THE EFFECTS OF ME* •xbKA.i iL OXYGENATION

DESIGN ON OX FGLNATION PERFORMANCE & BLOOD DAMAGE•

A THESIS SUBMITTED e CR THE DEGREE OF

MASTER OF PHILOSOPHY,

by

R .S . B r id g e s

U n i v e r s i t y o f S u r r e y .

J a n u a r y 1977•

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summary.

The s u p e r i o r i t y o f th e membrane o x y g e n a to r o v e r i t s

g a s c o n t a c t i n g c o u n t e r p a r t i n m in im is in g b lo o d t ra u m a i s

n o t c o n s i d e r e d p ro v e d . To t h i s end a model membrane

o x y g e n a to r and p e r f u s i o n c i r c u i t w ere d e s ig n e d t o t e s t ways

o f im p ro v in g g a s t r a n s f e r and co m paring th e h e m o ly s i s and

p r o t e i n d e n a t u r a t i o n c a u se d by th e two t y p e s o f a r t i f i c i a l l u n g .

E x p e r im e n ts u sed human t r a n s f u s i o n b lo o d a t p h y s i o l o g i c a l

t e m p e r a t u r e and g a s t e n s i o n s .

From d a t a g a in e d and from th e 1 ,0 0 0 p a p e r s r e v ie w e d ,

membrane o x y g e n a to r d e s ig n c r i t e r i a were p ro d u c e d .

A t h e o r e t i c a l a n a l y s i s o f th e g a s t r a n s f e r a c r o s s th e

membrane s u g g e s te d t h a t th e a c t i v e v i b r a t i o n o f t h e o x y g e n a to r

e f f e c t i v e l y e l i m i n i a t e d th e r e s i s t a n c e o f th e p la sm a t o g a s

f lo w .

ACKNOWLEDGMENT.

I would l i k e to e x p r e s s rny g r a t i t u d e t o Dr.

J . Edw ards, my S u p e r v i s o r , and R ead e r i n B io m ech an ic s

a t th e U n i v e r s i t y o f S u r r e y , f o r i n i t i a l l y s t i m u l a t i n g ,

c o n t i n u a l l y g u id in g and e n c o u r a g in g my e n d e a v o u rs i n

b i o e n g i n e e r i n g .

- -if -

TO MY WIFE AND PARENTS

W ith o u t whose h e lp and c o - o p e r a t i o n

t h i s work w ould n o t have b een p o s s i b l e .

- - 5 -

PREFACE.

"Of a r t i f i c i a l sy s te m s th e m ost a t t r a c t i v e i s t h a t w here

i n i m i t a t i o n o f th e n a t u r a l pu lm onary anatom y, a membrane

s e p a r a t e s b lo o d from g a s . "

" H e a r t l u n g m a ch in es have b een d e s c r i b e d a s a s t r i n g o f

b lo o d sm ash in g d e v ic e s i n s e r i e s w i th a p r o t e i n d e n a t u r a t i o n

a t t a c h m e n t . "Long,more 19 6 8 .

The above q u o te s sum m arise th e p ro m ise and p ro b le m s o f t h e

modern a r t i f i c i a l l u n g . The a b i l i t y to p ro d u c e t h i n s i l i c o n e

r u b b e r s h e e t h a s made th e membrane o x y g e n a to r a v i a b l e m ach ine

and h e r a l d s a s o l u t i o n to a w hole new r a n g e o f c l i n i c a l p ro b le m s .

However, th e b e n e f i t s o f membrane d e v i c e s a r e f e l t r a t h e r t h a n

p ro v e d , t h e i r d e s i g n s v a r y w id e ly and t h e i r e f f i c i e n c e s a r e

lo w .

- 6 -

CONTENTS.P a g e .

C h a p te r 1 . I n t r o d u c t i o n .

1 .1 Summary 21 . 2 The f u n c t i o n o f an o x y g e n a t io n . 11

1 . 3 Types o f o x y g e n a to r . 12♦1 B u b b le r s 12

.2 F i l m e r s . 15

.3 L i q u i d - L i q u i d o x y g e n a to r s . 15

.4 Membrane o x y g e n a to r .: 1*4 Unique a p p l i c a t i o n s o f membrane o x y g e n a to r s . 15

,1 R ep lacem en t o f e x i s t i n g o x y g e n a to r s i n

r o u t i n e s u r g e r y . 12.2 P r o v i s i o n o f l o n g te rm s u p p o r t 14

•3 P e d i a t r i c s u r g e r y . . 1 4.4 S to r a g e and t r a n s p l a n t o f o r g a n s . 15

.3 Summary. 151 .3 H i s t o r i c a l r e v ie w o f p r o g r e s s i n membrane o x y g e n a t io n 15

1 .6 The a d v e n t o f s i l i c o n e . 17

1 . 7 C u r r e n t w ork . 18C h a p te r 2 . O x y g en a to r D esig n C o n s i d e r a t i o n s & Program o f Work.

2 .1 R e q u i re m e n ts o f a membrane o x y g e n a to r . 20.1 P h y s i o l o g i c a l r e q u i r e m e n t s . 2.0

.2 Hemodynamic r e q u i r e m e n t s . 21

.3 G e n e ra l r e q u i r e m e n t s . 21

.4 Summary 222 . 2 D esign c o n s i d e r a t i o n s . 22

.1 The membrane. 22

.2 C a p i l l a r y o r s h e e t . 25

.3 Hemodynamics 25

.4 B i o c o m p a t i b i l i t y . 27

.5 P h y s i o l o g i c a l c o n s i d e r a t i o n s . 28

.6 Summary. 2$ ■2 .3 In v i t r o v e r s u s i n v iv o t e s t i n g . 29

2 .4 O b j e c t i v e s o f th e w ork..1 B lood damage i n v e s t i g a t i o n .

.2 O x y g en a tio n e f f i c i e n c y . ^1

2 . 3 Programme o f w ork . ^1

- 7 -P ag e .

C h a p te r 3 . S e l e c t i o n o f eq u ip m en t and e x p e r i m e n t s . 333 . 1 . S e l e c t i o n o f t e s t s . 33

.1 M easurem ent o f o x y g e n a t io n p e r fo rm a n c e . 33

.2 B lood damage. 34

.1 H em olysis - D i s c u s s i o n . 34

.2 H em olysis a s s a y m e th o d s . 36•3 S e l e c t i o n o f m ethod . 36.4 O r t h o t o l i d e n e m ethod . 36

•5 C yanm ethaem oglobin m ethod . 37.6 C r ip p s M ethod. 37.7 Atomic a d s o r p t i o n m ethod . 38

•9 P r o t e i n d e n a t u r a t i o n - d i s c u s s i o n . 3 9

.1 0 M ethods o f p r o t e i n d e n a t u r a t i o n a s s a y 40

.11 S h o r t r a n g e p r o p e r t i e s . 41

.1 2 S e l e c t i o n o f m ethod . 42

.13 ' S e l e c t i o n o f e l e c t r o p h o r e t i c m ethod . 42

.1 4 A c e ta te e l e c t r o p h o r e s i s 43

.1 5 M ethods o f a n a l y s i s o f e l e c t r o - p h e r o g r a m s 43

.16 S e l e c t i o n o f m ethod . 44

.1 7 A g g l u t i n a t i o n . 46

.1 8 Em boli 46

.19 P l a t e l e t and w h i te c e l l l o s s . 46

.2 0 S lu d g in g . 46

3 . 2 C ho ice o f i n s t r u m e n t a t i o n . 47

3 . 2 . 1 . O x y g en a tio n p e r fo rm a n c e . 47

.2 B lood c o n d i t i o n m easu rem en t. 47

.3 C o n s t r u c t i o n o f a w o rk in g model o x y g e n a to r . 47.1 O x y g e n a to r . 48.2 V i b r a t o r . 55

.3 D eo x y g en a to r 55

.4 Pump. 58

.5 H eat ex ch an g e r . 58

.6 B ubble t r a p . 58

.4 S e l e c t i o n o f e x p e r im e n t s . 58

C h a p te r 4 . E x p e r im e n ta l Work and R e s u l t s . 634*1 E x p e r im e n ts t o a s s e s s i n c r e a s e s i n p la sm a h e m o g lo b in 63

.1 I n t r o d u c t i o n 63

.2 E x p e r im e n ta l d e s c r i p t i o n . ^

4 - 2

4 .3

C h a p te r 5

3 .1

3 .2C h a p te r 6

- 8 -P age.

. 1 . Pump t e s t s . £3

.2 Component t e s t s .

.3 T e s t s t o compare membrane and f i l m o x y g e n a to r s . gg•4 G raphs 1 - 8 .•3 A n a ly s i s o f g r a p h s . 68

E x p e r im e n ts to a s s e s s a l t e r a t i o n s t o p la sm a p r o t e i n s ^ and to r e l a t e t h e s e to I ie m o ly s is .

.1 I n t r o d u c t i o n . ^

.2 E x p e r im e n ta l d e s c r i p t i o n .

•3 G raphs 9 - 1 1 . 79.4 A n a ly s i s o f G rap h s . 78E x p e r im e n ts t o a s s e s s m ethods o f im p r o v in g o x y g e n a t io n g£

.1 I n t r o d u c t i o n . ■ g2

.2 E x p e r im e n ta l d e s c r i p t i o n . 82

.3 G raphs 12 - 1 8 . 33

.4 A n a ly s i s o f G rap h s . 90

T h e o r e t i c a l A n a ly s i s and r e l a t i o n t o E x p e r im e n ta l Work 92

T h e o r e t i c a l A n a ly s i s o f Gas T r a n s f e r . 92

.1 Gas t r a n s p o r t th r o u g h membrane. 92

.2 Gas t r a n s p o r t by b lo o d . 93.1 Oxygen. 93

.1 D is s o lv e d i n p la sm a . 93

.2 Combined .w ith h e m o g lo b in . 93.2 C arbon d i o x i d e . 93

.1 D is s o lv e d i n p la sm a and r e d c e l l 95

.2 As b i c a r b o n a t e . 95

.3 Combined w i th p r o t e i n s . 95.3 Gas t r a n s p o r t th ro u g h p la sm a . 97.Zf Gas t r a n s f e r i n t o th e r e d c e l l . 93

G raphs 19 - 20 . 100C om parison o f a n a l y s i s and p r a c t i c a l w ork . 99

An A p p r a i s a l and S u g g e s t io n s f o r F u r t h e r Work. 103

A p p r a i s a l o f th e w ork. 103.1 The b lo o d 103

.2 H e m o ly s is . 103

.3 P r o t e i n d e n a t u r a t i o n . 104

.4 V i b r a t i o n . 103

.3 O th e r c o n s i d e r a t i o n s . 106

- 9 -

. P ag e .

6 . 2 S u g g e s t io n s f o r f u r t h e r w ork . 107

R e f e r e n c e s . 3.Q9

C ro s s R e f e r e n c e I n d e x . 1^2

A l p h a b e t i c a l S u b je c t I n d e x .

- 10 -

CHAPTER 1 .

AN INTRODUCTION.

1 .1 I n t r o d u c t i o n .

I n 1952 , Dr. G ibbon o p e r a t e d on an e i g h t e e n - y e a r - o l d g i r l who had d e v e lo p e d a h o le i n t h e h e a r t w a l l w hich s e p a r a t e s th e

a t r i a . F o r 26 m in u te s s u rg e o n s worked to s e a l t h e h o l d , . w h i l e ' a m achine pumped and o x y g e n a te d th e g i r l ' s b lo o d . The o p e r a t i o n

was a c o m p le te s u c c e s s .

The h e a r t - l u n g m ach in e , c o m p r i s in g a pump and an o x y g e n a to r ,

i s now a h i g h l y d e p e n d a b le , e v e ry d a y p i e c e o f s u r g i c a l e q u ip m e n t . However, th e d i s c o v e r y o f a m ethod o f p ro d u c in g t h i n membrane s h e e t

e n a b l i n g m ach in es t o be c o n s t r u c t e d w hich mimic t h e l u n g ’ s m ethod

o f o x y g e n a t in g b lo o d h e r a l d e d a w hole new r a n g e o f p o s s i b i l i t i e s

f o r th e h e a r t - l u n g m a ch in e .T h is t h e s i s e x p l o r e s some o f th e p ro b le m s i n v o l v e d i n

p e r f e c t i n g su ch a m o d i f ie d o x y g e n a to r and r e v ie w s a w ide r a n g e o f

r e c e n t W ork i n t h i s f i e l d .

- 11 -

1 . 2 The F u n c t io n o f an O x y g e n a to r .

I n an o x y g e n a to r , v e n o u s b lo o d g i v e s up i t s c a rb o n d i o x i d e i n exch an g e f o r a f r e s h s u p p ly o f oxygen . A b e t t e r name f o r i t m ig h t be an ’a r t i f i c i a l l u n g 1 o r a ’g a s e x c h a n g e r 1.

To u n d e r s t a n d w hat i s r e q u i r e d o f su ch a d e v i c e , i t i s b e s t t o l o o k a t w hat i t h a s to r e p l a c e - th e l u n g s . The t o t a l u s e f u l a r e a o f e ach p a i r o f l u n g s i s 50 - 70 a b o u t e q u a l to th e g ro u n d f l o o r a r e a o f an a v e ra g e h o u s e . The 75° m i l l i o n a l v e o l i o f t h e l u n g s a r e e n c lo s e d i n a f i n e mesh o f c a p i l l a r i e s o n ly 5 - 1 0 jol i n d i a m e t e r , b u t whose l e n g t h t o t a l s s e v e r a l h u n d re d k i l o m e t r e s . At any one t im e , t h e s e c a p i l l a r i e s c o n t a i n 70 - 80 ml o f b lo o d and s i n c e th e c a p i l l a r y w a l l s and t h e i r e n d o t h e l i a l l i n i n g a r e eac h o n ly 0 . 1 ,y\ t h i c k , d i f f u s i o n t a k e s p l a c e th ro u g h a b a r r i e r o n ly 2 u t h i c k . .

t T R U C T u t t E Q f T H E A l_V £O L A R W A U L .

I n s p i t e o f t h e i r n a r ro w n e s s and l e n g t h , th e c a p i l l a r i e s o n ly r e q u i r e a b o u t 100 mm Hg p r e s s u r e to m a i n t a i n a 3 1 /m in f lo w r a t e .Even d u r in g e x e r t i o n when b lo o d f lo w q u a d r u p le s t o 20 1 /m in . th e p r e s s u r e o n ly r i s e s t o 20 mm Hg.

The a v e r a g e t im e s p e n t by a r e d c e l l i n th e l u n g i s 0 .7 3 s a t r e s t and 0 .3 3 s d u r in g e x e r t i o n . S in c e i t o n ly t a k e s a r e d c e l l one m i l l i s e c o n d to e s t a b l i s h e q u i l i b r i u m w i th i t s s u r r o u n d i n g s t h e r e i s more th a n s u f f i c i e n t t im e f o r e f f i c i e n t g a s e x c h a n g e .

At r e s t , t h e body m ust e l i m i n a t e 0 .2 3 1 /m in . o f c a r b o n d i o x i d e

and t a k e i n 0 .2 3 1 /m in . o f oxygen , w h i le d u r in g e x e r t i o n t h e s e -

f i g u r e s may r i s e to 3 .3 1 /m in . - s t i l l w e l l s h o r t o f maximum c a p a c i t y .

12 -

To sum m arise , th e l u n g h a s a v a s t a r e a o f u l t r a t h i n membrane i n i n t i m a t e c o n t a c t w i th a t i n y amount o f b lo o d w hich f lo w s q u i c k l y i n and o u t o f t h e c a p i l l a r i e s u n d e r m in im al p r e s s u r e . Were we r e q u i r e d to mimic th e c a p a b i l i t y , t h e t a s k would be h o p e l e s s .

F o r t u n a t e l y , th o u g h , t h r e e f a c t o r s a r e on o u r s i d e : -

1 . I n b y p a s s s u r g e r y , we need o n ly s u p p o r t t h e body a t r e s t .T h is r e q u i r e s a b lo o d f lo w r a t e o f 3 1 /m in . and a g a s

t r a n s f e r r a t e o f 0 .2 3 1 /m in .

\ 2 . We can r e p l a c e a i r w hich c o n t a i n s 20% oxygen w i th 100% • oxygen to g r e a t l y i n c r e a s e th e p a r t i a l p r e s s u r e g r a d i e n t .

3* The l u n g h a s so much s p a r e c a p a c i t y t o m eet t h e 1 a t r e s t 1

r e q u i r e m e n t s t h a t o n ly 1 . 3 m2 o f i t s t o t a l a r e a w ould be

. n e c e s s a r y .1 . 3 Types o f O x y g e n a to r .

In a r t i f i c i a l l u n g s , a l a r g e s u r f a c e f o r g a s e x ch an g e i s o b t a i n e d e i t h e r by d i s p e r s i o n o f th e g a s i n b lo o d a s a b u b b le o r foam o x y g e n a to r s o r by d i s p e r s i o n o f b lo o d i n th e g a s , a s i n s p r a y and f i l m o x y g e n a to r s . The l a t t e r r e q u i r e s a b lo o d f i l m to be m a in ta in e d c o n t i n u o u s l y e i t h e r by r u n n in g th e f i l m down a s t a t i o n a r y s c r e e n o r s u r f a c e , o r by a m oving d i s c o r drum. The t h i r d m a jo r c a t e g o r y c o v e r s membrane o x y g e n a to r s i n w hich th e b lo o d and g a s p h a s e s a r e s e p a r a t e d by a g a s - p e r m e a b le membrane t o e l i m i n a t e t ra u m a c a u s e d by a raw b lo o d - g a s i n t e r f a c e .

1 . 3 . 1 . B ubble O x y g e n a to r s .I n th e b u b b le o x y g e n a to r , g a s i s d i s p e r s e d upward th ro u g h th e

v e n o u s b lo o d f i l m from h o l e s i n th e g a s m a n i f o ld , and g a s ex ch an g e t a k e s p l a c e d u r in g t h i s a s c e n t . The r e m a in in g foam i s e l i m i n a t e d by 1 a n t i f o a m ' s u r f a c e s , s e t t l i n g , t r a p p i n g , f i l t r a t i o n o r c e n t r i f u g i n g .

B ubble s i z e i s a c r u c i a l f a c t o r i n a t h r e e way com prom ise b e tw ee n m in im is in g h e m o ly s is ( r e d c e l l damage), g i v i n g s u f f i c i e n t oxygen to th e

b lo o d and rem o v in g th e c o r r e c t p r o p o r t i o n o f c a rb o n d i o x i d e from i t .B ubble o x y g e n a to r s a r e c la im e d to c a u se s e v e r e p r o t e i n d e n a t u r a t i o n

(Longmore 1 , Lee 1 ) , b u t K i r s h (2 ) s t a t e s t h a t t h i s form o f damage i s n o t s i g n i f i c a n t l y more i n ’b u b b l e r s ' t h a n i n co m p arab le membrane

o x y g e n a to r s . In d e e d th e Eygg. bag and o t h e r t y p e s o f b u b b le s a r e p o s s i b l y th e m ost w id e ly u sed fo rm s o f o x y g e n a t io n i n t o - d a y ' s

o p e r a t i n g t h e a t r e s . P r o c t o r (1973) s u p p o r t s th e v iew t h a t t h e b u b b l e r

- 13 -

i s more th a n a d e q u a te f o r p r e s e n t r e q u i r e m e n t s and t h i s t y p e c e r t a i n l y h a s t h e a d v a n ta g e o f s i m p l i c i t y .

1 . 3 . 2 . F i lm O x y g e n a to r s .I n f i l m o x y g e n a to r s a l a r g e b lo o d s u r f a c e i s p r e s e n t e d t o an

oxygen a tm o s p h e re . To be e f f i c i e n t some m ix in g o f th e b lo o d m ust

O ccu r. T h is may be a c h ie v e d by a l l o w in g th e b lo o d to f lo w o v e r a s c r e e n by g r a v i t y o r by r o t a t i n g c y l i n d e r s o r d i s c s w h ich ' p i c k up* a f i l m o f b lo o d a s th e y r o t a t e . D is c s a r e th e m ost e f f i c i e n t c l a s s o f f i l m o x y g e n a to r . F i lm o x y g e n a to r s have a t h i c k f i l m , low e f f i c i e n c y and a l a r g e p r im in g vo lum e. The r i s k s o f a i r em bolism , b a c t e r i a l i n f e c t i o n and b lo o d trau m a a r e c o n s i d e r a b l e .1 . 3 . 5 . L iq u id L iq u id O x y g e n a to r s . (W a llace (2) 1973)

Gas b u b b le s a r e e n c a p s u l a t e d w i t h i n a t h i n f i l m (< lyu ) o f i n e r t f l u o r o c h e m ic a l p r e v e n t i n g a b lo o d g a s i n t e r f a c e . The g a s b u b b le s a r e p a s s e d c o u n t e r c u r r e n t to th e b lo o d . As th e b u b b le s em erge from

th e g a s p h a s e , th e y c o l l a p s e , r e l e a s i n g CC>2 . The F lu o r o c h e m ic a l i s r e u s a b l e and v e r y h ig h p e r fo rm a n c e f i g u r e s a r e c la im e d w i th no

m e a s u re a b le a l t e r a t i o n s t o p r o t e i n s , form ed e le m e n ts o r c l o t t i n g

f a c t o r s a t t r i b u t a b l e to th e u se o f th e f lu o r o c h e m ic a l*

1 . 3 . 4 . Membrane O x y g e n a to r s .I n membrane o x y g e n a to r s , t h e b lo o d and g a s p h a s e s a r e s e p a r a t e d

by a g a s - p e rm e a b le membrane i n th e form o f t h i n s h e e t o r t u b i n g .I f th e membrane i s t u b u l a r , th e b lo o d p h a se may be e i t h e r i n t e r n a l

o r e x t e r n a l . The a d v a n ta g e s c la im e d f o r membrane o x y g e n a to r s a r e

low p r im in g volum e and m in im ised h e m o ly s i s and p r o t e i n d e n a t u r a t i o n . K a y s e r , (1974) ^ m a i n t a i n s t h a t t h i s s u p e r i o r i t y i s n o t y e t c l i n i c a l l y

p ro v e d .1 . 4 . Unique A p p l i c a t i o n s o f Membrane O x y g e n a to r s .

The b e n e f i t s o f membrane o x y g e n a t io n may n o t be p ro v e d , b u t even i f t h e y w ere , what p ro m ise i s t h e r e f o r th e f u t u r e ? The a p p l i c a t i o n s f o r e s e e n f o r membrane l u n g s can be d iv id e d i n t o f o u r c a t e g o r i e s : -1 . 4 . 1 . The R ep lacem en t o f E x i s t i n g O x y g e n a to rs i n R o u t in e S u r g e r y .

The a n t i c i p a t e d r e d u c t i o n o f b lo o d damage i n p ro lo n g e d h e a r t l u n g

b y p a s s c o u ld m in im ise s l u d g in g , a s s o c i a t e d e m b o l i , p o s t - o p e r a t i v e

t ra u m a and p o s s i b l e d e a t h . .20 y e a r s o f e x p e r i e n c e i n th e u s e o f h e a r t l u n g m ach in es have p ro v e d g a s c o n t a c t i n g o x y g e n a to r s a d e q u a te

f o r m ost c a r d i a c o p e r a t i o n s . However, i f su ch o p e r a t i o n s r e q u i r e

- 1 4 -

more t h a n , s a y , 2 h o u r s , u n f o r s e e a b l e c o m p l i c a t i o n s may a r i s e (G erbode 1 9 6 7 ) .

To p e r s u a d e s u rg e o n s t o r e p l a c e t h e i r e x i s t i n g o x y g e n a to r s , t h e membrane o x y g e n a to r m ust be e c o n o m ic a l , r e l i a b l e , e a s y t o u s e and

c a u s e fe w e r c o m p l i c a t i o n s and h en ce im p ro v e p a t i e n t s u r v i v a l .A l th o u g h th e c o s t o f u s i n g membrane o x y g e n a to r s h a s f a l l e n i n r e c e n t y e a r s , t h e y w i l l , p r o b a b ly n e v e r be c o m p e t i t i v e a t t h i s l e v e l . I t

w i l l be t h e lo w e re d c o m p l i c a t i o n r a t e w hich w i l l l e a d t o t h e e v e n t u a l a d o p t io n o f membrane o x y g e n a t io n , I f a n y th in g .1 . 4 . 2 .... l.The P r o v i s i o n o f Long Term S u p p o r t .

W ith m in im al b lo o d t ra u m a b e in g c a u s e d th e p a t i e n t may be a b l e to d e a l w i th w hat l i t t l e damage i s c a u s e d and th e t im e c o n s t r a i n t on

b y p a s s may be rem oved . The p r o v i s i o n o f e x t r a c o r p o r e a l s u p p o r t l a s t i n g d ay s o r p o s s i b l y weeks i n c a s e s o f a c u t e b u t p o t e n t i a l l y r e v e r s i b l e r e s p i r a t o r y o r c a r d i a c f a i l u r e m ig h t a l lo w t im e t o r e c o v e r s u f f i c i e n t l y t o p e r m i t d e f i n i t i v e t r e a t m e n t ( D r in k e r 1 9 7 2 ) .R e s p i r a t o r y f a i l u r e i s r o u t i n e l y t r e a t e d w i th a r t i f i c i a l v e n t i l a t o r s . T hese have t h e i r l i m i t a t i o n s , e s p e c i a l l y when th e c a u s e o f th e d i s t r e s s , i s a t t h e a l v e o l a r membrane l e v e l a s i n h y a l i n e membrane

d i s e a s e (W ild ev u u r 1971 , W hite 1 9 7 0 ) .' J - ' ' ' .

D r in k e r (1972) s u g g e s t s two exam p les w here e x te n d e d b y p a s s w ould n o t be e x p e c te d i n i t s e l f to p ro d u c e s i g n i f i c a n t o r p e rm a n en t im p ro v em en t, b u t m ig h t a l lo w th e r e c o v e r y t im e f o r t r e a t m e n t t o be a p p l i e d . The f i r s t i s v e n o - a r t e r i a l b y p a s s i n c a s e s o f c a r d i o g e n i c sh o ck p r i o r t o and d u r in g m y o c a r d ia l r e v a s c u l a r i z a t i o n , and th e se c o n d , e x t r a c o r p o r e a l s u p p o r t o f p a t i e n t s ■■with c y s t i c f i b r o s i s who, d u r i n g a c u t e c r i s e s , c o u ld b e h e lp e d by pu lm onary l a v a g e . I t h a s a l s o b e en

s u g g e s te d t h a t e x t r a c o r p o r e a l s u p p o r t f o l l o w i n g pneum onia (S penny 1 9 7 3 )

a s p i r a t i o n p n e u m o n i t i s and i n c a s e s o f w et lu n g syndrome m ig h t be

p o s s i b l e u s in g an im p ro v ed membrane o x y g e n a to r s y s te m .H i l l and Z apol a r e among th e l e a d e r s i n t h i s f i e l d .

1 . 4 . 3 . P e d i a t r i c S u r g e r y .Gas c o n t a c t i n g d e v ic e s have p ro v e d so u n s u c c e s s f u l t h a t o p e n - h e a r t

s u r g e r y on new -born i n f a n t s i s n o t u n d e r t a k e n . P a l l i a t i v e m e a su re s

w i th o u t b y p a s s a r e f a v o u r e d . Membrane o x y g e n a to r s , h ow ever , have

b e en u s e d i n b y p a s s a t t e m p t s (D orson 1970 , Z ingg 1967 , W hite 1 9 7 1 ) .

- 1 3 - .

Deep h y p o th e rm ia w i th c i r c u l a t o r y a r r e s t ( D i l l a r d 1963) h a s b e en

a p p l i e d s u c c e s s f u l l y t o f o r m e r ly u n t r e a t a b l e c o n d i t i o n s .Such o p e r a t i o n s a r e s t i l l t im e l i m i t e d and b e s t c a r r i e d o u t i n

o l d e r i n f a n t s . W rig h t (1 9 7 3 ) , w i th th e e x p e r i e n c e o f many s u c c e s s f u l

i n f a n t o p e r a t i o n s u s in g th e L ande-E dw ards membrane o x y g e n a to r , c l a i m s t h a t t h e e a s e o f th e o p e r a t i o n , c o m p ac tn e ss and low p r im in g volum e g i v e s s p e c i a l p ro m ise f o r p e d i a t r i c s u r g e r y .1 . 4 . 4 . The S to r a g e and T r a n s p l a n t o f O rg a n s .

I n s t o r a g e , p r o t e i n s m ust n o t be d e n a tu r e d s i n c e t h e r e a r e .n o mop up s y s te m s . A meth.brane o x y g e n a to r sy s te m o f o rg a n p e r f u s i o n h a s b e en s u g g e s te d (Brown 1971) and f o r te m p o ra ry s u p p o r t i n l u n g t r a n s p l a n t a t i o n o p e r a t i o n s (C orso 1 9 7 3 )•1 . 4 . 5 . Summary.

I t h a s b e e n s u g g e s te d t h a t i n p e d i a t r i c s u r g e r y and c a s e s w here

l o n g - t e r m b y p a s s f o r p a l l i a t i v e t r e a t m e n t c a n a l lo w t im e to r e c o v e r f o r an a p p r o p r i a t e o p e r a t i o n , t h e b e n e f i t s o f membrane o x y g e n a t io n

m ig h t b e u t i l i s e d . I t m ig h t a l s o r e p l a c e b u b b l e r s i n l o n g e r r o u t i n e c a r d i a c o p e r a t i o n s l i k e v a l v e r e p l a c e m e n t , s u p p o r t o rg a n s p r i o r to t r a n s p l a n t and even a l lo w th e lu n g to be c o l l a p s e d d u r in g c a r d i a c

o p e r a t i o n s t o a l lo w th e s u rg e o n more ro o m .. The g r e a t e s t im m e d ia te

p ro m ise would, a p p e a r to be i n th e t r e a t m e n t o f n e o n a t a l r e s p i r a t o r y

d i s t r e s s .1 . 5 . H i s t o r i c a l Review o f P r o g r e s s i n Membrane O x y g e n a t io n .

The h i s t o r y o f membrane o x y g e n a t io n g o es b a ck o n ly 3 ° y e a r s ;e a r l y p r o g r e s s was s low s i n c e th e membrane m a t e r i a l s f i r s t c h o se n w ere

• o f v e r y low p e r m e a b i l i t y .S in c e th e p r o d u c t i o n o f s i l i c o n e r u b b e r i n t h i n s h e e t s p r o g r e s s

h a s b e en d ra m a t ic and c o m m e rc ia l ly v i a b l e membrane o x y g e n a to r s a r e now a v a i l a b l e . Below i s a summary o f th e m a jo r la n d m a rk s i n t h e

d ev e lo p m en t o f th e membrane l u n g .I 9 4 4 . Gas exchange th ro u g h s y n t h e t i c membranes was o b s e r v e d

by K oIff (1 9 4 4 ) i n h i s k id n e y m a ch in e .

L a te '4 0 s S i l i c o n e s were i n t r o d u c e d .1955 The f i r s t t r u e membrane o x y g e n a to r , a c a p i l l a r y ty p e

u s i n g p o l y e t h y l e n e t u b i n g was d e s c r i b e d . I t was u se d

f o r a n im a l p e r f u s i o n s . (C lo w e s (2 ) 1 9 5 6 ) .Clowes c o n f i rm e d t h a t E t h y l C e l l u l o s e and P o l y e t h y l e n e

w ere t h e m ost s u i t a b l e membrane m a t e r i a l s a v a i l a b l e t o d a t e .

(C lowes (1 , 3 ) 1 9 3 6 ) .

- 16 -

1937 Kammermeyer r e p o r t e d th e h ig h p e r m e a b i l i t y o f D im ethy l S i l i c o n e E la s to m e r , f o r t y t im e s t h a t o f T e f lo n .

1938 Clowes r e p o r t e d t h a t T e f lo n had im proved p e r m e a b i l i t y o v e r P o ly e t h y l e n e , b u t th e c o s t and f r a g i l i t y o f T e f lo n p e r s u a d e d him to c o n t in u e u s i n g P o ly e t h y l e n e .

Thomas d ip p e d n y lo n mesh i n S i l i c o n e r u b b e r to p ro d u c e t h e f i r s t S i l i c o n e membrane.

1962 Marx a p p l i e d T hom as 's t e c h n i q u e to make an e x p e r im e n t a l membrane o x y g e n a to r .

1963 B o d e l l p ro d u c e d th e f i r s t S i l i c o n e c a p i l l a r y membrane

o x y g e n a to r .Mid 6 0 s S e v e r a l com pan ies were p ro d u c in g s i l i c o n e f i l m f o r o x y g e n a to r s

by d ip c o a t i n g , b a t c h c a s t i n g and l a t e r c a l e n d e r i n g . The . d e v e lo p m en t o f e x t r u s i o n p r o c e s s e s l e d t o th e m a n u fa c tu r e o f

t h i n w a l l e d t u b e s . T e f lo n , how ever, was s t i l l t h e w id e s t u sed m a t e r i a l .

1963 The f i r s t p r a c t i c a l membrane sy s te m was p ro d u c e d - t h e Bramsonlu n g .

I 967 I l l i c k a l showed t h a t membrane l i m i t e d t r a n s f e r c o u ld be

a c h ie v e d by a d i s c s p i n n i n g t e c h n i q u e . •

1969 B urns p ro d u c e d u l t r a t h i n s i l i c o n e r u b b e r f i l m .The L ande-E dw ards o x y g e n a to r was p ro d u c e d .D r in k e r u se d an o s c i l l a t i n g t o r o i d a l c a p i l l a r y membrane

o x y g e n a to r to im prove p e r fo rm a n c e .1971 The o s c i l l a t i n g t o r u s sy s tem was p ro d u c in g p e r fo rm a n c e s o f

230 ml/m^min, 8 -1 0 t im e s b e t t e r t h a n t h e a v e r a g e s t a t i c

o x y g e n a to r .

R e s e a rc h h a s mushroomed s i n c e B urns d i s c o v e r y i n 1969 , w o rk e r s a r e s t u d y i n g t h e t r a u m a t i c e f f e c t s o f o x y g e n a to r s , im p ro v in g p e r fo rm a n c e by b e t t e r d e s i g n s , o r c a r r y i n g o u t c l i n i c a l work to g a in

p r a c t i c a l kno w led g e .

- 17 -

1 . 6 The A dvent o f S i l i c o n e .

The a b i l i t y t o p ro d u c e s i l i c o n e r u b b e r t u b i n g and s h e e t gave d e s i g n e r s an o p p o r t u n i t y to p ro d u c e w o rk in g m ach in es c a p a b le o f s u p p o r t i n g th e a t - r e s t r e q u i r e m e n t s o f th e bo d y . D ram a tic p r o g r e s s was made and p e r fo rm a n c e o f t h e s e m a ch in es s t e a d i l y im p ro v ed a s i l l u s t r a t e d hy th e t a b l e b e lo w : -

A u th o r Year Membranem a t e r i a l

T h ic k ­n e s s?

BloocV ol.Ml/ra2

A g i t a t i o n A ream2

P e r f o r mance Oxygen cc/m^/m

-BloocPlowml/m2m in .

1 Clowes 1936 T e f lo n 12 130 M. 0 . 3 22 _ .

2 P e i r c e 1966 11 12 140 - 0 .1 3 30 300

3 C r e s c e n z i 1963 n 6 Gas p u l s e 0 .6 2 - 800

4 K y l s t r a 1961 11 3 . ISO C ascade 0 .3 7 69 700

3 Bramson 1966 S u p p o r te dS i l i c o n e

230 180 I n s e r t 3 .6 33 1000

6 Marx 1962 ti ii 123 34 0 n O.3 2 63 1800

7 B o d e l l 1963 S i l i c o n e 163 230 B lood p u lf e 0 .1 83 3008 . Day 1964 S u p p o r te d 30 230 H ocking 0 .6 3 100 1000

9 Kolobov/ 1963S i l i c o n e

n it 100 90 Gas p u l s e 1 .2 100 11001 ° Lande 1970 S i l i c o n e 100 200 no 1 , 3 36 1000

11 P e i r c e 1968 S i l i c o n e / P o ly c a rb o n ­a t e V

30 230 no 1 ,2 60 2000

12 M elro se 1971 S i l i c o n e 73 600 y e s 0 .3 6 130 4 0 0

x High p e r fo rm a n c e f i g u r e u s i n g membrane o n ly 0 .0 0 3 mm t h i c k ,

y Low ” 11 n " ‘0 .2 5 mm t h i c k ,z 11 " . n ■" " 0 .1 mm t h i c k and no a t t e m p t

to a g i t a t e th e b o u n d a ry Uyer.

P r o g r e s s became even more m arked when B urns (1969) d i s c o v e r e d a m ass

p r o d u c t io n p r o c e s s to p ro d u c e s i l i c o n e r u b b e r s h e e t w e l l u n d e r O.O j. mm

t h i c k . T he r e q u i r e m e n t s o f a membrane m a t e r i a l a r e t h a t i t s h o u ld have h ig h d i f f u s i o n c o e f f i c i e n t s f o r oxygen and c a r b o n d i o x i d e , n o t be t r a u m a t i c t o b lo o d , be a v a i l a b l e i n t h i n s h e e t s , be r o b u s t and h a n d l e a b l e be f r e e from p i n h o l e s and be ch eap f o r d i s p o s a b i l i t y . B u rns was a b l e

t o i n c r e a s e t h e t e n s i l e s t r e n g t h and t e a r r e s i s t a n c e up t o f o u r t im e s* N e v e r t h e l e s s , s i l i c o n e r u b b e r s h e e t d e v e lo p s a h ig h s t a t i c c h a r g e and i s t a c k y , m aking i t d i f f i c u l t t o h a n d l e .

C u r r e n t l y , i n membrane 23 - 30 p. t h i c k , th e p o re s i z e i s b e tw ee n

4 - 8 x l< £ 0m malting a p o re 3 0 ,0 0 0 - 1 2 3 ,0 0 0 t im e s a s long , a s i t i s w ide - l i k e a r a i l w a y t u n n e l 60 - 240 m i l e s l o n g I I t may s t i l l n o t

be t h e i d e a l m a t e r i a l , b u t a s shov/n by th e c h a r t be low , i t i s t h e

b e s t so f a r and a l l c u r r e n t work c e n t r e d , ro u n d i t .

too 1000f?e.lofiv«. P tv m e a b 'i t i f y Ho Oxyfg

10 00010

C u r r e n t Work1 100 ooo

The o n ly common f a c t o r i n c u r r e n t r e s e a r c h i s t h e u se o f s i l i c o n e r u b b e r a s t h e membrane m a t e r i a l . The work on d e s ig n and d e v e lo p m en t

o f o x y g e n a to r s can be c l a s s i f i e d u n d e r two m a jo r h e a d in g s , t u b u l a r membrane o x y g e n a to r s and f l a t bed ( s h e e t ) membrane o x y g e n a to r s .

Of t h e fo rm e r c a t e g o r y , t h e r e a r e a t l e a s t tw e n ty s t a t i c c a p i l l a r y

membrane l u n g s u n d e rg o in g t r i a l s , i n c l u d i n g th o s e o f B u ck ley ( 1 9 6 9 ) ,

D orson (1 9 6 9 ) , Z ingg (1 9 7 0 ) , B a r t l e t t (1 9 7 2 ) , C l e v e r t (1973) and Kolobow ( ( 6 ) 1 9 7 1 ) . N o ta b le among t h o s e p e r f e c t i n g t h e t e c h n i q u e o f o x y g e n a t in g b lo o d u s i n g a c o i l e d tu b e i s M e lro se ( ( 1 ) 1 9 7 2 ) . By

r a p i d o s c i l l a t i o n o f th e c o i l a b o u t i t s a x i s , he h a s p ro d u c e d a g r e a t l y

im p ro v ed p e r fo rm a n c e f i g u r e w i th m in im al i n c r e a s e i n b lo o d dam age.Of t h e s t a t i c , f l a t - b e d membrane o x y g e n a to r s i n u s e , t h e L a n d e -

Edwards (Lande r e f s ( 1 - 1 9 ) ) and th e G e n e ra l E l e c t r i c - P e i r c e ( P e i r c e

r e f s . ( 2 - 1 3 ) ) a r e i n e v e ry d a y u se i n r o u t i n e s u r g e r y . These and o t h e r s have b e en u sed i n p ro lo n g e d b y p a s s by H i l l r e f s ( 1 - 1 0 ) , C a r l s o n

( ( 5 ) 1 9 7 2 ) , Awad (1 ) (2 ) (4 ) and o t h e r s , u s u a l l y i n t h e t r e a t m e n t o f r e s p i r a t o r y d i s t r e s s o r i n s u f f i c i e n c y . L i t t l e a t t e m p t h a s b e e n made

- 19 -

t o im p ro v e t h i s ty p e o f o x y g e n a to r by v i b r a t i o n , th o u g h some in g e n i o u s

i d e a s have b e en s u g g e s t e d and u sed i n t h e i r d e s i g n . C l a f f (1967) i n t r o d u c e d p u l s e s t o b o th g a s and b lo o d p h a s e s g i v i n g a s i m i l a r e f f e c t t o L ongm ore’s p u m p -o x y g en a to r (Longmore ( 1 ) ) . P a lm er (1970) u sed a r o c k i n g o x y g e n a to r .

I n a d d i t i o n to r e s e a r c h on d e s ig n , and p o s s i b l y i n t h e l o n g r u n more i m p o r t a n t , work c o n t i n u e s t o im prove t h e b i o c o m p a t i b i l i t y o f

o x y g e n a to r m a t e r i a l s (Chang T, 1973 , G a l l e t t i (3 ) 1970 ,. Grode ( 1 , 2 ) 1969 e t a l . ) and to p ro d u c e more e f f i c i e n t membrane m a t e r i a l s (E isem an 1 9 7 2 ) . O th e r s a r e s t u d y i n g th e f a c t o r s c a u s in g h e m o ly s i s ( B la c k s h e a r

19 7 2 , B e r n s t e i n 1 9 7 1 } C a s te n a d a 1 9 6 9 , Chang H.(2)1972 e t a l . ) th r o m b o s i s (S a lzm an ( 1 - 3 ) , S to rm o rk en 1 9 7 1 ) , and p r o t e i n d e n a t u r a t i o n i n e x t r a c o r p o r e a l c i r c u i t r y . F i n a l l y d e t a i l e d s t u d i e s i n hem odynam ics

may a l t e r t h e d e s ig n c r i t e r i a o f f u t u r e membrane o x y g e n a t o r s .

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CHAPTER 2 .

2 .1 R e q u i re m e n ts o f a Membrane O x y g e n a to r . .A membrane o x y g e n a to r m ust be a b l e t o p e r fo rm i t s t a s k o f g a s

ex ch an g e w i th a minimum o f b lo o d t r a u m a . A more d e t a i l e d b reakdow no f th e p h y s i o l o g i c a l , hemodynamic and g e n e r a l r e q u i r e m e n t s i s g iv e nb e lo w .

2 . 1 . 1 P h y s i o l o g i c a l R e q u i r e m e n t s .The ' a t r e s t ' r e q u i r e m e n t s o f th e body m ust be m e t . : -

1 . 250 c c /m in . o f oxygen and 200 c c /m in . o f c a rb o n d i o x i d e m ust be exchanged ( G a l l e t t i and B re c h e r - HL B y p a s s ) . P r e f e r a b l y t h e m achine s h o u ld be c a p a b le o f e x c e e d in g t h e s e l e v e l s and o f

a c h i e v i n g p e r fo rm a n c e f i g u r e s ( G a l l e t t i (11 ) 1972) i n e x c e s s o f

30 cc/m lm ^m in.2 . 5 1 /m in . o f b lo o d m ust be r e t u r n e d a g a i n s t 180 ram Hg p r e s s u r e (Lowe)

3 . The p a r t i a l p r e s s u r e o f oxygen (PO2 ) i n t h e a r t e r i a l b lo o d m ust b e r e s t o r e d t o 100 mm Hg (95 - 100% s a t u r a t e d ) w h i l e t h a t o f c a r b o n d i o x i d e , PCO2 , m ust be c o n s t a n t l y r e s t o r e d t o a b o u t 40 mmHg

■ : ( P i g . p . 94. ) . CO2 r e t e n t i o n c a u s e s r e s p i r a t o r y a c i d o s i s w h i l e

CO2 d e p l e t i o n c a u s e s r e s p i r a t o r y a l k a l o s i s (D a v en p o r t 1 9 6 9 )*4 . The pH o f t h e b lo o d m ust be h e ld c o n s t a n t . T h is i m p l i e s t h a t t h e

g a s i n p u t t o t h e o x y g e n a to r s h o u ld be a c a r e f u l l y c o n t r o l l e d m ix tu r e , e . g . , 94% oxygen, 6% c a rb o n d io x id e (Chapman 1 9 7 0 ) .

5 . The sy s tem m ust a l lo w c h an g e s o f t e m p e r a t u r e b e tw e e n 30 and 3$°Qi

b u t n o t ex p o se b lo o d t o more th a n 40°C (Longmore 1 9 6 9 ) •6 . L i t t l e b lo o d tra u m a s h o u ld o c c u r .7 . P a t i e n t s u r v i v a l m ust be im p ro v ed and th e c o m p l i c a t i o n r a t e m ust

be lo w e re d com pared t o c u r r e n t l y u sed o x y g e n a to r s .8 . A n t i th ro m b o g e n ic b io c o m p a t ib l e m a t e r i a l s m ust b e u s e d and a s few

a s p o s s i b l e d i f f e r e n t m a t e r i a l s .9 . Some form o f c l o t t i n g i n h i b i t i o n m ust be a l lo w e d f o r .

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1 0 . The p r im in g volume m ust b e low t o m in im ise t h e r i s k o f i n f e c t i o n

and immune r e a c t i o n . I f t h i s volum e were l e s s th a n 1 l i t r e , i t

w ould be p o s s i b l e t o p r im e th e c i r c u i t w i th p l a s m a - l i k e f l u i d s :

w i t h o u t d i l u t i n g th e p a t i e n t ’ s b lo o d to o much. Volumes o v e r 1 . 5

l i t r e s m ust be p rim ed w i th b o t t l e d b lo o d w i th i n h e r e n t r i s k s o f i n f e c t i o n , e s p e c i a l l y o f j a u n d i c e and o f s e n s i t i z a t i o n t o serum

p r o t e i n s and t o m ino r b lo o d g ro u p s . I d e a l l y th e p r im in g volum e o f a b y p a s s c i r c u i t s h o u ld n o t ex ceed 0 .5 l i t r e s so t h a t s t e r i l e f l u i d

o r even th e p a t i e n t ’s own b lo o d can be u s e d . P a t i e n t s w i th r a r e b lo o d g ro u p s would r e q u i r e m in im al q u a n t i t i e s o f t r a n s f u s i o n b lo o d from th e b lo o d b a n k s .

2 . 1 . 2 . Hemodynamic R e q u i r e m e n ts .

1 . The p r e s s u r e d ro p th ro u g h th e sy s te m s h o u ld be a s low a s p o s s i b l e . S u b a tm o s p h e r ic p r e s s u r e s s h o u ld be a v o id e d a s f a r a s p o s s i b l e .

2 . The membrane s h o u ld have t h e s m a l l e s t a r e a w hich f u l f i l s 2 . 1 . 1 - 1 .3 . The h y d r a u l i c geo m etry s h o u ld be a s s im p le a s p o s s i b l e w i th a u n i fo rm

a r e a o f f lo w and no su d d en c h a n g e s .A. T h e re s h o u ld b e no su d d en d e c o m p re s s io n , s n a p - s h u t v a l v e s , t u r b u l e n c e ,

t a p s , s h a r p b e n d s , n o z z l e s o r c a n n u la e .5 . I d e a l l y th e c i r c u i t s h o u ld be c l o s e d so t h a t no l e v e l c o n t r o l i s

n e c e s s a r y .6 . F o r oxygen t r a n s p o r t th e l i m i t i n g f a c t o r i s t h e b lo o d f i l m , b u t f o r

CO2 t r a n s p o r t , t h e membrane p r o p e r t i e s im pose t h e l i m i t .

7 . The i n t e r n a l f lo w v e l o c i t i e s s h o u ld be low .

8 . A l l s u r f a c e s s h o u ld be sm ooth w i th no dead s p a c e s .9 . I f t h e c i r c u i t l e a k s i t s h o u ld l e a k o u tw a rd s .

2 . 1 . 3 . G e n e ra l R e q u i r e m e n t s . ■A w e l l - d e s i g n e d o x y g e n a to r s h o u ld have th e f o i l o w i n g c h a r a c t e r i s t i c s

1 . H ig h e r e f f i c i e n c y th a n e x i s t i n g o x y g e n a to r s .

2 . R e l i a b i l i t y .3 . S a f e t y a s a m a jo r p r i o r i t y . Tv/in s y s te m s , f a i l s a f e d e v i c e s and

w a rn in g s y s te m s s h o u ld be i n c l u d e d . T he re s h o u ld a l s o be an

a l t e r n a t i v e power s o u r c e t o m a in s .if . S im p le c o n s t r u c t i o n w i th e a s e o f d i s m a n t l i n g and a s s e m b ly .5* The o x y g e n a to r and i t s a s s o c i a t e d eq u ipm en t s h o u ld be d i s p o s a b l e o r

s t e r i l i z a b l e . The l a t t e r p r o c e s s m ust n o t a f f e c t c o m p o n en ts .

- 22 -

6 . R o b u st and com pact c o n s t r u c t i o n .

7 . R e l i a b l e i n s t r u m e n t a t i o n e s p e c i a l l y o f f lo w r a t e s . The o p e r a t o r m ust be a b l e t o c o n t r o l f lo w and p r e s s u r e t o s u i t

d i f f e r e n t p a t i e n t s and t o cope w i th th e c h a n g e s i n demand d u r in g t h e o p e r a t io n *

I d e a l l y c l o s e d lo o p c o n t r o l o f g a s t e n s i o n s i n t h e b lo o d s h o u ld be em ployed .

8 . The o x y g e n a to r s h o u ld be in e x p e n s i v e and e a s y t o u s e .2 .1 .4 * Summary.

The above r e q u i r e m e n t s a r e a b ly sum m arized by L o n g m o re 's i d e a l m ach ine (1 9 6 9 ) “A l i t t l e box m ounted o v e r th e p a t i e n t ' s s to m ach v / i th two k n o b s , one f o r f lo w , one f o r t e m p e r a t u r e , o p e r a t e d by t h e s u rg e o n o r h i s a s s i s t a n t . I t s h o u ld be so g e n t l e t h a t no h a s t e i s r e q u i r e d by t h e s u rg e o n and t h a t no l a r g e team i s r e q u i r e d t o o p e r a t e i t 1’

2 .2 D esig n C o n s i d e r a t i o n s .

2 . 2 . 1 The Membrane.

The i n t e r p o s i t i o n o f a membrane b e tw een th e b lo o d and g a s p h a s e s ' s o l v e s ' t h e p ro b le m s a l l e g e d to be c a u se d by th e raw b lo o d g a s . i n t e r f a c e o f o t h e r t y p e s o f o x y g e n a to r , b u t c r e a t e s two new o n e s - The membrane i t s e l f p r o v i d e s a r e s i s t a n c e to g a s f lo w and i t s p r e s e n c e a l s o c a u s e s a s low moving b o u n d a ry l a y e r t o be s e t up .

The membrane can be made t h i n n e r to red u ce , t h e r e s i s t a n c e , b u t Abel (1 ) c l a im s t h i s i s n o t a key f a c t o r i n o x y g e n a t io n and t h a t i n c r e a s i n g membrane t h i c k n e s s f o u r f o l d o n ly r e d u c e s d i f f u s i o n by 10%. Membrane t h i c k n e s s does become an i m p o r t a n t f a c t o r , th o u g h , i n c a r b o n

d io x i d e e l i m i n a t i o n . W ith e f f i c i e n t m ix in g c a rb o n d i o x i d e t r a n s f e r becom es s e v e r e l y l i m i t e d by membrane r e s i s t a n c e and w i th t h e o x y g e n a to r w o rk in g a t th e membrane l i m i t c an o n ly r e a c h h a l f t h e oxygen u p ta k e

r a t e .The i n t r o d u c t i o n o f th e membrane t o t h e b lo o d p h a se c a u s e s s k i n

f r i c t i o n and s e t s up a r e l a t i v e l y s t a g n a n t b o u n d a ry l a y e r o r zone

w hich i n h i b i t s g a s t r a n s f e r by im p e d in g th e p r o g r e s s o f t h e b l o o d .

T h is p ro b lem , u n iq u e to t h e membrane o x y g e n a to r , i s i l l u s t r a t e d

o v e r l e a f .

- 23 -

mm

The s t a g n a n t l a y e r r e c e i v e s t h e oxygen w h i le t h e f a s t e r s t r e a m s p a s s th ro u g h th e o x y g e n a to r h a v in g r e c e i v e d a m in im al q u o ta o f o x y g en .

A more d e t a i l e d d i s c u s s i o n i s p r e s e n t e d i n S e c t i o n 2 .2 .3 *S i l i c o n e membrane d o es p r e s e n t o t h e r p ro b le m s a s s o c i a t e d v / i th

i t s p h y s i c a l and c h e m ic a l s t r u c t u r e . I t i s a t a c k y m a t e r i a l v/hich

makes h a n d l i n g and a sse m b ly d i f f i c u l t . One s u g g e s t i o n v/as t o powder

w i th sodium b i c a r b o n a t e to e a s e th e p ro b le m . The s u r f a c e t e x t u r e shov/s r i d g e - l i k e p r o t r u s i o n s u n d e r th e e l e c t r o n m ic ro g ra p h w hich can p ro d u c e e d d i e s and t h e r e f o r e m ix in g , b u t Z ingg (2 ) c l a i m s t h a t t h e s e

may form b u b b le s a t th e membrane s u r f a c e by e n t r a i n m e n t .S t r e n g t h w i s e , s i l i c o n e r u b b e r h a s a low t e a r r e s i s t a n c e w hich

g i v e s a s eco n d r e a s o n f o r ex trem e c a r e i n h a n d l i n g . Thomas, Marx

and Kolobow (2 ) ana o t h e r s p r e f e r t o r e i n f o r c e t h e membrane i n woven mesh to r e d u c e th e r i s k t o p a t i e n t s a t th e e x p en se o f d i f f u s i o n

e f f i c i e n c y .The d i f f u s i o n o f g a s e s th ro u g h th e membrane i n c r e a s e s w i th

t e m p e r a t u r e and more i m p o r t a n t l y r e d u c e s on c o o l i n g , s i n c e many o p e r a t i o n s a r e c a r r i e d o u t u s in g a b lo o d t e m p e r a t u r e o f a s low a s 3 0 °C. T h is e f f e c t i s r e d u c e d , how ever, by th e f a c t t h a t i n c r e a s e d te m p e r a t u r e d e c r e a s e s oxygen f i x a t i o n by th e b lo o d ( d i s s o c i a t i o n

c u rv e moves t o th e r i g h t - s e e f i g ) .

50

- 24 -

T h i s s u g g e s t s t h a t oxygen s h o u ld n o t be p r e h e a t e d , b u t t h a t a

h e a t e x c h a n g e rb e em ployed t o m a i n t a i n e x t r a c o r p o r e a l b lo o d t e m p e r a t u r e .S i w i r i l and H e r s c h b e r g e r fo u n d t h a t membrane w a te r c o n t e n t

i n c r e a s e d g a s t r a n s f e r , B enevenu to ( 1 ) how ever, c la im e d t h e o p p o s i t e . O th e r i d e a s f o r im p ro v in g t r a n s f e r a r e b y : -

a ) D e v e lo p in g t h i n n e r membranes o f a d e q u a te s t r e n g t h .

b ) E x p l o i t i n g th e u s e o f y e t more p e rm e ab le m a t e r i a l s .

c ) P r e s s u r i s i n g th e g a s p h a se to i n c r e a s e th e oxygen p r e s s u r e

g r a d i e n t (D agher 1939) o r c y c l i n g g a s p r e s s u r e ( C l a f f 1 9 6 7 )•d) T e m p o ra r i ly b u t r e v e r s i b l y a l t e r i n g th e c h e m i s t r y o f t h e b lo o d

t o im p ro v e th e r a t e o f t r a n s f e r th r o u g h th e p la sm a o r a c r o s s t h e r e d c e l l w a l l , p o s s i b l y a t t h e c o s t o f c e l l f r a g i l i t y .

e ) Im p ro v in g f lo w c h a r a c t e r i s t i c s .

f ) T r e a t i n g t h e membrane i n some way t o im p ro v e i t s p e r m e a b i l i t y .

H ydrogen P e ro x id e h a s b e en s u g g e s te d a s a c a t a l y s t t o g a s t r a n s f e r .

Most w o rk e rs te n d to r e j e c t t h e i d e a o f p r e s s u r i s i n g t h e g a s p h a s e . V/hile s t r i v i n g to m a n u fa c tu r e y e t t h i n n e r membrane, th e y s e e t h e i n c r e a s e d d a n g e r s o f a i r em bolism f o i l o w i n g p i n h o l e s a n d .t e a r i n g . I t i s th o u g h t e s s e n t i a l t h a t b lo o d s h o u ld l e a k o u t r a t h e r t h a n a i r i n , i n t h e e v e n t o f a f l a w . The i m p l i c a t i o n i s t h a t o x y g e n a t io n p r e s s u r e s h o u ld be lo w e r th a n b lo o d p r e s s u r e f o r s a f e t y , p r e f e r a b l y m a r g i n a l l y ■ s u b a tm o s p h e r i c .

Some r e q u i r e m e n t s f o r e f f i c i e n t g a s t r a n s f e r a r e i m p o s s i b l e t o a c h ie v e s i m u l t a n e o u s l y . The t im e n eed ed to o x y g e n a te a f i l m o f b lo o d , f o r exam ple , v a r i e s a s th e s q u a r e o f t h e f i l m t h i c k n e s s , im p ly in g

l a r g e p a s s a g e s a r e i n e f f i c i e n t , , how ever, m ix in g by p a s s i v e o r a c t i v e

means i s n o t r e a l l y p o s s i b l e i n n a r ro w c h a n n e l s . The g r e a t e r t h e b lo o d t r a n s i t t im e , t h e g r e a t e r i s th e o x y g e n a t io n e f f i c i e n c y (B e n ev e n u to ) b u t t o m a i n t a in a g iv e n f lo w r a t e , t h e a r e a o f th e membrane w ould have

t o b e p r o p o r t i o n a t e l y l a r g e .B enevenu to c o n c lu d e s t h a t th e b e s t o x y g e n a t io n o c c u r s w i t h h i g h e r

oxygen t e m p e r a t u r e and p r e s s u r e , lo w e r oxygen h u m id i ty and t h e t h i n n e s t

p o s s i b l e membrane.

- 25 -

2 . 2 . 2 C a p i l l a r y o r S h e e t ?S i l i c o n e r u b b e r i s more d i f f i c u l t t o make i n t o t h i n tu b e th a n

s h e e t o f t h e same t h i c k n e s s . The s m a l l e s t d i a m e te r o f tu b e c u r r e n t l y p ro d u c e d i s 100 ^i, m aking p r e c i s e m im ic in g o f t h e a l v e o l a r c a p i l l a r i e s i m p o s s i b l e .

The d i f f i c u l t i e s w i th p l a t e d e s ig n o x y g e n a to r s l i k e t h e Bramson, L ande-E dw ards , G e n e ra l E l e c t r i c - P e i r c e l i e i n t h e c o n t r o l o f t h e b lo o d

f i l m t h i c k n e s s and i n t h e p r o d u c t i o n o f u n ifo rm p l a n a r f lo w .U n m od if ied , t h e b lo o d t e n d s t o form t h i c k r i v u l e t s . B o th t h e s e d i f f i c u l t i e s c an l a r g e l y be overcome by th e a d d i t i o n o f some d e s ig no f M b lo o d s c r e e n 1 u s u a l l y g ro o v ed a s i n th e L ande-E dw ards and G E -P e irc eo r meshed a s i n t h e Bramson l u n g . The i n t e r p o s i t i o n o f t h e s c r e e n i n t u r n i n c r e a s e s t h e p r e s s u r e d rop and r e d u c e s b o th th e b lo o d f lo w and t h e e f f e c t i v e membrane a r e a . The m a n i f o ld in g n e c e s s a r y i n b o th

p l a t e and c a p i l l a r y o x y g e n a to r s , th o u g h more p a r t i c u l a r l y i n t h e l a t t e r , can c a u s e th ro m b u s f o r m a t i o n , due to r e d u c e d v e l o c i t y .

The a d v a n ta g e s o f c a p i l l a r y membrane c o n s t r u c t i o n l i e i n t h e

e a s i e r c o n t r o l o f f lo w , t h e l a c k o f o b s t r u c t i o n s t o f lo w and i n t h e

n a t u r a l l y o c c u r r i n g s e c o n d a ry f lo w s o r T a y lo r v o r t i c e s . The c a p i l l a r i e s

do n o t t h e n need to be o f s m a l l d i a m e te r b e c a u s e o f t h i s m ix in g e f f e c t .

The m a jo r d i s a d v a n ta g e o f c a p i l l a r y d e s ig n i s t h e h i g h e r c o s t p e r u n i t

a r e a com pared to t h a t o f s h e e t , a p r im e c o n s i d e r a t i o n s i n c e th e

membrane m ust be d i s p o s a b l e .

2 . 2 . 3 . Hemo dynami c s .The b o u n d a ry l a y e r p ro b lem , to u c h e d on i n 2 . 2 . 1 , w ould e x i s t

w h a te v e r l i q u i d p a s s e d th r o u g h th e o x y g e n a to r , b u t t h e p r e s e n c e o f d i s c o i d , r e d c e l l s i n t h e b lo o d c o n s i d e r a b l y c o m p l i c a t e s t h e f lo w

p a t t e r n

oO

a ^ o ^ ° o ^c=3 CZ=> c—, Co 0=1 c=>^ ^ ° O o

° 00 ^ ° ^O co ° ,—.. ^ jj—, o co"77 / 7 7 / V/1 / / / / / ; / 7 V ^ X / 7 7 /7 7 V / / V /

T he s i g m a e F p e 'c .r

- 26 -

D epending on th e s i z e o f c h a n n e l , th e w a l l m a t e r i a l and th e f lo w

v e l o c i t y , an a x i a l c o r e o f o r i e n t e d e r y t h r o c y t e s , t o g e t h e r w i th a r e l a t i v e l y c e l l f r e e p l a s m a t i c zone i s e s t a b l i s h e d - t h e s ig m a e f f e c t . The a n n u lu s h a s an im m obile p o r t i o n n e a r th e w a l l s u r f a c e , w here t h e

s t r e a m i s s l u g g i s h and c e l l s t e n d t o t e t h e r and s h e a r ( B la c k s h e a r ( 1 - 6 ) ( 8 ) , and h a s an i n n e r m ix in g and s h e a r i n g p a r t . As f lo w i s i n c r e a s e d

c e l l s i n t h e c o r e t e n d to o r i e n t t o p r e s e n t th e l e a s t r e s i s t a n c e to

f lo w and r o u l e a u x b r e a k u p . B oth th e t e t h e r e d c e l l s and t h e p la sm a

zone i n h i b i t g a s t r a n s f e r . A c t iv e o r p a s s i v e m ix in g s h o u ld a l l e v i a t e b o th p ro b le m s , s h a k i n g / t h e t e t h e r e d c e l l s f r e e o r p r e v e n t i n g t e t h e r i n g

and c a u s i n g an exch an g e o f c e l l s b e tw een th e c o re and t h e a n n u l u s .

What w i l l n e v e r be p o s s i b l e i s th e m im icry o f th e l u n g w here c e l l s a r e p r e s e n t e d s i n g l y t o th e a l v e o l a r membrane.

S in c e membrane o x y g e n a to r s w ere f i r s t c o n c e iv e d m ix in g h a s b e e n a f e a t u r e o f many o f t h e d e s i g n s : -

G e n e ra l Type S p e c i a l F e a t u r e

Sandw ich S c re e n i n b lo o d p h a se P neu m atic o r H y d ra u l ic shim M u l t i p o i n t s u p p o r t R e c i r c u l a t i o n

O s c i l l a t i n g g a s p r e s s u r e P a t t e r n on membrane.

(L an d e -E d w ard s )

( G L -P e i r c e )

(A bel (1), C l a f f )

C o i l O s c i l l a t i n g g a s p r e s s u r e

C a p i l l a r ya ) B lood i n s i d e

b ) B lood o u t s i d e

P u l s a t i l i t y

I n t e r w e a v i n gP u l s a t i l i t y

E n v e lo p e Rhythmic t i l t i n g

V e r t i c a l c a s c a d e s .

- 27 -

G e n e ra l Type S p e c i a l ’ F e a t u r e .

S p in n in g Hollow

S i l i c o n e D isc

4

R ap id r o t a t i o n i n b lo o d ( I l l i c k a l )

T o r o i d a l . T a y lo r v o r t i c e s

R ap id o s c i l l a t i o n (M e lro s e )

F o r e f f i c i e n t g a s t r a n s f e r w i th m in im a l b lo o d t ra u m a , c o n v e c t i o n and d i f f u s i o n a r e r e q u i r e d . S in c e d i f f u s i o n i s a f u n c t i o n o f c o n c e n t r a t i o n g r a d i e n t s and th e p r o p e r t i e s o f t h e c o n v e y in g and d i f f u s i n g s u b s t a n c e s , t h e b e s t ch an ce f o r g a s t r a n s f e r im provem en t l i e s i n t h e c o n v e c t io n p r o c e s s . As p r e v i o u s l y s t a t e d , t h i s r e q u i r e s r e l a t i v e l y l a r g e c h a n n e l s .

I l l i c k a l (1967) showed t h e membrane l i m i t c o u ld be p a s s e d and t h a t a n e a r - l i n e a r i n c r e a s e i n o x y g e n a t io n w i th sp e e d o f a c t i v e m ix in g c o u ld b e a c h i e v e d . M e lro se (1972) h a s s i n c e d i s c o v e r e d t h a t o s c i l l a t i n g a - t o r o i d a l c a p i l l a r y membrane o x y g e n a to r , i n t e n s i f y i n g ttoe r e v e r s e d

s e c o n d a ry flow , i s n e a r l y a s good . He f u r t h e r shov/ed t h a t h ig h e n e rg y m ix in g v e l o c i t i e s o f 100 - 200 c m /s , c o m p arab le t o t h o s e fo u n d i n t h e

a r t e r i a l sy s te m , do n o t s e r i o u s l y i n c r e a s e b lo o d t ra u m a and s u g g e s t e d

t h a t a n t i c o a g u l e n t s may n o t be n eed ed a t su ch f lo w v e l o c i t i e s .

C e r t a i n l y , t h e p ro b le m s o f d e p o s i t i o n and th ro m b i c a u s e d by f lo w b e in g

to o s lo w m ust be m in im a l .' Only now a r e th e b e n e f i t s o f c r e a t i n g l a t e r a l m ix in g by r e m ix in g ,

s c r e e n s , c u rv e d p a s s a g e s , p u l s a t i o n o r a g i t a t i o n b e in g f u l l y e x p l o r e d .

I t i s r e a l i s e d t h a t t h e r i s e i n e f f i c i e n c y p ro m ise d c o u ld r e d u c e t h e

r e q u i r e d membrane a r e a by up t o 80% and t h e r e f o r e make t h e o x y g e n a to r

c h e a p e r , s i m p l e r , more r e l i a b l e and l e s s dam aging t o b lo o d u l t i m a t e l y .

2 . 2 . 4 B i o c o m p a t i b i l i t y .M a t e r i a l s fo u n d to be l e a s t t r a u m a t i c t o b lo o d have i n common a

h ig h d e g re e o f c h e m ic a l i n e r t i a (Lowe 1969)? sm o o th n ess o f s u r f a c e ( S t e w a r t and S u r r i d g e ) and u n w e t t a b i l i t y . These q u a l i t i e s a r e t o

some e x t e n t i n t e r r e l a t e d . P r e s e n t t r e n d s o f r e s e a r c h i n t o b lo o d

c o m p a t ib le m a t e r i a l s d i v i d e i n t o t h e f o l l o w i n g c a t e g o r i e s (Chang T 1973)

a ) S u r f a c e s w i th a n i o n i c r a d i c a l s .

b ) S u r f a c e s o f i n e r t m a t e r i a l s

- 2 8

c ) H e p a r i n i s e d s u r f a c e s .d) A lb u m in ise d s u r f a c e s .

To d a t e t h e m ost e x t e n s i v e l y u sed c o n s t r u c t i o n m a t e r i a l s f o r e x t r a c o r p o r e a l c i r c u i t r y a r e : -

a ) S t a i n l e s s S t e e l .

b ) G la s s - p r e f e r a b l y s i l i c o n i s e d .c ) S i l a s t i c

d) T e f lo n

e ) Some p l a s t i c s .

Most common m e t a l s , o t h e r th e n s t a i n l e s s s t e e l , t e n d t o be t o x i c . . ;

2 . 2 . 3 P h y s i o l o g i c a l C o n s i d e r a t i o n s .The d a n g e r s o f low f lo w r a t e s c a u s in g th ro m b i have a l r e a d y b e en

m e n t io n e d . These c a u s e em bo li and g r e a t l y r e d u c e membrane a r e a . S im p le r h y d r a u l i c g eo m etry and s m a l l e r b a s i c membrane a r e a r e d u c e h e m o s t a s i s and th r o m b o s i s .

The p o s s i b i l i t y o f a i r em bolism may b e m in im ise d by s u p p l y i n g t h e

membrane o x y g e n a to r w i th a t o t a l g a s p r e s s u r e b e low t h a t o f t h e b lo o d , so t h a t i n t h e e v e n t o f a p e r f o r a t i o n , b lo o d l e a k s o u t , n o t a i r i n .I t i s c la im e d t h a t even i n t h e s e c i r c u m s t a n c e s a i r b u b b le s may be •

e n t r a i n e d a t th e membrane w a l l .The m a jo r a d v a n ta g e c la im e d f o r th e membrane o x y g e n a to r i s t h a t

t h e a b se n c e o f a raw b l o o d - g a s i n t e r f a c e m in im is e s b lo o d t r a u m a .The a i r i n t e r f a c e s h o u ld be a v o id e d a t a l l t im e s even when f i l l i n g t h e

c i r c u i t ( S t e w a r t , M ddx.H osp .) The t ra u m a m ost l i k e l y t o b e c a u s e d , h e m o ly s i s and p r o t e i n d e n a t u r a t i o n , a r e d i s c u s s e d f u l l y i n s e c t i o n 3 *I»

P l a t e l e t c o u n t s d e c r e a s e d u r in g p e r f u s i o n and t h e i r f u n c t i o n c an be im p a i r e d t o th e p o i n t where h e m o s t a s i s f a i l s . T h i s l o s s i s n o t s u r p r i s i n g s i n c e th e y p e r fo rm by a d h e r in g t o any ro u g h s u r f a c e and th e n

b u r s t t o r e l e a s e r e p a i r - p r o m o t i n g c h e m i c a l s . They t e n d t o s t i c k to

a l l a r t i f i c i a l s u r f a c e s (w hich a r e much ro u g h e r th a n any b lo o d v e s s e l ) b u t t h e i r a d h e s iv e n e s s can b e c o n t r o l l e d w i th d e x t r a n s , a s p i r i n and

a n t i h i s t a m i n e s .F i n a l l y e v id e n c e e x i s t s o f g r e a t l y r e d u c e d p h a g o c y t i c a c t i v i t y

f o l l o w i n g p e r f u s i o n . S e p s i s i s an e v e r - p r e s e n t t h r e a t and t h e b o d y ’s

norm al im m unolog ic d e f e n c e s a r e i m p a i r e d . A l b u m in i s a t io n may w e l l h e l p t o a l l e v i a t e some o f t h e h a rm fu l e f f e c t s t o t h e fo rm ed e le m e n t s

o f t h e b lo o d by a r t i f i c i a l c i r c u l a t i o n .

- 29 -

2 . 2 . 6 Summary.Most membrane o x y g e n a to r s p ro d u c e p e r fo rm a n c e f i g u r e s o f 30 -

AO cc/mm m^min. and a r e l e s s th a n 20% e f f i c i e n t . I n c r e a s e d e f f i c i e n c y c o u ld q u a r t e r th e r e q u i r e d membrane a r e a and l e a d t o a

c h e a p e r , s i m p l e r , s a f e r and more r e l i a b l e m a ch in e . T h in n e r membrane i n c r e a s e s e f f i c i e n c y b u t a l s o t h e l i k e l i h o o d o f p i n h o l e s , t e a r s and

h a n d l in g d i f f i c u l t i e s .

2 . 5 . I n V i t r o v e r s u s i n Vivo T e s t i n g .B a s ic p e r fo rm a n c e d a t a f o r membrane d e v i c e s a r e b e s t o b t a i n e d

i n v i t r o where a c c u r a t e c o n t r o l o f b lo o d f lo w , g a s f lo w , t e m p e r a t u r e e t c . i s p o s s i b l e . D a ta may be o b ta in e d o v e r a w id e r r a n g e and u n d e r s t e a d i e r c o n d i t i o n s th a n i s p o s s i b l e w i t h an ex v iv o p e r f u s i o n .

P a i n s t a k i n g t e s t s w i l l g l e a n r e l i a b l e i n f o r m a t i o n on g a s e x ch an g e , p e r f u s i o n p r e s s u r e and b lo o d volume w hich w i l l n o t be augm ented by

i n v iv o t e s t s .One im p o r t a n t a s p e c t o f su ch i n v i t r o t e s t s i s t h e e x a m in a t io n

o f t h e e f f e c t s . o f m o d i f i c a t i o n s t o th e d e s ig n and o f su d d en c h a n g e s i n th e i m p o r t a n t p a r a m e te r s o f b lo o d f lo w and g a s f lo w . The a d v a n ta g e s and p ro b le m s a r e com pared i n th e t a b l e be low (S alzm an 1971)

A d v an tag es P rob lem s

I n V i t r o

B e s t s t a n d a r d i s e d E a s i e s t t o s tu d y i n d e t a i l

A r t e f a c t s e a s i l y o c c u r May n o t be r e l e v a n t

------ ;------------------------------.— ------ ———---------—1

Ex Vivo

S u b j e c t - d e v i c e i t e r a t i o n Tends t o be s e n s i t i v eTime l i m i t a t i o n s

S u b je c t i n t e r a c t i o n

C o n d i t io n s te n d t o ch an g e w i th t im e A c t i v a t i o n o f s u b s t a n c e s .E x h a u s t io n o f s u b s t a n c e s Pange o f t e s t i n g l i m i t e d .

- 30 -

A d v an tag es P ro b le m s .

I n Vivo

Sub j e c t - d e v i c e i n t e r a c t i o n L a rg e e x p e r im e n t a l e r r o r s

D is c o n t in u o u s o b s e r v a t i o n s . Few d a t a p o i n t s .E x p e n s iv e .

D i f f i c u l t t o s tu d y t r a n s i e n t s .

I n v i t r o t e s t s s h o u ld be c a r r i e d o u t u s i n g human b l o o d .

S u b s t i t u t e s su ch a s an im a l b lo o d , w a t e r / g l y c e r o l m ix tu r e o r even w a te r

w i l l n e v e r p ro d u c e r e s u l t s w hich a r e c l i n i c a l l y u s e f u l ; a t b e s t th e y w i l l m e re ly be i n t e r e s t i n g . I d e a l l y th e b lo o d s h o u ld be f r e s h , h e p a r i n i s e d and human.

The s u p e r i o r i t y o f t h e membrane o x y g e n a to r i s n o t y e t p ro v e d

(K a yser 1 9 7A). S u p e r i o r i t y , i f i t e x i s t s , s h o u ld be m easu red by

r e d u c e d b lo o d t ra u m a ,, i n c r e a s e d p e r fo rm a n c e o r b o t h . U n f o r t u n a t e l y th e i n t e r p o s i t i o n o f a membrane b e tw een th e b lo o d and g a s p h a s e s r e n d e r s t h e s e c o n d .o f t h e s e p a r a m e te r s u n l i k e l y t o b e a c h i e v a b l e s i z e f o r s i z e .

Membrane o x y g e n a to r s a r e l i k e l y to be more e x p e n s iv e and more c o m p l i ­c a t e d i n c o n s t r u c t i o n , so th e y m ust c o m p e te .o n a m in im i z a t io n o f b lo o d damage p l a t f o r m . They m ust a l s o a t t e m p t t o co m p en sa te f o r th e h a n d ic a p o f membrane r e s i s t a n c e and b o u n d a ry l a y e r e s t a b l i s h m e n t by

b e in g h i g h l y e f f i c i e n t .As s u g g e s te d i n s e c t i o n 1 . A, t h e membrane o x y g e n a to r i s a l r e a d y

m aking p o s s i b l e new l i f e - s a v i n g o p e r a t i o n s and h o ld s even g r e a t e r p ro m ise f o r th e f u t u r e . C l e a r l y , th e o b j e c t i v e s o f m in im i s in g b lo o d

t ra u m a and im p ro v in g e f f i c i e n c y a r e w o r th e x p l o r i n g .C u r r e n t p r o g r e s s h a s no s e t d i r e c t i o n . R a r e l y . a r e t h e two

o b j e c t i v e s e x p lo r e d t o g e t h e r . K ayser (197A) s e t s o u t a d e t a i l e dc r i t i c i s m o f c u r r e n t work and th e c o n c l u s i o n s drawn from i t .

The o b j e c t i v e s o f t h i s t h e s i s a r e t w o f o l d : -

2 .A .1 B lood Damage I n v e s t i g a t i o n - A im s.2 . A .1 .1 To p ro d u c e d e f i n i t e d e s ig n c r i t e r i a f o r t h e membrane oxy­

g e n a t o r t a k i n g i n t o a c c o u n t b lo o d damage and o x y g e n a t io n c o n s i d e r a t i o n s .

- 3 1 -

2 . 4 . 1 . 2 To p ro v e o r d i s p r o v e t h e s u p e r i o r i t y o f membrane o x y g e n a t io n

o v e r g a s - c o n t a c t ty p e o x y g e n a t io n i n r e s p e c t o f p r o t e i n d e n a t u r a t i o n . .2 . 4 . 1 . 3 To r e l a t e th e hemodynam ics and b i o c o m p a t i b i l i t y o f a b y p a s sc i r c u i t t o t h e i r e f f e c t on b lo o d .2 . 4 . 2 O x y g e n a t io n E f f i c i e n c y Im provem ent - Aims.

To d e te r m in e th e e f f e c t on o x y g e n a t io n a b i l i t y o f : -a ) Gas p r e s s u r e .

b) Gas c o m p o s i t io n .c ) V i b r a t i o n f r e q u e n c y .d) Time from commencement o f t e s t .e ) B lood f i l m t h i c k n e s sf ) Membrane t h i c k n e s s .

2 .5 Programme o f Work.

The c h r o n o l o g i c a l o r d e r o f work to be c a r r i e d o u t i n an a t t e m p t toa c h ie v e th e o b j e c t i v e s o f 2 .4 i s shown b e lo w :-1 . M a n u fa c tu re o f o x y g e n a to r and o f o t h e r c i r c u i t com ponen ts n o t

c o m m e rc ia l ly o r e a s i l y a v a i l a b l e .2 . O r g a n i s a t i o n o f r e m a in in g c i r c u i t com ponen ts , g a s and b lo o d s u p p l i e s

and a n t i c o a g u l e n t s .

3 . C o n d u c t io n o f p r e l i m i n a r y t e s t s w i t h w a te r f o r f a m i l i a r i z a t i o n w i th t e c h n i q u e s o f m e a su r in g p e r fo rm a n c e and c a l i b r a t i o n o f pump.

4 . P ro o f t h a t s a m p l in g o f b lo o d i s non t im e d e p e n d e n t - o t h e r w i s e

c a l i b r a t i o n .5 . C o n d u c t io n o f t e s t s w i th 1 a n a lo g o u s f l u i d * .6 . D evelopm ent o f s t e r i l i z a t i o n t e c h n i q u e s .

7 . C ho ice o f i n s t r u m e n t a t i o n and m e a s u re m e n t■t e c h n i q u e s .

8 . D evelopm ent o f com pute r p rogram to c o n v e r t PO^ t o SOg t a k i n g pH and t e m p e r a t u r e f a c t o r s i n t o a c c o u n t .

9 . D e te r m in a t io n o f h e m o ly s is a n d / o r p r o t e i n d e n a t u r a t i o n a t t r i b u t a b l e t o each s e p a r a t e com ponent i n o r d e r to i s o l a t e t h a t due t o t h e .

membrane o x y g e n a to r .1 0 . R e s e l e c t i o n o f eq u ipm en t and r e p e a t o f above i f n e c e s s a r y1 1 . P e r fo rm a n ce o f e x p e r im e n t s t o show how o x y g e n a t io n and b lo o d damage

v a r y w i th g a s p r e s s u r e , g a s c o m p o s i t io n , t im e from commencement

o f t e s t , membrane t h i c k n e s s and b lo o d f i l m t h i c k n e s s .1 2 . E x a m in a t io n o f th e membrane b e f o r e and a f t e r t e s t s u n d e r e l e c t r o n -

m ic ro s c o p e f o r s i g n s o f membrane damage and c l o g g i n g .

- 32 -

1 3 . E x a m in a t io n o f b lo o d sam p le s to s tu d y o x y g e n a t io n and c e l l dam age.14* E x a m in a t io n o f t e c h n i q u e s t o e l i m i n a t e c lo g g in g i f p ro v e d to

e x i s t , o r im prove o x y g e n a t io n by b r e a k in g up o f b o u n d a ry l a y e r by v i b r a t i o n (lo\y f r e q u e n c y to u l t r a s o n i c ) , s t a t i c c h a r g e ,

c h e m ic a l a d d i t i v e s o r b lo o d s c r e e n s .1 5 . E x a m in a t io n o f t h e e f f e c t o f t h e s e t e c h n i q u e s on t h e b lo o d and

t h e membrane.

1 6 . P r o d u c t i o n o f f lo w v i s u a l i z a t i o n p a t t e r n f o r t h e membrane o x y g e n a t o r .

1 7 . Review and r e d e s i g n o f o x y g e n a to r w here n e c e s s a r y .1 8 . P r o d u c t io n of f i g u r e s f o r t h e p e r fo rm a n c e o f t h e membrane

o x y g e n a to r .1 9 . R e l a t i o n o f (18 ) t o t h e o r y .2 0 . R ecom m endations.

- 33 -

CHAPTER 3 .

SELECTION OP EXPERIMENTS.

3 . 0_____ I n t r o d u c t i o n .

T h is c h a p t e r c o v e r s s e l e c t i o n o f i n s t r u m e n t a t i o n and m easu rem en t t e c h n i q u e s and th e d e s ig n o f c i r c u i t com ponen ts , i t e m s 1 , 2 and 7 i n

t h e programme o f work on page 3 1 .-

The p o s s i b l e m ethods o f m e a s u r in g eac h p a r a m e te r a r e l i s t e d and a c h o ic e made b a s e d on c u r r e n t l i t e r a t u r e , a v a i l a b l e e q u ip m e n t , e a s e o f u s e and r e l e v a n c e .

The c h a p t e r ends w i th th e s e l e c t i o n o f s p e c i f i c e x p e r im e n t s t o a c h ie v e th e a im s l i s t e d i n s e c t i o n 2 . 4 .

3 .1 S e l e c t i o n o f T e s t s to m easu re P e rfo rm a n ce and B lood Damage.3 . 1 . 1 M easurem ent o f O x y g en a tio n P e r f o rm a n c e .

No s t a n d a r d h a s b e en a g re e d w hich would a l lo w th e many d i f f e r e n t o x y g e n a to r s i n c u r r e n t u se to be com pared . G a l le t tL ( ( 7 ) 1971) s u g g e s te d a ’r a t e d flow* m ethod, b e in g t h e f lo w r a t e a t w h ich b lo o d w i th a p ack ed c e l l volum e o f 4 Q% e n t e r s th e d e v ic e 65% s a t u r a t e d and l e a v e s 93% s a t u r a t e d . The p e r fo rm a n c e o f an o x y g e n a to r o r i t s ' r a t e d o x y g e n . t r a n s f e r ' i n m l/m 2/M in. a t th e ' r a t e d f l o w ' c o u ld th e n

b e q u o te d .The d i f f i c u l t y l i e s i n th e m a in te n a n c e o f th e p a r a m e t e r s q u o te d

a t t h e i r c a l i b r a t i n g l e v e l s l o n g enough to r e c o r d t h e n e c e s s a r y d a t a t o c a l c u l a t e g a s f lo w . C e r t a i n l y , th o u g h , i t i s n e c e s s a r y t o m easu re

t h e a r t e r i a l and v e n o u s p a r t i a l p r e s s u r e s o f oxygen and c a r b o n d i o x i d e

t o g e t h e r w i th th e f lo w r a t e . I t i s a l s o n e c e s s a r y to m a i n t a i n a

r e c o r d o f b lo o d pH and t e m p e r a t u r e .Knowledge o f th e d i s s o c i a t i o n c u rv e ( J App Phys 2 1 :3 > 1 9 6 6 ) o r a

monogram (Aberman 1973)» e q u a t i o n o r a n a lo g u e p ro d u c e d from i t w i l l a l lo w th e p e r c e n t s a t u r a t i o n d i f f e r e n c e b e tw een th e a r t e r i a l and v e n o u s

l i n e s t o b e c a l c u l a t e d . T h is can be a c h ie v e d more r a p i d l y , l e s s

a c c u r a t e l y , b u t by c o n t in u o u s m o n i to r in g u s in g one o f s e v e r a l t y p e s

o f o x im e te r . The p r i n c i p l e o f t h e s e l i e s i n th e c o l o u r d i f f e r e n t i a l

b e tw een a r t e r i a l and v en o u s b l o o d : -

- 34 -

L o c e:

505805 Wavelength

The s p e c t r a c o r r e s p o n d a t v a r i o u s i s o b e s t i c p o i n t s a t w h ich c a l i b r a t i o n i s p e r fo rm e d . The c o lo u r o f th e r e f l e c t e d o r t r a n s m i t t e d l i g h t i s th e n u sed to g iv e a m easu re o f oxygen s a t u r a t i o n .

The p e r fo rm a n c e o f th e o x y g e n a to r i s c a l c u l a t e d from

B lood f lo w r a t e x (A r t - Ven) s a t u r a t i o n P e rfo rm a n ce » x hem o g lo b in c o n t e n t .

membrane a r e a .

3 . 1 . P . B lood Damage.B e r s t e i n (1971) h a s s t a t e d t h a t w a l l i n t e r a c t i o n i s t h e m ost

i m p o r t a n t c a u s e o f b lo o d damage, F i r s t l y a p r o t e i n m o n o lay e r fo rm s

on t h e a r t i f i c i a l s u r f a c e s (w hich may s u b s e q u e n t ly be d e n a t u r e d ) f o l l o w e d by th e a d h e s io n o f p l a t e l e t s , t h e n o f r e d and w h i t e c e l l s .

F i n a l l y f i b r i n i s d e p o s i t e d and b r e a k s down (F o rs trcu n 1 9 7 1 ) .The tra u m a c a u se d may i n c l u d e h e m o ly s i s , p r o t e i n d e n a t u r a t i o n ,

a g g l u t i n a t i o n , em b o li , s l u d g in g , p l a t e l e t l o s s and p h a g o c y t i c dam age.

3 . 1 . B . I . H em olys is - D i s c u s s i o n .H e m o ly s is , w hich i s th o u g h t to be o f m e c h a n ic a l o r i g i n , i s

e v id e n c e d by an i n c r e a s e i n serum h em o g lo b in , a v i r t u a l a b s e n c e o f h a p t o g l o b i n , a r e d u c t i o n i n e r y t h r o c y t e l i f e sp an and th e p r e s e n c e o f

f r a g m e n te d c e l l s i n c i r c u l a t i n g b lo o d . I t i s th e p r o c e s s o f l y s i s o f th e r e d c e l l membrane and th e s u b s e q u e n t r e l e a s e o f c e l l c o n t e n t s

i n t o th e p la sm a .P lasm a h em og lob in i n c r e a s e s th e v i s c o s i t y and o sm o t ic p r e s s u r e

and t h e r e f o r e u p s e t s th e oxygen e x c h a n g e . Normal p h y s i o l o g i c a l l e v e l s

a r e 0 . 6 - 4 mg p e r 100 m l. Above 130 mg p e r 100 m l, h e m o g lo b in

a p p e a r s i n u r i n e and i n B la c k w a te r f e v e r when th e l e v e l r i s e s t o 1000 mg p e r 100 ml th e u r i n e i s b l a c k b u t p a t i e n t s s t i l l s u r v i v e . The r e t i c u l o -

e n d o t h e t i a l sy s te m c an c l e a r 13 mg p e r 100 ml p e r h o u r i n d e f i n i t e l y . i n a h e a l t h y i n d i v i d u a l , b u t u n d e r b y p a s s c o n d i t i o n s , r e n a l f a i l u r e ,

i n t h e p r e s e n c e o f a c i d o s i s , sh o ck , r e n a l i s c h a e m ia and d e h y d r a t i o n and

d e a th may r e s u l t (A n d e rsen 1 9 6 6 ) . K idneys c l e a r th e b lo o d s t r e a m b u t h y p o th e rm ia and h y p o te n s io n r e d u c e t h e i r e f f i c i e n c y ( G a l l e t t i & B recK er IILB - 2 6 6 ) . Longmore (1 9 6 8 ) h o ld s an e n q u i r y i f h e m o ly s i s r i s e s above l}0 mg p e r 100 ml d u r in g an o p e r a t i o n .

H em o ly s is can be a g g r a v a t e d by s e v e r a l f lo w c h a r a c t e r i s t i c s .B lood i s i n t o l e r a n t t o sudden d e c o m p re s s io n , f o r i n s t a n c e , when m e c h a n ic a l v a l v e s s h u t and when f lo w i s t u r b u l e n t . Y arborough (1 9 6 6 ) s t a t e s t h a t r a p i d h e m o ly s i s o c c u r s w here R e y n o ld ’s number e x c e e d s 4 2 0 0 . Under t h e s e c i r c u m s t a n c e s h em og lob in comes o u t w i th e x p l o s i v e v i o l e n c e to r u p t u r e r e d c e l l s , hence f o r a g iv e n tu b e s i z e , t h e r e i s a c r i t i c a l ■ f lo w r a t e w h ich , i f ex ceed ed can c a u se h e m o ly s i s . S u r f a c e m a t e r i a l ( H i r o s e 1 9 6 9 )* s u r f a c e ro u g h n e s s (Longmore 1 9 6 8 ) , ( S t e w a r t Sc S t u r r i d g e

1 9 3 9 ) &frd o v e r h e a t i n g a l s o p rom ote h e m o ly s i s , a s do o v e r o r u n d e r o c c l u s i o n o f t u b in g o r p e r i s t a l t i c ( r o l l e r ) pumps. ( B e r n s t e i n 1967)

A h o s t i l e pH l e v e l i n th e p la sm a p ro m o te s h e m o ly s is and may c a u s e g r o t e s q u e d i s t o r t i o n o f th e e r y t h r o c y t e ’s "b iconcave d i s c s h a p e .

R r e c o a t in g c i r c u i t r y w i th album en may r e d u c e h e m o ly s is and i s s t a n d a r d

p r a c t i c e fcr t h e L ande-E dw ards Membrane O x y g e n a to r . Most i m p o r t a n t o f

a l l , b u b b le s and c a v i t a t i o n m ust be a v o id e d , im p ly in g t h a t t h e r e s h o u ld

be no sudden e n la r g e m e n ts i n th e c i r c u i t r y ( G a l l e t t i Sc B r e c h e r ) .

B lood i s g e n e r a l l y more t o l e r a n t to p o s i t i v e p r e s s u r e s th a n to even v e r y s m a l l s u b a tm o s p h e r ic p r e s s u r e s , v i z . , c a rd io to m y s u c t i o n l i n e (Me Caughan 1 9 5 8 ) . I n t e r m i t t e n t h ig h p r e s s u r e s , th o u g h , a r e t h o u g h t

to be d e t r i m e n t a l (C h e v re t & B esson 1938 , B j / r k & R o d r ig u e z 1 9 3 9 ) .B la c k s h e a r ( 1 - 3 ) » ( 8 ) r e l a t e s h e m o ly s is to c e l l s i n t e r a c t i n g w i th an

a d j a c e n t w a l l . T h is h e m o ly s i s dep en d s on th e w a l l a r e a , t h e ’ s t i c k i n e s s ' o f th e w a l l m a t e r i a l and th e b lo o d f lo w r a t e . He a l s o d e s c r i b e s two t im e d e p e n d e n t fo rm s o f damage u n r e l a t e d to su ch i n t e r ­a c t i o n : a. low l e v e l o f s h e a r s t r e s s (1000 d y n es /cm ^) a p p l i e d f o rs e v e r a l s e c o n d s o r a v e r y h ig h l e v e l (4 0 ,0 0 0 dynes (cm^) a p p l i e d f o r l e s s th e n 0 .1 s e c o n d s . The seco n d o f t h e s e may o c c u r i n p r o s t h e t i c

v a l v e r e c i p i e n t s who have h ig h b lo o d p r e s s u r e * H e a r t pumps ( C a s te n a d a

1964 , B e r n s t e i n 1967) and membrane and non-membrane o x y g e n a to r s

- 36 -

( P e i r c e (1 4 ) 1969) have a l l b e en c l o s e l y exam ined and com pared f o r h e m o ly s i s . T h e re i s , how ever, no a g re e m e n t a s to t h e m ethod o f h e m o ly s is m easu rem en t, n o r h a s th e h e m o ly s is been r e l a t e d to o t h e r fo rm s o f damage su ch a s p r o t e i n d e n a t u r a t i o n .

One f i n a l p o i n t i s o f r e l e v a n c e t o t h i s t h e s i s : t h e d i l u t i o n .o f b lo o d w i th p h y s i o l o g i c a l s o l u t i o n s su ch a s s a l i n e o r ACD d e c r e a s e t h e l i a b i l i t y o f e r y t h r o c y t e d e s t r u c t i o n .

3 . 1 . 2 . 2 M ethods o f I-Iemolysis A ssay .

Most o f th e m ethods s u g g e s te d f o r h e m o ly s i s m easu rem en t d e te r m in e

t h e q u a n t i t y o f h e m o g lo b in r e l e a s e d i n t o th e p la sm a . Some o f t h e s e t e c h n i q u e s a r e l i s t e d b e lo w : -

1 . Wu ' s m ethod . (W\i 1 9 2 3 )2 . B en z id en e M ethod.3 . O r t h o t o l i d e n e m ethod .

, 4 . M o d if ie d B en z id en e m ethod (C ro sb y & F i r t h 1936)3* C r ip p s method (C r ip p s 1 9 6 8 )6 . C yanm ethem oglobin m ethod ( F l e i s c h i 960)

7 . Atomic a d s o r p t i o n o f p la sm a i r o n ( A tk in s M.Sc. 1974)8 . R a d i o a c t iv e t a g g in g (B la c k s h e a r ( 3 ) )9« S ta n d a r d S h e a r t e s t . ( P e i r c e (19 ) 1972)

1 0 . M easurem ent o f Endogenous P r o d u c t i o n o f Carbon Monoxide (W a l la c e(1 ) 1969)

I n a l l c a s e s , i t i s e s s e n t i a l t o e l i m i n a t e w hole r e d c e l l s from p la sm a s i n c e th e y c o n t a i n 1 3 ~ l 8g p e r 100 m l.

3 . 1 . 2 . 3 . S e l e c t i o n o f h e m o ly s i s M e th o d s .

M ethods 3 j 3» 6 and 7 w ere s e l e c t e d f o r f u r t h e r s t u d y . The B en z id en e m ethods ( 2 , 4 ) w ere e l i m i n a t e d on h e a l t h g ro u n d s a s b e n z id e n e i s a c a r c e n o g e n ic m a t e r i a l . M ethods 8 , 9 and 10 have n o t b e en

g e n e r a l l y a c c e p te d i n th e f i e l d o f a r t i f i c i a l lu n g r e s e a r c h .

3 . 1 . 2 . 4 . The O r t h o t o l i d e n e M ethod.P lasm a i s s e p a r a t e d , by c e n t r i f u g i n g a t 3000 r e v / m i n . f o r 13

m in u te s , drawn o f f and r e f r i g e r a t e d u n t i l n eed ed f o r m e asu re m e n t .

1 ml o f a known s o l u t i o n o f o r t h o - t o l i d e n e i s added t o 0 .0 2 ml

o f p la sm a . 1 ml o f h y d ro g en p e r o x id e i s th e n added , w h ich s t a r t s a p e r o x id e r e a c t i o n c a t a l y s e d by h e m o g lo b in . A f t e r e x a c t l y 10 m in u te s

th e r e s u l t i n g d a r k g re e n s o l u t i o n i s d i l u t e d w i t h 10 ml o f a c e t i c a c i d

s lo w in g th e r e a c t i o n to a n e a r s t a n d s t i l l . An e x t i n c t i o n c o - e f f i c i e n t

i s th e n r e a d w i th o u t d e la y on th e s p e c t r o p h o t o m e t e r .

- 37 -

A c a l i b r a t i o n c u rv e i s drawn on r e a d i n g s f o r v a r i o u s d i l u t i o n s o f w hole l y s e d b lo o d .

3 . 1 . 2 . 5 . C yanm ethem og lob in .M ethod .0 .0 2 ml o f th e p la sm a i s d i l u t e d i n if ml o f D r a b K . in ’s s o l u t i o n

made up from ' a c u l n t e 1 d i l u e n t p e l l e t s . H em oglobin , m eth em o g lo b in and ca rb o x y h em o g lo b in (but h o t s u lp h e m o g lo b in ) a r e c o n v e r t e d t o cy anm ethem og lob in i n th e t e n m in u te s a l lo w e d f o r th e s o l u t i o n t o s t a n d . The o p t i c a l d e n s i t y (OD) o f t h e s o l u t i o n a t 5L\0 nrn i s com pared to t h a t o f a s t a n d a r d s o l u t i o n (BDH) and to a r e a g e n t b la n k ( w i th an I l fo rd 623 f i l t e r ) . The p la sm a hem o g lo b in l e v e l i n t h e sam ple i s c a l c u l a t e d b y : -

OD sam ple x c o n c . s t d . (mg%) x d i l u t i o n f a c t o r Hemoglobin (ms%) = OD s t a n d a r d .

A l t e r n a t i v e l y a s t a n d a r d c u rv e i s p ro d u c e d o f O p t i c a l D e n s i ty a g a i n s t P la s m a H e m o g lo b in c o n c e n t r a t i o n by d i l u t i n g th e s t a n d a r d i n

w i th th e r e a g e n t i n i n c r e a s i n g am ounts and d e t e r m in in g t h e o p t i c a l d e n s i t y o f e a c h . The o p t i c a l d e n s i t y o f th e sp ec im en i s th e n m e re ly t r a n s l a t e d i n t o a h em o g lo b in c o n c e n t r a t i o n from t h e c u r v e .

3 . 1 . 2 . 6 . C r ip p s M ethod .A s t o c k s o l u t i o n o f oxyhem oglob in i s made by h e m o ly s in g r e d c e l l s

o f p o o le d h e p a r i n i s e d b lo o d w i th d i s t i l l e d w a te r , t h e s o l u t i o n t h e n

b e in g s e p a r a t e d by c e n t r i f u g a t i o n .S u i t a b l e d i l u t i o n s o f t h i s s o l u t i o n a r e made i n p h o s p h a te b u f f e r

(pH 7 .3 ) t o o b t a i n f i n a l c o n c e n t r a t i o n s o f oxyhem oglob in i n t h e r a n g e

3 -1 3 0 The h e m o g lo b in c o n t e n t i s fo u n d by m aking p a r a l l e l d i l u ­t i o n s i n D r a b k in ’s s o l u t i o n and co m p ar in g w i th a known cy anm ethem og lob in s t a n d a r d a s i n th e p r e v io u s , m ethod .

576 5?2.5£oW A m e l E U C T M V\V<r\

- 38 -

The a b s o r p t i o n o f oxyhem oglob in i s d e te r m in e d a t 360 n m ^ *

376 n n / ^ and 392 n m ^ and th e q u a n t i t y 2y - (x + z ) i s c a l c u l a t e d

f o r e ac h s a m p le . The g ra p h o f oxyhem og lob in c o n c e n t r a t i o n i n mg% a g a i n s t t h i s q u a n t i t y i s l i n e a r .

An a l lo w a n c e can be made f o r e r r o r s i n t r o d u c e d by t h e p r e s e n c e o f b i l i r u b i n i n th e sam p le .

3 * 1 . 2 . 7 . The Atomic A b s o r p t io n M ethod.

The p la sm a sam ple i s su ck ed i n t o th e i n j e c t o r p i p e and v a p o r i s e d .

a

The Atomic A d s o r p t io n S p e c t r o p h o to m e te r

The serum i r o n i n th e sam ple i n c r e a s e s th e a to m ic a d s o r p t i o n and r e d u c e s

th e l i g h t e n e rg y r e c e i v e d a t th e d e t e c t o r . The a d s o r p t i o n i s a l i n e a r

f u n c t i o n o f i r o n i n th e sam ple and i s com pared w i t h th e a d s o r p t i o n

o f a c o m m e rc ia l ly p ro d u c e d , f r e e z e - d r i e d serum s t a n d a r d . The m ethod i s c a p a b le o f r e c o r d i n g ch an g e s a s low a s 1 mg i r o n p e r 100 ml se ru m .

S in c e 100 gm o f h em o g lo b in c o n t a i n s 0 .3 3 gm i r o n , th e a c c u r a c y o f t h e method s h o u ld be - 0 .2 8 mg% p la sm a h em o g lo b in B i l i r u b i n w h ich i s n o t

an i r o n d e r i v a t i v e c a u s e s no p ro b le m s .

- 39 -

3 « 1 * 2 .9 . P r o t e i n D e n a t u r a t i o n - D i s c u s s i o n .I t h a s b e en c la im e d t h a t d e n a t u r a t i o n r e s u l t s from th e u s e o f

h e a r t - l u n g m a c h in e s , c a u s i n g : -

1 . M o r t a l i t y o f s e v e r a l p e r c e n t o f p a t i e n t s , w hich r a t e i n c r e a s e s w i th p e r f u s i o n t im e .

2 . S lu d g in g .

3 * 100% i n c i d e n c e o f c e r e b r a l f a t em bolism .A* N e u r o lo g ic a l c o m p l i c a t i o n s i n 6 - 20% o f h e a r t l u n g c a s e s .

F a c t o r s w hich c a u s e h e m o ly s i s c o u ld a l s o c a u s e d e n a t u r a t i o n , b u t

one f a c t o r w hich i s th o u g h t t o b e c o n c l u s i v e l y l i n k e d t o d e n a t u r a t i o n i s t h e b lo o d g a s i n t e r f a c e (Anson (1945 , D o b e l l (1963)> Lee (1 9 6 1 ),0^2.)

W rig h t (1 9 6 2 ) , Z a p o l5 (1 9 7 2 ) .D e n a tu r a t io n c h an g e s p h y s i c a l and p h y s i o l o g i c p r o p e r t i e s and

r e s u l t s i n an u n f o l d i n g o f th e p r o t e i n m o le c u le . The h y d ro g e n bond

i n th e main l i n k a g e i s d e s t r o y e d , th e s p a t i a l a r ra n g e m e n t o f

p o l y p e p t i d e c h a i n s i s changed to a more d i s o r d e r e d a r r a n g e m e n t w i t h i n th e m o le c u le . The p r o t e i n s a r e s u b t l y a l t e r e d so th e y no l o n g e r f u n c ­t i o n p r o p e r l y . S u r f a c e t e n s i o n i s ch an g ed , e n z y m a tic a c t i v i t y i s ;, lo w e re d and t h e r e i s a l o s s o f a n t i g e n i c i t y * B o i le d egg w h i t e i s o f t e n q u o te d a s an exam ple o f th e e f f e c t o f d e n a t u r i n g p r o t e i n .

As w e l l a s th e b lo o d - g a s i n t e r f a c e , , x - r a y , ...and u l t r a v i o l e t

i r r a d i a t i o n ( H a r p e r ) , h e a t ( L e e -1 9 7 1 ) , pH c h a n g e s , membranes w i t h h ig h

d i e l e c t r i c c o n s t a n t ;, and c o n t a c t w i th heav y m e t a l s , e . g . , z i n c , a l l c au se , d e n a t u r a t i o n . D e n a tu red p r o t e i n i s l e s s s o l u b l e , can be rem oved by f i l t r a t i o n , and h a s a lo w e re d b i o l o g i c a l a c t i v i t y . Under

c e r t a i n c i r c u m s t a n c e s . t h e p r o c e s s o f d e n a t u r a t i o n may be r e v e r s i b l e .D e n a tu r a t i o n i n c r e a s e s p la sm a t u r b i d i t y and v i s c o s i t y and may

a f f e c t th e m o b i l i t y o f th e p r o t e i n i n e l e c t r o p h o r e s i s . O th e r m e th o d s

w hich m ig h t be employed to d e t e c t th e p r e s e n c e o f d e n a tu r e d p r o t e i n i n c l u d e g e l f i l t r a t i o n , u l t r a c e n t r i f u g a l , o p t i c a l r o t a r y d i s p e r s i o n , c i r c u l a r d ic h r o i s m , h y d ro g en exchange v i s c o s i m e t r y , x - r a y d i f f r a c t i o n

and n u c l e a r m a g n e t ic r e s o n a n c e .No a g re em e n t i s r e a c h e d on th e e f f e c t s o f d e n a t u r a t i o n o r on i t s

q u a n t i f i c a t i o n . Lee ( ( 1 ) 1961) s u g g e s t s t h a t m o r b i d i t y and m o r t a l i t y

may be c o n n e c te d t o d e n a t u r a t i o n by e i t h e r ’ s l u d g i n g 1 o r by a l t e r a t i o n s

- 4 0 -

i n b lo o d l i p i d s . H is a n a l y s i s t e c h n i q u e a p p e a r s t o b e a v i s u a l i n s p e c t i o n o f t h e p a p e r e l e c t r o p h e r o g r a m and he c l a im s an 8 - 10%

i n c r e a s e i n g l o b i n s f o r non-membrane o x y g e n a to r s and o n ly 2 - 6% f o r

t h e membrane o x y g e n a to r . I n a more r e c e n t p a p e r (Lee (3 ) 1971) he c l a i m s d e n a t u r a t i o n may a l s o a l t e r immune o r h o s t r e s i s t a n c e

m echan ism s . W rig h t (1 9 6 2 ) , a l s o h i g h l i g h t s t h e p o s s i b l e r e l a t i o n s h i p .

b e tw een d e n a t u r a t i o n and c o m p l i c a t i o n s f o l l o w i n g p r o lo n g e d b y p a s s .H is e x p e r im e n t s co m p arin g th e e f f e c t s o f membrane and non-membrane o x y g e n a to r s u s e d th e S p in c o A n a l y t r o l t o a n a l y s e p a p e r e l e c t r o p h e r o g r a m s . He o b s e r v e d s l i g h t c h a n g e s i n th e e l e c t r o p h o r e t i c p a t t e r n and an i n c r e a s e d m o b i l i t y o f t h e g l o b u l i n b u t th o u g h t t h e s e t o be i n s i g n i f i c a n t . P e i r c e ((10) 1 9 7 3 ) i how ever, b a s e d on t h e e v id e n c e o f

D o b e l l (1963)* Z apo l (( 3 ) 1972) and o t h e r s , i s c o n v in c e d t h a t d e n a t u r a t i o n i s l e s s m arked i n th e membrane Lung and i n h i s r e f . ( ( 9 ) 1 9 7 3 ) r e q u o t e s L e e ’s ( ( 2 ) 1961) r e s u l t s .

. I n a r e c e n t p a p e r , K ayser (1974) exam ines th e work o f Lee ,Kauzmann, Anson and o t h e r s w o rk in g on th e r e l a t i o n s h i p b e tw ee n d e n a t u r a t i o n and th e ty p e o f o x y g e n a to r u s e d . He c r i t i c i z e s th e l a c k o f e x p e r im e n t s c o n d u c te d u n d e r p h y s i o l o g i c a l c o n d i t i o n s and .

t h e i r r e l e v a n c e o f many o f th e e x p e r im e n t s p e r fo rm e d to c l i n i c a l a p p l i c a t i o n . He c o n c lu d e s t h a t th e mechanism o f p r o t e i n d e n a t u r a t i o n d e s c r i b e d i n p r o t e i n c h e m i s t r y l i t e r a t u r e may n o t be r e l e v a n t t o .

modern o x y g e n a to r s , t h a t t h e r e a r e no p ro v e n s i g n i f i c a n t d i f f e r e n c e s b e tw ee n membrane and non-membrane o x y g e n a to r s and t h a t t h e u s e o f membrane o x y g e n a to r s on th e a s s u m p t io n t h a t th e y a r e more p h y s i o l o g i c a l

i s u n j u s t i f i e d . He q u o te s P e i r c e ( (1 4 ) 1969) to c o n f i rm h i s v i e w s . 3 . 1 . 2 . 1 0 M ethods o f P r o t e i n D e n a tu r a t io n A ssay . (Kauzmann)

The f o i l o w i n g t a b l e s l i s t m ethods o f d e t e c t i n g a l t e r a t i o n s t o t e r t i a r y s t r u c t u r e o f p r o t e i n s and to s h o r t r a n g e p r o p e r t i e s b o t h

o f w hich a r e r e c k o n e d to o c c u r i n p r o t e i n d e n a t u r a t i o n .

T a b le 1 . Shape P r o p e r t i e s

Hydrodynamic p r o p e r t i e s

A) F r i c t i o n R a t ioB) V i s c o s i t y in c r e m e n tC) R o ta ry d i f f u s i o n c o n s t a n t ( f lo w b i r e f r i n g e n c e , d i e l e c t r i c

r e l a x a t i o n , f l u o r e s c e n c e d e p o l a r i z a t i o n ) .

' - 41 -

R a d i a t i o n s c a t t e r i n gA) L i g h t s c a t t e r i n gB) S m all a n g le x - r a y s c a t t e r i n g

L o n g -ra n g e e l e c t r o s t a t i c e f f e c t s on t i t r a t i o n c u r v e s , L inderstrjzfm - Lang*s , »W»

E l e c t r o n m ic ro sc o p y

Second v i r i a l c o e f f i c i e n t o f m o d e ra te s a l t c o n c e n t r a t i o n s S u r f a c e p r o p e r t i e s

A) F o r e e - a r e a c u r v e s a t m o d e ra te p r e s s u r e sB) S u r f a c e d i p o l e moment

C) A rea o f s o l i d f i l m .D ip o le moment

D i f f u s i o n th ro u g h membranes w i th c o n t r o l l e d p o r e s i z e s , C r a ig

3»1»2»11 T a b le 2. S h o r t - r a n g e p r o p e r t i e s .Thermodynamic P r o p e r t i e sA) E nergy and H ea t c a p a c i t yB) E n tro p y ,;C) (Free energy )

D) Volume, c q n p r e s s i b i l i t y and c o e f f i c i e n t o f e x p a n s io nE) S o l u b i l i t y , a c t i v i t y , d i s t r i b u t i o n b e tw een s o l v e n t s .O p t i c a l P r o p e r t i e sA) O p t i c a l r o t a t i o n and d i s p e r s i o n

B) I n f r a r e d a b s o r p t i o nC) V i s i b l e and u l t r a v i o l e t a b s o r p t i o n

D) Wide a n g le x - r a y d i f f r a c t i o nE) In d e x o f r e f r a c t i o n ( p o l a r i z a b i l i t y , a n i s o t r o p y )F) D e p o l a r i s a t i o n o f f l u o r e s c e n c e ( i n some c a s e s ) .C hem ical P r o p e r t i e sA) R e a c t i v i t yB) I n t r i n s i c pH 1 s o f a c i d i c and b a s i c g ro u p sC) Hydrogen - d e u te r iu m o r h y d r o g e n - t r i t i u m ex ch a n g e .D) B in d in g o f s m a l l m o le c u le s , d y e s , i o n s and th e l i k e .

E) Immunochemical p r o p e r t i e sF ) D i g e s t i b i l i t y by p r o t e o l y t i c enzymes

G) B i o l o g i c a l a c t i v i t y

H) E l e c t r o p h o r e s i s ( i s o e l e c t r i c p o i n t , z e t a p o t e n t i a l )

N u c le a r and e l e c t r o n i c m a g n e t ic r e s o n a n c e ,

- 42 -

S u r f a c e phenomena

A) S p r e a d a b i l i t yB) S u r f a c e v i s c o s i t y

C) ( S u r f a c e d i p o l e moment)

3 . . 1 .2 .1 2 . S e l e c t i o n o f p r o t e i n D e n a tu r a t io n A ssayOf a l l t h e m ethods o f a s s a y l i s t e d none i s - b e t t e r known th a n

e l e c t r o p h o r e s i s . W ith th e l i m i t a t i o n o f a v a i l a b l e e q u ip m en t andtim e c o n s t r a i n t s i t was d e c id e d to a d o p t t h i s m ethod . However, w i t h i n t h i s c a t e g o r y a r e a number o f t e c h n i q u e s : -

1 . P a p e r e l e c t r o p h o r e s i s a t low v o l t a g e2 . High v o l t a g e p a p e r e l e c t r o p h o r e s i s .3* T h in l a y e r e l e c t r o p h o r e s i s4 . C e l l u l o s e a c e t a t e e l e c t r o p h o r e s i s 3* I m m u n o - e l e c t r o p h o r e s i s 6 . Agar g e l e l e c t r o p h o r e s i s 7* S t a r c h g e l e c l e c t r o p h o r e s i s8 . A cry lam id e g e l d i s c e l e c t r o p h o r e s i s

9* C o n c e n t r a t i o n g r a d i e n t p o ly a c r y la m id e g e l e l e c t r o p h o r e s i s .

5 . 1 . 2 . 1 3 S e l e c t i o n o f E l e c t r o p h o r e t i c M ethod .E l e c t r o p h o r e s i s on c e l l u l o s e a c e t a t e membrane i s p a r t i c u l a r l y

s u i t e d to th e s tu d y o f serum p r o t e i n s (Kohn) and th e e l e c t r o p h e r o g r a m p ro d u c e d i s p a r t i c u l a r l y c o n v e n ie n t to a n a l y s e q u a n t i t a t i v e l y . Themethod h a s th e f o l l o w i n g a d v a n ta g e s o v e r p a p e r e l e c t r o p h o r e s i s .

1 . S a t i s f a c t o r y s e p a r a t i o n c an b e a c h ie v e d o v e r a r e l a t i v e l y s h o r t d i s t a n c e a f t e r a r e l a t i v e l y s h o r t r u n n i n g t im e a t

low v o l - t a g e .2 . B ackground s t a i n i n g i s m in im al and p h o t o e l e c t r i c s c a n n in g

g i v e s r e l i a b l e q u a n t i t a t i v e r e s u l t s .3 . C e l l u l o s e a c e t a t e i s s o l u b l e i n some s o l v e n t s (A c e to n e )

making c o l o r i m e t r i c e s t i m a t i o n o f t h e s e p a r a t e d z o n e s c o n v e n ie n t and a c c u r a t e .

4* P r o t e i n s b e in g non. a d s o r b e d c an be s t u d i e d above and b e lo w

t h e i r i s o e l e c t r i c p o i n t s ,3« A b e t t e r s e p a r a t i o n o f <*, g l o b u l i n can b e o b t a i n e d .6 . Serum p r o t e i n s s t a i n p a r t i c u l a r l y w e l l and t h e i r dye

u p ta k e i s v e r y s i m i l a r .

7 . Very s m a l l s am p le s can b e s t u d i e d ( . 1 mg / . I S)v 8 . C e l l u l o s e a c e t a t e membrane i s v i r t u a l l y f r e e o f c o n ta m in a n t s

- 43 -

3 . 1 . 2 . 1 4 The Method o f A c e t a t e E l e c t r o p h o r e s i s

The a c e t a t e s h e e t i s f i r s t so ak e d , r i g h t way up i n ( 8 . 6 3 : 0 . 1 )"buffer by r e s t i n g i t on t h e s u r f a c e th e n su b m erg in g a f t e r f i v e m in u te s .To a s m a l l sm ear o f B rom o-Phenol B lue i s added t h e serum on e ac h segm ent

o f t h e a p p l i c a t o r p l a t e . The a c e t a t e s h e e t i s rem oved and g e n t l y b l o t t e d and th e a p p l i c a t o r h a v in g b e en t e s t e d once o r tw ic e on b l o t t i n g p a p e r i s to u c h e d l i g h t l y and e v e n ly on th e s h e e t a t one i n c h from th e ' b l a c k l e a d 1 en d . The s h e e t i s th e n p la c e d s q u a r e on th e c l o t h e l e c t r o d e , th e l i d r e p l a c e d and t h e c u r r e n t (210 V) s w i tc h e d on f o r 20 m in u te s .

The s t r i p i s th e n rem oved and p l a c e d i n 0.3% P onceau S o l u t i o n ■7 .05% TCA f o r s i x m in u te s and su bm erged . The s t r i p i s f i n a l l y c l e a r e d i n two o r t h r e e r i n s e s of 3% a c e t i c a c i d .

3 . 1 . 2 . 1 5 M ethods o f A n a ly s i s o f E i e c t r o p h e r o g r a m s (W h ita k e r 1967)I f e l e c t r o p h o r e s i s i s c a r r i e d o u t u n d e r s t r i c t l y c o n t r o l l e d

c o n d i t i o n s q u a n t i t a t i v e a n a l y s i s may be a c h ie v e d i n any o f th e f o l l o w i n g w a y s : - V : .

1 . V is u a l c o m p ar iso n - The d e n s i t y o f c o lo u r and t h e s i z e ' o f

zone a r e com pared v i s u a l l y w i th t h o s e o f a known s t a n d a r d . A c c u ra c y i lO - 20%.

2 . A rea o f zone ( F i s h e r ) - The a r e a s o f zone o f known and unknown a r e d e te rm in e d f o l l o w i n g p h o to g r a p h ic e n la r g e m e n t

and w e ig h in g . A ccuracy ±5%3 . T o t a l c o lo u r d e n s i t y (B lo ck 1 , B u l l , P e d f i e l d ) - The

e l e c t r o p h e r o g r a m i s s ca n n e d i n a d e n s i t o m e t e r a t t h e w a v e le n g th maximum o f th e d e t e c t e d z o n e s . The b a s e l i n e i s d e te r m in e d by s c a n n in g b la n k s t r i p s . The a b s o r b a n c e v e r s u s t h e d i s t a n c e a lo n g th e e l e c t r o p h e r o g r a m i s p l o t t e d m a n u a l ly or a u t o m a t i c a l l y . The a r e a u n d e r t h e c u r v e f o r e ac h f r a c t i o n i s th e n d e te r m in e d a u t o m a t i c a l l y ( e . g . u s i n g t h e S p in eo A n a l y t r o l - L e e ) , by w e ig h in g o r u s i n g a

p l a n i m e t e r . These a r e a g a in com pared w i th s t a n d a r d

c o n c e n t r a t i o n s . A ccu racy ±-5%.4 . Maximum C o lo u r D e n s i ty (B lo ck 2 ) - As above, t h e t r a c e i s

s c a n n e d i n th e d e n s i t o m e t e r b u t h e r e t h e maximum c o l o u r

d e n s i t y i s com pared to th e s t a n d a r d . A ccu racy ± 3%•

3 . A rea X A bso rbance Method - com bines m ethods 2 and 4 b u t

a p p e a r s to o f f e r no a d v a n ta g e s o v e r 4«

(D en t, -.Coueden, D ixon , W i ls o n ) .

6 . E T u j t io n - The m ost a c c u r a t e m ethod b u t one r e q u i r i n g enorm ous c a r e and p r e c i s i o n

A wedge sh ap ed s t r i p i s c u t from th e zone and by a v a r i e t y o f p o s s i b l e m ethods i s s o ak e d i n t h e e l u ^ t i n g f l u i d and th e e le m e n t i s c o l l e c t e d and a p p l i e d to a seco n d s u p p o r t . The c o n c e n t r a t i o n o f th e

s o l u t e i s t h e n d e te r m in e d by t h e u s u a l fo rm s o f a n a l y s i s .3 . 1 . 2 . 1 6 S e l e c t i o n o f M ethod .

Of th e s i x l i s t e d m ethods (1 ) was e l i m i n a t e d oh th e g ro u n d s o f lo w a c c u r a c y , ( 2 ) b e c a u s e o f t h e d i f f i c u l t i e s o f u s i n g th e m ethod on a sam p le

c o n t a i n i n g s e v e r a l f r a c t i o n s , ( 5 ) s i n c e i t o f f e r e d no a d v a n ta g e s o v e r

( k ) and ( 6 ). b e c a u s e o f t h e h ig h l e v e l o f s k i l l , p r e c i s i o n and t im e

i n v o l v e d .Of th e two r e m a in in g m e thods , ^ was c o n s i d e r e d to have t h e g r e a t e r

r e l e v a n c e to e x p l o r i n g th e ch an g e s o f t h e r e l a t i v e p r o p o r t i o n s o f f r a c t i o n s

i n th e sa m p le .The a r e a s , a s s t a t e d p r e v i o u s l y , can b e fo u n d u s i n g a p l a n i m e t e r

o r by c u t t i n g o u t and w e ig h in g . The p ro b lem th o u g h , i s t o e s t i m a t e a r e a s

a t an o v e r l a p .

C—

\&X

T h is may be done i n t h r e e w ays.1 . Where t h e o v e r l a p i s s m a l l , a p e r p e n d i c u l a r may be drawn

b e tw een each ’ t r o u g h 1 and t h e b a s e l i n e .

2 . By i s o s c e l e s t r i a n g l e s : -

1> £ F £

AB i s drawn from a p e ak down t h e ' r e m o t e s id e * o f th e c u rv e from th e t r o u g h . CD i s s i m i l a r l y drawn f o r t h e sec o n d p e a k . AE and CF c o m p le te i s o s c e l e s t r i a n g l e s , CDF andAIB. The sh ad e d a r e a i s s h a r e d b e tw een l e f t and r i g h thand 'p e a k s '

3 . By a n a lo g u e c o m p u te r .

The f i r s t o f t h e s e ways was s e l e c t e d f o r c o n v e n ie n c e . The m ethod r e q u i r e d th e u se o f a d e n s i t o m e t e r w h o s e s e t t i n g s a r e shown b e lo w .

3 U C ,

The t r a c e was p ro d u c e d by a pen r e c o r d e r from th e e l e c t r o p h o r g r a m . One su ch t r a c e i s shown below. . .

CLC cxeo pntsRocreflM

- 46 -

5 . 1 . 2 . 1 7 A g g l u t i n a t i o n

The s u r f a c e o f th e r e d c e l l c a r r i e s p r o t e i n a g g l u t i n o g e n s w h ich combine w i th ' f o r e i g n * a g g l u t i n to form p r o t e i n a t t a c h m e n t s w hich i r r e v e r s i b l y cem ent th e r e d c e l l s t o g e t h e r i n c lu m p s . I t o c c u r s i n a

•m ism atch o f b lo o d g ro u p s and f o l l o w i n g pumping th ro u g h an in -~ v i t ro c i r c u i t .M easurem ent o f th e E r y t h r o c y t e S e d im e n ta t io n H a te (ESR - n o r m a l l y

1 -1 2 m m /hour), t h e r a t e a t w hich r e d c e l l s s e t t l e i n p la sm a , g i v e s an i n d i c a t i o n a s t o t h e e x t e n t o f c lu m p in g . I t dep en d s on s u r f a c e t e n s i o n and s u r f a c e a r e a and t h e r e f o r e i n c r e a s e s w here r o u l e a u x a r e fo rm ed i n v/hich c a s e t h e r e i s i n c r e a s e d f i b r i n o g e n and g l o b u l i n b u t r e d u c e d a lb u m in .

The r o u l e a u x a r e h a r m le s s i n th e m s e lv e s b u t p ro m o te th rom bus f o r m a t i o n , r e d u c i n g o x y g e n a to r e f f i c i e n c y .3 . 1 . 2 . 1 8 Em boli

Em boli may b e th ro m b i , f a t g l o b u l e s , tum our c e l l s , g h o s t c e l l s o r

even a i r b u b b l e s . Poor hemodynamics e s p e c i a l l y low f lo w r a t e s , p ro m o te th ro m b i a s d o es t h e p r e s e n c e o f p o s i t i v e e l e c t r i c a l c h a r g e s . They g r e a t l y r e d u c e e f f e c t i v e membrane a r e a and a r e one o f th e m a jo r c a u s e s o f d e a th on th e o p e r a t i n g t a b l e . A v i s u a l o b s e r v a t i o n o f m acro em b o li w i l l

be' u n d e r t a k e n .

3 . 2 . 1 9 P l a t e l e t l o s s and W hite c e l l l o s s .E x t r a c o r p o r e a l c i r c u l a t i o n i s known to lo w e r p l a t e l e t c o u n t

i m p a i r i n g f u n c t i o n som etim es to th e p o i n t w here h e m o s t a s i s f a i l s . As w i th o t h e r p a r t i c l e s , d e p o s i t i o n o f p l a t e l e t s i s m ost l i k e l y to o c c u r a t s t a g n a t i o n p o i n t s . I n i n v i t r o t e s t s , w h i te c e l l c o u n t f a l l s d r a m a t i c a l l y However, i n v i v o , t h e o p p o s i t e h a p p en s a s th e body b u i l d s up d e f e n c e s i n t h e p r e s e n c e o f a l a r g e amount o f f o r e i g n m a t e r i a l . A l th o u g h p l a t e l e t and w h i t e c e l l c o u n t s a r e i n t e r e s t i n g th e y a r e n o t c o n s i d e r e d h i g h l y

r e l e v a n t t o t h i s t h e s i s .3 . 1 . 2 . 2 0 S lu d g in g

I n t r a v a s c u l a r s lu d g in g i s d i r e c t l y r e l a t a b l e to t h e i n v i t r o ESR.

I t i s th e i r r e g u l a r m a ss in g o f r e d b lo o d c e l l s and em b o li and i s t h e n e x t s t a g e f o l l o w i n g r o u l e a u x f o r m a t i o n . I t can b e a g g r a v a t e d by c o n t a c t w i th h ig h m o le c u la r w e ig h t d e x t r a n o r g e l a t i n . S lu d g in g i s a d i f f i c u l t

p a r a m e te r t o q u a n t i f y and a m ere ly v i s u a l ch eck on th e e x t e n t o f i t s

p r e s e n c e w i l l be n o t e d .A c h ec k w i l l be made, how ever, on th e e f f e c t o f s l u d g i n g on th e

membrane, m a t e r i a l u s in g th e s c a n n in g e l e c t r o n m ic r o s c o p e . S am ples o f th e

membrane b e f o r e and a f t e r u s e w i l l be com pared f o r s i g n s o f 'c lo g g e d * p o r e s .

- 47 -

3 . 2 . C h o ice o f I n s t r u m e n t a t i o n .

3 . 2 . 1 . O x y g e n a t io n p e r fo rm a n c e

The g a s s u p p l i e s from B r i t i s h Oxygen s p e c i a l g a s e s a r e m o n i to r e d f o r f lo w r a t e u s i n g G E C /E l l i o t t r o t a m e t e r s and f o r p r e s s u r e u s i n g s im p le g l a s s (w a te r o r m e rc u ry ) m an o m ete rs .

The b lo o d g a s c o n t e n t i s r e c o r d e d by d raw in g s am p le s s lo w ly th ro u g h

a s h o r t s e c t i o n o f s i l i c o n e r u b b e r tu b e i n t h e c i r c u i t (w h ich s e l f s e a l s ) a n d - w i th d i s p o s a b l e n e e d le and s y r i n g e . (N eed le gauge a s recommended i n Dacey an d L e w is ) . The sam ple i s i n s e r t e d i n t h e R a d io m e te r BMS 3

i n s t r u m e n t and th e PO^, PCO^, and pH a u t o m a t i c a l l y i n d i c a t e d on t h e R a d io m e te r D i g i t a l A cid Base A n a ly s e r PHM 7 2 c .

3 . 2 . 2 . B lood c o n d i t i o n m easurem en t

The i n i t i a l c o n d i t i o n o f th e b lo o d i s n o te d by e x a m in a t io n u n d e r t h e m ic ro s c o p e f o r c r e n a t e d o r damaged c e l l s and by a m i c r o h e m a t o c r i t

u s i n g a Gallen^Kamp J u n i o r c e n t r i f u g e and a H awkesiey r e a d e r to d e te r m in e

packed c e l l yo lum e. The l a t t e r r e q u i r e s a m o d i f i c a t i o n t o a l lo w f o r t h e d i l u t i o n of b lo o d by ACD

H em o ly s is m easurem en t i s a c h ie v e d a s d e s c r i b e d u s i n g e i t h e r t h e Pye U n ic a m SP 600 S p e c t r o p h o to m e te r o r th e Atomic A d s o r p t io n

S p e c t r o p h o to m e te r .E l e c t r o p h o r e s i s m easurem ent em ploys th e Shandon e l e c t r o p h o r e t i c

t a n k and t h e V i t a t r o n D e n s i to m e te r and R e c o r d e r .Red C e l l c o u n t s , where e x e c u te d u s e d th e m o d i f ie d Ne-uba-u-er cham ber.

3 . 3 . The C o n s t r u c t i o n o f a W orking Model O xygena to rAs s t a t e d i n s e c t i o n 2 . 2 . 3 and 2 .3 , b lo o d i s a h i g h l y com plex f l u i d

w hich l e n d s i t s e l f n e i t h e r to a n a l y s i s n o r to a n a lo g y . The s u p e r i o r i t y o f th e membrane o x y g e n a to r i s f e l t r a t h e r th a n p ro v e d , t h e r e l a t i o n s h i p , i f any e x i s t s , b e tw een h e m o ly s is and p r o t e i n d e n a t u r a t i o n h a s n o t b e e n

s a t i s f a c t o r i l y d e m o n s t r a t e d n o r have th e e f f e c t and i n t e r d e p e n d e n c e o f a l l t h e r e l e v a n t p a r a m e te r s o f b lo o d f lo w , g a s f lo w e t c . b e e n s t u d i e d

s i m u l t a n e o u s l y . The o n ly way to u s e f u l l y a s s e s s a membrane o x y g e n a to r i s t o b u i l d one and t e s t i t a s n e a r u n d e r p h y s i o l o g i c a l c o n d i t i o n s a s

p o s s i b l e .The o n ly s i l i c o n e r u b b e r a v a i l a b l e was a v e r y l i m i t e d s u p p ly o f

01003 i n t h i c k s h e e t . T h is p u t d e s ig n c o n s t r a i n t s on t h e model o f b o t h

ty p e and d im e n s io n s ( s e e f o l l o w i n g d r a w in g s ) .

- iiS -

The m ain f e a t u r e s o f t h e d e s i g n a r e : -

a ) M a n u fa c tu re d i n p e r s p e x , r e l a t i v e l y b i o c o m p a t ib l e and t r a n s p a r e n t so t h a t th e b lo o d f lo w can b e s t u d i e d and l e a k s d i s c o v e r e d e a s i l y .

b ) E a s i l y d i s m a n t l e d f o r c l e a n i n g , ( c h e m i c a l l y ) .c ) F a c i l i t y t o v i b r a t e o x y g e n a to r l i n e a r l y i n any d i r e c t i o n

and to r e c o r d th e a m p l i tu d e and f r e q u e n c y o f t h e v i b r a t i o n .e ) S m all p r im in g volum e so t h a t o n ly s m a l l q u a n t i t i e s o f b lo o d

n e ed be u s e d .

To t e s t t h e g a s t r a n s f e r c a p a b i l i t i e s o f t h e o x y g e n a to r th e f o l l o w i n g com ponen ts a r e a l s o r e q u i r e d : -

a ) F i lm d e o x y g e n a to rb ) P e r i s t a l t i c pumpc ) H eat e x c h a n g e r •d) P ipew ork and c o n n e c t o r s .

e ) G as- s u p p l i e s and i n s t r u m e n t a t i o nf ) B ubb le t r a pg). V i b r a t o r .

I t e m s , a , f and g were a l s o d e s ig n e d b y th e a u t h o r f o r t h i s s e r i e s o f e x p e r im e n t s .

3 . 3 . 1 C o n s t r u c t i o n a l D e t a i l s The O xygena to r

S in c e t h e o n ly form o f s i l i c o n e r u b b e r r e a d i l y a v a i l a b l e and s u i t a b l e f o r u s e i n an a r t i f i c i a l l u n g was i n 2/f cm. wide' s h e e t , t h e o x y g e n a to r was n e c e s s a r i l y d e s ig n e d a s a f l a t p l a t e t y p e . The s c a r c i t y o f t h e

m a t e r i a l c o n f in e d th e d im e n s io n s to a s m a l l s c a l e and r e n d e r e d th e

p o s s i b i l i t y o f a m u l t i s t a g e o x y g e n a to r i m p r a c t i c a b l e .The o x y g e n a to r d e s ig n e d by a u th o r f o r t e s t i n g p u r p o s e s , c o n s i s t s o f a

sandw ich o f f i v e p e r s p e x com ponents (see, f i g s . 1 - 6 ) . The c e n t r e

c o m p o n e n t , th e b lo o d s c r e e n , i s shown i n f i g u r e 3« I t c o n s i s t s o f a

f ram e c o n t a i n i n g a d r i l l e d m a n i fo ld o f u n ifo rm s e c t i o n a r e a e ac h l e a d i n g

from th e e n t r y and e x i t n i p p l e s to a l a r g e c e n t r a l a r e a w hich i s d e s ig n e d to t a k e an a n n e a le d g l a s s f i b r e s c r e e n o r t o r e m a in o p en .

The membrane s h e e t s a r e m ounted on e i t h e r s i d e o f t h e b lo o d s c r e e n

and a r e r e t a i n e d and s e a l e d by t h i n r u b b e r g a s k e t s . T h ic k g a s f r a m e s a r e added to e ac h s i d e o v e r th e s e a l s , th e t h i c k n e s s a i d i n g t h e s p r e a d i n g

o f th e c lam p in g f o r c e s and to i n c r e a s e th e s t r e n g t h o f t h e u n i t .

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F i n a l l y t h e two c o v e r s a r e p l a c e d -w ith f u r t h e r r u b b e r s e a l s t o r e n d e r ' t h e two g a s cham bers g a s - t i g h t . The chamber may t a k e a m e ta l s u p p o r t f r a m e , a s u p p o r t sponge o r a m u l t i p o i n t s u p p o r t .

The p r e s s u r e i n th e b lo o d p h a se i s d e s ig n e d to b e s l i g h t l y h i g h e r th a n t h a t o f th e g a s p h a se so t h a t b u b b le s w i l l n o t a r i s e i n t h e b lo o d . s h o u ld th e membrane be p e r f o r a t e d .

B lood i s i n t r o d u c e d from b o th s i d e s o f th e i n l e t m a n i f o ld and l e d from b o th s i d e s o f th e o u t l e t m a n i f o ld . Gas may b e i n t r o d u c e d i n t o

b o th cham bers s i m u l t a n e o u s l y i n e i t h e r p a r a l l e l o r c o n t r a f l o w o r a l t e r n a t i v e l y f lo w from one chamber to th e sec o n d i n s e r i e s .

The p e r s p e x c o v e r s e n a b le th e b lo o d f lo w to be s t u d i e d w i t h i n t h e o x y g e n a to r i f t h e m e ta l s u p p o r t f ram e i s .used and th ro m b o s e s , l e a k s and f lo w c h an g e s may be o b s e rv e d a s th e y h a p p en . The m e ta l s u p p o r t s c r e e n how ever, s e v e r e l y r e d u c e d th e e f f e c t i v e a r e a o f t h e membrane by more th a n 50?o. The a l t e r n a t i v e s a r e : t o l e t g a s p r e s s u r e a lo n e

s u p p o r t th e membrane i n w hich c a s e t h e r e i s no c o n t r o l o v e r b lo o d f lo w ; t o u s e a m u l t i p o i n t s u p p o r t o r to u s e a sponge s u p p o r t .

3 , 5 . 2. The v i b r a t o r .The o x y g e n a to r was d e s ig n e d to be c lam ped i n any a t t i t u d e on t h e

s t r i p s t e e l beam shown ( f i g . ? ) The beam may. b e f o r c e d t o v i b r a t e u s in g one o f a s e r i e s o f d i s c s on an e c c e n t r i c p i v o t d r i v e n by an e l e c t r i c m otor a t b e tw een 0 and 4-00 rev/m m . The a m p l i tu d e o f m o t io n

i s c o n t r o l l a b l e by a l t e r i n g th e r a d i u s a t w h ich th e l i n k arm p i v o t i s

c lam p ed . A l t e r n a t i v e l y a L r a g - d y n a m ic s v i b r a t o r may be u s e d b e in g d i r e c t l y c o n n e c te d to th e beam c e n t r e and d r i v e n by an o s c i l l a t o r . The

c o n t r o l o v e r t h e a m p l i tu d e o f m o tio n i s th e n l o s t b u t b o th f r e q u e n c y and

a m p l i tu d e a r e m o n i to re d by an end-m oun ted r e c o r d p l a y e r p i c k - u p , t h e s i g n a l from w hich may be f e d to a p e n r e c o r d e r .

5 . 3 . 5 . The d e o x y g e n a to rThe d e o x y g e n a to r ( f i g . 8 ) i s a g l a s s f i l m - t y p e m a n u f a c tu r e d i n th e

U n i v e r s i t y . I t c o n s i s t s o f a c e n t r a l v e r t i c a l i n l e t tu b e w h ich f e e d s

b lo o d t o t h e to p o f an u n d u l a t i n g c a s c a d e . At th e b a s e a r e s e v o i r c o l l e c t s th e b lo o d and t h i s i s d r a i n e d o f f th ro u g h t h e o u t l e t t u b e .The c a s c a d e i s s i t u a t e d i n a g l a s s g a s cham ber whose i n l e t i s above th e r e s e rv o i r l e v e l and whose e x i t i s a t th e to p o f t h e ch am b er. The o x y g e n a to r i& h i g h l y , e f f i c i e n t s i n c e i t i s t h e f a s t e r o u t s i d e ' l a y e r s 1

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o f b lo o d t h a t a r e p r e s e n t e d t o th e g a s . C o n t r o l o v e r th e r e s e rv o i r h e i g h t i s a c h ie v e d by r a i s i n g o r l o w e r in g th e w hole o x y g e n a to r on i t s s t a n d s i n c e th e o u t f lo w i s p r o p o r t i o n a l to th e head o f th e r e s e v o i r .3 . 3 . 4 The Pump

A s t a n d a r d V/atson-Marlow, 3 - i ‘o l l e r , p e r i s t a l t i c pump was u s e d .T h is gave a p u l s i n g f lo w up to a maximum r a t e of 100 m l/m in . S i l i c o n e r u b b e r t u b i n g w a s . u s e d .

3 . 3 . 5 The H eat E x ch an g erA s m a l l g l a s s c o i l h e a t e x c h a n g e r p ro v e d u n s a t i s f a c t o r y . I n i t s

p l a c e a G allenkam p r e s e r v o i r p lu s , h e a t e r v t h e r m o s t a t and s t i r r e r u n i t p r o v id e d th e c o n s ta n c y o f t e m p e r a t u r e . A l a r g e volum e o f w a te r was u sed and e v a p o r a t i o n from i t s s u r f a c e was i n h i b i t e d by a s u r f a c e c o v e r in go f s m a l l p l a s t i c c a p s u l e s . The c o i l w a s su sp e n d e d w i th t h e s t i r r e ra lo n g i t s a x i s .

3 . 3 . 6 The B ubb le T ran ( f i g . 9)T h is was d e s ig n e d a s an i n v e r t e d U - tu b e w i th a c e n t r a l

v e r t i c a l t a p p i n g . . The b lo o d i s s low ed th ro u g h th e w id e r s e c t i o n and th e b u b b le s s e p a r a t e o u t and c o l l e c t i n th e t a p p i n g . The g a s may be r e l e a s e d by o p e n in g th e c o ck .3 . 4 S e l e c t i o n o f E x p e r im e n ts

F iv e s e r i e s o f e x p e r im e n t s were d e s ig n e d to a c h ie v e t h e a im s

l i s t e d i n 2.Zf

a ) G S e r i e s - H em olys is t e s t s on c i r c u i t r y

b ) P » : ■ " '.'■■■ ■ " " pumpc ) F 11 . - P e r fo rm a n ce and trau m a t e s t s on F i l m e r c i r c u i td) M 11 - n n 11 n on Membrane Lunge ) E n - ii it ii it ii ti ti

e x p l o r i n g c h a n g e s o f p a r a m e t e r .

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E 11 P ig -f- EDTA ti

E 12 ii it ii

E 13 B ovine +■ EDTA tt ii

E lZf Human 0++• ACD tt V i b r a t i o n t r a n s i e n t s

Key:.F - F i lm Oxygenator.P ' - Pump ;M - Membrane O xygena to r H - H eat e x c h a n g e r

P - R eservoirT B ubble t r a p

V - V a lv e sFrom th e above e x p e r im e n t s th e 18 g r a p h s l i s t e d w ere drawn

- 62 -

Graph No. Axes Aim

1- P lasm a Hb.v t im e D e te rm in e damage by pump2 it ii 11 n c i r c u l a t i o n

3 Red c e l l c o u n t v P lasm a lib

P lasm a Hb.v t im eR e l a t e r e d c e l l c o u n t t o P la sm a Hb D e te rm in e damage by v a l v e s e t c .

3 ’ ** ii 11 n f i l m ox .6 ii ■ ii n ii v i b r a t i o n

7 ii . n 11 11 f i l m ox. c c t .8 i i it 11 “ membrane o x . c c t

9 % Albumin v t im e D ete rm in e p r o t e i n a l t e r a t i o n sm e a s u ra b le

1 0 ti it 11 a l t e r a t i o n s f o r f i l m ox

1 1 n ii n a l t e r a t i o n s f o r membrane ox

1 2 (A-V)S02 v b lood flow D e te rm in e e f f e c t o f b lo o d f lo w

13 Performance v n ii optimum b lo o d f lo w

::A- U : (A-V)S02 V t im e tt p r e s s u r e change t r a n s i e n t s

13 (A-V)S02 v pressure ii e f f e c t s o f o x y g e n a to rp r e s s u r e

16 (A-V)S02 v tim e it v i b r a t i o n change t r a n s i e n t s

17 (A-V ) SO^ v vilratiQr £ ii e f f e c t s o f v i b r a t i o n

18 (a- v ) so2 » ii ti

CHAPTER 4 EXPERIMENTAL WORK AND RESULTS

4 . I E x p e r im e n ts to a s s e s s i n c r e a s e s i n p la sm a hem o g lo b in4* 1 . 1 I n t r o d u c t i o n

F o u r s e r i e s o f e x p e r im e n t s were e x e c u te da ) P ’l - P 12 - Pump t e s t sb ) G 1 - G 6 - Component t e s t s

c ) F 1 - F 18 F ilm o x y g e n a to r t e s t sd ) M l - M 23 - Membrane o x y g e n a to r t e s t s

The a im s o f t h e s e t e s t s w i th r e f e r e n c e t o p la sm a h e m o g lo b in w ere t oa ) q u a n t i f y t h e h e m o ly s i s r a t e f o r t h e pump and o t h e r c i r c u i t

com ponents a lo n e i n o r d e r t o i s o l a t e , t h e p r o p o r t i o n o f damage b e i n g done by th e o x y g e n a to r s

b ) E n su re t h a t damage was due to c i r c u l a t i o n o f b lo o d n o t m e re ly i t s p r e s e n c e in th e circu.it/

c ) q u a n t i f y th e i n c r e a s e i n h e m o ly s is r a t e a t t r i b u t a b l e t o

a c t i v e v i b r a t i o n of t h e o x y g e n a to rd ) compare t h e h e m o ly s is r a t e s o f a f i l m and a membrane

o x y g e n a to r u n d e r i d e n t i c a l t e s t se ) r e l a t e r e d c e l l c o u n t to h e m o ly s is l e v e l . .

4 . 1 . 2. E x p e r im e n ta l D e s c r i p t i o n

4 . 1 . P . 1 Pump T e s t sTwo d i f f e r e n t t e c h n i q u e s .were u sed and t h e s e a r e i l l u s t r a t e d b e lo w ;

A i r d u c t

0Control.

Pi — P S

C Rsom Te>vij=>

aC O N T R O L .

E X 1 P T S P V - P q , P U .

The p e r i s t a l t i c pump sp ee d and t h e p ip e b o re and l e n g t h w ere i d e n t i c a l i n e ac h e x p e r im e n t . F o r t h e f i r s t s e r i e s P I - P 5 t h e pump d i r e c t i o n was r e v e r s e d eac h t im e a r e s e r v o i r e m p t ie d . F o r th e s e c o n d

s e r i e s P 7 - P 9» P 11 , th e r o t a t i o n d i r e c t i o n was m a i n t a i n e d . I n b o t h , b lo o d f lo w r a t e was ch eck ed by c o l l e c t i o n (93 m l / m i n . ) . S am ples w ere

drawn a t 30 m in u te i n t e r v a l s d u r in g t e s t s l a s t i n g up to f o u r h o u r s and t e s t e d f o r p la sm a h em o g lo b in by th e a to m ic a d s o r p t i o n m ethod and p la sm a p r o t e i n a l t e r a t i o n by p r o t e i n b i u r e t and c e l l u l o s e a c e t a t e e l e c t r o p h o r e s i s

m e th o d s . The b lo o d was i n a l l c a s e s t r a n s f u s i o n b lo o d a b o u t , t h r e e weeks

o ld and i n e ac h c a s e a m ic r o h e m a to c r i t was p e r fo rm e d a t s t a g e s d u r i n g

th e e x p e r im e n t . At t h e end o f each e x p e r im e n t th e b lo o d was a l lo w e d to s t a n d f o r a t l e a s t 30 m in u te s . The r e s u l t s a r e i l l u s t r a t e d i n

g ra p h s 1 and 2 .i-. 1 . P . P . Component t e s t s .

E x p e r im e n ts P 6, P 10 , P 12 and G 1 - G 2 w ere s p e c i f i c a l l y d e s ig n e d to i s o l a t e th e p r o p o r t i o n o f t h e h e m o ly s is c a u s e d by i n d i v i d u a l

com ponents o f t h e f u l l t e s t c i r c u i t .

j

C o n t r o l

RE’S

E x p t s . P 6, P 1 0 , P 1 2 ,(Room Temp.)

The f i r s t t h r e e o f t h e s e w ere d e s ig n e d t o d e te r m in e th e h e m o ly s i s

a t t r i b u t a b l e to t h e f i l m o x y g e n a to r .

f o

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RES - R e s e r v o i r BT - Bubble t r a p HE - H ea t e x c h a n g e r

MO - Membrane o x y g e n a to r

EO - F ilm o x y g e n a to r

f S am pling p o i n t X V alve o r clam p f Gas e n t r y

f B lood e n t r y

oo o P e r i s t a l t i c pump

E x p e r im e n ts G 1 and G 2 w ere c a r r i e d o u t w i th b o v in e b lo o d c o n t a i n i n g EDTA o v ACD a n t i c o a g u l a n t , a s w ere a l l t h i s s e r i e s , a t p h y s i o l o g i c a l t e m p e r a t u r e s w i th th e f u l l c i r c u i t . T h i s i n c l u d e d T p i e c e s and c lam ps, had b o t h o x y g e n a to r s s u p p l i e d w i th gasc and , i n t h e c a s e o f G 2, had th e membrane o x y g e n a to r v i b r a t i n g . Red c e l l and w h i te c e l l c o u n t s w ere p e r fo rm e d .

E x p e r im e n ts G 3 and 6 4 w ere c a r r i e d o u t w i t h o u t t h e membrane

o x y g e n a to r . G 3 u se d v a l v e s i n s t e a d o f c la m p s . G & was p e r fo rm e d w i t h a n i t r o g e n g a s s u p p ly i n p l a c e of a i r . I n a l l s i x e x p e r im e n t s , sam p le s

w ere drawn a t 30 m in u te i n t e r v a l s and t e s t e d f o r p la sm a h em o g lo b in by

C r i p p s 1 m ethod . The r e s u l t s a r e i l l u s t r a t e d i n g ra p h s 3 - 6» k . 1 . 2 . V T e s t s t o com pare Mambrane t o F i lm O x y g e n a to r s .

E x p e r im e n ts F 1 — F 18 and M 1 - M 23 w ere c a r r i e d o u t w i th human .

t r a n s f u s i o n b lo o d , 3 - 4 weeks o ld , c o n t a i n i n g 120 m l ACD to 420 ml. b lo o d .

C o n t r o l

f i t S k BT

E x p t s . F 1 - F 18

E x p e r im e n ts M 1 - M 23 w ere p e r fo rm e d u s i n g th e c i r c u i t f o r e x p e r im e n t s G I and G 2 w i th t h e o x y g e n a to r v i b r a t i n g a t d i f f e r i n g r a t e s .

I n a l l e x p e r im e n t s , t e m p e r a tu r e was m a in t a in e d w i t h i n 0 .2 3 deg .C

o f p h y s i o l o g i c a l l e v e l s . The o x y g e n a to r g a s s u p p l i e s w ere a d j u s t e d

to m a i n t a i n PCO^ b e tw een p h y s i o l o g i c a l l i m i t s . B lood pH i n a l l e x p e r im e n t s te n d e d to f a l l and no a t t e m p t was made t o r e c t i f y t h i s

c h e m i c a l ly . •

B lood s a m p le s w ere drawn a t 30 m in u te i n t e r v a l s and t e s t e d f o r

h e m o ly s i s by t h e cy anom ethem og lob in m ethod f d r t o t a l p r o t e i n by t h e b i u r e t m ethod , f o r p r o t e i n c h a n g e s by e l e c t r o p h o r e s i s , f o r PO^PCO^ and pH l e v e l s u s in g t h e BMS 3 i n s t r u m e n t .

The h e m o ly s i s r e s u l t s a r e p r e s e n t e d i n G raphs 7 and 8 .

4 . IV 4 . R e s u l t s o f g ra p h s

4 . 1 . 4 . 1 . Graph 1

Graph o f P la sm a Hem oglobin l e v e l a g a i n s t c i r c u l a t i o n t im e to q u a n t i f y damage by pump.

The r e s u l t s gave a s e r i e s o f s t r a i g h t n e a r l y p a r a l l e l l i n e s s u g g e s t i n g t h a t t h e damage c a u se d to th e r e d c e l l s i s a l i n e a r f u n c t i o n o f c i r c u l a t i o n t im e and i s i n d e p e n d e n t o f th e b lo o d type* and i n i t i a l

c o n d i t i o n . The a v e r a g e damage c a u se d v/as 6 .8 mg.% p e r h o u r . E x p t . P 2

gave a v a l u e t h r e e t im e s t h i s f i g u r e f o r no a p p a r e n t r e a s o n a l t h o u g h th e b lo o d was fo u n d to be m a s s iv e ly hemolysed. on r e c e i p t ( 3 0 .2 mg.%).

No s i g n i f i c a n t i n c r e a s e was: n o t i c e d on th e c o n t r o l b lo o d sam ple a t

th e end o f any o f t h e t e s t s . No s u b s t a n t i a l - d i f f e r e n c e s w ere n o t i c e d b e tw een t e s t s c a r r i e d o u t u s in g c o n t in u o u s c i r c u l a t i o n i n t o a s i n g l e r e s e r v o i r and t e s t s u s i n g a l t e r n a t e f lo w d i r e c t i o n s b e tw ee n two r e s e r v o i r s .

4 . 1 . 6 . 2 Graph. 2

Graph o f P lasm a Hem oglobin l e v e l a g a i n s t C i r c u l a t i o n t im e t o , v e r i f y damage n o t due to mere p r e s e n c e o f f o r e i g n s u r f a c e s

The r e s u l t s gave t h r e e s i m i l a r l i n e s e ac h w i th a s t r a i g h t , n e a r l y p a r a l l e l s e c t i o n o f s lo p e a b o u t 7 m g .% /h r. becom ing p a r a l l e l when th e b lo o d f lo w was d i s c o n t i n u e d . These show c o n c l u s i v e l y t h a t t h e b u l k

o f h e m o ly s i s i n t h e lo n g te rm c i r c u l a t i o n i s c a u s e d by th e a c t u a l c i r c u l a t i o n o f th e b lo o d th ro u g h th e components o f th e c i r c u i t , n o t j u s t

i t s c o n t a c t w i th f o r e i g n s u r f a c e s . The n a t u r e o f th e s u r f a c e s th o u g h ,

i s o f fu n d a m e n ta l s i g n i f i c a n c e when an a n a l y s i s o f t h e s h e a r f o r c e s on th e b lo o d i s made and th e s u b s e q u e n t h e m o ly s is s t u d i e d .4 . 1 . 4 . 5 Graph 3

I n t e s t s G 3 and G 6 th e a t t e m p t t o c o r r e l a t e t h e f a l l i n

r e d c e l l c o u n t w i th th e r i s e i n h e m o ly s is f a i l e d to p ro d u c e any s i g n i f i c a n t r e l a t i o n s h i p . The f a l l i n h e m a t o c r i t was a l s o fo u n d to b e

to o s m a l l to be &f any s i g n i f i c a n c e .

4 . 1 . 4 . 4 . G raphs 4 , 3Graph o f P lasm a Hemoglobin l e v e l a g a i n s t C i r c u l a t i o n t im e ,

t o q u a n t i f y damage by o t h e r c i r c u i t r y .

The r e s u l t s gave a s e r i e s o f s t r a i g h t l i n e s e m a n a t in g from th e

o r i g i n , th e s lo p e o f each d ep en d in g on t h e com ponents u s e d i n e a c h c i r c u i t

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T e s t s G 3 and G 4 show a h e m o ly s i s r a t e o f 13 mg.% p e r h o u r .T e s t G 6 w hich had a g a s s u p p ly to th e d e o x y g e n a to r shows an i n c r e a s e

t o 1 7 .4 mg.% p e r h o u r .

The i n c l u s i o n o f c o n t r o l v a l v e s i n t e s t G 3 shows a m a s s iv e i n c r e a s e t o 28 mg.% p e r h o u r .

The t e s t s P' 6 , P 10 and P 12 show a h e m o ly s i s r a t e o f 13*5 mg*% f o r th e f i l m o x y g e n a to r , pump and r e s e r v o i r s .

4 . 1 . 4 . 5 Graph 6Graph o f P lasm a h em og lob in l e v e l a g a i n s t C i r c u l a t i o n t im e t o d e te r m in e damage by v i b r a t o r .

B lood was c i r c u l a t e d th ro u g h th e s t a t i o n a r y o x y g e n a to r f o r 90 m in u te s when, a v i b r a t i o n o f 400 Hz was a p p l i e d . The r e s u l t s gave a s t r a i g h t l i n e e x h i b i t i n g no change o f s lo p e a t t h e 90 m in u te p o i n t , im p l y i n g t h a t no m arked i n c r e a s e i n h e m o ly s is o c c u r s a s a r e s u l t o f v i b r a t i o n .

4 . 1 . 4 . 6 G raphs 7 and 8The f u l l p e r f u s i o n c i r c u i t was o p e r a t e d f o r b e tw een 3 and 5 h o u r s

u s i n g o u td a t e d t r a n s f u s i o n b l o o d . The h e m o ly s i s l e v e l s w ere c a l c u l a t e d and p l o t t e d a g a i n s t t h e t im e th e sa m p le s w ere draw n. Graph 7 i l l u s t r a t e s t h e c o r r e s p o n d i n g r i s e when t h e membrane o x y g e n a to r r e p l a c e d t h e f i l m

o x y g e n a to r .Graph 8 shows a mean h e m o ly s is r a t e o f i n c r e a s e o f 13 mg.% p e r h o u r

f o r t h e membrane o x y g e n a to r c i r c u i t w h i le Graph 7 shows a r a t e o f

23 mg.% p e r h o u r .F our t e s t s from e ac h o f th e F amd M s e r i e s a r e i l l u s t r a t e d a s b e i n g

r e p r e s e n t a t i v e o f t h e r e m a in d e r .

4 . 2 . E x p e r im e n ts to a s s e s s th e a l t e r a t i o n s t o p la sm a p r o t e i n s and t o r e l a t e t h e s e to h e m o ly s i s .

4 . 2 . 1 . I n t r o d u c t i o nT hree s e r i e s o f e x p e r im e n t s were p e r fo rm e d to c o v e r t h i s a s p e c t o f

t h e w o rk .

a ) P 1 - P 12

b ) F 1 - F 18

c ) M l - M 23The a im s o f t h e s e t e s t s w i th r e f e r e n c e to p la sm a p r o t e i n

d e n a t u r a t i o n w ere t o : -

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a ) q u a n t i f y th e p r o t e i n d e n a t u r a t i o n , i f p o s s i b l e f o r each o f th e c i r c u i t co m ponen ts .

b ) to i d e n t i f y a l l ch an g e s i n m o b i l i t y and p r o p o r t i o n o f each d i s c e r n a b l e p r o t e i n f r a c t i o n .

c ) to q u a n t i f y th e t o t a l p r o t e i n l o s s from th e c i r c u l a t i n g b lo o d f o r each com ponent o f c i r c u i t y .

d ) to c o r r e l a t e , i f p o s s i b l e th e r i s e i n p la sm a h e m o g lo b in w i th th e l o s s o f a lb u m in

T e s t s P 1 - P 12 w ere d e s ig n e d to e s t a b l i s h th e p r o t e i n a l t e r a t i o n due to th e c i r c u l a t i o n o f b lo o d th ro u g h th e pump a l o n e . T e s t s F 1 - F 18 and M l - M23 a l lo w e d th e f i l m amd membrane o x y g e n a to r s to be com pared f o r p r o t e i n damage.4 . 2 . 2 . E x p e r im e n ta l d e s c r i p t i o n - a s i n 4 . 1 . 2 .4 . 2 . 3 . G raphs 9 - 114 . 2 . 4 . A n a ly s i s o f G raphs

4 . 2 . 4 . 1 . Graph 9 . Graph o f Albumin c o n t e n t a g a i n s t t im e .The g ra p h shows a f a l l i n th e p e r c e n t a g e o f a lb u m in in . t h e b lo o d

w i th t im e . T h is f a l l i s much more m arked when th e f i l m o x y g e n a t^ o r i s i n c l u d e d i n th e c i r c u i t . The t o t a l p r o t e i n c o n t e n t f e l l from 4*76 t o

4*45 m g .% f o r th e f i l m o x y g e n a to r , a l o s s o f 6.3%-sV/hilst f o r t h e b a s i c c i r c u i t c o n t a i n i n g o n ly pump and r e s e r v o i r , th e d ro p was from £ .0 8 to

4*95 o r 2.3% f a l l . I n b o th c a s e s t h e r e was an im m e d ia te f a l l i nth e p e r c e n t a g e c o n t e n t o f a lb u m in a t t r i b u t e d to t h e c o a t i n g o f t h e s u r f a c e s o f th e c i r c u i t r y by th e p r o t e i n s . I t i s n o t uncommon f o r c i r c u i t r y t o be p rim ed w i th a lb u m in .

Only two o f th e tw e lv e t e s t s a r e r e p r e s e n t e d i n t h e g r a p h . The p r o t e i n a l t e r a t i o n a t t r i b u t a b l e to any i n d i v i d u a l com ponent o f c i r c u i t r y was n e i t h e r s u f f i c i e n t l y l a r g e n o r s . u f f i c i e n t l y c o n s i s t e n t t o b e w o r th

q u o t in g . Aims 4- 2 . 1 . a , c , were n o t th e n a c h i e v a b l e by t h e c h o se n

m e a s u r in g t e c h n i q u e s .4 . 2 . 4 . 2 . G raphs 10. 1 1 .

The g ra p h s a r e b a s e d on a r e a m easurem ent o f th e d e n s i t o m e t e r s c a n s t a k e n from p a p e r e l e c t r o p h o r e t i c e x a m in a t io n o f b lo o d s a m p le s . T hese

w ere drawn a t 30 m in u te i n t e r v a l s . The 4 t r a c e s i n f i g . 11 r e p r e s e n t f o u r o f th e t e s t s on t h e f u l l p e r f u s i o n c i r c u i t i n c l u d i n g t h e s t a t i c membrane o x y g e n a to r . Those i n f i g u r e 10 r e p r e s e n t t h e same c i r c u i t w i th a f i l m o x y g e n a to r r e p l a c i n g th e membrane o x y g e n a to r . The f i l m o x y g e n a to r

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g i v e s an a v e r a g e f a l l o f 1 . 3% p e r h o u r w h i le th e membrane o x y g e n a to r g i v e s 0 . 7% p e r h o u r .

The e f f e c t o f c h a n g in g o x y g e n a to r s i s to d e c r e a s e th e p r o p o r t i o n o f a lb u m in by 0.6% p e r h o u r . M easurem ents were a l s o t a k e n to o b s e r v e any a l t e r a t i o n s i n m o b i l i t y o f th e p r o t e i n f r a c t i o n s . Only th e f r a c t i o n e x h i b i t e d any d e f i n i t e t r e n d , i t s m o b i l i t y i n c r e a s i n g i n t h e c a s e o f th e f i l m o x y g e n a to r .

T here i s a l i n k b e tw een th e i n c r e a s e i n p la sm a -h e m o g lo b in l e v e l and th e c o r r e s p o n d i n g d e c r e a s e i n a lb u m in l e v e l . Comparing g ra p h s 7 and 10 T e s t s 1 0 F and 17 F f o r exam ple e x h i b i t t h i s p a t t e r n .4 . 3 . E x p e r im e n ts to a s s e s s m ethods o f Im p ro v in g o x y g e n a to r

p e r f o r m a n c e .

4 . 3 . 1 I n t r o d u c t i o n .Two o f th e s e r i e s o f e x p e r im e n t s p e r fo rm e d c o n t a i n e d a t l e a s t an

e le m e n t o f p e r fo rm a n c e m easurem ent r e l e v a n t t o t h e membrane o x y g e n a to r .

a ) M 1 ' - M 23

b ) E 1 - E 14The im provem ent o f o x y g e n a t io n p e r fo rm a n c e by th e f o i l o w i n g m ethods

was exam ined .a ) d e t e r m i n a t i o n o f optimum f lo w r a t eb ) p r e s s u r i z a t i o n o f oxygen p h ase

d) v i b r a t i o n o f th e o x y g e n a to rF i n a l l y th e t im e ta k e n f o r th e sy s tem to s e t t l e , f o l l o w i n g su d d en

c h an g e s i n o p e r a t i n g c o n d i t i o n s , was s t u d i e d .4 . 3 . 2 . E x p e r im en t D e s c r i p t i o n

E x p e r im e n ts M 1 - M 23 were a s d e s c r i b e d i n s e c t i o n 4* ! • 2 . 3«A l l t h e s e were e x e c u te d w i th th e membrane o x y g e n a to r v i b r a t i n g a t

f r e q u e n c i e s r a n g i n g from 0 - 400 Hz.E x p e r im e n ts E 1 - E 6, E 10 , and E 14 w ere u sed i d e n t i c a l a p p a r a t u s

to t h e *M* s e r i e s . E x p e r im e n ts E 11 - E 13 u s e d a n im a l b lo o d w i th

EDTA ( P ig o r B o v in e ) b u t th e same c i r c u i t .E x p e r im en t E 7 e x p lo r e d th e e f f e c t o f c h a n g in g o x y g e n a to r g a s

p r e s s u r e , e x p e r im e n t E 8 o f c h a n g in g punp s e t t i n g (b lo o d f lo w r a t e ) and

E 9 o f i n s e r t i n g a l a r g e r f i lm d e o x y g e n a to r .

4 . 3 . 3 . G raphs 12 - 18

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4 . 3 . 4 . A n a ly s i s -of G raphs4 . 3 . 4 . 1 Graph 12

Graph o f A - V oxygen s a t u r a t i o n a g a i n s t b lo o d f lo w r a t e The g ra p h b a s e d on d a t a from e x p e r im e n t E 8 shows an a p p r o x im a te ly

l i n e a r d e c r e a s e i n A - V oxygen s a t n r u a t i o n (SC^) d i f f e r e n c e .A. V. A. 2 . Graph 13

O xygenato r p e r fo rm a n c e a g a i n s t b lo o d f lo w r a t e

The g ra p h e x h i h i t s an optimum p e r fo rm a n c e a t a f lo w r a t e o f

90/ m l . / m i n .

A. 3 . 4 . 3 . Graph 14A - V s a t u r a t i o n d i f f e r e n c e (SOp) a g a i n s t t im e . Change i n oxygen p r e s s u r e .

The e x p e r im e n t was b a s e d on an i d e a e x p lo r e d by Dagher t h a t n o t o n ly

can a d v a n ta g e b e g a in e d o v e r th e n a t u r a l l u n g by b r e a t h i n g p u re oxygen b u t a l s o by p r e s s u r i z i n g t h e oxygen to y i e l d an even g r e a t e r d i f f e r e n c e

i n p a r t i a l p r e s s u r e s be tw een th e g a s and b lo o d p h a s e s . The p r e s s u r e s chosenic: l a y on either s i d e o f th e p r e s s u r e o f t h e b lo o d i n th e o x y g e n a to r £he g r e a t e r p r e s s u r e r e q u i r e d a g l a s s f i b r e s u p p o r t i n t h e b lo o d p h a s e .

The g ra p h shows a f a l l i n A-V s a t u r a t i o n from 8% dov/n t o 3%*T h is r e p r e s e n t s a 62% d ro p f o r a p r e s s u r e change o f o n ly 1.7%•A. 3 . A. A. Graph 15

Graph o f A - V s a t u r a t i o n d i f f e r e n c e (Ago )■ a g a i n s t

oxygen p r e s s u r e .The g ra p h shows a s i m i l a r t r e n d to Graph 8 A . F o r p r e s s u r e s b e lo w

th e b lo o d p r e s s u r e i n th e o x y g e n a to r , t h e A - V s a t u r a t i o n d i f f e r e n c e ish . 1 . U. 5. Graph I d • [m aA eily re d u c e d .

Graph o f A - V oxygen s a t u r a t i o n a g a i n s t t im e ( to e x h i b i t t h e e f f e c t o f commencing v i b r a t i o n ) .

The g ra p h w asp roduced from d a t a from e x p e r im e n t E 1 4 and i s t y p i c a l

o f a l l s i m i l a r l y c o n d u c te d t e s t s . The r e s t o r a t i o n o f s t e a d y c o n d i t i o n s

f o l l o w i n g th e commencement o f v i b r a t i o n r e q u i r e d n e a r l y 60 m i n u t e s . The

t r a n s i e n t c h a r a c t e r i s t i c s were a p p r o x im a te ly e x p o n e n t i a l w i th a t im e c o n s t a n t o f a p p r o x im a te ly 20 m in u te s .

A. 3 . 4 . 6 . Graph 17Graph o f A - V oxygen s a t u r a t i o n d i f f e r e n c e a g a i n s t

v i b r a t i o n sp ee d - s i n g l e e x p e r im e n t .The g ra p h was p ro d u ced from r e s u l t s t a k e n from a s i n g l e e x p e r im e n t

i n w h ich th e o x y g e n a to r was v i b r a t e d a t s u c c e s s i v e l y h i g h e r s p e e d s .

- 91 -

The a r t e r i a l and v e n o u s s a t u r a t i o n s were r e c o r d e d f o l l o w i n g s t e a d y •

c o n d i t i o n s . The t im e t a k e n f o r su ch c o n d i t i o n s to b e r e a c h e d made i t i m p o s s i b l e to t a k e more th a n f o u r o r f i v e r e a d i n g s to b e o b t a i n e d .

The g ra p h i s a p p r o x im a te ly l i n e a r show ing marked im provem ent o f p e r fo rm a n c e by th e u se o f v i b r a t i o n , A f o u r f o l d i n c r e a s e can b e o b s e rv e d f o r a v i b r a t i o n sp e e d o f /fOO Hz. A v e r y s i m i l a r i n c r e a s e f o r th e same v i b r a t i o n sp e e d was d i s c o v e r e d by I l l i c k a l on a v e r y

d i f f e r e n t e x p e r im e n t .

4 . 3 . A. 7 Graph 1 8Graph o f A - V oxygen s a t u r a t i o n d i f f e r e n c e a g a i n s t

v i b r a t i o n sp e e d - £7 d a t a p o i n t s .The g ra p h was p ro d u c e d from r e s u l t s t a k e n from 12 e x p e r im e n t s .

I n e a c h e x p e r im e n t b lo o d was o x y g e n a te d a t a f i x e d r a t e f o r up t o two

h o u r s t o e n s u r e s t e a d y c o n d i t i o n s .The g r a p h i s a p p r o x im a te ly l i n e a r w i th a s c a t t e r o f up

CHAPTER 5THEORETICAL ANALYSIS AND RELATION TO EXPERIMENTAL WORK.

5 / 1 T h e o r e t i c a l A n a l y s i s o f Gas T r a n s f e r .5 . 1 . 1 Gos T r a n s p o r t th ro u g h Membrane

The p r o c e s s o f g a s exchange th ro u g h a po lym er membrane was shown by B e l l and G ro sb e rg (1961) t o be m a in ly a p r o c e s s o f d i f f u s i o n w hich u n d e r s t e a d y c o n d i t i o n s obeys P i c k ' s f i r s t l 'aw :-

q = D» pt

pw here q i s t h e g a s f lo w r a t e p e r u n i t a r e a i n m l*/m in .m

i pD i s t h e membrane d i f f u s i o n c o e f f i c i e n t i n ml.mm./m min.mm. (H g/ ’ t i s th e f i l m t h i c k n e s s i n mm.P i s t h e p r e s s u r e g r a d i e n t i n mm.Hg.

The d i f f u s i o n c o e f f i c i e n t s f o r s i l i c o n e r u b b e r a s d e te r m in e d by s e v e r a l a u t h o r s i s t a b u l a t e d b e lo w . S in c e t h e r e i s no a g re e m e n t on th e

u n i t s , t h e s e have b e en com pared f o r a p a r t i a l p r e s s u r e g r a d i e n t o f

650 mrn/.Hg. and a membrane t h i c k n e s s o f 0 .0 0 1 5 in . ( O .O 38I mm.) .

R e f . M a t e r i a l / T h i c k n e s s■ 1D ° 2

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8 S i l a s t i c 3 m i l . 350 0 .2 7 ( 4 - 3 ) 1 .7 1 1 600

9 . M ethyl S i l c o n e 1 m i l . 1092 0 . 3 3 ( 5 . 3 ) 0 .5 7 0 622

1 0 . S i l i c o n e Rubber l i - r n i l . 520 0 . 3 4 ( 5 . 3 ) 0 .8 5 5 608

1 . Kamnermeyer (19572. Dow-Corning d a t a s h e e t (I960)3. McCaughan (i9 6 0) b* M e lro se (1972)3. Benvenuto (1959)

)) m l . c m . / cm* )

sec an Hg.

m l. / IQ O in day a tm o s p h e re6 , 7 ,G a l l e t t i , S n i d e r & S i l b e r t - A i d a n ( I 9 6 6 ) ml/m m in . 650 mm.Hg.8 , 9 » P e i r c e * D i b e l i u s (1968 ) 1 0 . B urns (1969) ml/m m in . a tm o sp h e re

W hile t h e s e v a l u e s v a r y from th e l o w e s t to t h e h i g h e s t by a f a c t o ro f 3 » m ost g iv e a maximum oxygen t r a n s f e r r a t e th r o u g h 1*5 th o u (.038! mm.)o f s i l i c o n e r u b b e r o f a b o u t 600 m l. /m min f o r an e f f e c t i v e p a r t i a lp r e s s u r e g r a d i e n t of 650 mm.Hg. The e q u i v a l e n t f i g u r e f o r c a rb o nd io x id e t r a n s p o r t a ssu m in g a p a r t i a l p r e s s u r e g r a d i e n t o f ifO m m v.H g.is

2180 m l. /m rain.

5 . 1 . 2 . Gas T r a n s p o r t by B lo o d .

5« 1 . 2 . 1 . Oxygen

5 . 1 . 2 . 1 . 1 . D is s o lv e d i n p la sm a

P lasm a c o n t a i n s 0 .0 2 3 c c . o f oxygen p e r m i l l i l i t r e when th e p a r t i a l p r e s s u r e o f t h e oxygen i s 760 mm.Hg. At d i f f e r e n t p r e s s u r e s i t c o n t a i n s a p r o p o r t i o n a t e amount

- p 0D is s o lv e d oxygen = 0 .0 2 3 x _ 2 c c /m l .

760 (D a v e n p o r t )The maximum p h y s i o l o g i c a l P 0^ i s a b o u t 100 mm. H g .g iv e n a

c o r r e s p o n d i n g d i s s o l v e d oxygen l e v e l o f 0 .3 ml.%. T h is f a l l s t o0 .1 2 m l . % i n t h e v e i n s (P a s s m o re ) .

I n an a r t i f i c i a l l u n g how ever p u re oxygen (assum ed w e t) may be b r e a t h e d g i v i n g f o r a v e n o u s P 0^ o f 40 mm.Hg. an e f f e c t i v e p a r t i a l p r e s s u r e g r a d i e n t o f : - "

760 - Z|7 - Z.0 - 673 mm.Hg.S in c e th e p a r t i a l p r e s s u r e o f w a te r v a p o u r , 100$ s a t u r a t e d , i s

b7 mm.Hg. t h i s i s e q u i v a l e n t to 2 ml% o f oxygen i n t h e p la s m a . A p r e s s u r i s e d oxygen s u p p ly c o u ld i n c r e a s e t h i s f i g u r e .5 . I . 2 . 1 . 2 . Combined w i th h e m o g lo b in .

The q u a n t i t y o f oxygen c a r r i e d i n c h e m ic a l c o m b in a t io n w i th hem og lob in a l s o d ep en d s on P 0 ?

CL*

1 mole 0^ (32 g ram s) com bines w i th 1 6 ,7 0 0 g . o f Hb. (M ^ 67»000)

and o c c u p ie s 2 2 , JfOO m l.i gram o f Hb. t h e r e f o r e com bines w i th 1.3*f m l. 0 ^ (P assm o re q u o te s

1 .3 8 ml 0^ p e r gram o f Hb).The p e r c e n t a g e oxygen s a t u r a t i o n , S 0^ i s r e l a t e d to th e p a r t i a l

p r e s s u r e o f oxygen P 0^ by t h e fo l lo v / in g e q u a t i o nS 0 i 100 k P 0

------------------ v;here k i s a c o n s t a n t1 - k P 02

- 94 -

I t s u g g e s t s a h y p e r b o l i c c u rv e b u t i n f a c t , b e c a u s e o f t h e oxygen d i s s o l v e d i n p la sm a i t i s a s ig m o id .

02

P 0

( D a v e n p o r t )

Aberman q u o te s an e q u a t i o n f o r t h i s c u r v e .At P 0 . - 1 0 0 m. m Hg , S 0 o i s n e a r l y 100}o. I f t h e h em o g lo b in

2 — ' 2c o n t e n t o f th e b lo o d i s 14*3 gm% (S a n d o z ) , th e n th e maximum oxygen

c o n t e n t C 0^ o f b lo o d i s : -

C 02 - (14*3 x 1 .3 4 ) ml% + 0 .3 m l / = 20 ml %hem o g lo b in p la sm a t o t a l

Oz Lens-iorv — mrn

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- 95 -

In t h e v e i n s w h e r e t h e P 0 ^ = ^ 0 m m .H g ( s a y ) , C 0 ^ c o u l d b e a s low a s 8 ml.% hence t h e o x y g e n a t o r w o u l d h a v e t o s u p p ly t h e b a la n c e o f

F o r a b o d y c o n t e n t o f 5 l i t r e s p u m p e d i n o n e m i n u t e a t r e s t , 6 0 0 m l/m in . m u s t b e t r a n s f e r r e d b y t h e o x y g e n a t o r . I n p r a c t i c e ,

how ever, t h e s a t u r a t i o n m a y o n l y v a r y b e t w e e n 70% a n d r e d u c i n g

t h i s demand t o 2 5 0 m l / m i n .

T h e s i g m o i d c u r v e o f S 0 ^ v P 0 ^ i s p u s h e d t o t h e r i g h t w h e n t h e

c a rb o n d i o x i d e c o n t e n t o f t h e b l o o d i s i n c r e a s e d , w h e n t h e t e m p e r a t u r e

r i s e s , when th e pH f a l l s a n d w h e n t h e HbC 0 l e v e l f a l l s . A c t iv e

t i s s u e h a s a h ig h P C 0^, low pH a n d r a i s e d t e m p e r a t u r e , a l l a i d i n g th e r e l e a s e of oxygen f o r i t s r e s p i r a t i o n .

C o r r e c t i o n s to t h e o x y h e m o g l o b i n d i s s o c i a t i o n c u r v e f o r

t e m p e r a t u r e a n d p H d e v i a t i o n s c a n b e m a d e u s i n g t h e n o m o g r a m b e l o w : -

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9 0 -

8 9 -— 4 0

gs - -

S i ­

sk—

85^—

■24 “- 5"|

mm

5. 1 . 2 . 2 C arbon D io x id e5 . 1 . 2 . 2 . 1 D i s s o lv e d in P lasm a and Red c e l l

D is s o lv e d c a rb o n d io x id e am ounts t o 1 , 6 - 1 . 8 ml% i n p la sm a f o r a P CO2 o f ZfO mm Hg. and 0 ,8 - 0 .9 ml% i n th e r e d c e l l . o Carbond i o x i d e i s much more s o l u b l e th a n oxygen .

5 . 1 . 2 . 2 . 2 As b i c a r b o n a t e90% o f c a rb o n d io x i d e i s c a r r i e d a s sodium b i c a r b o n a t e (3^-36ml%)

i n p la sm a and a s p o ta s s iu m b i c a r b o n a t e ( 9 .1 - 9 .9 ml#) i n t h e r e d c e l l ,

5 . 1 . 2 . 2 . 5 Combined w i th P r o t e i n sCarbon d io x id e fo rm s a n e u t r a l c a rb am in o compound w i th hem o g lo b in

and to a much l e s s e r e x t e n t w i th t h e p la sm a p r o t e i n s . U n l ik e oxygen w hich a t t a c h e s t o t h e haem r a d i c a l s , c a rb o n d io x i d e com bines w i th th e

amino g ro u p s . The p h y s i o l o g i c a l l e v e l s v a r y from 2 . 2 ml# i n th e a r t e r i e s t o 3*2 ml% i n th e v e i n s .

The t a b l e be low sum m arises th e d i s t r i b u t i o n o f c a rb o n d io x i d e (m l) i n 100 m l. o f b lo o d i n a s u b j e c t a t r e s t f o r a h e m a t o c r i t o f JfO# and

a pH s 7 *b ( a d a p te d from H enderson B .D .S .) .

ARTERY VEIN

Plasm a R .B .C . T o ta l P lasm a R .B .C . T o t a l

D is s o lv e d C O2 1 .6 0 .8 2 . A- 1 . 8 0 .9 2 .7C 02a s b i c a r b o n a t e 3b- 9 .1 4 3 .1 36 9 .9 4 3 .9Carbamino compounds 1 .1 2 .2 3 -3 1 .1 3 . 2 4 . 3

T O T A L 3 6 .7 1 2 .1 b 8 .8

6\•CO l b 3 2 .9

R educed b lo o d t a k e s up more c a rb o n d io x id e a t t h e same P CO^ th a n o x y g e n a te d b lo o d b e c a u s e r e d u c e d hem o g lo b in h a s a g r e a t e r c a p a c i t y f o r

b u f f e r i n g and ca rb am in o - c a rb o n d io x i d e f o r m a t i o n .F o r a P CO2 ' » 0 a l l t h e c a rb o n d io x id e i s r e l e a s e d , u n l i k e a s im p le

b i c a r b o n a t e s o l u t i o n w hich would l e a v e h a l f a s b i c a r b o n a t e .Sum m aris ing , th e c a rb o n d io x id e l e v e l i n v e i n s f o r a P CO^ =. bO mm.Hg

i s 33 ml.#, 75% o f w hich i s c a r r i e d i n th e p la sm a . T h is i s r e d u c e d to 1+8% i n th e a r t e r i e s w here th e P C O 1+6 mm. Hg, h en ce t h e lu n g m ust

remove 203 m l.C 02/m in . f o r a b lo o d volum e o f 3 l i t r e s pumped e a c h m in u te .

The m a jo r r e a c t i o n s w hich ta k e p l a c e when g a s exchange o c c u r s b e tw ee n b lo o d and a lv eo Ia?g as ( a f t e r B e l l , D av idson & S c a rb o ro u g h ) a r e shown overleaf:-

CO; CC\Cfttbontc -v _anH'ydiuseH COr

H* ° © t V \

Hcor

HHb CO;

\€2>HHb

c r Hb

Hb o.

M e m b r a n e RBC

AU*» 8*lt ,

5 . 1 . 5 G a s T r a n s p o r t T h r o u g h P l a s m a

T h e p a s s a g e o f o x y g e n t h r o u g h p l a s m a o b e y s F i c k ' s l a w

0 P___P a s b e f o r e — (e^ahonl)t

T h e p e r m e a t i o n c o e f f i c i e n t , D , f o r p l a s m a i s g e n e r a l l y a g r e e d t o-10 2

b e o f t h e o r d e r o f 6 . 5 x 1 0 m l . O p c m / c m s irnnHg 1 0 t i m e s b i g g e r a t-1 0 2

6 0 x 1 0 m l . ©2 c m / c m s mm Hg.I t i s v i t a l t h e n i n a m e m b r a n e o x y g e n a t o r e i t h e r t h a t t h e b l o o d f i l m

t h i c k n e s s ( t ) i s m a d e v e r y s m a l l o r t h a t i n t i m a t e m i x i n g o f e r y t h r o c y t e s

a n d p l a s m a i s a c h i e v e d .

E q u a t i o n 1 c a n b e r e a r r a n g e d

p qP =■ Q (Eo

cf . V - I R e l e c t r i c a l

( P o t e n t i a l P r o p ) _r_ ( C u r r e n t F l o w ) x ( R e s i s t a n c e )

T h e s e t w o e q u a t i o n s a r e a n a l o g o u s , P a n d V r e p r e s e n t i n g p r e s s u r e

d r o p a n d e l e c t r i c a l p r e s s u r e d r o p r e s p e c t i v e l y , Q a n d I b e i n g t h e f l o w( t )

r a t e s o f g a s a n d e l e c t r i c a l c u r r e n t r e s p e c t i v e l y a n d _ a n d R b o t h( P )

r e p r e s e n t i n g r e s i s t a n c e t o f l o w .

I n t h e l u n g , d i f f u s i o n i n t h e p l a s m a a c c o u n t s f o r 15 % o f t h e t o t a l

r e s i s t a n c e i n t h e p r o c e s s o f o x y g e n a t i o n a n d a b o u t 3 0 "% o f t h e b l o o d ' s

p r o p o r t i o n o f t h i s ( t h e a l v e o l a r c a p i l l a r y w a l l r e p r e s e n t s t h e o t h e r

45% o f t h e t o t a l - R o u g h t o n a n d R u p p 1 9 5 8 ) . I t i s r e c k o n e d t h a t i n t h e

a r t i f i c i a l l u n g , p l a s m a c o u l d r e p r e s e n t o v e r 70 % o f t h e b l o o d ' s

p r o p o r t i o n o f r e s i s t a n c e .

Carbon d io x i d e a l s o obeys F i c k ' s law b u t D f o r c a r b o n d io x i d e i s p r o b a b ly 85% o f D f o r oxygen s i n c e th e r a t e o f d i f f u s i o n o f d i s s o l v e d g a s e s i s p r o p o r t i o n a l t o th e s q u a r e r o o t o f t h e i r m o le c u la r w e ig h t

( >/%2./LfZf . 8 5 ) . The s o l u b i l i t y . c o e f f i c i e n t ( a ) o f c a rb o n d io x i d e i n p la sm a th o u g h i s 25 t im e s t h a t o f oxygen so t h a t D C=. axD) «. 139x 10“^ °

pinl'icm/cm s mm Hg. ,

The P CO^ o f v e n o u s b lo o d , k6 mm Hg, i s a p p r o x im a te ly t h e same a s t h e P 02 , so b e in g 25 t im e s a s s o l u b l e i n p la sm a , c a r b o n d i o x i d e s h o u ld t r a n s f e r a t up t o 25 t im e s t h a t f o r oxygen . I n an a r t i f i c i a l l u n g , how ever, w here t h e P 0^ g r a d i e n t may be 650 mm Hg, a b o u t 1A t im e s t h a t f o r C 0^ , c a rb o n d i o x i d e w i l l d i f f u s e o n ly tw ic e a s f a s t a s oxygen .

5 . I . A. Gas T r a n s f e r i n th e Fed C e l lThe g a s t r a n s f e r i n t o t h e c e l l c o n s i s t s o f d i f f u s i o n th r o u g h th e

c e l l membrane, d i f f u s i o n th ro u g h th e c e l l i n t e r i o r and f i n a l l y c h e m ic a l c o m b in a t io n .'with h em o g lo b in . The r e l a t i v e r e s i s t a n c e s o f t h e s e p r o c e s s e s t o oxygen and c a rb o n d io x id e a r e shown b e lo w : -

1+0 mm.Hg C o2 AO mm.Hg.

C h em .R eac tio n

D i f f u s i o ni n

R .B .C .

Chem.R e a c t io n

Membrane D i f f . i n R .B .C .

■ .v_ -Membrane

i100 mm.Hg 1+6 mm.Hg

(A dap ted from R oughton & Rupp 1958)

The d ia g ra m s a r e n o t i n t e n d e d to im p ly t h a t t h e r e i s e q u a l t o t a l

r e s i s t a n c e to t h e t r a n s f e r o f each g a s .I f th e g a s p r e s s u r e g r a d i e n t i s i n c r e a s e d th e d i f f u s i o n p r o c e s s e s

a r e a c c e l e r a t e d and th e p r o p o r t i o n s a f f e c t i v e l y change s i n c e t h e sp e e d o f

c h e m ic a l r e a c t i o n does. n o t . (M och izuk i 1 , 2 ) I n th e l u n g , t h e r e s i s t a n c e

o f t h e r e d b lo o d c e l l t o th e p r o c e s s . o f o x y g e n a t io n c o n t r i b u t e s 37% o f t h e t o t a l w h i le t o t h e p r o c e s s o f c a rb o n d io x i d e e l i m i n a t i o n , i t r e p r e s e n t s 87%.

To sum m arise , i n th e a r t i f i c a l lu n g , t h e c h i e f b a r r i e r s t o oxygen

t r a n s p o r t o v e r w h ich we may have some m easu re o f c o n t r o l a r e th e r e d b lo o d c e l l and more i m p o r t a n t l y , th e p la sm a . F o r c a rb o n d i o x i d e ,

how ever, th e lu n g membrane fo rm s th e g r e a t e s t b a r r i e r - v/e have l i t t l e

c o n t r o l o v e r th e sp ee d o f c h e m ic a l r e a c t i o n i n th e r e d c e l l . A l l t h a t

can be done th e n a s f a r a s c a rb o n d i o x i d e i s c o n c e rn e d i s to u s e t h e s m a l l e s t s a f e , t h i c k n e s s o f membrane o f a s h ig h a p e r m e a b i l i t y a s

p o s s i b l e . F o r oxygen t r a n s p o r t e i t h e r th e b lo o d f i l m s h o u ld be a s t h i n

a s p o s s i b l e o r a way be fo u n d o f p r e s e n t i n g e ac h r e d c e l l i n i n t i m a t ec o n t a c t ..w ith t h e membrane s u r f a c e .

I n a sandv/ich ty p e membrane o x y g e n a to r i t i s t h e o r e t i c a l l y p o s s i b l e

to p r e s e n t .3 2 ,0 0 0 r e d c e l l s p e r s q u a r e m i l l i m e t r e a t any one t im e . I f o n ly one m i l l i s e c o n d i s n e c e s s a r y t o e q u i l i b r a t e t h i s l a y e r w i t h oxygen and i t were p o s s i b l e t o i n s t a n t l y r e p l a c e t h i s w i th f u r t h e r l a y e r s r e q u i r i n g o x y g e n a t io n , th e n o n ly one s i x t h o f a seco n d w ould ber e q u i r e d to c o m p le te ly o x y g e n a te a 1 mm t h i c k n e s s o f b lo o d f i l m .T h e o r e t i c a l l y th e n , t h e p la sm a w ould p o se no b a r r i e r a t a l l .

F o r a f i n i t e b lo o d t h i c k n e s s , th e f lo w r a t e o f oxygen u n d e r s t e a d y c o n d i t i o n s i s g iv e n by

Q . .= ^ P . . -R

R - f "g"/ " t o t a l r e s i s t a n c e o fb lo o d and membrane com bined to g a s t r a n s f e r .

The p r o p o r t i o n o f t h e s e two r e s i s t a n c e s to th e t r a n s f e r o f oxygen

and c a rb o n d i o x id e i s i l l u s t r a t e d i n g ra p h s 19 and 20 .5 . 5 . C om parison o f A n a ly s i s and P r a c t i c a l Work

Graph 20 i l l u s t r a t e s c l e a r l y th e p e n a l t y o f l o s s o f e f f i c i e n c y

i n c u r r e d by u s in g a s t a t i c s y s t e n v / i th a d e f i n i t e b lo o d f i l m t h i c k n e s s .The t h e o r e t i c a l maximum g a s t r a n s f e r f o r th e model o x y g e n a to r

c o u ld be c a l c u l a t e d a s f o l l o w s : -2 2

Membrane a r e a = 2 x 63 x 1A0 mm & 17i 6U0 mmB lood f i l m t h i c k n e s s « 0 .2 3 x 23*4 x 1000/d » 6 ,3 0 0 jcl

Membrane t h i c k n e s s .= .1 .3 th o u 0 .0 3 8 mm.

Resistance

-1 0 1 -

Spedfic Bt&isl'oaccRow Rate ml/W-min.

GooBLOOCk P lL M T M l C U K T e ^ S

C R A P H 2 . 0

o k y " ^ c Ik j - r e . A r o s . p e R T h r o u c h \ L t a o x j M £ m R R A K le

G LI rvda-C ( r i^ O rrs m

10 2 -

T h i s d a t a would y i e l d a t h e o r e t i c a l oxygen s p e c i f i c f lo w r a t e o f2 ■

l e s s t h a n 1 ml/m m in . However, . ' th e n a t u r a l m ix in g c a u s e d by th et u r b u l e n c e a t e n t r y to th e b lo o d cham ber by th e ro u g h n e s s o f th emembrane and i n some c a s e s by th e i n t e r p o s i t i o n o f a b lo o d s c r e e n r a i s e d

• 2t h i s t o b e tw een 20 and 30 ml/m m in .

The i n t r o d u c t i o n o f s e c o n d a ry f lo w s by th e i n t r o d u c t i o n o f e x t e r n a l v i b r a t i o n o f th e o x y g e n a to r i n c r e a s e d th e p e r fo rm a n c e beyond

100 ml/m m in . Graph 20 s u g g e s t s t h a t t h i s l e v e l o f p e r fo rm a n c e i s c o n s i s t e n t w i th e l i m i n a t i o n o f p la sm a a s an e f f e c t i v e b a r r i e r - p r o b a b ly by th e h o p e d - f o r r e c i r c u l a t i o n o f r e d c e l l s a c r o s s t h e b o u n d a ry

l a y e r .

- 103 - CHAPTER 6

A% APPRAISAL AND SUGGESTIONS FOR FURTHER WORK.

6 . 1 A p p r a i s a l o f t h e work6 . 1 . 1 The b lo o d .

The m a j o r i t y o f e x p e r im e n t s were c o n d u c te d w i th human t r a n s f u s i o n b lo o d b e tw een t h r e e and f o u r weeks o ld c o n t a i n i n g 22% ACD. The b lo o d was g e n e r a l l y i n good c o n d i t i o n , o n ly two b o t t l e s b e in g fo u n d w e l l hem olysed on r e c e i p t . I t i s a p p r e c i a t e d t h a t e r y t h r o c y t e l i f e sp ani s a ro u n d 120 d ay s b u t th e c o ld s t o r a g e o f b lo o d f o r a b o u t 25 d ay s d idn o t a p p e a r t o g iv e a p r o - r a t a i n c r e a s e i n dead c e l l s . 'A n a lo g o u s 1 f l u i d s , even anim&l b lo o d , w ere a v o id e d a s b e in g c l i n i c a l l y o f d o u b t f u l r e l e v a n c e . Animal b lo o d was fo u n d to be o f u n r e l i a b l e q u a l i t y . I t

was th o u g h t e s s e n t i a l i n s t u d y in g th e e f f e c t o f v i b r a t i o n and o t h e r p a r a m e te r s on o x y g e n a t io n r a t e and o f c i r c u i t r y on b lo o d damage t o u se

w hole b lo o d . The e r y t h r o c y t e s a s d i s c u s s e d i n C h a p te r 5 a r e t h e m a jo r oxygen c a r r y i n g c o n s t i t u e n t and i n v iew o f t h e i r s t r a n g e f lo w c h a r a c t e r i s t i c s i n p la sm a (s ig m a e f f e c t ) t h e i r p r e s e n c e i s v i t a l .

I t was a l s o c o n s id e r e d e s s e n t i a l to s i m u l a t e p h y s i o l o g i c a l c o n d i t i o n s a s n e a r l y a s p o s s i b l e - P h y s i o l o g i c a l t e m p e r a t u r e and g a s p a r t i a l p r e s s u r e s w ere m a in ta in e d a l t h o u g h pH was found d i f f i c u l t t o c o n t r o l and

te n d e d to f a l l . . I t i s a p p r e c i a t e d t h a t t h i s i n i t s e l f c o u ld e f f e c t r e s u l t s e s p e c i a l l y t h o s e c o n c e r n in g h e m o ly s i s . An a d ju s tm e n t was made f o r pH

a l t e r a t i o n i n th e c a l c u l a t i o n o f oxygen t r a n s f e r .The p r e s e n c e of ACD i n th e b lo o d i n much h i g h e r p r o p o r t i o n s t h a n

would be fo u n d d u r in g b y p a s s o p e r a t i o n s h a s th e e f f e c t o f r e d u c i n g damage

by r e d u c i n g th e c o n c e n t r a t i o n o f e r y t h r o c y t e s . As f a r a s o x y g e n a t io n

i s c o n c e rn e d , th o u g h , th e e f f e c t o f ACD i s t o i n c r e a s e th e p la sm a b a r r i e r

and r e d u c e e f f i c i e n c y .The r e a s o n i n g b e h in d i n v i t r o t e s t i n g i s d i s c u s s e d i n 2* 3

6 . 1 . 2 . Haemol.ysi sThe im p o r ta n c e o f h e m o ly s is c o n t r o l l i e s i n th e a p p r e c i a t i o n o f i t s

r o l e i n i n c r e a s i n g s l u d g in g and th e l i k e l i h o o d o f r e n a l o r c e r e b r a l f a i l u r e due to em bolism ; The m a ss iv e r a t e s o f h e m o ly s i s w h ich a h e a l t h y body can t o l e r a t e c a n n o t be sv/ept up by th e r e t i c u l o - e n d o t h e l i a l sy s te m

o f a p a t i e n t u n d e r b y p a s s c o n d i t i o n s .H em o ly s is h a s b e en shown t o be due p r e d o m in a n t ly to th e c i r c u l a t i o n

o f t h e b lo o d th ro u g h th e com ponents o f th e c i r c u i t n o t m e re ly i t s c o n t a c t

w i th f o r e i g n : s u r f a c e s . Components w hich c a u s e a sudden ch an g e of. f lo w r a t e a g g r a v a t e r e d c e l l damage and t h e r e i s some e v id e n c e t h a t g a s c o n t a c t i n g d e v i c e s a l s o i n c r e a s e t h i s form o f damage. N u m erica l r e s u l t s f o r th e h e m o ly s i s a t t r i b u t a b l e t o e ach com ponent o f c i r c u i t r y u s e d i n t h i s s e r i e s o f e x p e r im e n t s a p p e a r i n S e c t i o n 4 . 1 4 .

The h e m o ly s i s c a u s e d by th e membrane and f i l m o x y g e n a to r c i r c u i t s

were r e s p e c t i v e l y 15 mg.% and 25 mg.%. The fo rm e r f i g u r e , w h i le th e low e^ i s to o h ig h f o r a p r a c t i c a l p e r f u s i o n c i r c u i t and a l th o u g h th e c i r c u i t c o n ta i n e d a f i l m d e o x y g e n a to r and o t h e r n o n - i d e a l com po n en ts , t h e membrane

o x y g e n a to r I t s e l f was p a r t i a l l y r e s p o n s i b l e . A lth o u g h some c a r e was t a k e n i n th e d e s ig n o f th e o x y g e n a to r , t h i s was c h i e f l y f o r t h e c o n v e n ie n c e o f e a s y c o n s t r u c t i o n and o f change i n p a r a m e te r s l i k e b lo o d cham ber t h i c k n e s s . I t i s th o u g h t p o s s i b l e t o d e s ig n a membrane o x y g e n a to r whose hemodynam ics a r e s u f f i c i e n t l y s im p le t o m in im ise

h e m o ly t ic damage. V e r v lo e t (1970) c l a im s t h i s f o r t h e LandeEdw ards membrane o x y g e n a to r .

S c re e n s i n t h e b lo o d p h a s e , a s s u g g e s te d by Bramson (1965*1972) were u sed i n an e a r l y a t t e m p t to c r e a t e s e c o n d a ry f lo w s and im p ro v e e f f i c i e n c y . T he re was e v id e n c e o f im p ro v ed g a s t r a n s f e r u s in g an a n n e a le d g l a s s f i b r e s c r e e n b u t m a ss iv e h e m o ly s i s r e s u l t e d .

T here was no e v id e n c e o f i n c r e a s e d b l o o d damage by e x t e r n a l v i b r a t i o n .I H ickel ( I 9 6 7 )whose s p i n n i n g t e c h n iq u e m ig h t have b e en e x p e c te d t o i n c r e a s e h e m o ly s is d id n o t o b s e r v e any m arked r i s e . I n f a c t , no w o rk e r h a s , i n th e f i e l d o f s e c o n d a ry f lo w s ( f o r th e im provem ent o f o x y g e n a t i o n ) o b s e r v e d

any s i g n i f i c a n t d e t r i m e n t a l e f f e c t ( A l to n Murphy 1 9 7 1 ) .

6 . 1 . 3 P r o t e i n D e n a tu r a t i o n

Lee (1971) h a s d i s c u s s e d i n some d e t a i l t h e e f f e c t o f d e n a t u r a t i o n on th e p r im a ry s e c o n d a ry and t e r t i a r y s t r u c t u r e o f p r o t e i n s . He h a s c la im e d (Lee I ) t h a t membrane o x y g e n a to r s have a lo w e r te n d e n c y to

p rom ote d e n a t u r a t i o n th a n t h e i r , g a s - c o n t a c t i n g c o u n t e r p a r t s and t h a t d e n a t u r a t i o n can c a u s e c o m p l i c a t i o n s o r d e a th f o l l o w i n g frypass (Lee 2)

K ayser (1974) c l a im s t h a t th e e v id e n c e f o r s i g n i f i c a n t d e n a t u r a t i o n i n any modern b l o o d - g a s i n t e r f a c e o x y g e n a to r a t p h y s io lo g ic a l g a s t e n s i o n s

and t e m p e r a t u r e s i s t h i n . W righ t (1 9 6 2 ) f a i l e d t o d e m o n s t r a t e any

s i g n i f i c a n t p r o t e i n d e n a t u r a t i o n i n s c r e e n o r membrane o x y g e n a t o r s .

This t h e s i s a ttem pted i n p a r t to re-exam ine the e f f e c t o f e x t r a - c o rp o re a l

c i r c u l a t i o n on plasma p r o t e in s . Using a v a i l a b le a p p a ra tu s , the convenience o f

the p r o te in b i u r e t procedure and c e l lu lo s e a c e ta te e l e c t r o p h o r e s i s to

determine changes in the r e l a t i v e p r o te in f r a c t i o n s was a t t r a c t i v e . S ta rch

o r o th e r g e l techn iques would have given b e t t e r d e f in i t i o n b u t was more

expensive , time consuming and d i f f i c u l t to analyse q u a n t i t a t i v e l y .

There d id appear to be a g r e a te r d e c l in e i n the r e l a t i v e albumin co n ten t

o f the serum f o r the f i lm oxygenator c i r c u i t s (1% p e r hour) th an f o r the

'■*membrane 'fbxygenat'or c i r c u i t ( 0 «6% p e r h o u r ) . The changes were sm all and

the s ig n i f ic a n c e o f the re d u c t io n i s n o t f u l l y a p p re c ia te d . There a lso

appeared to be an in c re a se i n the m o b il i ty o f the oCz f r a c t i o n w ith l i t t l e

measurable change i n the rem ainder. A ll th e se f in d in g were observed by

Wright (1 9 6 2 ) . Lee ( 2) a lso no ted the albumin l o s s caused by an a r t i f i c i a l

c i r c u l a t i o n .

There was an i n i t i a l l o s s o f p r o te in on prim ing the c i r c u i t mainly o f

albumin. T h e re a f te r the t o t a l p r o te in l e v e l f e l l only s l i g h t l y .

6. 1. 4 . V ib ra t io n

The c o n t ro l o f the hemodynamics of the e ry th ro c y te s by v i b r a t i o n and

by the design o f c i r c u i t r y can g r e a t ly enhance oxygen t r a n s f e r . The a t tem p t

i s to reduce the r e s i s ta n c e to gas flow by e l im in a t in g the e f f e c t i v e

r e s i s t a n c e o f the plasma. This a b i l i t y has been dem onstrated by I l l i c k a l

(1967) j Melrose (1) and o th e r s . Many techn iques have been employed b u t th e re

i s no p reced en t f o r v io r a t i n g a conventional s ta . t ic bed oxygenator to

improve gas t r a n s f e r . ' V ib ra t io n i n a p la n e , p e rp e n d icu la r to th e membrane,

proved to g ive s im i la r improvement to t h a t shown by o th e r workers on w idely

d i f f e r in g system s. I f , as suggested by t h i s s e r i e s o f exp er im en ts , v i b r a t i o n

causes improved oxygenation w ith no apparen t adverse e f f e c t s , c u r r e n t ,

c l i n i c a l l y ~ u s e d >s t a t i c membrane oxygenators l i k e the T raveno l, Lande^Edwards

and G.E.C. P e i rc e could have t h e i r performance in c re a se d and t h e i r s iz e

reduced. The b e n e f i t s would be a more compact machine, p o s s ib ly p o r t a b le ,

producing l e s s damage and c o s t in g l e s s to o p e ra te .

The mechanism which caused t h i s improved performance i s n o t known b u t i t/ 18 \appears from the quoted h e m ato c r i t f ig u r e s (on graph) t h a t t h i s may n o t be

exp la in ed away by changes i n the a f f i n i t y o f th e b lood f o r oxygen. There a re

a number o f p o s s ib le mechanisms, though, which might be r e l e v a n t .

While i t has o f t e n been thought d e s i r a b le to m a in ta in lam in a r flow

c o n d i t io n s , many workers have found l i t t l e damaging e f f e c t s by im posing a

r e l a t i v e l y h igh flow r a t e on b lood . Through the b lood sereen where th e

membrane p re s e n ts a rough tacky s u r f a c e , i t i s most u n l ik e ly t h a t t r u l y

lam in a r flow could be e s ta b l i s h e d (N ik u rad se 's work on rough p i p e s ) . C e r ta in ly

where l a t e r a l v i b r a t i o n i s brought i n t o p la y , the random and e r r a t i c motion

which i s superimposed on the mean v e lo c i ty o f a p o in t i n tu r b u le n t flow i s -

l i k e l y to be more pronounced. Small q u a n t i t i e s o f f a s t moving l i q u i d w i l l

move sideways i n to a slow la y e r in c r e a s in g the momentum o f the l a t t e r . A

corresponding motion o f the slower f l u i d i n to the f a s t l a y e r must take p lace

to avo id accum ulation . This l a t e r a l exchange o f f l u i d would r e s u l t i n a

s im i la r eddying o f c e l l s whose in t im a te c o n ta c t , w ith the membrane w a l l ,

however s h o r t , i s so e s s e n t i a l to e f f i c i e n t gas t r a n s f e r . C e r ta in ly such

momentum exchanges must le a d to the breakdown o f any c e l l d e p le t io n l a y e r

which e s t a b l i s h e s i t s e l f and whose e x is te n c e p re s e n ts h igh r e s i s t a n c e to

oxygen t r a n s f e r .

The e x p lan a t io n may be s im p le r . . I n view o f the v a s t l y d i f f e r i n g

d e n s i t i e s o f the c e l l s from t h e i r environm ent, the momentum g iven tp a c e l l

by l a t e r a l v ib r a t io n may enable i t to t r a v e r s e l a y e r s o f f l u i d and u l t im a te ly

p re s e n t i t s e l f to the membrane boundary*

The study o f the e f f e c t o f fo rc e d v ib r a t io n s on the moving b lo o d stream

i s a complex one* The membrane; i t s e l f i s e l a s t i c though no t p e r f e c t l y so . I t

was supported by a s o f t sponge which allow ed a d i s t o r t i o n o f membrane shape

and o f the b lood flow p a t t e r n . The motion o f the membrane i s fo rc e d by the

movement o f i t s edge su p p o rts . The r e s u l t i n g d e f l e c t i o n might be d i f f i c u l t

to analyse b u t the a n a ly s i s used f o r the d e f l e c t i o n o f t h i n sh e l ls ,m a y c lo s e ly

approxim ate. The rh e o lo g ic a l analogue which one cou ld c o n tru c t to s im u la te

the mechanism o f v ib r a t i o n might c o n s i s t o f a s p r in g , mass, dam system f o r

th e membrane g iv in g a motion o f the c e n tre o f the membrane o f th e same frequency

as the membrane supports bu t o f d i f f e r i n g phase. T h is phase s h i f t would va ry

from zero a t the support to a maximum a t the membrane c e n t r e , each p o in t on

the membrane t r y in g to impose i t s own motion on the a d ja c e n t f l u i d . The f l u i d ,

a lso e s s e n t i a l l y a s p r in g , mass, damper system w i l l i n tu r n respond b u t w ith

f u r t h e r phase s h i f t s . The n e t e f f e c t w i l l be to produce a l a y e r o f f l u i d w ith

c e l l s v ib r a t in g ac ro ss i t w ith d i f f e r i n g phases and th e r fo r e d i f f e r i n g v e l o c i t i e s .

At any g iven c ro ss s e c t io n , the phase l a g between the membrane w a ll and the

a d ja c e n t f l u i d w i l l ten d to cause the r e l a t i v e motion o f b lood c e l l s to be

d i r e c te d toyfards the membrane w all w h i l s t the membrane i s a c c e l e r a t i n g and

away w h i l s t the membrane i s d e c e le r a t in g . This a c t io n may w ell enhance gas

t r a n s f e r by e l im in a t in g an accum ulation o f s a tu r a te d c e l l s &t th e f l u i d

boundary. There may a lso be an e f f e c t on the t e t h e r i n g o f c e l l s observed

by B lackshear where v ib r a t io n might p rev en t the e s ta b l ish m e n t o f t h i s

phenomenon.

A l te rn a t iv e ly the v ib r a t io n o f the f l u i d boundary may s e t up l a t e r a l

p re s su re waves a c ro ss the medium caus ing reg io n s o f r e l a t i v e l y h ig h and o f

r e l a t i v e l y low p re s su re w ith a r e s u l t i n g change i n the r e l a t i v e p o s i t io n s o f

the f l u i d m o lecu les . Again the e f f e c t would be to e l im in a te an accum ulation

o f s a tu r a te d c e l l s a t the boundary and to enhance mixing. A com plica tion

to the flow p a t t e r n i s the r e l a t i v e l y massive w e ig h t 'o f r e d c e l l s . L e f t to t h e i r

own d ev ice s , even i n a moving stream , th e re would be a tendency f o r th e se to

g r a v i t a t e to the lower membrane w a l l . The e f f e c t o f v i b r a t i o n may be to

c o n s ta n t ly r e p e l l c e l l s from the lower su r fa ce l i k e peas on a drum and hence

cause an in te rc h a n g e .

The mechanism may a l t e r n a t i v e l y be due to the e n try c o n d i t io n s to the

d i s to r t e d b lood l a y e r where b lood flow i s fo rc e d t o 'n e g o t i a t e a bend on e n t r y

producing l a t e r a l c e l l u l a r motion Tinder c e n t r i f u g a l a c t io n (T ay lo r v o r t i c e s )

Whether any o r a combination o f the above mechanisms i s o p e ra t iv e i n

enhancing oxygenation performance r e q u i r e s f u r t h e r study - p o s s ib ly by flow

v i s u a l i s a t i o n o f heavy p a r t i c l e s i n an analogous medium. I t i s thought n o t to

be due to any a l t e r a t i o n i n th e b lo o d 's a f f i n i t y f o r oxygen n o r can i t be

a t t r i b u t e d to suggested v a r i a t i o n s i n i n i t i a l b lood q u a l i t y . C e r ta in ly the

o p t im iz a t io n o f v ib r a t i o n techn ique i s im p o r tan t and the p o s s i b i l i t y o f u l t im a te

e l im in a t io n o f b lood screens i n f l a t bed oxygenations could have an im p o r tan t

b e n e f i c i a l e f f e c t .The in c re a se i n oxygenation was a l i n e a r fu n c t io n o f v ib r a t i o n frequency

and was approxim ately fo u r f o ld a t 400 Hz. The im p l ic a t io n i s

■ - 1 ( ? 6 -

t h a t t h e p e r fo rm a n c e c o u ld be im p ro v ed f u r t h e r a t y e t h i g h e r

f r e q u e n c i e s . U n f o r t u n a t e l y , a l t h o u g h p r o v i s i o n was mad.e t o u s e a s i g n a l g e n e r a t o r t o e x p l o r e t h e h i g h e r r a n g e o f f r e q u e n c i e s - a m p l i tu d e c o n t r o l was l o s t .

6 . I . 5 . O th e r C o n s i d e r a t i o n s .

I t was n o te d d u r in g t h e c o u r s e o f t h e e x p e r im e n t t h a t t h e ' t i m ec o n s ta n t* o f th e t r a n s i e n t r e s p o n s e o f t h e o x y g e n a to r t o any change o fp a r a m e te r , v i b r a t i o n s p e e d , oxygen p r e s s u r e on f lo w r a t e , was o f t h e o r d e r o f tw e n ty m in u te s . T h is w ould make management o f p e r f u s i o n

d i f f i c u l t and p ush L o n g m o re 's dream o f t h e ' t w o - c o n t r o l p o r t a b l e b o x ' f u r t h e r i n t o t h e f u t u r e .

E x p e r im e n ts on th e p r e s s u r i z a t i o n o f t h e g a s p h a se i n an a t t e m p t to . . im p ro v e o x y g e n a t io n showed a tw o f o ld i n c r e a s e i n g a s t r a n s f e r f o r p r e s s u r e s e x c e e d in g th e b lo o d p r e s s u r e . The e f f e c t i s n o t p r o p o r t i o n a l t o t h e b lo o d p r e s s u r e s i n v o lv e d b u t much g r e a t e r . The r e a s o n f o r t h i s ’i s n o t f u l l y u n d e r s to o d a l t h o u g h i t i s i n p a r t due t o th e r e d u c t i o n o fth e b lo o d f i l m t h i c k n e s s by t h e e x t e r n a l p r e s s u r e on th e membrane.

Work by Dagher (1959) showed p r e s s u r i z a t i o n c a u se d o x y g e n a t io n enhancem en t b u t th e t e c h n i q u e i s f r e q u e n t l y c r i t i c i z e d on th e g ro u n d s t h a t i t i n c r e a s e s t h e d a n g e r s o f a i r em bolism . I t was t h o u g h t t h a t p r e s s u r i z a t i o n m ig h t m in im ise t h e known a d h e s io n o f e r y t h r o c y t e s t o t h e membrane- s u r f a c e . I t was hoped t h a t e l e c t r o n m ic ro g ra p h s m ig h t be u se d to show t h i s e f f e c t . The p r i n t s , how ever, p ro v e d i n c o n c l u s i v e .

T here a p p e a re d to be a l i n e a r d e c r e a s e i n o x y g e n a t io n w i th i n c r e a s e d b lo o d f lo w r a t e . When r e p l o t t e d a t o x y g e n a t io n p e r fo rm a n c e ■ -. a g a i n s t b lo o d f lo w a c u rv e was p ro d u c e d w hich s u g g e s t e d an optimum f lo w r a t e g i v i n g maximum p e r fo rm a n c e . Oxygen f lo w r a t e c o u ld n o t be shown to a f f e c t t h e o x y g e n a to r s p e r fo rm a n c e b u t th e s m a l l n e s s o f th e

membrane a r e a made s m a l l c h an g e s d i f f i c u l t t o d e t e c t . T h e re was no d e t e c t a b l e d e t e r i o r a t i o n i n o x y g e n a to r p e r fo rm a n c e a l t h o u g h s m a l l

th ro m b i w ere o c c a s i o n a l l y s e e n to d e v e lo p n e a r th e e n t r y o f t h e b lo o d cham ber. V i b r a t i o n had th e e f f e c t o f m in im is in g t h e s e and no th ro m b i

w ere u s u a l l y v i s i b l e . .V a r io u s fo rm s o f membrane s u p p o r t w ere t r i e d . The m e ta l s c r e e n s ,

a l t h o u g h g i v i n g good s u p p o r t , s e v e r e l y d e c r e a s e d th e e f f e c t i v e membrane

a r e a , i n one c a s e by o v e r 50%• Sponge s u p p o r t s p ro v e d m ost

s a t i s f a c t o r y a l t h o u g h th e y p r e v e n te d t h e v ie w in g o f th e b lo o d f lo w

p a t t e r n .

- 107

B lood s c r e e n s o f v a r i o u s k in d s w ere t r i e d , t h e s e a r e h i g h l y n e c e s s a r y i n t h e ^control o f b lo o d f i l m t h i c k n e s s , a v i t a l p a r a m e te r i f no s e c o n d a ry f lo w s a r e im p o se d . Most i n c r e a s e d h e m o ly s i s b u t by m a r g in a l am o u n ts .

O th e r b lo o d damage m easu rem en ts were a t t e m p t e d . H e m a to c r i t and e r y t h r o c y t e counts f e l l d u r in g a l l e x p e r im e n t s b u t to o s l i g h t l y t o b e s i g n i f i c a n t . W hite c e l l s were c l e a r e d from th e b lo o d , p r o b a b ly by­a d h e s io n to th e c i r c u i t w a l l s , w i t h i n two m in u te s o f i n d u c t i o n i n t o t h e c i r c u i t .

6 . 2 . S u g g e s t io n s f o r f u r t h e r w o rk .The g r e a t e s t n e ed i s f o r t h e s e l e c t i o n o f i n s t r u m e n t a t i o n and t e s t s

w h i c h 'a r e c o n s i s t e n t , r e l i a b l e and m in im ise t im e . The a c c e p t a b i l i t y o f t h e a to m ic a d s o r p t i o n m ethod f o r p la sm a i r o n d e t e r m i n a t i o n h a s n o t b e en shown s a t i s f a c t o r i l y and i t i s s u g g e s t e d t h a t s e v e r a l m e th o d s o f

h e m o ly s i s a s s a y b e a t t e m p te d s i m u l t a n e o u s l y f o r d e t a i l e d c o m p a r is o n .T here a r e a l s o many f e a s i b l e m ethods f o r e x a m in a t io n o f p r o t e i n

d e n a t u r a t i o n (Kauzman 1959) and t h e s e r e q u i r e f u l l e x p l o r a t i o n . The e f f e c t o f d e n a t u r a t i o n o f p r o t e i n s on t h e body i s n o t w e l l u n d e r s to o d n o r i s th e c o n t r o l of, d e n a t u r a t i o n .

C o n t in u o u s oxygen s a t u r a t i o n m o n i to r in g s h o u ld be em ployed f o r

f u t u r e t e s t s . The u s e o f th e R a d io m e te r BMS 3 i s t im e consum ing and a l lo w s r e a d i n g s a t b e s t e v e ry f i v e m in u te s . I t a l s o s u f f e r s from h u m a n ; 'e r ro rs i n t r o d u c e d by th e d raw in g o f t h e s am p le . O x im e try h a s l o n g b e e n em ployed t o m o n i to r oxygen s a t u r a t i o n . I t was once common p r a c t i c e to d e te r m in e t h e a r t e r i a l o f a p a t i e n t b e f o r e a m a jo r

o p e r a t i o n u s in g an e a r o x im e te r . - The p r i n c i p l e o f t h e o x im e te r ( R e i c h e r t 1966) i s c o l o r i m e t r i c u s in g e i t h e r r e f l e c t e d o r t r a n s m i t t e d l i g h t .

S ys tem s f o r c o n t in u o u s m o n i to r in g a r e d e s c r i b e d by B lu m e n fe ld (1 ^ 7 3 ) and C le rb a u x (1973)*

B e t t e r know ledge o f th e hemodynamics o f th e r e d c e l l i n s e c o n d a ry f lo w s i s r e q u i r e d i n o r d e r t o e n a b le d e s ig n c r i t e r i a t o b e f o r m a l i s e d . C u r r e n t , r e s e a r c h i s by s e r e n d i p i t y . A d e s ig n i s p ro d u c e d , p a r a m e t e r s a r e ch anged and t h e e f f e c t n o te d - t h e r e i s no u n i f y i n g l i n e t o t h e r e s e a r c h . P o s s i b l y t h e s i m u l a t i o n o f t h e r e d c e l l movement by p a r t i c l e s i n an a n a lo g o u s f l u i d whose m o tio n c o u ld b e b e t t e r o b s e r v e d th ro u g h th e v i b r a t i n g o x y g e n a to r /■* o r a s i m u l a t i o n o f i t w ould p ro d u c e

f i r m e r i d e a s .

- 108 -

The e f f e c t o f c h a n g in g t h e a m p l i tu d e and f r e q u e n c y o f v i b r a t i o n o f c u r r e n t l y u s e d s t a t i c - b e d o x y g e n a to r s t o enhance t h e i r p e r fo rm a n c e r e q u i r e s f u l l e r i n v e s t i g a t i o n . The h i g h e r f r e q u e n c i e s c o u ld be e x p lo r e d t o d e te r m in e t h e p o i n t a t w hich th e o x y g e n a t io n t r a n s f e r r a t e

s a t u r a t e s o r a t w h ich b lo o d t ra u m a r a p i d l y I n c r e a s e s .The p ro m ise f o r t h e f u t u r e makes th e p u r s u i t o f t h e i d e a l

o x y g e n a to r w o r th w h i le . O p e r a t io n s w hich a r e n o t now c l i n i c a l l y v i a b l e

may become r o u t i n e . Where t im e i s a t a premium, th e membrane

o x y g e n a to r may be a b l e t o buy t h a t t im e . E c o n o m ic a l ly , i t w i l l n e v e r b e a b l e to com pete w i t h i t s r i v a l s and w i l l o n ly s u c c e e d i f i t s s u p e r i o r i t y and r e l i a b i l i t y a r e p ro v e d beyond d o u b t .

- 109 -

ABEL, K..

.ABERMAN. A e t

a l .ADAMS, A .P .

e t a l . ALLAN, D avid

ALLEN, J .G .

ALTHAUS, U.

- ' e t a l .

ALTON MURPHY

D. e t a l .

ANDERSEN M.N.

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ANSON, M.L. ANZAI, N.

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Mt. S i n a i J . Med. 4 0 :1 8 9 -9 8 1973P ro lo n g e d e x t r a c o r p o r e a l o x y g e n a t io n f o r a c u t e p o s t - t r a u m a t i c r e s p i r a t o r y f a i l u r e ( s h o c k lu n g s y n d ro m e ) . Useo f t h e Bramson membrane lu n g .

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T r a n s p l a n t a t i o n . P r o c . 3 .1 4 3 7 - 4 3 1971.7 . C l i n i c a l p ro lo n g e d e x t r a c o r p o r e a l c i r c u l a t i o n f o r r e s p i r a t o r y

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8 . A cu te r e s p i r a t o r y i n s u f f i c i e n c y . . T re a tm e n t w i th p r o lo n g e d e x t r a c o r p o r e a l o x y g e n a t io n .

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A r t . O rgans 8; Car d io p . s u p p o r t s y s te m s 4 3 -9 ■ 19711 1 . P l a t e l e t k i n e t i c s d u r in g e x t r a c o r p o r e a l c i r c u l a t i o n .

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e t a l . T ran s A n n . S o c . A r t i f . I n t . O r g s . 1 3 :1 3 1 - 4 1969H em olys is o f b lo o d due to e x p o su re to d i f f e r e n t t y p e s o fp l a s t i c t u b i n g and th e i n f l u e n c e o f e t h y l e n e - o x i d es t e r i l i z a t i o n .

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e t a l . 1 . c a p a b i l i t y o f membrane l u n g s .

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HUNG,T.k * A model s tu d y o f w a l l - e f f e c t on th e hydrodynam ic c h a r a c -1 . t e r i s t i c s o f e r y t h r o c y t e - s h a p e d b o d i e s .

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pu lm onary b y p a s s i n c a l v e s .

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P r o c . A r t . H e a r t P r o g .C o n f . 3 9 3 : - 4 °3 1969KETTERINGHAM,Polyalkylsulfone: a new p o lym er f o r membrane o x y g e n a to r s J . M . e t a l . T r a n s . Ann. S o c ♦ A r t i f . ' I n t . O r g s . 1 9 : 6 1 -5 1973KIRSH, MM e t C l i n i c a l u se o f P e i r c e - G e n e ra l E l e c t r i c membrane o x y g en a-

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Organ P r e s , and P e r f . 1 5 : 1 5 5 -7 5 19682 . C o n s t r u c t i o n and e v a l u a t i o n o f an a l v e o l a r membrane a r t i ­

f i c i a l h e a r t - l u n g .

T r a n s . A n n . S o c . A r t i f . I n t . O r g s . 9 : 2 3 8 -4 3 19633* P a r t i a l e x t r a c o r p o r e a l g a s exchange i n a l e r t new born lam b s

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KOLOBOW T. P a r t i a l c a r d io p u lm o n a ry b y p a s s l a s t i n g up t o s e v e n d ay s i n e t a l* 5 * a l e r t lam bs w i th membrane b lo o d o x y g e n a t io n .

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w i th th e s p i r a l membrane lu n g .

Adv. C a r d io l 6 : 1 1 2 -1 3 2 K a rg e r B a s e l

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A r t i f i c i a l c a p i l l a r y l u n g .

U .M ich .M ed .C en tre J . 3 4 : 1 9 4 -6 1968P l a t e l e t s , th ro m b o s is and h e m o ly s i s .

F e d .P r o c . 3 0 : 1 3 3 1 -3 1971H e a r t s u r g e r y w i th a membrane o x y g e n a to r i n i n f a n t s .

J . T h o rac . C a r d io v a s c . S u r g . 6 7 :3 9 3 -3 9 8 1974O p t i c a l t e c h n iq u e f o r c o n t in u o u s m o n i to r in g o f hemo­l y s i s i n a f lo w s y s te m . .

24 ACEMB 18A : 144 1971 .

T

TAYLOR, M.S. Hemodynamics

A nn.Rev. P h y s i o l . 3 3 : 8 7 -1 1 6 1973

PEIRCE, E .C . A s i m p l i f i e d h e a t ex change f o r p e r f u s i o n h u p o th e rm ia

1 6 . Arch S u r g . 8 4 :3 2 9 - 333 196217* D esig n and f a b r i c a t i o n o f b lo o d o x y g e n a to r f o r

c i r c u l a t o r y a s s i s t d e v i c e s .

P r o c . A r t i f . H e a r t P ro g . C o n f . 33 19691 8 . C l i n i c a l u se o f th e membrane lu n g .

S u r g e r y A n n u a l . 4 : 1 9 1 - 2 1 2 1 9 7 2

1 9 . An a t t e m p t t o a s s e s s o c c u l t r e d b lo o d c e l l damage by a s t a n d a r d s h e a r t e s t .

T ra n s A n n . S o c . A r t i f . I n t . O r g s . 1 8 :3 4 2 - 7 19722 0 . P ro b lem s o f l o n g - t e r m p e r f u s i o n w i th membrane lu n g .

NY S t a t e J Med. 2347 - 31 1973PELLERCHIA*JA D e te r m in a t io n o f h em o g lo b in oxygen c o n t e n t from p e r

c e n t s a t u r a t i o n by nomogram.

Ann H e a r t J . 8 4 : 371 1972PETSCHEK, H. S t a g n a t i o n f lo w th rom bus f o r m a t i o n

T ran s Ann. S o c . A r t i f . I n t . O rg s . 1 4 :2 3 6 - 6 0 1968PHIBBS, R .H. A rrangem en t o f e r y t h r o c y t e s i n f lo w in g b lo o d .

e t a l , F e d . A n n . S o c . f o r E x p .B io l . F ed . P r o c . 2 4 :1 3 6 1963PITZELE, S. A l i q u i d - l i q u i d o x y g e n a to r u t i l i z i n g o x y g e n - s a t u r a t e d

i n e r t f l u o r o c a r b o n f o r o rg a n p e r f u s i o n p r e s e r v a t i o n .

S u rg e ry 6 8 :1 0 7 9 -8 6 1970POLLOCK, A. Oxygen t r a n s p o r t i n an aem ia

e t a l . B r i t J . H aem 23: 6 3 1 -6 1973PONDER, F . Shape c h an g e s accom pan ied by volum e c h a n g e s .

H em olys is and r e l a t e d phenom ena. 1 1 1 :3 0 -9 2 6 -5 7PRADOS, J .W . The i n f l u e n c e o f membrane p e r m e a b i l i t y and o f d e s ig n

e t a l . on g a s exchange i n t h e membrane l u n g .T ran s A n n . S o c . A r t i f . I n t . O r g s . 6 :3 2 - 6 1 i 960

PUTNAM, F.W. The p la sm a P r o t e i n s , Vol 1 .Academic P r e s s NY and London I 9 6 0

PROCTOR, E. A r a n g e o f r e s e a r c h o x y g e n a to r s f o r e x p e r im e n t a l e t a l . c a rd io p u lm o n a ry b y p a s s . •

J . S u r g . R e s ' . 1 5 : 1 1 2 -6 1973

R AWITSCHER, RE E v a l u a t i o n o f h o l lo w f i b e r and s p i r a l c o i l membrane

o x y g e n a to r s d e s ig n e d f o r c a r d io p u lm o n a ry b y p a s s i n

i n f a n t s .

S u p p i . I l l C i r c u l a t i o n . 4 7 /8 I I U O 3 1973

- 138 -

TIMMONS, E .H . /L o n g - te r m - v e n o - v e n o u s p e r f u s i o n w i th a membrane e t a l . o x y g e n a to r i n p u p p i e s . »

T r a n s . Ann. S o c . Ar t i f . I n t . O rg s . 1 6 :3 3 9 -4 4 1970TORJUSSEN, W. pH and pC02 i n c a p i l l a r y b lo o d from th e e a r - l o b e .

e t a l . J . C I i n - L a b . I n v e s t . 1 9 :7 9 -8 1 196?

TRUDELL, L .A . E v a l u a t i o n o f a d i s p o s a b l e membrane o x y g e n a to r ,

e t a l . • T ra n s Ann.Soc . A r t i f . I n t . O r g s . 1 8 :3 3 8 -4 3 1972TURINA, M. e t S e rv o c o n t r o l l e d e x ten d e d , c a rd io p u lm o n a ry b y p a s s ,

a l . 1 . T ran s A n n . S o c . A r t i f . I n t . O rg s . 1 9 : 3 0 4 -9 19732 . S e rv o c o n t r o l l e d p e r f u s i o n u n i t w i th membrane o x y g e n a to r

f o r e x te n d e d c a r d io p u lm o n a ry b y p a s s .B iom ed.E ng . : 1 0 2 -7 Mar. 1973

. 3* An a u to m a t ic c a r d io p u lm o n a ry b y p a s s u n i t f o r u s e i ni n f a n t s .

T ra n s A n n . S o c . A r t i f . I n t . O r g s . 1 7 :3 7 6 - 8 0 1 9 7 i

U V '

UPDIKE, S . J .

e t a l , 1 .

2.

' ' ' V

VALITOV, S .S . An e l e c t r o n m ic r o s c o p ic s tu d y o f th ro m b o c y te s i n

e t a l . e x t r a c o r p o r e a l c i r c u l a t i o n .

V e s tn .-K h ir . 1 1 0 :7 6 - 8 1973VERVLOET,A.F.C M inimal a p p a r e n t b lo o d damage i n Land& Edw ards membrane

e t a l . o x y g e n a t io n a t p h y s i o l o g i c g a s t e n s i o n s .

J . T horac C a r d io v a s c . S u r g . 6 0 :7 7 4 -8 1970VILLARROEL, F . R e s p i r a t o r y g a s ex change i n e x t r a c o r p o r e a l s y s t e m s .

23 ACEMB 2 2 .8 :2 9 1 1970A d e s ig n c a l c u l a t i o n m ethod f o r c a p i l l a r y tu b e o x y g e n a to r s

23 ACEMB 463 1972Dual w a v e le n g th r e f l e c t a n c e o x im e te r f o r l o n g - t e r m e x t r a c o r p o r e a l m o n i to r in g .

23 ACEMB 1 0 .2 : 113 1970

e t a l . 1 .2 .

VUREK, G.G.

e t a l . 1 .

O x y g e n a t io n by transm em brane c a t a l y s i s o f hydrogorperoxide

; J . A pp l. P h y s i o l . 5 /f . 2 7 1 - 3 1 9 7 3R e s p i r a t o r y g a s e x c h a n g e b y h e m o - d i a l y s i s .

T ran s A n n . S o c . A r t i f . I n t . O r g s . 1 9 ? 3 2 9 -3 4 1973

- 139 -

VUREK, G.G.

' e t a l* 2 *

WALLACE,H.W.1 .

2 *.

WEISSMAN*M.H ■ e t a l . 1 «

2 .

3 .

: 5* '

6 .

7 .

WHITAKER,J .P ,

WHITE, J . J .. r

e t a l . 1 .

2 .

3 .

Oxygen s a t u r a t i o n m o n i to r f o r e x t r a c o r p o r e a l c i r c u l a t i o n .

a p p l i c a t i o n s .

• A s s n .A d v .M e d . I n s t . ? i 2 6 2 -7 1973

. W • ;

r L i q u i d - l i q u i d o x y g e n a t io n : a new a p p ro a c h .T ran s A n n .S o c .A r t i f .O r g s . 1 9 : 80 - 1973

A new c o n c e p t i n b lo o d o x y g e n a t io n .

F ed . P r o c . 836 1973 1• The m oving r o d membrane o x y g e n a to r . :

23 ACEMB 22w27 J 310 1970 jOxygen t r a n s f e r to b lo o d f lo w in g i n ro u n d t u b e s . |

J . E n g .M e c h .D iv . - P ro c .A n n .S o c .C iv .E n g . 2 2 5 -4 4 1967 Gas t r a n s f e r t o b lo o d f lo w in g i n c o i l e d c i r c u l a r tubes*.

J .E n g .M e c h .D iv . - P r o c .A n n .S o c .C iv .E n g . 8 3 7 -7 2 1968 j Oxygen and c a rb o n d io x id e t r a n s f e r i n membrane oxy­g e n a t o r s . " " . ...............■

Med. & v i o l . E ng . 7 :1 6 9 -1 8 4 1969 ;D i f f u s i o n i n m e m b ra n e - l im i te d b lo o d o x y g e n a to r s . ,

A 1 Ch E J . . 1 3 :6 2 7 - 3 0 1969E f f e c t o f c h e m ic a l r e a c t i o n r a t e i n membrane b lo o d

o x y g e n a to r s .

. 24 ACEMB 3 4 .1 0 : 301 1971A n a ly s i s o f an im proved o x y g e n a t io n m echanism .

21 ACEMB - 1 2 .2 . 1968

, P ap e r c h ro m a to g ra p h y and e l e c t r o p h o r e s i s .

V o l . 1 . E l e c t r o p h o r e s i s i n S t a b i l i z i n g M edia P . 4 2 -9Academic P r e s s . NY & London 1967

S t u d i e s o f a membrane o x y g e n a to r f o r p ro lo n g e d r e s p i r a t o r y s u p p o r t . .

J . P e d i a t r i c S u rg . 3 :6 1 0 - 8 .1970

P ro lo n g e d r e s p i r a t o r y s u p p o r t i n newborn i n f a n t s w i th

a ’ membrane o x y g e n a to r .Sur g e r y . 7 0 :2 8 8 -9 6 1971

P ro lo n g e d r e s p i r a t o r y s u p p o r t i n i n f a n t s w i th t h e Kolobow s p i r a l c o i l r e s p i r a t o r .

Mt. S i n a i J . Med. 4 0 :1 7 3 - 8 0 1973

€>

- 140 -

V/ILDEVUUEj CRH The u s e o f a membrane, o x y g e n a to r f o r t r e a t m e n t o f e t a l . ‘ r e s p i r a t o r y i n s u f f i c i e n c y .

T ran s A n n . S o c . A r t i f . I n t . O r g s . 1 7 :3 6 2 -3 6 8 1971.WILLIAMS, J .D . MSc. ( P r o t e i n D e n a t u r a t i o n ) U n i v e r s i t y o f S u r r e y 1969WILLIAMS, T .L . A h o l lo w f i l a m e n t f a b r i c b lo o d o x y g e n a to r .

e t a l , P r o c . A r t . H e a r t P r o g .C o n f . 3 1 :3 6 3 - 9 1969WILSON, A .T . ' e t a l . J .A n n .C h e m .S o c . 7 7 : 3948 1933

WILSON, R . e t a l . A membrane o x y g e n a to r w i t h low p r im in g volum e f o re x t r a c o r p o r e a l c i r c u l a t i o n . '

C a n . J . S u r g . 8 :3 0 9 -3 1 1 1963x WRIGHT, E .S . P lasm a p r o t e i n d e n a t u r a t i o n i n e x t r a c o r p o r e a l

e t a l . 1 . c i r c u l a t i o n .

J . T h o rac . C a r d io v a s c . S u r g . 44 : 3 3 0 -6 19622 . P e d i a t r i c a p p l i c a t i o n o f Land& Edwards o x y g e n a to r .

J . Thorac C a r d io v a s c . S u r g . 63 : 3 0 3 -1 0 1973

" \ ■ Y- .

■ YARBOROUGH,K.A. Hydrodynamic h e m o ly s is i n e x t r a c o r p o r e a l m a c h in e s .

.. e t a l , , J . T h o r a c .C a r d i o v a s c .S u r g . 3 2 :3 3 0 - 7 1966YODER,R.D. e t a l .M e a su re m e n t o f oxyhem oglob in d i s s o c i a t i o n c u r v e s w i th

c o m p u ta t io n a l d a t a r e d u c t i o n .

Computer & Biomed. R e s e a rc h 6 :1 4 - 2 6 1973

Z

ZAPOL,W.et a l . ; C l i n i c a l membrane l u n g s u p p o r t f o r a c u t e r e s p i r a t o r y1 . i n s u f f i c i e n c y .

T ran s A n n . S o c . A r t i f . I n t . O r g s . 1 8 :3 3 3 - 6 2 19722 . ‘ B uying t i m e ’w i t h ' a r t i f i c i a l l u n g s .

New E ng land & Med. 286 : 6 3 7 -8 1972

3* I n v i t r o d e n a t u r a t i o n o f p la sm a a l p h a l i p o p r o t e i n s byb u b b le o x y g e n a t io n i n th e dog.

C u r r e n t t o p i c s S u rg . R e s . 1 : 449 1969ZIJLSTRA, W.G. O x im etry i n v i v o . The nc y c l o p s n o x im e te r .

C l i n i c a l O x im e try . 3 : 4 2 -6 9ZINGG,W, e t a l . B ubble f o r m a t io n a t a l iq u id -m e m b ra n e i n t e r f a c e d u r i n g

1 . oxygen t r a n s f e r .

23 ACEMB 3 .6 :1 4 1972

141 -

ZING, W. e t a l* Membrane o x y g e n a to r f o r i n f a n t s .2 . T ran s Ann. S oc .-A r t i f . I n t . O rg s . 1 3 :3 3 4 - 8 19673# A t u b u l a r membrane o x y g e n a to r .

Bioined.- Eng. 3 0 1 -3 O c t . 1970

- 142 -

CROSS REFERENCE INDEX.

I t e m s m a r k e d t h u s a r e n o t i n c l u d e d i n R e f e r e n c e s .

- 143 -

A ntic oagu lan ts

X CPD v ACD Koch ( 1)

. ^ f o r prolonged e x tra c o rp o re a l membrane■ oxygenation Buky ( 1) 1973

x . Simple method o f h e p a rin management H i l l ( 16) 1974

A r t i f i c i a l Kidney

x U l t r a f i l t r a t i o n d esign c o n s id e ra tio n s Dorson W

m achine. Thin f ilm s or e lse? F ro s t 4 ( 1) 1973

Membrane' lung xidnqy G a l le t t i . ( 2) 1962

D iscu ssio n Lande ( 12) 1967

x D esign o f Leonard ( 2) 1969

A r t i f i c i a l Lungs

x P ro v is io n o f space f o r M elrose (7) 1971

B

B io c o m p a tib ility

B iocorapatlb le p la s t i c s in membrane ax y g a ia to rs

R isk in e s tim a tin g ______

B lood-com patible p la s t i c s

E f fe c t of m etal in te r la c e s on blood

Chang T

G a l l e t t i

Muir

Grode

Sawyer

( i )

(5)

( l )

( i )

( 1)

1973

1971

1973

Blood Flow - see Hemodynamics

- 144 -

B (continued)

Blood Gas A nalysis ( s e e a lso oxim etry)

H is to ry of Adams ( 1) 1973

Membrane f o r by mass spec trom etry B ran tigan a ) 1970

H is to ry of B reathnack ( l ) 1972

Oxygen d i f f u s iv i ty by commercial C alk ins ( 2) 1970

C om ing EEL model 165 machine E lse ( 1) 1972

Simple ta b le to in te r p r e t Lewis ( i ) 1973

Development o f a con tiguous P(£ m easuring system R eichner a ) 1969

M odified S inger H astin g s Nomogram R ispens ( 1) 1973

c a lc u la to r . S ev erin^fiaus (2) 1966

S inger H astin g s Nomogram S inger ( i ) 1948

E x e rc ise s w ith a blood gas A nalyser Buchanan ( 1) 1973

Blood C hem istry changes in hypotherm ia Osborn (5 ) 1961

E f fe c t o f h e p a rin on J o ly ( 1) 1973

X E v a lu a tio n of C lerbaux ( 2) 1973

X O p tica l d if f u s io n in blood Johnson (4) 1970

X Hon l i n e a r i t y o f -----PO2 measurement Key ( 1) 1974

X P r a c t ic a l ap p ara tu s f o r d e te rm in a tio n o f 02cor.itent K irk ( 1) 1973

X S02 v P02 , M artin ( 1) 1973

X Continuous m on ito ring of SC^in man . M artin ( 2) 1973

Normal blood gases and a l t e r a t io n s in d ise a se McHardy ( 1) 1973

ABC of Acid-Base Chem istry Davenport 1969

Sramson Lung

Lung, morphology fo llo w in g v -v p e rfu s io n H i l l ( 1) 1968

Developments to improve the E b e rh a rt ( 2) 1969

: . - 1 4 5 -

B (con tinued)

B ry s o n Lung (continuedV

E xperiences in the development o f t h e Gerbode ( l ) 1967

C lin ic a l experience w ith the Osborn ( l ) 1966

w ith in te g r a l h e a t exchange Bramson ( l ) 1965

D esign and perform ance of the __ ' Bramson ( 4 ) 1972

Bubble Oxygenator

x H eat exchanging Esmond ( l ) 1965

S e lf co n ta in ed d isp o sa b le G ott ( l ) 1957

Comparison.with GE P e irc e ; K irsh (2) 1975

Range of r e s e a r c h f o r e x tra c o rp o re a l bypass P ro c to r ( l ) 1975

Bubbles

U ltra so n ic d e te c tio n o f Austen ( 2) 1965

B hysics of growth. B uckles (2) 1968

Porma t io n a t membrane fa c e Zingg ( i ) 1972

B u ffe rin g

Defence o f pH and oxygen d e liv e ry A ustin . (1) 1974

G

S tew art (1) 19&8

B odell B (2) 19^5

C le v e rt ( l ) 1975

C a p il la ry Membrane Oxygenator

A r t i f i c i a l c a p i l l a r y lung

A r t i f i c i a l g i l l

Double

- 146 -

G (co n tin u ed )

C a p il la ry Membrane Oxygenator (continued)

; and o s c i l l a t i o n

A Use on sheep

Development and e v a lu a tio n of____

In v i t r o and in v ivo gas measurement i n _

Development of

x f o r in fa n ts

S h e ll and tube oxygenator

Development and e v a lu a tio n o f a n ew ____

Use o f on hyp ereapn ic dogs

Tubular membrane ox y g a ia to r

f o r ex v ivo p e rfu s io n o i sm all organs

Development of _ _ _ _ _

S in g le pass oxygenator

^ se f o r to t a l cardiop. bypass in caLves

A r t i f i c i a l c o i l lung

. u s in g gas d isp e rse d in o i l

Small tube s ta g e oxygenators

D esign c a lc u la t io n method f o r _

Hollow f ila m e n t f a b r ic oxygenator

Membrane oxygenator w ith low prim ing v o l .

C ard iogenic Shock

x Use o f membrane oxygenator in ___

C irc u la t io n Support

Physical and P h y s io lo g ic a l c o n s id e ra tio n s

A r t i f i c i a l M ain taiance o f’

Anzai (1) 1972

B odell B (1) . 1965

Buckley ( l ) 1969

Be F i l l i p p i ( l ) 1968

( 4 f 1969

Dorson ( 9) 1969

( 11) 1968

D alton (1) 1971

G il le (2) 1970

Zingg ( 3) 1970

Habal ( l ) 1973.'

H auser ( l ) 1969

H iro se (2 ) 1969

Kaye ( l ) 1973

K o lff (1) 1944

Marx G (1) 1970

Palm er ( 3) 1972

V i l la r r o e l ( 2 ) 1972

W illiam s T (l) 1969

W ilson R. ( 1) 1965

Lande (18) 1973

B e rn s te in (1) 19^5

Gibbon (2) 1937

G,‘ (continued.)

C oagulation

fo llo w in g e x tra c o rp o re a l c i r c u la t io n

E f fe c t of ■'chemical-'and s u r f see p ro p e r t ie s on

x Pump-oxygenation w ith re fe re n c e to ___

R eg u la tio n o f in prolonged bypass

Boyd A

Lyman

Osborn

Ryan

( 1)

(4 )

(1)

1972

1968

1955

1973

C oating of c i r c u i t r y

by p ro te ic or-.-enzym atic 'm aterials,

by polymers

x Adjunct use o f su rfa c e a c t iv e agen t

x G raphite - .benzine dnd h ep a rin

Brown ( l ) 1971*'

Lyman ( l ) 1968

M iyauchi ( l ) 1966

G ott ( 4)

Com puterised B ata A nalysis

x Showing t ru e membrane a re a

Systems a n a ly s is s tu d y f o r r e s p i r a to r y d ev ices

Servo c o n tro lle d extended cardiopulm onary bypasi

K rava ( l ) 1970

K i t r i l a k i s ( l ) 1972

T urina (1) 1973

B

x B ialung Esmond ( 2) 1968

D isc Oxygenators

X C o n stru c tio n to te m p o ra rily re p la c e t ie lu n g Bubbelman( x) 1951

- 148 -

D (continued)

Disc O xygenators(continued)

x R o t a t i n g a n d h e a t exchange Osborn (5) 19&0

x Comparison o f m ic ro p a r t ic le s pioauced b,y Simmons ( l ) 1972

E f fe c ts onBlood

B io lo g ic a l ev a lu a tlo n a f t e r f ilm and inembrane. o x y g a ia tio n D obell ( i ) 1965

Comparison o f by v a rio u s membrane oxygeiacors Gollub ( i ) 1967

X A cidosis c o r re c t io n by HUM P e irc e (? ) ■ i 960

X by blood su rfa ce in te r a c t io n Schoen CP 1975

X by veno-venous p e rfu s io n Schramel ( i ) 1965

X by n itro p ru s s id e Adams ( i ) 1975

by a r t i f i c i a l boundary (on p ro te in s ) B a ie r (a.) 1971X B e rn s te in m 1965

Clower (9 ) 1970

in p a t ie n ts d u rin g bypass De-Wall( 1 ) ' 1959

X of CPD v ACD Dawson ( 1)

o f prolonged r e c i r c u la t io n through oxygenators D obell ( 1) 1965

of d isp o sa b le membrane oxygenator Douglas(1 ) 1971

X of bypass on hemodynamics Evans ( 2) 1971

B xtraco rpo real C irc u la tio n

X Litw ah ( 1) 1972

Equipment P e irc e ( 1) 1969

- 149 -

E Continued.

E x trac o rp o rea l C irc u la tio n

x _ by V*A.bypass w ith oxygaaator

x Homologous blood syndrome i n __

x a s s i s t o f anhepa tic anim als

x A r t i f i c i a l blood c i r c u la t io n

TJse o f in c h ild re n

Blood oxygenation in Theory

x A n ti'p h y sio lo g ica l p ro p e r t ie s and hemodynamics

Hopes of e x tra c o rp o re a l r e s p i r a to r y a s s is ta n c e

E v a lu a tio n o f Membrane Oxygei a to r s

S tandard ized method fo r

Experim ental model f o r ____

x Com puterised d a ta a n a ly s is

T es t and ____

Use of r a te d blood flow in _____

C on tro l and m o n ito rin g system f o r ______

x In v ivo _

Use of models f o r o p tim isa tio n

Embolic f a t as a measure of adequacy

F

F i l t r a t i o n

x Blood c le a n s in g .b y d i a f i l t r a t i o n

x D isp o sab le f i l t e r fo r m icroem boli

Lefemine (1) 1971

Litwak ( 3) 1965

Soyer ( l ) 1973

G a l l e t t i ( 15) 1959

A llan (1) 1971

Spaeth (2) 1973

M an te tif fe l( l) 1973

Sadoul ( l ) 1972

G a l l e t t i ( l l ) 1972

L efrak ( l ) 1973

Mrava (1) 1970

G a l l e t t i ( 7) 1971

H o ld efe r (1) 1973

L aing ( l ) 1968

Lande ( 12) 1968

L a u tie r (2) 1971

Owens ( 1) I 960

H am ilton (1 ) 1971

P a t te r s o n ( l ) 1971

- 150 -

^ (c.ontinuedj

F i l t r a t i o n

E v a lu a tio n of m icropore ____ Katsumoto ( l ) 1973Johnson ( l ) 1972

x F a t m acroglobules in e x tra c o rp o rea l c i r c u la t io n A raki ( l ) 1973

Lande Edwards Membrane Oxygenator m icroem boli coun ts C.ai*lson (9) 1973

Flow m etering

x by u l t r a s o n ic d o p p le r B e rn s te in ( 6) 1970

F reez in g of Blood B arron ( l ) 1966x

Ga s T ran sfe r

Upper and low er bounds o f O2 t r a n s f e r D r in k e r (2) 1971

a n a ly s is o f th e membrane Lung EberhaTt (3 ) 1968

E f fe c t of plasm a c o n s t i tu e n ts on N avari (1)

In f lu e n c e of membrane and design on P e irc e ( 8 ) 1963

in a he p a rin ised membrane oxygenator Rea ( 3) 1971

to blood in membrane oxygenators R ich ard so n (l) 1971

- . " in c re a s e by hydrogen, peroxide c a ta ly s t Updike ( l ) 1973

_ to blood flo w in g in tubes V/eissman ( 2, 3) 1967/8

E f fe c t o f ch em ica l. re a c tio n r a t e in membrane o:<ygena to r s *' ( 6) 1971

and thrombogen in an n u lar membrane o x y g e ia to rs Gaylor ( l ) 1973

Mechanics of Open U n iv e rs ity ( l )

- 151 -

G (Continued)

Gas T ran sfe r

X T ran sp o rt of oxygen through membranes S r iv a s ta v a (1) 1970

D iffu s io n o f g ases in flow ing blood Spaeth (1 ) 1967

R e sp ira to ry by hem odia lysis Updike (2) 1973

X A model o f mass t r a n s f e r in r e s p i r a to r y system s Warner (1)

X Oxygen and COo in membrane oxygeutors Weissman ( 4) 1969

Low o rd e r approxim ation fo r membrane . oxygen a t or 3 L ig h tfo o t (1) 1968

COo in a r t i f i c i a l lungs S n ider (1 ) 1974

D eterm ination of CO2 t r a n s f e r in membrane oxygenators G a l l e t t i (8) 1970

X Comparison of c a p a b i l i t i e s Ifran tz G ) 1965

T est dev ice f o r e v a lu a tio n L a u tie r ( i ) 1970

Comparison of ft! ( 5) 1969

D iffu s io n of oxygen in f ilm of blood Marx (2 ) I 960

F a c to rs in f lu e n c in g in membrane oxygenation it-G)'. 1962

a c ro ss po lyethy lene M elrose (2) 1958

X acres s te f lo n P e irc e (16) 1958

In f lu e n c e of m em braneperm eability and desig n on Prados (1 ) I960

E f fe c t of i r r e g u la r membrane su rfa ce on Chow (2 ) 1972

through p la s t i c f ilm s Clowes ( 3) 1955

E f fe c t of boundary c o n d itio n s on ____ to blood in tubesC olton (1 ) 1971

P re d ic t io n of oxyg a ia tio n r a t e s D indorf ( l ) 1971

____ to b lood . D ata and th eo ry Dorsa n (10) 1971

in blood and plasm a i i ' (1 ) 1971

COg exchange in membrane oxygena to r s hi (3 ) 1972

to b lood in tubes »• (4 ) 1971

to blood in c o ile d tubes II ( 5) 1970

X The m athem atics of II' (16) 1970

- 152 -

G (Continued)

Gas T ransf e r (oontinued)

x The m athem atics o f ' '

R esp ira to ry ' i n e x tra c o rp o rea l c i r u l a t i o n

T h e o re tic a l a n a ly s is o f _

Seagrave ( i )

V i l l ^ r r o e l ( l )

B radl ey ( &

A nalysis of oxygen t r a n s f e r in tube membrane oxygenators Buckles ( l )

The m athem atic s of a c ro ss plasm a

i n curved c h an n e ls . An an a ly sis

M ulticomponent _

in alveolar d u c ts

: i n an annulus

E f fe c t o f re d blood c e l l d i s t r i b u t io n on,

_ through a hemoglobin s o lu tio n

C alk in s ( l )

Chang H ( l )

" : (3 )

(4)

(5 )

Chow ( l )

S ch o lan d er(l)

1968

1970

2) 1972

1968

1971

1971

1972

1971

1968

1971

I960

G rav ity Flow Membrane Oxygenator

H

C ry s ta l ( l ) 1964

H eart Lung Bypass

L aborato ry experience w ith 24 h r p a r t i a l G a l l e t t i ( 6) 1965

Heart~Lung Machines

R ecent advances in h e a r t lung appara tu s

. B e t te r t w ith s i l ic o n e rubber membrane

Hew low c o s t

M il le r ( l ) 1951

M elrose ( 4) 1972

P au l ( 1) 1971

- 155 -

H. ( Continued)

HeaTt-Lung Machines (Continued!

x _____________ f o r experim ental work S e d la r ik ( l ) 1972

Auto cardiopulm onary bypass u n i t T u rina ( l ) 1971

Servo c o n tro lle d p e rfu s io n u n i t w ith membrane oxygai a tio n 1,1 (2) 1975

A n alysis of m echanical c a rd ia c a s s is ta n c e

A p p lica tio n of ____ to c a rd ia c su rg ery

Wemple

Gibbon

(1) 1973

(1) 1954

H eat Exchanger

S im p lified fo r p e rfu s io n by p o tte ru n ia P e irc e ( 27)

Hemodvncimics

Blood flow in smal l curved tubes Hung (2) 1971

Boundary, la y e r in membrane oxygen a to rs I l l i c k a l (1) 1967

X Two dim ensional n o n - lin e ar th eo ry Lou (1) 1972

X A nalysis o f in c a p i l l a r i e s Masao (1) 1971

P u l s a t i l e blood flow in membrane oxygenators Rush (1) 1969

X Blood flow v e lo c i ty from decay tim e Sanderson ( l ) 1971

X i n and n ea r pumps Seal a (1 ) 1969

Theory and experim ent Arimai (1) 1972

ne«r w a lls B la ck sh ea r(1,5>4>6,)1971

T ay lo r (1) 1973

in tu b es Hershey (1) 1966

X , f a c to r s o f m echanical hem olysis B le i f e ld (1) 1973

Arrangement o f e ry th ro c y te s in ' flow ing' blood Phibbs (1) 1965

Hemoglobin - oxygen eq u ilib riu m and co ronary blood flo w .D u v e lle ro y( i ) 1973

Blood in t e r f u c i a l phenomena G a l l e t t i ( 5) 1971

- 154 -

H (Continued)

Hemodynamics

R ole of m ic ro c irc u la tio n in oxygen t r a n s p o r t G o ld s tick 1) 1968

Model of w a ll e f f e c t Hung 1) 1972

Hemoglobin

D eterm ination of in m inute amounts of blood ( YIu.) Bing 1) 1951

M o d ific a tio n of O2 a f f i n i t y •Sol y 2) 1972

Hemolysis

X Automated blood coun ts 0 *N e il l 1) 1975

in long. term ex trac .co rp o rea l c i r c u la t io n H i l l 7) 1972

Mechanis ms o f plasm a hemoglobin c lea ra n c e Andersen 1,2)1966

Measurement of e l a s t i c moduli f o r red c e l l membrane B lackshear 7) 1973

Assessment of by s tan d ard & e a r t e s t P e irc e 19) 1972

X Plow dynamic f a c to r s of m echanical B leifeL d l ) 1973

D ete im in a tio n of im p o rtan t cause of Castonguay l ) 1973

X D isc sphere tran s fo rm a tio n Ponaer l )

Shape changes w ith volume changes It: 2)

Surface adhesion , d e fo rm a tio n .e tc . B lackshear 8) 1972

. A lte ra t io n of c o rp u scu la r elem ents o f blood A lthaus , 1) 1973

caused by pumps C a h ill 1>) 1956

a r t e f a c t s induced in r o ta t in g sh ear d ev ices Lo 1) 1974

D eterm ination of hemoglobin in m inute amounts of blood. -Bing 1) 1931

Hydrodynamic in e x tra c o rp o re a l c i r c u la t io n Yarborough 1) 1966

X Measurement of mechanic a l ly induced W allace 1) 1969

F a c to rs in f lu e n c in g B e rn s te in 2) 1967

I n te r f ^ c i a l phenomena u (5) 1971

Overview B lackshear (5 ) 197'

Near w a lls u (3) 1971

- 155 -

H (continued)

Hemolysis

Red blood c e l l s h i t t i n g w a lls

Shear, w all in te r a c t io n

T olerance to chron ic ___

________ following bypass in in f a n t dogs

Shear induced su rfa ce

P l a t e l e t s , th ro m b o s is -a n d _____

Method f o r plasm a hemoglobin

H em atological o b se rv a tio n s during' p e rfu s io n s in sheep Shea (1

B lackshear (4

" ( 2

C astenada ( l

" ( 2

Chang H. (2

S to r m orken (l

C ripps (1

_______ due to exposure to p la s t i c tubes

M echanical f a c to r s in ____ , s u b le th a l damage

S e le c tiv e l i p i d lo s s fo llo w in g ■

x

M o d ific a tio n o f benzidene method fo r

. ' ~ by sxiear s t r e s s

P h y sica l e f f e c t s of

Comparison of ___ in membrane and d isc oxygenator P e irc e

x and l i p i d changes Shohet

H iro se ’ (1

In d e g lia (2

(1

Crosby (1

L e v e re tt (1

N ev aril 'l ( l

H yperbaric C ondition

Perform ance of a membrane oxygenator under Lesage»o‘

R esp ira to ry f a i l u r e t r e a te d in

- ao -

w ith membrane

oxygenator L ip ton

P e irc e

(4

( 2

(1

(1

1971

1966

1966

1969

1972

1971

1963

1968

1969

1968

1970

1956

1972

1967

1969

1972

1967

1971

1972

In fan ts*

Prolonged r e s p i r a to r y support in

P e rfu s io n system f o r ____

C oiled tube MO f o r ___

w ith MO W hite (2 ) 1971

Dorson (12) 19&9

11 ( 6) 1969

I (Continued)

Dorson ( 7) 19^9

" , (8) 1970

G a l l e t t i ( 9 ) 1963

Housman ( l ) 197 2

" (2 ) 1 9 7 2

W right (2 ) I 97I

Zingg (2) 1967

B afi'es ( l ) 1972

G eldof ( 4) 1972

IC

K o lo b o w S p i r a l M em brane L u n g

Development of f o r organ p e rfu s io n Kolobow

D esign and in v ivo s tu d ie s of _________________ "

C o n stru c tio n and e v a lu a tio n of _ "

P a r t i a l c a rd iac bypass up to 7 days in lam bs w ith »!

P a r t i a l and t o t a l e x tra c o rp o re a l r e s p i r a to r y gas exchange "

P a r t i a l experim ental r e s p i r a to ry gas exchange in __ "

Extended term use (16 days) "

Long term re s p ir a to ry support w i t h White

(1) 1968

(4) 1970

( 2) 1962

(5) 1970

( 6) 1971

( 3) 1968

(7) 1969

(3) 1973

In f a n ts

MO f o r

Response o f to p a r t i a l lung bypass

P e d ia tr ic p e rfu s io n system s

H em odilution fo r

E v a lu a tio n o f Travenol and Lande-Edwarcis MO

P e d ia t r ic a p p lic a t io n of Laide-Edwards MO

MO f o r

In f e c t io n ;

_ fo llo w in g bypass

______ through blood from h e a r t lung machine

- 157 -

%

Lande-Edwards Membrane Oxygenator

A ss is te d c i r c u la t io n w ith ___ Land 6 (9 1971

P r e c l in ic a l e v a lu a tio n of i t (5 1969

A new d isp o sab le membrane oxygenator i i (2 1968

C lin ic a l experience w ith in emergency use i i (3 1970

C ardiac su rg ery with. _____ i i (6 1972

f o r h e a r t su rgery and prolonged bypass n (15 1967

I n v iv o e v a lu a tio n of i i (5 1968

f o r h e a r t su rg ery and r e s p ir a to ry support C arlson ( l 6 1975

____ d u rin g h e a r t su rg ery i i (9 1975

P e d ia t r ic a p p lic a t io n of ____ W right (2 1973

T o ta l cardiopulm onary bypass w ith ____ B af£es (1 1972

Pulmonary sup p o rt in 100 men w ith ___ C arlson (2 1972

f o r g r a f t o p e ra tio n s i i (5 1972

Prolonged support in 85 men w ith ___ i t (5 1972

___ f o r h e a r t su rg e ry . Method ana oxygen t r a n s f e r i i (1 1975

___ f o r g r a f t o p e ra tio n s (55 men) t i (4 1973

____ in 100 p a t ie n ts i t (6 1972

C lin ic a l experience w ith __ f o r prolonged bypass Lande (8 1970

do. H ayashi (1 1973

Minimal damage i n __ V ervloet (1 1970

E v a lu a tio n o f Travenol a n d ___ Housman (2 1972

Use of ___ d u rin g AV g r a f t o p e ra tio n C arlson (4 1971

New membrane oxygenator - d ia ly s e r Landfe (4 1967

In v iv o e v a lu a tio n of i i (12 1968

24 hour p e rfu s io n w i t h ___ i i (7 1969

L (c ontinuedjl

Methods of in c re a s in g e f f ic ie n c y of _____ Landd t11) 1 9 6 8

C lin ic a l experience w ith ______ in long term bypass u ( e) 1970T est and developm ent of _ f o r cardiopulm onary a s s i s t m (15) 1969Prolonged use of _____ f o r cardiopulm onary a s s i s t 11 ( 6 ) 1970Comparison of __ and GE P e irc e oxygenator .P e irc e ( 2) 1970

L iqu id -L iq u id O xygenator.

Development o f

C e n tr ifu g a l

______ A new approach

L iv e r P re s e rv a tio n e tc ,

x Long t e r m ____

x F u n c tio n of th e p e rfu sed l i v e r

x P e rfu s io n of th e l i v e r in v iv o and in v i t r o

x P e rfu s io n of th e p regnan t sheep u te ru s .

Lung •• ..&V

x F u n c tio n and hemodynamics of ___

Im plan tab le a r t i f i c i a l ___

Morphology fo llo w in g vv p e rfu s io n o f ___

Review of 23 tra n s p la n ts

x . P e rfu s io n ap p ara tu s f o r ___ f i x

Membrane oxygenator f o r support o f t r a n s p la n t

De F i l i p p i ( 2

(3

M alchesky ( l

P i t z e le (1

S c h rib e r ( l

W allace ( l

( 2

1969

1969

1971

1970

1971

1973

1973

Birnbaum ( 3) 197 2

Eiseman (2) 1964

McLaughlin (1 ) I 966

P e irc e (10) 1970

B erglund (2 ) 1972

Bodell (3) 19 5

H il l (1) 1963

W ildevuur ( l ) 1971

Brody ( l ) 1973

Corso (1 ) 1973

M a te r ia ls

T h ro m b o re s is ta n t___

Antithrom bogenic su rfa ce s

Non thrombogenic ___

Development o f _ f o r membrane oxygenator

Non thrombogenic su rfa ce s

E f fe c ts of m eta l in te r f a c e s on blood

x ____ in the body

x R eac tion of th e body to sp are p a r ts

Membrane Oxygenation

A u x ilia ry lung - s t a t e of th e a r t

x D iscu ssio n

x C lin ic a l experience w ith hypotherm ia

x Theory and fu n c tio n of th e membrane lung .

_________ i t s excuse, s ta tu s and prom ise

C l in ic a l use of ___

Moving ro d ___

E xtraco rp o r e a l 80 c a rd iac o p e ra tio n s

P ro g ress in d esig n o f •

E n g ineering view and p ro g ress re p o r t

C u rren t s ta tu s in ____

do.

• D iscu ssio n

' D esign c o n s id e ra tio n s i n _

and prolonged cardiopulm onary support

G ott (3) 1969

" (2) 1971

Grode (1} I 971

Lee (1 ) 1961

S altzm an(l) 1^71

Sawyer ( 1)

Myers ( 1) —

Cowan ( l ) . . .

P e irc e ( 15) 1971

" ( 52) 1953

" ( 1) I96I

" (29) 1973

" ( 9) 1973

" (18) 1972

W eissman(l) 1970

L ip to n 1974

D i t t r i c h ( l ) 1973

D rin k er ( 7) 1968

(5) 1970

G a l le t t i ( lO ) 1971

(4 ) 1972

H o ld e fe r(2) 1973

Mockros ( l ) 1972

N e v ille ( l ) 1971

- 160 -

M (c ontinuedjl

Membrane Oxygenation (continued).

S ta g in g i n ___

Membrane c h a r a c te r i s t i c s and lung d esign

Hydrogen p erox ide as an . oxygen source in ____

Membrane

x Gas p e rm e a b il ity of polymer f ilm s

How m olecules pass th ro u g h __

x Gas t r a n s f e r a c ro ss p o ly e th y len e ,____

x Theory of io n ic d if f u s io n th ro u g h _

D iffu s io n throug^i te f lo n ___

S tu d ie s w ith a new h igh p e rm e ab ility ___

Ways to r e n d e r a n t i thrombogenic

. supports

x O ptim iza tion of c o lla g en d ia ly s e s

x U l t r a th in s i l ic o n e polyrrxer __ _

P o ly a lk y lsu lfo n e - a new polymer f o r MO

Improved s i l i c o n e _

P ro d u c tio n df.; f irm

S tu d ie s Yjith p l a s t i c s f o r o x y g e n a to r___

P ro p e r t ie s of in e x tra c o rp o re a l c i r c u i t s

New gas p e rm eab le ___

P erm se lec tiv e u l t r a th in s i l ic o n e ru b b er ___ _

x Study o f : • ’'-permeabili'by in hem odialysis

A p p lic a tio n o f p la s t i c s in __ o:xygenators

Gas p e rm e ab ility of p l a s t i c s _____

S il ic o n e rubber ___

Palm er (2 ,3 ) 1971 >2

P e irc e (8) 1963

Jo rg e n se n (l) 1973

Osipov (2) 1972

S te in (1) 1974

M elrose (2 ) 1958

O ffner ( l ) 1971

P e irc e (15) 1958

" ( 2 )1 9 6 9

Awad ( 3) 1972

BluemTe ( 1) i 960

S ten ze l ( l ) 1971

Bum s ( 4) 1973

K e tte r in g h a m (l)197 3

Burns ( 3) 197-1

" . (1 )1 9 6 9

Clowes ( 3) 1956

Day ( l ) I 967

Eiseman ( l ) 1972

Esmond ( l ) 1965

Evans ( l ) ------

G a l l e t t i (5) 1970

» ( 1) 1966

S & N (1)

- 161 -

M (continued)

Membrane fc on tinued l

; in a r t i f i c i a l kidney, dev ices Lyman* (2) 1973

x Model of o fc o li th Hudetz3( l ) 1971

Comparison of ___ gas t r a n s f e r c a p a b i l i t i e s Kranz 3( l ) I 965

x bysbarism -osm osis caused by d is so lv e d gas K y ls tra (2 ) I 968

Development o f u l t r a - t h in te f lo n 11 (p) I 96I

T es tin g d ev ice f o r gas t r a n s f e r ev a lu a tio n L a u t ie r ( l ) 1970

Comparison of gas t r a n s f e r « ( 3) 1969

E v a lu a tio n of d i a l y s i s L eonard (l) 1962

E v a lu a tio n of new m acroporous ___ M cCaughan(l)l960

S il ic o n e lung M elrose(5) 1972

Thin s i l i c o n e perm eation p ro p e r t ie s Robb ( l ) I 968

0

Oxim etry.

Theory and c o n tru c tio n o f oxim eters R e ic h e r t( l ) 1966

Photom eter f o r SO2 ' Rem ( l ) 1972

x Analog computer f o r e a r _____ T a i t ( 1 ) 1 9 6 7

x 'P o la rg ra p h ic method f o r oxygen co n ten t V o lte r • ( l ) 1972

x . Z i j l s t r a ( 1-4)1958

x Comparison of ___ _ and ang iocard iography V ere l ( l ) 1973

A pparatus f o r ra p id oxygen c o n ten t measurement K irk ( l ) 1973

x C o lo rim e tric method f o r oxygen co n ten t S in e t ( l ) 1972

Dual w avelength r e f l e c t a n c e ____ Vurek ( l ) 1978

x ______ in v iv o w ith a cyclops in s tru m en t Z i j l s t r a ( 5 ) 1958

x Cole ( l ) 1967

- 162 -

0 (c ontinued)

Oximetry (Continued!

x F ib re o p tic _____ E f fe c t of pH and h em ato crit

x 11 _An improved system

x " __P re se n t and fu tu re a p p lic a tio n s

x P r in c ip le and d e s ig n of a hemoglobin oxim eter

x New in s tru m en t fo r ra p id oxygen s a tu ra t io n measurement

x Measurements of l i g h t s c a t te r in g c h a r a c te r i s t i c s

x F ib re o p tic r e f l e c t io n photom etry

New in s tru m en t f o r oxygen s a tu r a t io n

f o r ex trac o rp o rea l c i r c u la t io n

Spectrom etry o f hemoglobin d e r iv a t iv e

F ib re o p t i c and r e f l e c t io n ___

x R e f le c tio n and tran sm iss io n of l i g h t by ___ of blood

x L ig h t adso rb ing and s c a t te r in g p r o p e r t i e s .of blood

O n-line r e s p i r a to r y gas m onito ringV.

Dynamic method f o r continuous reco rd in g

x . D eterm ination o f oxygen s a tu r a t io n o f blood

x O p tic a l d if f u s io n in blood

x In f lu e n c e o f oxygen s a tu r a t io n e tc on th e tra n sm itta n ce

of red l i g h t

x A nalysis o f a micromethod o f tran sm iss io n

Changes o f p e rm e ab ility of e ry th ro c y te s by l i g h t

D egenera tion of c e l l s in l i g h t

Oxygen. .

C on tro l of __ s a tu r a t io n d u rin g exco rpo rea l c i r c u la t io n

dynamics in s t a t i c membrane oxygenation

F ib re o p tic c a th e te r f o r measurement of P02

x Oxygenation in fem oral bypass .

Johnson ( l ) 1972

" ( 2) 1972

(3 )1 9 7 1

Jan sse n ( l ) 1972

P h i l ip s ( l ) 1970

K reid ( l ) .1971

Mook ( l ) I 968

P h i l ip s ( l ) 1970

Vurek (2 ) 1973

A ss e n d e lf t( l) -

Ish ik aw a(1) 197 3

A nderson(l) 1967

" (2 )1 9 6 7

B lum enfeld(l) 1973

C le rb au x (l) 1973

Gordy (1) 1957

Jonnson ( 4 ) 1970

Kramer .? ( l ) 1951

L oew inger(l) -

Lepreshkin(4) 1932

E a r le ( l ) 1926

Gomes ( l ) 1972

S an tiago ( l ) 1973

Wi ed ermei e r ( 4 )1971

Roshe ( l ) 1973

- 163 -

0 (Continued)

Oxygen D is so c ia tio n Curve.

C o rrec tio n o f ___ f o r tem perature and pH Severinghaus ( l ) 1953

Measurement of __ w ith computer Yoder ( l ) 1975

An eq.uat io n f o r ___ Aberman (1) 1975

__ f o r c l i n i c a l use Mays ( l ) 1975

Computer program fo r pH /log pC02 Nomogram D ell (1) 1967

X pH and pCOg in c a p i l la r y blood T o rju ssen (1 ) 1967

A ccurate d e te rm in a tio n f ro m ___ above 9 8 .7 ^ s a t . Roughton ( l ) 1975

X Response of ___ to pH induced changes Mehrael (1 ) 1975

Berglund (1) 1972

Bock (1 ) 1924

X Nomograms f o r in te rd ep en d en t param eters Grote (1 ) 1972

X Response to a h y p e rb a ric environm ent Kiesow (1 ) 1972

A lte red hemoglobin oxygen a f f in i t y Kostuk ( 1) 1975

V elo c ity of oxygen d is s o c ia t io n M ochizuki ( 1 , 2) 1966

X Hemoglobin oxygen c o n ten t from s a tu ra t io n P e l le r c h ia ( l ) 1972

Oxygen Measurement.

X Cole ( 2) -

X New method o f .___ com parison w ith Van Sly ke Blayo ( 1 ) -

Assessment of Van Slyke method Gregory ( 1) 1975

C a p illa ry blood measurement Hofford ( 1) 1975

O xygenators.

H is to ry o f ___ B a r t l e t t ( 5) 1971

Pumping and oxygenating systems M elrose (5) 1971

D iffu s io n in membrane l im ite d ___ V/eissman (5) 1969

Buying time w i t h ___ Zapol (2 ) 1972

P e irc e - GE O xygenator.

Comparison o f and b ubb ler f o r c h ild re n K irsch ( 2) 1973 '

C l in ic a l use o f " ( 3.) 1972

x D iscu ssio n of experience w i t h « ( 2) - 1

Design and f a b r ic a t io n o f P e irc e ( 17) 1969

New concept in membrane support 11 (12) 1966

M u ltip o in t support f o r te f lo n 11 ( 3) 1962

Comparison of ___ w ith Landfe-Edwards ( 2) 1970

C lin ic a l com parison w ith b u b b le r Chopra ( l ) 1973

P e rfu s io n .

x Pulmonary le s io n s produced by ________________ Schramel (2) -

x S im p le ap para tu s f o r lung f i x Brody ( l ) -

P l a s t i c s .

A p p lica tio n of to membrane oxygenation G a l l e t t i (5) 1970

P l a t e l e t .

_ _K in e tic s H i l l (.11) 1972

Comparison of adhesion and ag g reg a tio n of R ozenburg(l)

x ____ k in e t ic s Leval ( l ) -

R ole of- d ia l.y s is membrane in throm bosis L indsay ( l ) 1973

x Emerging concep ts o f fu n c tio n Deykin ( l )

. emboli in oxygenators and f i l t e r s D utton ( 2) 1974

Prim ing.

Frozen blood f o r o x y g e ^ to r prim ing H5anson (2) 1972

P (Continued)

Prolonged use o f Membrane Oxygenation.

______ Awad ( 4) 1973

C lin ic a l experience o f Land£ (8) 1970

Hematologic e f f e c t s H i l l . ( 7) 1972

" ( 6) ' 197.2

i n r e s p ir a to ry support W hite (1 ,2 ,3 )1 9 7 0

• .x ________________________________ S oeter ( l ) 1973

i n puppies L i tc h fo rd ( l) 197.5

Problem s o f ___ _ P e irc e ( 20) 1973

_ _ Awad (1 ,2 ) 1973

Experim ent and c l i n i c a l ex periences of .___ H i l l ( 4) 19^9

S p ec ia l problems in _____________________ " ( 9 ) 1973

P hysio logy of Maloney ( l ) 1966

_ in cardiopulm onary support P e irc e (7) 1971

Techniques in t h e Re‘a (2 ) 1972

Assessment o f __ Ryan ( l ) 1973

R eg u la tio n o f co ag u la tio n in __ S ch u lte ( l ) 1973

in v-v p e rfu s io n in puppies T immons ( l ) 1970

P ro te in s and p ro te in d e n a tu ra tio n.

S tr u c tu ra l e f f e c t s a t b lood-gas in te r f a c e s Lee ( 3) 1971

D en a tu ra tio n as a cause of dea th Lee (1 ) 1961

Comparison o f the e f f e c ts o f IvlOs and non MOs o n n ( 2) I 96I

D en a tu ra tio n in e x tra co rp o rea l c i r c u la t io n Y /right ( l ) 1962

x n o f f o e ta l and n eo n a ta l blood B rea th n ach (2) 19^4

P u l s a t i l e Membrane/'Oxygenator.

D esign p a te n t o f ___ C la f f ( l ) 19^7

C re sc e n z i(2) 19^3

P (Continued)

Pumps.

In v i t r o e v a lu a tio n o f th e army pump

x P o lyu re thane chamber r o l l e r pump

E f fe c t of ___ on leu co cy te s

.____ and oxygenating; system s

x Blood flow in and n e a r

x Use o f as flow m eters. Hemolysis of

Hemolysis caused b y _

" " 3 types o f _ _

x " "

Pump O x /sen a to rs .

D iscu ssio n

x E xperience w ith ____ w ith re s p e c t to co ag u la tio n

x P h y s io lo g ic a l f a c to r s in th e use o f _

x L a c ta te p ro d u c tio n in blood c i r c u la t io n tnrough

Membrane p r in c ip le s

High e f f ic ie n c y ___

x Cardiopulm onary bypass w i t h ___

C astenada ( 3) 1964

Kolobow (5) 1969

Kusserow ( 3) 1963

M elrose ( 3) 1971

S c a la (1) 1969

McCaughan (2) i 960

C a h il l (1) 1956

C a p p e l le t t i ( 1)1961

K o lle r ( l ) 1967

Lande ( 13)1967

Osborn ( 4) 1955

S a lisb u ry ( l ) 1955

Kara ( l ) 1971

F ra n tz ( l ) 1968

B ellhouse ( l ) 1 9 .7 3 .

Agarwal ( l ) 1973

R

Red C e l l .

x membrane shape and s t a b i l i t y Shohet ( l ) 1972

x I n te r a c t io n o f p ro te in w ith membrane S in e t ( l ) 1972

S urface adhesion , deform ation and a ttachm ent B la ck sh ea r(8) 1972

x M echanics o f lov/ oxygen a f f in i t y in the __ May ( l ) 1972

In tr a e ry th r o c y t ic r e g u la t io n of blood oxygen Garby ( l ) 1972

m etabolism 'and methemoglobinemia H a r r is , J . ( l )

R (Continued.)

Red C e ll (Continued^)

R ecent advances in . th e f i e l d of ___ s t r u c tu r e Baker ( l ) -

E f f e c t o f z in c on in c re a s in g the oxygen a f f i n i t y of ___ O e lsh le g e l( l) 1973

x __ shape B recher (2)

_____ su rv iv a l a f t e r prolonged pumping Kusserow (4) 1966

E f fe c ts o n __ of *' 11 " (6) 1965

Changes in the _____ du rin g flow in tubes " ( 2) 1963

E f fe c t o f tem peratu re in deoxygenation r a t e Lawson ( l ) 1965

V e lo c ity o f oxygen d is s o c ia t io n in the ___. Kochizuk( 1 , 2) I 966

D iffu s io n and chem ical re a c t io n v e lo c i ty R o u g h to n (3 ) 1959

x Scanning e le c tro n m icroscoping of th e su rfa ce of __ C larke ( l ) 1971

Changes in p e rm e ab ility i n by l i g h t Lepreschkin( 1) 1932

S tru c tu re of normal ana p a th o lo g ic , B ess is ( l ) 1973

Changes of th e ___ in d ise a se Hayhoe ( l ) I 969

x S p h ero cy to sis . Brown . ( l ) 1971

R e sp ira to ry F a i lu r e .

Hemalogic e f f e c ts of prolonged e x tra c o rp o re a l c i r c u la t io n

i n _ H i l l • (7) 1972

C lin ic a l prolonged e x tra co rp o rea l c i r c u la t io n f o r " ( 6) 1971

C lin ic a l membrane oxygenator f o r Zapol ( l ) 1972

su p p o rt w ith p a raco rp o rea l MO C haroenku l(l)

Membrane oxygenation i n L ip ton

x Prolonged e x tra co rp o rea l oxygenation f o r S o e te r

_____ in o b s tru c tiv e lung d ise a se Moser

Membrane oxygenation f o r tem porary support in _____ of

tr a n s p la n t lung Corso

in in f lu e n z a pneumonia Spenny,

( 5) 1971

( 1) 1975

( 1) 1971

( 1) 1975

( 1) 1973

R (Continued)

R esp ira to ry F a i lu r e (Continued).

R esp ira to ry D is tr e s s syndrome a f t e r prolonged

e x tra c o rp o re a l c i r c u la t io n Llamas

MO support in acu te Joseph

Experim ental model f o r e v a lu a tio n of MO support in _ L efrak

x

x

■ • t r e a te d in hyperchamber v/ith MO

do.

Role o f a r t i f i c i a l lungs in th e trea tm en t o f __

Hopes of a s s is ta n c e by e x tra c o rp o re a l c i r c u la t io n

Long ___ support in in f a n ts w ith MO

Use o f MO in re s p ir a to ry f a i l u r e

C u rren t s ta tu s of prolonged e x tra c o rp o re a l c ir c u ­

l a t i o n f o r ___

Longt.exm M. Oxygenation i n ___

MO support in ___

11 n . in puppies

in in f a n ts . P a r t i a l a s s i s t .

C l in ic a l prolonged e x tra c o rp o re a l c i r c u la t io n in _

Use of MO in ___

u '

Prolonged use of MO in hypoxia

C l in ic a l use of MO f o r Rocking Membrane Oxygenator.

Low p r e s s u r e ___

L ip ton

(1) 1975

( 2) 1975

(1) 1973

( l ) 1971

P e irc e ( 30) 1973

( 6) 1972

Sadoul (1) 1972

White (1-3)1970

W ilaevuur( 2) 1971

L efrak (2) 1973

Rea (1) 1973

B ryan-B row n(l)1973

D obell . (5) 1970

Dorson ( 8) 1970

H i l l (10) 1971

Cillfe ( 1) 1972.

" (3 ) 1972

Hanson ( l ) 1973

J i l l (2 ,8 ,5 ,7 ,3 )1 9 7 2 1971

Joseph ( l ) 1973

Palm er ( l ) 1970

R (Continued)

R o ta tin g C y linder Oxygenator.

x K o lff A pparatus and m u lti p .le K arlson (1) 1949

x V e r t ic a l revolving* cone a n d " (2) 1949

Development o f a co u v e tte oxygenator K e lle r ( l ) 1969

S creens.

E f fe c ts o f s o l id and hollow f ib r e ____

Sources o f M edical in fo rm a tio n .

A nnotated gu ide to ___

x Index m eaicus

Science C ita t io n Index

S ta t ic Membrane O xygenators.

L abora to ry in v e s t ig a t io n of ___

Design of

v-v p e rfu s io n w ith l a s t in g 6^ days

L e f t h e a r t bypass by .

x

Development o f __ _

F u r th e r development of .___

Exposed type __

Oxygen dynamics i n _

P re ssu re ____

Membrane l in e d c a p i l la r y channels

/ d ia ly z e r

B io lo g ic a l e v a lu a tio n o f ________

E b e rh a rt ( l ) 1973

K e ttle w e ll ( l , 2)1974

Developments to improve the Bran son Oxygenator

Birnbaum (2)

Brains on ( 2) 19 69

" (1) 1965

(3) 1970

Byrne ( l ) 1973

Clowes (2 ) .1956

C rescenzi ( l ) 1959

(3 ) 1963

(4) -

S an tiago ( l ) 1973

Dagher ( l ) 1959

D a n to w itz ( l, 2)1973

Day (2) 1964

Douglas (]) 1971

E b e riia rt (2)19^9

S ta t ic Membrane O xygenators (Continued).

Experim ental and c l i n i c a l use of C low es _

Development o f u l t r a th in te f lo n __

A m o d if ic a tio n of Clowes ___

Gas tran sfe r.-an d 'th ro m b o g en esis in __

D isposab le and t h e i r use

ix C lin ic a l com parison of th e G.E. P e irc e and

b u b b le rs

S im p lified model of b ip lan e

E ff ic ie n c y o f v a r io u s membranes & p la te p r o f i le s

S t e r i l i z a t i o n .

Swing Type Membrane Oxygenator.

T

Thrombosis.

R ole o f p l a t e l e t s in b lo o d -su rface in te r a c t io n

C e l lu la r re a c t io n s to th e su rfa ce

P l a t e l e t and hem olysis

Ways of re n d e rin g membrane an tith ro m b ic

Gas t r a n s f e r and .____ in an an n u la r MO

Role of p l a t e l e t (membrane in te r a c t io n i n _

, A lte ra t io n o f c o rp u scu la r elem ents of blood

E lec tro n m icrograph study of

Surface phenomena i n ___

T hrom boresistan t m a te r ia ls

Gentsch ( l ) i 960

K y ls tra ( l ) 1961

P e irc e (5) I960

Gayford ( l ) 1973

B f f le r ( 1) 1956

Chopra ( l ) 1973

L a u tie r ( 4) 1973

Rdver (1 ) 1973

K a tsu h a ra ( l) 1968

Salzman ( 4) 1971

" (5 )1 9 7 1

S torm orken(l) 1971

Awad ( 3) 1972

Gay l o r Q.) 1973

L indsay ( l ) 1973

A lthaus (1 ) 1973

V a lito v (1) 1973

B la c k s h e a r ( l)1971

G ott ( 3) 1969

T (continued.)

Thrombosis (Continued).

Non-thrombogenic su rfa c e s

Dynamics o f ___

S ta g n a tio n flow

Non-thrombogenic su rfa c e s

" . Developments

in a r t i f i c i a l organs

T o ro id a l Flow Membrane Oxygenator.

A r t i f i c i a l c o i l lung

R e sp ira to ry gas exchange w ith ___

w ith o s c i l l a t i o n

C oiled tube

Secondary flow s in an o s c i l l a t i n g .

E v a lu a tio n of a ___ f o r in fa n ts

'Sm all __ . f o r use in p e rfu s io n

A r t i f i c i a l g i l l

I n v i t r o use of __

w ith o s c i l l a t i o n

, M 11 11 Use on dogs

Design of 1

_ w ith o s c i l l a t i o n , D esign and prolonged bypass

11 P re d ic t io n of gas t r a n s f e r

f o r in i 'a n ts

Secondary flow s in a

Grode (2 ) 1969

Madras (1) 1971

P e ts c h e le ( l ) 1968

Salzman (1)1971

" (2 )1 9 6 7

" (3) 1971

K o lff (1) I 944

McCullough(1)1973

M elrose ( l ) 1972

Mockrov (2 ) 1968

Moss (1) 1971

R a w its c h e r ( l)197 3

F e l t s ( 1) 1973

B odell B (2) 1965

A lton Murphy( l ) 171

Bar 11e 11(1) 19 69

" ( 2) 1969,

” • ( 5) 1970

(4) 1972

Benn ( l ) 1971

Abel (1) 1969

Dorson ( 6) 1969

(9) 1971

, T (continued.)

Travenol Membrane O xygenator.

O perations in in f a n ts w ith Boyd J . ( l ) 1972

E v a lu a tio n of _____ and Land6 Edwards Housinan (2) 1972

"_______ :__ .( d is p o s a b le ) T ru d e ll ( l ) 1972

Treatm ent of MO Systems.

w ith c ro s s lin k e d h eo a rin b in d in g Ehft-rTft ( 1 ) 1 9 7 3

2-5 PPG

x M echanics of low oxygen a f f in i t y in red c e l l s May (1) 1972

In tr a e ry th ro c y te r e g u la t io n of blood oxygen re le a s e

c a p a c ity Garby ( l ) 1972

Red c e l l __ B eilingham (l) 1973

R egu la tion o f hemoglobin oxygenation H arkness ( l ) 1973

Oxygen t r a n s f e r in anemia P o llo ck (1 ) 1973

. ■ ■ ■ ■ 1 w /

/ W hite C e lls

E f fe c ts of bypass o n Kaplan ( l ) I 96S

A lte ra t io n of b a c te r ic id a l p o te n t ia l H a irs to n ( l ) I 968

S tu d ies of leukocy te response to pumping Kusserow ( 3) 1968

P e rfu s io n and su rfa ce induced in ju ry to - —:------------ " ( l ) 1969

; Changes to ____ a f t e r prolonged pumping (5) 1971

x M d u rin g flow in tubes ” (6) 1965

D epression o f h o s t defence mechanism " (2) 1963

E le c tro n ic co u n ter f o r .---------- Landfe ( l ) 1969

x D epression of immunological s u rv e il la n c e H a irs to n ( 2) 1969

D egeneration in v i t r o of unuer l i g h t E a r le ( l ) 1926

V ib ra tio n ana Secondary Flow s.

E f fe c ts o f on J.O perform ance Dors on (2) 1972

Secondary flow s in 1.10s » ' ( 9 ) 1971

Augmentation of gas t r a n s f e r by secondary flov/s D rinker ( l ) 1969

Boundary la y e r - in MO I l l i c k a l ( l ) 1967

E f fe c ts o f on oxygenation Maloney (1) I 966

O s c i l la t in g s i l ic o n e ru b b er membrane ta b es M elrose ( l ) 1972

Secondary flow s and mass t r a n s f e r in an o s c i l l a t i n g

to ru s . Moss ( l ) 1971

" " to augment gas t r a n s f e r R ich ard so n (2) I 96S

Improved oxygenation mechanism Weissman ( 7) 1968

x Development o f an o s c i l l a t i n g pump oxygenator M elrose ( 8) 1974