p e a t e d m e a s u r e s A N O V A for standard b a s e e x c e s s ( S B E ) corrected to e s o p h a g e a l temperature. S o u r c e of V a r i a n c e  DF  SS  MS  F  P  Condition  1  11.20  11.19  2.21  0.17  Time  7  3394.40  484.91  127.52  <0.01  Condition x T i m e  7  10.80  1.55  0.92  0.50  Residual  76  127.90  1.68  T a b l e 2 9 : P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for standard b a s e e x c e s s ( S B E ) corrected to e s o p h a g e a l temperature (Bonferroni's method). Time comparison 0 v s 6.5 0 vs 6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 v s 6.5 1 vs 6.0 1 vs 5 1 vs 4 1 vs 3 1 vs2 2 vs 6.5 2 vs6 2 vs 5 2 vs 4 2 vs 3 3 v s 6.5 3vs6 3 vs 5 3 vs4 4 v s 6.5 4 vs 6 4 vs 5 5 vs 6.5 5 vs 6 6 v s 6.5  Difference of m e a n s  t  P < 0.05  12.42 12.25 10.98 9.69 7.89 5.75 2.93 9.49 9.32 8.05 6.75 4.95 2.82 6.66 6.50 5.23 3.93 2.13 4.53 4.36 3.10 1.80 2.73 2.56 1.30 1.44 1.27 0.17  21.74 21.69 19.45 17.15 13.97 10.19 5.19 16.61 16.50 14.25 11.96 8.77 4.99 11.67 11.50 9.26 6.97 3.78 7.93 7.72 5.48 3.19 4.78 4.54 2.29 2.51 2.24 0.30  Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No No No No  89 Table 30: Repeated measures e s o p h a g e a l temperature.  ANOVA  for  bicarbonate  (HC0 ") 3  corrected  S o u r c e of V a r i a n c e  DF  SS  MS  F  P  Condition  1  22.46  22.46  9.22  0.01  Time  7  2183.85  311.98  179.99  <0.01  Condition x T i m e  7  4.54  0.65  0.73  0.65  Residual  76  67.64  0.89  to  T a b l e 3 1 : P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for bicarbonate ( H C 0 ) corrected to e s o p h a g e a l temperature (Bonferroni's method). 3  Time comparison 0 v s 6.5 0 vs 6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 vs 6.5 1 vs 6.0 1 vs 5 1 vs 4 1 vs 3 1 vs2 2 vs 6.5 2 vs 6 2 vs 5 2 vs4 2 vs 3 3 v s 6.5 3 vs 6 3 vs 5 3 vs 4 4 vs 6.5 4vs6 4 vs 5 5 v s 6.5 5 vs 6 6 v s 6.5  Difference of m e a n s  t  P < 0.05  9.81 9.71 8.67 7.69 6.19 4.29 2.11 7.71 6.70 6.56 5.58 4.08 2.18 5.52 5.42 4.38 3.40 1.90 3.62 3.52 2.48 1.50 2.12 2.02 0.98 1.15 1.04 0.11  25.41 25.47 22.74 20.18 16.24 11.26 5.53 19.95 19.94 17.21 14.65 10.71 5.73 14.30 14.21 11.48 8.92 4.99 9.38 9.23 6.49 3.94 5.49 5.29 2.56 2.97 2.73 0.27  Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No No  90 T a b l e 32: R e p e a t e d m e a s u r e s A N O V A for e s o p h a g e a l temperature. S o u r c e of V a r i a n c e  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 T i m e  7  0.13  0.02  0.40  0.90  Residual  77  3.50  0.05  T a b l e 33: P a i r w i s e multiple (Bonferroni's method). Time comparison 0 vs 6.5 0 vs 6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 v s 6.5 1 vs 6.0 1 vs 5 1 vs 4 1 vs 3 1 vs2 2 v s 6.5 2 vs 6 2 vs 5 2 vs4 2vs3 3 vs 6.5 3vs6 3 vs 5 3 vs4 4 vs 6.5 4 vs 6 4 vs 5 5 v s 6.5 5 vs 6 6 vs 6.5  comparison procedures  for e s o p h a g e a l  temperature  Difference of m e a n s  t  P < 0.05  -2.97 -2.83 -2.55 -2.35 -2.14 -1.86 -1.55 -1.42 -1.28 -1.00 -0.80 -0.59 -0.31 -1.11 -0.97 -0.69 -0.48 -0.28 -0.83 -0.69 -0.42 -0.21 -0.63 -0.21 -0.63 -0.48 -0.21 -0.14  -35.57 -33.87 -30.58 -28.08 -25.59 -22.30 -18.56 -17.01 15.31 -12.02 -9.53 -7.03 -3.74 -13.27 -11.57 -8.28 05.79 -3.29 -9.98 -8.28 -4.99 -2.49 -7.48 -5.79 -2.49 -4.99 -3.29 -1.70  Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No Yes Yes No  91 Table 34: R e p e a t e d m e a s u r e s A N O V A for A l v e o l a r P 0 . 2  S o u r c e of V a r i a n c e  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 T i m e  7  20.8  2.97  0.79  0.59  Residual  76  284.0  3.74  Table 35: P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for alveolar P 0 method). Time comparison 0 v s 6.5 0 vs 6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 v s 6.5 1 v s 6.0 1 vs 5 1 vs 4 1 vs 3 1vs2 2 v s 6.5 2 vs 6 2vs5 2 vs4 2vs3 3 v s 6.5 3 vs 6 3 vs 5 3 vs4 4 v s 6.5 4 vs 6 4 vs 5 5 v s 6.5 5 vs 6 6 v s 6.5  2  (Bonferroni's  Difference of m e a n s  t  P < 0.05  -1.90 -1.92 -1.69 -1.77 -1.30 -0.92 0.88 -2.78 -2.80 -2.57 -2.64 -2.17 -1.80 -0.97 -0.99 -0.76 -0.84 -0.37 -0.61 -0.63 -0.40 -0.47 -0/14 -0.15 0.08 -0.21 -0.23 0.01  -2.04 -2.08 -1.83 -1.91 -1.40 -1.00 0.95 -2.98 -3.02 -2.78 -2.86 -2.35 -1.95 -1.04 -1.07 -0.82 -0.91 -0.40 -0.65 -0.68 -0.43 -0.51 -0.15 -0.17 0.08 -0.23 -0.25 0.19  No No No No No No No No No No No No No No No No No No No No No No No No No No No No  92 Table 36: R e p e a t e d m e a s u r e s A N O V A for P . 5 0  S o u r c e of V a r i a n c e  DF  SS  MS  F  P  Condition  1  16.85  16.85  6.87  0.02  Time  7  1343.45  191.92  108.56  <0.01  Condition x T i m e  7  7.06  1.01  1.78  0.10  Residual  76  42.98  0.57  Table 37: P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for P Time comparison 0 v s 6.5 0 vs 6 0 vs 5 0 vs 4 0 vs 3 0 vs 2 0 vs 1 1 v s 6.5 1 v s 6.0 1 vs 5 1 vs 4 1 vs 3 1vs2 2 v s 6.5 2 vs 6 2 vs 5 2 vs 4 2 vs 3 3 v s 6.5 3 vs 6 3 vs 5 3 vs4 4 v s 6.5 4 vs 6 4 vs 5 5 v s 6.5 5vs6 6 v s 6.5  5 0  (Bonferroni's method).  Difference of m e a n s  t  P < 0.05  -8.13 -7.90 -6.82 -5.96 -4.89 -3.67 -2.22 -5.91 -5.68 -4.61 -3.74 -2.67 -1.45 -4.46 -4.23 -3.16 -2.30 -1.23 -3.23 -3.00 -1.94 -1.07 -2.16 -1.94 -0.87 -1.30 -1.07 -0.23  -20.91 -20.50 -17.72 -15.47 -12.70 -9.52 -5.76 -15.20 -14.74 -11.96 -9.71 -6.94 -3.76 -11.47 -10.98 -8.21 -5.96 -3.18 -8.31 -7.80 -5.02 -2.77 -5.56 -5.02 -2.25 -3.33 -2.78 -0.58  Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes No Yes No No  93 Table 38: R e p e a t e d m e a s u r e s A N O V A for m e a n pulmonary transit times at 3rd minute of e x e r c i s e during the 6.5 minute e x e r c i s e tests. S o u r c e of V a r i a n c e  DF  SS  MS  F  P  Condition  1  0.83  0.83  0.85  <0.01  Method  1  0.00  0.00  65.60  0.43  Condition x M e t h o d  1  0.00  0.00  2.17  0.16  Residual  8  0.01  0.00  Table 39: R e p e a t e d m e a s u r e s A N O V A for distribution of pulmonary transit times at 3rd minute of e x e r c i s e during the 6.5 minutes e x e r c i s e tests. S o u r c e of V a r i a n c e  DF  SS  MS  F  P  Condition  1  0.048  0.048  0.85  0.38  Time  8  33356.40  6671.28  65.60  <0.01  Condition x T i m e  5  692.11  138.42  2.17  0.08  Residual  40  2553.38  63.83  Table 40: P a i r w i s e multiple c o m p a r i s o n p r o c e d u r e s for distribution of pulmonary transit times at 3rd minute of e x e r c i s e during the 6.5 minute e x e r c i s e tests. T i m e interval comparison <1 v s 1 - 1.8 <1 v s 2 - 2.8 <1 v s 3 - 3.8 <1 v s 4 - 4 . 8 <1 v s >5 1 - 1 . 8 v s 2 - 2.8 1 - 1.8 v s 3 - 3 . 8 1 - 1 . 8 vs 4 - 4 . 8 1 - 1.8 v s >5 2 - 2.8 v s 3 - 3.8 2 - 2 . 8 vs 4 - 4 . 8 2 - 2.8 v s >5 3-3.8vs4-4.8 3 - 3.8 v s >5 4 - 4 . 8 v s >5  Difference of m e a n s  t  P < 0.05  -16.93 -50.54 -23.85 -5.14 -1.03 -33.61 -6.92 11.79 15.90 26.69 45.40 49.51 • 18.70 22.81 4.11  -5.21 -15.55 -7.21 -1.56 0.31 -10.34 -2.09 3.57 4.81 8.07 13.73 14.97 5.56 6.79 1.22  Yes Yes Yes No No Yes No Yes Yes Yes Yes Yes Yes Yes No  94 T a b l e 4 1 : O n e w a y A N O V A for day-to-day variability [intraobserver error] in a s s e s s i n g m e a n pulmonary transit times at 3rd minute of e x e r c i s e during the 6.5 minutes e x e r c i s e tests. S o u r c e of V a r i a n c e  DF  SS  MS  F  P  B e t w e e n treatments  2  0.007  0.00  0.04  0.95  Residual  51  3.94  0.077  Total  53  3.95  T a b l e 4 2 : O n e w a y A N O V A for day-to-day variability [intraobserver error] in a s s e s s i n g ejection fraction at 3rd minute of e x e r c i s e during the 6.5 minutes e x e r c i s e tests. S o u r c e of V a r i a n c e  DF  SS  MS  F  P  B e t w e e n treatments  1  3.56  3.56  0.134  0.72  Residual  32  847.06  26.47  Total  33  850.62  T a b l e 4 3 : O n e w a y A N O V A for day-to-day variability [intraobserver error] in a s s e s s i n g m e a n e n d diastolic v o l u m e at 3rd minute of e x e r c i s e during the 6.5 minutes e x e r c i s e tests. S o u r c e of V a r i a n c e  DF  SS  MS  F  P  B e t w e e n treatments  1  Z38  2^38  0.002  097  Residual  32  40860.35  1276.89  Total  33  40822.74  T a b l e 4 4 : O n e w a y A N O V A for ratings of perceived exertion ( R P E ) b e t w e e n all three exercise sessions. S o u r c e of V a r i a n c e  DF  SS  MS  F  P  B e t w e e n treatments  2  1.56  1.30  1.88  0.18  Residual  22  9.11  0.78  0.41  Total  35  24.97  95 Table 4 5 : S u m m a r y of F v a l u e s from the repeated m e a s u r e s A N O V A tables.  Condition 0.84  Variables V0  F Values Time Condition x T i m e 0.82 <0.01  2  0.61  <0.01  0.69  0.04  <0.01  0.79  <0.01  —  ~  0.38  <0.01  0.08  E s o p h a g e a l temperature  0.58  <0.01  0.90  C o r r e c t e d to e s o p h a q e a l temperature %Sa0  0.20  0.01  0.33  Pa0  0.24  <0.01  0.14  0.74  <0.01  0.16  0.71  <0.01  0.53  0.02  <0.01  0.10  0.09  0.03  0.60  SBE  0.16  <0.01  0.50  HCO3"  0.01  <0.01  0.65  PH  0.02  <0.01  0.13  V  E  Heart rate M e a n P T T at 3  r d  minute  Distribution of P T T at 3  2  2  AaD0 PaC0  2  2  P50 P 0 A  2  r d  minute  96  if) UJ CO  < o Q O O  3» X -•— CO  OQ •  CD Q.  mJ -I <  \  UJ ffi CO  co o  2> oo l_  co  <  j=  (/> UJ -I  OQ  i Q  I  Q ><  I eg 1  CD CO  CO  Tj cl X II <» UJ £>UJ  o co IS  CO  co .E s ~  o  CO •#-» (0 TJ  a: + .-  i'i. 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Co" tf co CO is rs CN tf CJ) CO 00 LO CM c is oo ts co LU CO CO ro CD rs |s co 00 CO CD oo CO CO rs 00 c 'O rs ECO- T ' C D CO O ts co LO CO LO oo T— CD ts tf CO - i -e is fs |s co CJ) oo oo CO CD cn 00 O) oo ro co E  S  Max  Min  x) — ro SD  Mean  PG  AF  SP  SS  BW  AC  LZ  S  ON  a> si CO  O  69.7  0.70  16.7  CM CO  o LO LO  JB  O o> u>  E  c CO = CQ  rs o CD LO oo LO CO CD CO rs o CD tf CN LO CJ) CJ) LO CO CD CO CD CN o CD tf co CO CM o CD CM T — CM T— T— CM  PC  O CO TJ i— CO  "  HR  >+—  CO  12.97  ii  39.1 41.4  0.61  0.72  1 1  §1  Subject Name  -Q O CO +J CO TJ c g c  co rs ^ tf  ESV (mL)  -•—»  35.69  •a  CD  34.29  SV index Q. d-  ME  CO TJ CD C CO  >  MV  o CO CD D C  O .E  BSA  4—  X CD _, TJ  CO CO  138.3  93.8  95.4 166.9  162.6  95.1 155.3  89.9 95.2 168.6  138.3  94.8  94.4 165.0  168.9  92.5  93.2 165.6  94.8  92.6  PBV index ESV index  _c CD CO  CD > CD CO  6  ^<  'E  H—  £  cq  CO LO CO CO is oo co co o LO CM CM CN co -tf co co co co co CM co CM o  c g CO CO CD CO c o CO ZJ  CD X CD  16.3  |s  -17.8  4.88  3.99 4.65 4.42  CJ) CD  16.3  4.29 4.58  5.34  5.40 15.3  4.91  4.73 -17.8  3.91 3.88  4.08 5.43 42.1  4.26  5.13 5.40  4.19 -2.6  5.67 5.48 -6.7  4.80  5.02 5.03  4.67 -4.7  5.36  CD i  EDV index  Hb  O  00  170.9  CO  186.5  CN o  |s  °-  S~E 93.5  0" s  tf  168.5  CO  CD  141.0  CO  26.4  CM O > o CM o  93.7  CM O Q  156.3  CN O >  4.56  109  C  —  ! »' =  X 3  CD  O  •§ ro .E o  110  c g TJ C  o o  TJ  c  CO TJ O  J Z  *CD — 8 <= 42 1  3 C CD O  •9 !t£= 10 _  LO  TJ ^  S 1J 8  _ CD  CD O C3) C  C OJ  CO TJ  O O  ^  O  TJ  co o ci  o  LO  LO  2 £ CD 1 > £ CD > fc CD -£ "55 ^  <  o o  LO CM  LO LO  o  o  o CM o  o ci  -D.  cn  0 LO LO  co o  o  10  10  o  10  cn  -*—' CD  CD — 0 CD CD P?TJ CO CD  E  > 2  CT) C  "i—  0  §  C  CO CD  -Q to  CO O-  CO  Z  o  LO  T—  tf  co  0  o o  CD  g> o CO oj  CD CO  o Is q  CD  cd CO  o  CD X CD  2 > CD  3  UL  8  c  co  C  CD  TJ  > CD CO  Q "  Tj" CO O  c o  Q  c g co  in  cn  I** I  CN  cn  cn  CM CM CO  CM  g 'co ^  co o  tf o  CM  o  CO  00  0  q o  q  CO  0  c g 'co  3 c  ^  "3 o  u  o co  '% o C CD  CD  co  CO LO CM  110 CM  CM Is CMl  CO CM  cn CM CM |CM CO  0  3  CD TJ  o  in  CM Is CM  o CM CM  |s  CD co  CM  ZJ  CM I cd  C  E D) C 'L_  ZJ  TJ CO CD  E co c  in  c z  CM CM  0  < 0 _ CO o c TJ c m 0 O O Z o > > x : i_ 0 0 £. £ •« p eo  0  o o  LO Is Is CM  LO  c?  CM  I CM I  CO  o  o o  o  0  0  in  CM  o  9  0  •3  c o  O  ^  CO  CJ  [s  CO CM  > 0 tz co o o 0  ZJ Q.  CM  TJ C CO  |TJ CO CO CO CL  CO  •n  CO  CM  CM  0  |fs|  2  z ~  E  2  TJ  CL  o  o 0  I CM  C CO <D •—' O  or  CM  ro g 'c .c o 0  [s  CO  CM  CO  d co a) JQ to  3 CO 3  c o  (0  0  0  .O CO  c 0  CO l_  TJ  c o c  CO  O o  TJ  3  **—  —5  D* -4C—  0  E  c "co c o o  M—  CO CO  E o o  _  g 'co  CO  0  d  ci  o o  LO  LO CO CM  CO  0  c  0 CO  O  ca  o CL  CO  CO S  1 TJ  c  111  CD CO  o cu X CD  CO  2 > CD  s  > CD CO  II  a.S  i O .. X C a > c"  tr  T3 CO  o  o c  m  co  0) c  4—  QJ  o  = E 2 •co c  CO  CO CD Zi  C ™ CO L CO  g  co —  'to  c  CD  O J to TJ CU > JP. CO  c  Zf XJ  c o o c  Zi 4—  •c o  c o 'to  c  Q J co  LOCO  .3 II  .2 5  CO ^ co lo Q. . . „ CO O CD TJSg Cj) L L O w  LO  3  co 3  o TJ "S O m O ^ E  CD "S E to 0  CO  rj  O O  CD  1LT  d  ZJ CO JZ  c o  CO CD  E C COCO COoJ=  <t  CM  co o o  s i o co  cn  E  d  TJ  Q.2 f O o -Q  TCO J «0iT _Q CO  II E S ti— 3 _ n  C  CD  o  co  C O CD E C D °  CD  3 s  H—  c  to to to  — 0  •i I s  '•*-» Zf J3 'i_ 4 •—< CO  E  5 5  CO TJ -j  g o  b  J3 CO I—  « ]=  55  o  CO  > X co fits  C CO CO  CO  CL  O CO 0 T3  CD CD  c cz >  CO  o g.  co E E  O CO C co c g CD = E 3 ox ^ CL CO  to to  c o o  o  J3  CO  CO CO  'w o  to  o  CO  la  3  CO  0 — "ft D T CJ?O CD "C S  XJ XI ro  00  LU  CD  5 g.s 5 Ji g a -  112  APPENDIX F. FIRST PASS RAW DATA AND GAMMA VARIATE FIT FOR CALCULATION OF RED CELL PULMONARY TRANSIT TIME Figure 9: R a w d a t a a n d g a m m a variate fit for subject A C at minute 3 of constant-load, severe exercise.  500 i  Non-infusion session  450 400 -*w -» c O  o co E E CO O  — R V g a m m a variate fit L V g a m m a variate fit O R V raw data • L V raw data :  350 300 250 200 150 -  CP -  100 -  O  O  rrf^QAt  O c>  Ooo °o  50 -  ° ° o  0< 5  6 7 8 9 Time (seconds)  10  11  12  13  Infusion session o  o  0  o o  5  6 7 8 9 Time (seconds)  10  11  CO  14  113 F i g u r e 1 0 : R a w data a n d g a m m a variate fit for subject J B at minute 3 of constant-load, severe exercise.  Non-infusion session 300  RV gamma variate fit  o  LV gamma variate fit  250  O  R V raw data  •  LV raw data  <> / 200 o o  ro  150  E E  ro O  CPQDQOO  O  o  100  0  1  2  3  4  5  6  7  8  9  10  11  12  13  14  Time (seconds) Infusion session  c/> o  O ro  E E  ro O  o.ooo  0  1  8 Time (seconds)  10  11  12  0  o  o  13  14  114 F i g u r e 1 1 : R a w d a t a a n d g a m m a variate fit for subject L Z at minute 3 of constant-load, severe exercise.  250  Non-infusion session  RV gamma variate fit LV gamma variate fit RV raw data LV raw data  200  150  100  co„  5  6  7  8  10  11  12  13  14  Time (seconds)  Infusion session  800  O O°  0  1  7  8  Time (seconds)  10  11  •  12  0-03  13  14  115 F i g u r e 1 2 : R a w d a t a a n d g a m m a variate fit for subject A C at minute 3 of constant-load, severe exercise.  Non-infusion session •—— RV gamma variate fit LV gamma variate fit O RV raw data • LV raw data  2  c  3. O  O  03  E E ro O  0  1 2  3  5  6 7 8 9 Time (seconds)  10  11  12  13  14  Infusion session o  2  3  4  5  6 7 8 9 Time (seconds)  10  11  12  13  14  116 F i g u r e 1 3 : R a w data a n d g a m m a variate fit for subject M V at minute 3 of constant-load, severe exercise.  Non-infusion session O •  RV gamma variate fit LV gamma variate fit RV raw data LV raw data  QDCD  o o  5  6 7 8 9 Time (seconds)  Infusion session  o o  ro  E E ro O  Time (seconds)  10  11  12  13  14  117 F i g u r e 1 4 : R a w d a t a a n d g a m m a variate fit for subject N C at minute 3 of constant-load, severe exercise.  R V g a m m a variate fit LV g a m m a variate fit  0  1  300  5  O  R V raw data  •  L V raw data  6 7 8 9 Time (seconds)  10  11  12  13  14  Infusion session  250 A  <> / 200 c 3 O o 150 A co E E  CO  O  100 A  50 A  0  1  5  6 7 8 9 Time (seconds)  10  11  12  13  14  118 F i g u r e 1 5 : R a w data a n d g a m m a variate fit for subject P C at minute 3 of constant-load, severe exercise.  Non-infusion session RV gamma variate fit LV gamma variate fit RV raw data LV raw data  O •  o CD  •mm  0 350  1  10  6 7 8 9 Time (seconds)  11  12  13  14  Infusion session  300 -\ 250  c  3 200 o O ra E 150 E rs O 100 CCD  o  G0 0 0 ° o 0  1  5  6  7  8  9  Time (seconds)  10  11  •mm  ' •°o*  0  12  13  14  119 F i g u r e 1 6 : R a w data a n d g a m m a variate fit for subject P G at minute 3 of constant-load, severe exercise.  Non-infusion session  700  O •  RV gamma variate fit LV gamma variate fit RV raw data LV raw data  o O  Q  o  Cft)  oo  0  1  2  \ 3  1 4  1 5  I 1 1 6 7 8 9 Time (seconds) 1  I I 10 11  cH5* JT ^  8  C  1 12  I 13  1 14  120 F i g u r e 1 7 : R a w d a t a a n d g a m m a variate fit for subject S S at minute 3 of constant-load, severe exercise.  Non-infusion session  O •  RV gamma variate fit LV gamma variate fit RV raw data LV raw data  3 O  o  ro E E  ro O  2  3  4  5  6 7 8 9 Time (seconds)  T  1  1  1  1  10  11  12  13  14  Infusion session  3 O  o  ro E E  ro O  o 0  1  2  3  4  5  6 7 8 9 Time (seconds)  10  11  12  13  14  121 F i g u r e 1 8 : R a w d a t a a n d g a m m a variate fit for subject B W at minute 3 of c o n s t a n t - l o a d , severe exercise.  Non-infusion session 300 n (  u n a b l e  t  o  o  RV gamma variate fit  ^ curves)  LV gamma variate fit  o  250  O  R V raw data  •  L V raw data  o  w 200 +J  c 3 O  « E | O  o  rP o  150 -\  •  o o o  100 H  50  ftp  o o  o  CO o  o Q  1 2  4  3  5  ^CCDacCCCflO^S 6 7 8 9 Time (seconds)  10  11  12  13  14  300 Infusion sessioji o  CcD  •  Cb  ^  O OD  CCcCCco^ 0  1  3  4  5  6 7 8 9 Time (seconds)  10  11  12  13  14  122 F i g u r e 1 9 : R a w d a t a a n d g a m m a variate fit for subject S P at minute 3 of constant-load, severe exercise.  300 Non-infusion session RV gamma variate fit LV gamma variate fit RV raw data LV raw data  O •  O  0  1 2  3  5  4  6 7 8 9 Time (seconds)  10  11  12  13  14  Infusion session 200 i (unable to fit RV gamma c^irve)  150 J j^  o  42 c 3 O ° 100 H Co  I  o  E E co CD  o  >  o  d l°o o»»J o o  50  \ \m  oo oo o o  \  \  \  o  cP,  o COD• c P  o 1  o  CO  /  4 ^ 0  1  5  6 7 8 9 Time (seconds)  10  11  12  13  14  123 Figure 20: R a w d a t a a n d g a m m a variate fit for subject A F at minute 3 of constant-load, severe exercise.  700 i Non-infusion session 600 O •  500 w c3 O 400 o cs E 300 E CO O 200 -  1 2 3 4 5 6 7 8 9 Time (seconds) Infusion session (unable to fit curves)  700  RV gamma variate fit LV gamma variate fit RV raw data LV raw data  10  11  12  13  14  600 500 B  | 400 -| O  co | 300 co CD  200 ^ 100  0 0  1  2  3  n 4  1 5  .re,  —I 1—^"T 6 7 8 9 10 Time (seconds)  1 11  1 12  1 13  1 14  124 APPENDIX G.  ANALYSIS  OF  DATA  F i g u r e 2 1 : Best-fit linear regression line utilized for temperature correcting fifty-six blood g a s s a m p l e s during the 6.5 minutes, constant-load, s e v e r e cycling e x e r c i s e s e s s i o n s .  37.0 -I  1  1  0  1  2  1  1  3 4 Time (minutes)  .  1  1  5  6  7  125 Figure 22: Correlation b e t w e e n c h a n g e s in blood v o l u m e v e r s u s c h a n g e s in pulmonary transit time at minute 3 of constant-load, s e v e r e e x e r c i s e in both infusion a n d n o n infusion conditions.  16  C  o co  r = -0.31; P = 0.42; n = 9  14  H  3  c co c CD 110 CO CO  £2  !•  CD i e E o co 4 >  TJ O  o  Si  &  c .E CD cn o c CO TJ SZ O 5-6 -0.1  0.0 0.1 0.2 0.3 0.4 0.5 0.6 Change in pulmonary transit time between infusion and non-infusion conditions (sec)  0.7  126 Figure 23: Correlation between c a r d i a c index a n d blood v o l u m e v e r s u s pulmonary transit time at minute 3 of constant-load, s e v e r e e x e r c i s e in both infusion a n d n o n infusion conditions.  = 0.47; r = 0.22; P = 0.03 cardiac index = 23.1 - ( 2.97 * PTT) S E E = 1.7 r  19 ^18 i C E17 CM'  J 16  x o "§15 u 114 •p  ro O  13 12  120  r = 0.39; r =0.15; P = 0.08 B V = 116.5 - ( 1 3 . 2 * PTT) S E E = 9.4  110 -* 100 cu E 90 J3 O  ts  o o  CO  80  AA  70 60 1 2.0  r-  2.2  ,  ,  ,  ,  2.4 2.6 2.8 3.0 Pulmonary transit time (sec)  r-  3.2  127 Figure 24: Correlation between P a 0 , A a D 0 , a n d % S a 0 time in both infusion a n d non-infusion conditions. 2  86 -i 2.0  2  • . . . . 2.2 2.4 2.6 2.8 3.0 3.2 Pulmonary transit time (seconds)  2  v e r s u s pulmonary transit  128 Figure 25: Correlation between % S a 0 and A a D 0 v e r s u s P a 0 , a n d % S a 0 v e r s u s A a D 0 during minute 3 of constant-load, s e v e r e e x e r c i s e in both non-infusion and infusion conditions. 2  2  2  10 -J 65  10  . 70  , 75  15  . . , 80 85 90 Pa02 (mm Hg)  20 25 AaDC*2 (mm Hg)  , 95  , 100  30  , 105  35  2  2  129 F i g u r e 2 6 : Correlation between P a 0 , P a C 0 v e r s u s V / V 0 during minute 3 of constant-load, s e v e r e e x e r c i s e in both non-infusion and infusion conditions. 2  VE/V0  2  2  E  2  130 F i g u r e 2 7 : Correlation b e t w e e n alveolar P 0 ( P A 0 ) v e r s u s arterial P 0 ( P a 0 ) , a n d b e t w e e n pulmonary blood v o l u m e v e r s u s o x y g e n uptake a n d b e t w e e n during minute 3 of constant-load, s e v e r e e x e r c i s e in both non-infusion a n d infusion conditions. 2  2  2  2  131 F i g u r e 2 8 : Correlation b e t w e e n arterial P 0 ( P a 0 ) a n d arterial P C 0 ( P a C 0 ) during minute 3 of constant-load, s e v e r e e x e r c i s e in both non-infusion a n d infusion conditions. 2  2  2  2  r = -0.57; r = 0.33; P < 0.01 P a Q = 136.48 -(1.2*PaC0 ) S E E = 6.86 2  2  32  34  2  36  38  40  42  44  46  P a C 0 ( m m Hg) 2  48  50  52  54  132 Figure 29: (A) Correlation b e t w e e n the c h a n g e in arterial P C 0 ( A P a C 0 ) a n d the c h a n g e in arterial P 0 ( A P a 0 ) b e t w e e n minute 0 a n d minute 1 of constant-load, s e v e r e e x e r c i s e in both non-infusion a n d infusion conditions; (B) Correlation between red cell pulmonary transit time a n d pre-exercising circulating pool of white blood cells ( W B C ) in both infusion a n d non-infusion conditions. 2  2  2  4.0  r = -0.56; r = 0.31; P = 0.009 PTT = 3.19 - (0.12*WBC) SEE = 0.25 2  o  CD 3.5 A  m CD  V AC  E  z  •  3.0 ^  •  CO  •  •  c  2  O •  £2.5  re c o  I  A  •  2.0  o 0  a.  75 u  TJ CD  T  1.5  NC LZ PC ME SS PG MV JB SP AF BW  1.0 2.0  2.5  3.0  3.5 4.0 4.5  5.0  5.5  6.0  6.5  7.0  7.5  8.0  8.5  Pre-exercising WBC count in circulating pool (g • L )  9.0  2  133 Figure 30: R e l a t i o n s h i p b e t w e e n pulmonary transit time ( P T T ) a n d c a r d i a c index from the literature ( m e a n s b a s e d o n 152 different subjects from 13 different studies). T h e relationship o b e y s a single, 3 parameter exponential d e c a y function. S h a p e of curve r e s e m b l e s that of D e m p s e y a n d F r e g o s i (46) a n d W a r r e n et al. (213). N o plateau in V c is o b s e r v e d a s P T T fails to d e c r e a s e in the f a c e of increasing Q index.  o •  r = 0.97, r : 0.94, S E E = 0.51 2  PTT  2.57+46.72e  0.725X  Present study--Non-infusion condition [exercise] Present study—Infusion condition [exercise] Hopkins et al. (1996)-exercise  A •  Hopkins et al. (1996)-rest  •  Iskandrian e t a l . (1982)-rest  o  Rerych et al. (1980)--after training [exercise]  Iskandrian e t a l . (1982)~exercise Rerych et al. (1980)-before training [exercise] Reyrch et al. (1980)-before training [rest] Rerych et al. (1980)-after training [rest] Capderou et al. (1997)-rest  10.0 9.5 9.0 H 8.5 8.0 CO TJ 7.5 C o 7.0 u CD 6.5 -\ •HI CD 6.0 E 5.5 CO 5.0 E 2 4.5 4.0 CO 3.5 c o 3.0 E 3 2.5 Q_ 2.0 -\ 1.5 1.0 0.5 -\ 0.0  Hannon e t a l . (1981)-rest Markewitz and Hemmer (1991)—rest Markewitz and Hemmer (1991)—exercise Behr et al. (1981)-rest Behr et al. (1981)-exercise Guintini et al. (1963)-rest M a c N e e et al. (1989)-rest Kuikka and Lansimies (1999)-rest Kuikka et al. (1979)-rest Kuikka et al. (1979)~moderate exercise Kuikka et al. (1979)~heavy exercise Kuikka and Lansimies (1999)-exercise Rerych et al. (1978)-rest Rerych et al. (1978)-exercise  QO  3  6  7 8 9 10 11 12 13 Cardiac index ( L m • min" ) 2  1  14  15  16  17  18  134 F i g u r e 3 1 : P o o l e d data o n the relationship b e t w e e n pulmonary transit time (PTT), pulmonary blood v o l u m e ( P B V ) , a n d c a r d i a c output ( Q ) from including the present study.  5 different  studies,  D a t a from 7 2 different healthy subjects from 5 different studies at various Q ' s . M e a n a g e = 31 y e a r s old. P o o l e d data from studies (30, 8 8 , 1 1 2 , 164) a n d the current study. The  relationship  o b e y s a single, 3 parameter  exponential  d e c a y function.  The  relationship b e t w e e n P T T v s Q closely r e s e m b l e s that of capillary transit time ( P C T T ) vs Q from D e m p s e y a n d F r e g o s i (46) a n d W a r r e n et a l . (213). reaches ~20 - 25 L  H o w e v e r , after Q  min" , no further d e c r e a s e in P T T is o b s e r v e d , w h e r e a s D e m p s e y ' s 1  theoretical curve s h o w s drastic d e c r e a s e s P C T T at Q ' s greater than ~ 2 5 L • min" . T h e 1  present curve s h o w s P B V i n c r e a s e s to c o m p e n s a t e for the increasing Q s u c h that P T T r e m a i n s u n c h a n g e d (predicted P T T at 2 5 L • min" = 2.45 s e c ; P T T at 4 0 L • min" = 2 . 2 5 1  1  s). Notice h o w P B V fails to r e a c h morphological limit. T h e s y s t e m a t i c i n c r e a s e in P B V with increasing Q d i s p l a y s a n adaptive r e s p o n s e of the cardiopulmonary s y s t e m to prevent capillary transit times from falling below the ~ 0 . 5 2 s e c o n d s theoretical limit for partial p r e s s u r e equilibrium at t h e s e high Q ' s .  Cardiac output (L min" ) 1  A P P E N D I X H. R E F E R E N C E S 1.  Aaron, E. A., K. G. Henke, D. F. Pegalow, and J . A. Dempsey. Effects of m e c h a n i c a l unloading of the respiratory s y s t e m o n e x e r c i s e a n d respiratory m u s c l e e n d u r a n c e [abstract]. Medicine  and Science  in Spods  and  Exercise.  17(suppl): S 2 9 0 , 1 9 8 5 . 2.  Aaron, E. A., K. C. Seow, B. D. Johnson, and J . A. Dempsey. O x y g e n cost of e x e r c i s e h y p e r p n e a : implications for performance. Journal  of Applied  Physiology.  72: 1 8 1 8 - 2 5 , 1992. 3.  Aguilaniu, B., P. Flore, H. Perrault, J . E. Page, E. Payan, and J . R. Lacour. 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