Polymeric Membranes for Artificial Lungs - ACS Symposium Series

9 Polymeric Membranes for Artificial Lungs DON N. GRAY

Downloaded by IOWA STATE UNIV on October 14, 2014 | http://pubs.acs.org Publication Date: June 8, 1984 | doi: 10.1021/bk-1984-0256.ch009

Owens-Illinois, Inc., Corporate Technology, Toledo, OH 43666

Artificial membrane lungs are devices that perfuse c i r c u l a t i n g blood by membrane transport of gases. The development of membrane lungs was prompted by a need for an e f f i c i e n t device that could be used longer and that would damage the blood less than the d i r e c t blood-gas contact oxygenators. The evolution of the membrane lung during the last twenty-five years was dependent on advances made in permselective and microporous polymers with the required c h a r a c t e r i s t i c s for the critical membrane portion of the device. In most commercial membrane artificial lungs, the most s i g n i f i c a n t resistant to gas-transfer is the laminar boundary layer of blood near the membrane. Artificial lungs designed to improve the e f f i c i e n c y of gas transfer per unit area of membrane by minimizing the effect of the stagnant blood boundary layer are now a v a i l a b l e . These new designs take advantage of the inherently high permeability of new membrane materials. B r e a t h i n g i s s o m e t h i n g we do c o n t i n u a l l y from b i r t h t o d e a t h a b o u t t e n t i m e s a m i n u t e , 600 t i m e s an h o u r o r 1 4 , 0 0 0 t i m e s a day t o change t h e c o m p o s i t i o n o f t h e gaseous m i x t u r e i n c o n t a c t w i t h o u r l u n g s . The l u n g i s one o f t h e most c o m p l e x v i t a l o r g a n s and t h e one o f t e n a s s a u l t e d by p o l l u t e d a i r , b i o l o g i c a l enemies and i n d i v i d u a l s e l f - d e s t r u c t i v e h a b i t s and l a c k o f concern. C e r t a i n l y w i t h t h e modern e m p h a s i s on a r t i f i c i a l body r e p l a c e m e n t p a r t s and t h e s u c c e s s o f i m p l a n t e d b i t s o f h a r d w a r e and a s s i s t d e v i c e s f o r t h e h e a r t ( v a l v e s , h e a r t b y p a s s and p a c e makers) and k i d n e y s ( r e n a l d i a l y s i s ) , a s u b s t i t u t e d e v i c e f o r t h e n a t u r a l l u n g s h o u l d be c o n s i d e r e d . A r t i f i c i a l l u n g s a r e used d a i l y f o r s h o r t - t e r m ( 3 - 4 h o u r s ) h e a r t - l u n g bypas i n l a r g e , specialized health care centers. These a r e e x t r a c o r p o r e a l

0097-6156/ 84/ 0256-0151 $06.00/ 0 © 1984 American Chemical Society

In Polymeric Materials and Artificial Organs; Gebelein, C.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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d e v i c e s l i k e k i d n e y d i a l y s i s u n i t s r a t h e r than i m p l a n t s l i k e h e a r t a s s i s t d e v i c e s . These d e v i c e s f u n c t i o n l i k e f i s h " g i l l s " e x c h a n g i n g b l o o d g a s e s d i r e c t l y ( F i g u r e 1) r a t h e r t h a n a s s i s t i n g r e s p i r a t i o n l i k e a b e l l o w s o r r e s p i r a t o r . The t e c h n o l o g y o f t h e s e d e v i c e s i s now a t t h e s t a t e , many e x p e r t s b e l i e v e , t h a t a r t i f i c i a l k i d n e y s were t h i r t y y e a r s a g o . The w i d e s p r e a d use and a c c e p t a n c e o f t h i s t e c h n i q u e w i l l depend t o a l a r g e e x t e n t on t h e a v a i l a b i l i t y o f s i m p l e r , e a s i e r t o u s e , s a f e r and l o w e r cost devices. The p r i m a r y p u r p o s e o f t h e n a t u r a l l u n g i s t o b r i n g a i r i n t o c o n t a c t w i t h t h e l u n g membrane. B l o o d on t h e o t h e r s i d e o f t h e membrane r e l e a s e s c a r b o n d i o x i d e and t a k e s up o x y g e n . Two f l u i d movement s y s t e m s a r e i n v o l v e d i n t h i s dynamic p r o c e s s , one moving a i r and t h e o t h e r ( t h e h e a r t ) moving b l o o d . The s u r f a c e a r e a o f t h e n a t u r a l l u n g i s v e r y h i g h ( o v e r 70 s q u a r e m e t e r s ) , w h i l e t h e a r t i f i c i a l l u n g membrane s u r f a c e a r e a i s much lower (3~6 s q u a r e m e t e r s ) . F o r t u n a t e l y , a r t i f i c i a l membrane l u n g s c a n f u n c t i o n t o a c h i e v e a d e q u a t e gas exchange w i t h lower s u r f a c e a r e a s b e c a u s e , w h i l e the n a t u r a l lung r e c e i v e s i n s p i r e d a i r c o n t a i n i n g o n l y 21% o x y g e n , t h e membrane o f t h e a r t i f i c i a l l u n g s e e s 100% o x y g e n . The d e v e l o p m e n t o f a p p a r a t u s t o o x y g e n a t e b l o o d p r e c e d e d modern a d v a n c e s i n c a r d i a c and t h o r a c i c s u r g e r y and was a b s o l u t e l y n e c e s s a r y f o r open h e a r t s u r g e r y . Between t h e 1930's and 1950 s, s u r g e o n s e x p e r i m e n t e d w i t h b l o o d o x y g e n a t o r s by t a k i n g the s t r a i g h t f o r w a r d a p p r o a c h o f c o n t a c t i n g w h o l e venous b l o o d w i t h a i r o r oxygen and r e c i r c u l a t i n g t h e o x y g e n a t e d form i n t o t h e body's c i r c u l a t o r y s y s t e m . T h i s p r o c e d u r e gave t h e s u r g e o n what he needed most, t i m e f o r s u r g i c a l r e p a i r o f a s t i l l h e a r t . To i n c r e a s e t h e b l o o d - g a s c o n t a c t s u r f a c e a r e a i n t h e s e d e v i c e s , oxygen was b u b b l e d t h r o u g h t h e b l o o d ( b u b b l e o x y g e n a t o r s ) o r d i s c s were used t o c o n s t a n t l y e x p o s e t h e b l o o d s u r f a c e t o t h e gas phase ( d i s c o x y g e n a t o r s ) . D i r e c t c o n t a c t o f b l o o d and gas l e a d s t o p r o t e i n d e n a t u r a t i o n and b l o o d c e l l d e s t r u c t i o n w h i c h l i m i t s t h e u s e o f b u b b l e and d i s c o x y g e n a t o r s t o a maximum o f s i x h o u r s ; p e r f e c t l y s a t i s f a c t o r y f o r most s u r g i c a l p r o c e d u r e s . I t i s i n t e r e s t i n g t h a t o t h e r a p p r o a c h e s were a l s o t r i e d w i t h some s u c c e s s , s u c h as u s i n g a human donor t o c o n s t a n t l y "breathe" f o r a p a t i e n t v i a cross blood c i r c u l a t i o n °. Even more d a r i n g was s u c c e s s f u l e x - v i v o u s e o f d i s s e c t e d , s p e c i a l l y t r e a t e d a n i m a l l u n g s f o r b l o o d oxygénâtion ,an i n t e l l e c t u a l p r e c u r s o r i n t h e d e v e l o p m e n t o f t h e a r t i f i c i a l membrane l u n g . As e a r l y as 1955, K o l f f and B a l z e r d e s c r i b e d a d e v i c e p a t t e r n e d a f t e r an e a r l y r e n a l d i a l y s i s u n i t ( t h e Inouye a r t i f i c i a l k i d n e y ) w h e r e i n p o l y e t h y l e n e t u b i n g was used i n a c o i l configuration. W h i l e t h e c o n c e p t was s o u n d , t h e membrane m a t e r i a l c h o i c e s a v a i l a b l e a t t h a t t i m e were l i m i t e d . In 1956 Clowes and c o w o r k e r s d e s c r i b e d an o x y g e n a t o r u s i n g f l a t s h e e t s o f membrane t o s e p a r a t e t h e b l o o d and gas ( F i g u r e 2). Clowes examined T e f l o n , e t h y l c e l l u l o s e , p o l y e t h y l e n e , c e l l o -


1

1

2

3

1

9

,

2

21

H

5



9.

GRAY

Polymeric Membranes for Artificial Lungs

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Blood i n l e t groove Gasket

P l a s t i c membranes Compressed a i r : 160mm Hg

Blood f i l m f l o w i n g ]' between p l a s t i c membranes

L o n g i t u d i n a l blood channel L o n g i t u d i n a l oxygen channel Oxygen f l o w i n g i n diagonal rubber grooves

Figure 2 . The Clowes membrane oxygenator. (Reproduced w i t h permission from Ref. 5 . Copyright 1 9 5 6 , J . Thoracic Surg.)



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POLYMERIC MATERIALS A N D ARTIFICIAL ORGANS

phane, PVC, p o l y s t y r e n e , M y l a r and c h l o r i n a t e d r u b b e r . Note t h a t some o f t h e s e m a t e r i a l s a r e c o n s i d e r e d b a r r i e r p o l y m e r s ( M y l a r and c h l o r i n a t e d r u b b e r ) . However, e t h y l c e l l u l o s e and Teflon gave p r o m i s i n g r e s u l t s . T h e s e e a r l y w o r k e r s were u s i n g t h e p e r m s e l e c t i v e p r o p e r t i e s o f p o l y m e r i c membranes f o r g a s , a l t h o u g h one m i g h t s u s p e c t t h a t a p o r t i o n o f t h e gas p a s s a g e was due t o d i f f u s i o n v i a m i c r o p o r o u s d e f e c t s i n t h e f i l m s . Table 1 i s a c o m p a r i s o n o f t h e p e r m e a b i l i t y one hundred t i m e s t h a t o f Teflon . It i s i n t e r e s t i n g t o compare t h e h i s t o r i c a l t i m e t a b l e f o r c l i n i c a l a d v a n c e s v e r s u s t h e c o m m e r c i a l s t a t u s o f membrane m a t e r i a l a t t h e same p o i n t i n t i m e . (Table 2 - S i g n i f i c a n t M i l e s t o n e s - Development o f A r t i f i c i a l Membrane L u n g s ) . Note t h a t t h e f i r s t s y n t h e t i c m a t e r i a l used f o r b l o o d o x y g e n a t i o n (albeit i n a d v e r t e n t l y ) was c e l l o p h a n e , and t h e mode o f oxygen t r a n s f e r must have been v i a s o l u b i l i t y i n t h e h y d r a t e d "aqueous p h a s e " o f t h e s w e l l e d p o l y m e r . By 1955, t h e c l i n i c i a n s had e x p e r i m e n t e d w i t h and c o n c e p t u a l l y o p t i m i z e d t h e b a s i c g e o m e t r i e s o f membrane oxygenators. However, t h e membrane m a t e r i a l s a v a i l a b l e t o them were t h o s e o f f e r e d by i n d u s t r y f o r o t h e r p u r p o s e s , u s u a l l y packaging. The c r i t e r i a f o r c h o o s i n g t h e m a t e r i a l s w e r e s t r e n g t h , c o n s i s t e n t q u a l i t y ( i . e . l a c k o f p i n - h o l e s ) and t h i n n e s s . If the m a t e r i a l s had some d e g r e e o f p e r m e a b i l i t y , a l l t h e b e t t e r . T h e p e r i o d 1955-1956 was i m p o r t a n t t o the e v e n t u a l d e v e l o p m e n t o f s u p e r i o r p e r m s e l e c t i v e membranes. P r o f e s s o r Kammermeyer d i d h i s f i r s t s t u d i e s on t h e p e r m e a b i l i t y o f s i l i c o n e f i l m s t o gases a b o u t t h i s t i m e and p u b l i s h e d h i s much r e f e r e n c e d a r t i c l e " S i l i c o n e Rubber a s a S e l e c t i v e B a r r i e r " i n I n d u s t r i a l and E n g i n e e r i n g C h e m i s t r y d u r i n g 1957. The v e r y h i g h p e r m e a b i l i t y o f t h e s i l i c o n e f i l m s , e s p e c i a l l y compared w i t h m a t e r i a l s p r e v i o u s l y a v a i l a b l e , c o u p l e d w i t h what was known a b o u t optimum g e o m e t r i e s r e s u l t e d i n a number o f l a s t i n g d e v i c e d e s i g n s i n t r o d u c e d i n t h e e a r l y 1960's. The c o m m e r c i a l a v a i l a b l i t y o f m i c r o p o r o u s p o l y o l e f i n s and p e r f 1 u o r o - p o l y o l e f i n s i n t h e 1970's f o l l o w e d w i t h t h e i n t r o d u c t i o n o f membrane o x y g e n a t o r d e v i c e s u s i n g t h e s e materials. Note t h a t w i t h p o s s i b l e e x c e p t i o n o f s i l i c o n e p a s s i v a t e d , microporous c e l l u l o s e a c e t a t e ( t h e Rhone-Poulenc l u n g ) , no p o l y m e r i c m a t e r i a l i n any c o m m e r c i a l a r t i f i c i a l l u n g was e s p e c i a l l y designed f o r t h e purpose o f blood oxygenation. Howe v e r , two p o l y m e r s , e t h y l - e e l 1ulose p e r f 1 u o r o b u t y r a t e (EFB) and t h e p o l y ( a l k y l s u l f o n e s ) have been e s p e c i a l l y d e v e l o p e d s i n c e t h e mid 1970's a s t h e base f o r membranes f o r b l o o d o x y g e n a t o r s . E t h y l c e l l u l o s e p e r f 1 u o r o b u t y r a t e was d e v e l o p e d by N o r t h s t a r Research. The p o l y ( a l k y l s u l f o n e s ) were d e v e l o p e d by OwensI l l i n o i s and a r e now o f f e r e d under t h e BIOBLAND name by Shenandoah R e s e a r c h , I n c . W h i l e t h e m a t e r i a l s have n o t y e t been used c o m m e r c i a l l y i n d e v i c e s , c o n s i d e r a b l e e v a l u a t i o n and t e s t i n g on t h e s e m a t e r i a l s has been r e p o r t e d ( R e f s . 7 and 9 and p e r t i n ent r e f e r e n c e s c i t e d t h e r e i n ) . The e a r l y e x p e r i m e n t a l d e v i c e s were g r a d u a l l y improved by 6


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Table I P e r m e a b i l i t y o f v a r i o u s polymers to oxygen and carbon d i o x i d e Polymer

p

Polydimethyl siloxane Silicone r u b b e r / p o l y c a r b o n a t e c o p o l y m e r ( M E M 213

160

970

60

250

50

250

Poly ( 4 - m e t h y l p e n t e n e - ï ) (TPX

30

90

5

13

2

9

0.4

1.8

0.08

0.016

Polyvinylchloride (unplasticized)

0.045

0.016

Polyethylene terephthalate-oriented

0.035

0.017

)

)

Poly (tetrafluoroethylene ) (Teflon

)

P o l y p r o p y l e n e (density 0.91) Polyethylene (density Pre

2

2700

Ethylcellulose perfluorobutyrate (EFB)

Poly ( a l p h a - h e x a d e c e n e sulfone) (Biobland-16 1955

)

co

500

Cellulose acetate

Units =

0.96)

(unplasticized)

cm

3

(STP), cm

n

2

,sec, cm H g

--i

Ο

73

π > r Ο

> 73 Η

α

>

GO

73

m

ο

73

m

Ο

9.

GRAY

157


o p t i m i z i n g membrane m a t e r i a l a n d f l o w c h a r a c t e r i s t i c s , a n d by t h e e a r l y 1 9 7 0 ' s s u f f i c i e n t e x p e r i m e n t a l d a t a was a v a i l a b l e t o i n d i c a t e t h a t membrane o x y g e n a t o r s were l e s s damaging t o b l o o d t h a n the blood-gas d i r e c t c o n t a c t type ( d i s c and b u b b l e ) . Therefore, t h e newer b l o o d o x y g e n a t o r s c o u l d be used f o r l o n g e r p e r i o d s ' . The improvements made i n m a t e r i a l s a n d o x y g e n a t o r designs a l l o w e d c l i n i c i a n s t o c o n s i d e r l o n g - t e r m (days r a t h e r t h a n h o u r s ) oxygenation f o r the f i r s t time. Here a g a i n t h e hope was t o "buy t i m e " n o t f o r s u r g e r y , b u t f o r an i n j u r e d o r d i s e a s e d l u n g t o r e p a i r i t s e l f o r h e a l . The w o r k e r s d e v e l o p i n g t h e s e t e c h n i q u e s w e r e u s i n g a s a model a w e l l - p r o v e n e x t r a c o r p o r e a l t e c h n i q u e temporary d i a l y s i s w i t h the a r t i f i c i a l kidney. A distinct d i f f e r e n c e between r e n a l d i a l y s i s a n d l o n g - t e r m o x y g e n a t i o n i s t h a t r e n a l d i a l y s i s may be i n t e r m i t t e n t and s t i l l be e f f e c t i v e , w h i l e o x y g e n a t i o n must be c o n t i n u o u s i n o r d e r t o be e f f e c t i v e . T h i s r e q u i r e m e n t p u t s g r e a t e r demands on t h e r e l i a b i l i t y o f t h e s u p p o r t d e v i c e s . As n a t u r a l h e a l i n g o f t e n d i d n o t o c c u r d e s p i t e b u y i n g t i m e w i t h a r t i f i c i a l l u n g s , p h y s i c i a n s have now t u r n e d t h e i r thoughts t o u s i n g a r t i f i c i a l lungs as support o r r e p l a c e ment d e v i c e s f o r i n s u f f i c i e n t n a t u r a l l u n g s . M a t e r i a l s used f o r t h e g a s t r a n s f e r membrane i n a r t i f i c i a l l u n g s c a n be o f two t y p e s , p e r m s e l e c t i v e s u c h a s t h o s e p r e v i o u s l y discussed o r microporous. In e i t h e r c a s e , g a s p a s s a g e p r o p e r t i e s must be h i g h , b l o o d c o m p a t i b i l i t y must be o p t i m a l a n d t o x i c a g e n t s must n o t be r e l e a s e d f r o m t h e membranes. Z a p o l a n d Ketteringham g i v e the f o l l o w i n g c h a r a c t e r i s t i c s r e q u i r e d f o r membrane m a t e r i a l s f o r an a r t i f i c i a l l u n g : 1. They must have h i g h o x y g e n a n d c a r b o n d i o x i d e p e r m e a b i l i t y . 2. They s h o u l d be c h e m i c a l l y s t a b l e w i t h o u t l e a c h a b l e m o i e t i e s and be b l o o d c o m p a t i b l e , m i n i m i z i n g t h r o m b o s i s , p l a t e l e t a c t i v a t i o n and i n j u r y , and p r o t e i n d e n a t u r a t i o n . 3. They must be s t r o n g , p i n h o l e - f r e e a n d c a p a b l e o f w i t h s t a n d i n g a p r e s s u r e g r a d i e n t o f 15 p s i f r o m t h e b l o o d s i d e w i t h o u t l e a k i ng. k. They must be c a p a b l e o f s t e r i l i z a t i o n p r e f e r a b l y by e t h y l e n e o x i d e o r by a u t o c l a v i n g . 5. They s h o u l d be e a s i l y f a b r i c a t e d i n t o p i n h o l e - f r e e membranes ( c o n t a i n i n g a s u p p o r t i n g component i f n e c e s s a r y ) w i t h a s u r f a c e c o n f o r m a t i o n w h i c h can be d e s i g n e d t o augment s e c o n d a r y blood flow a g a i n s t the s u r f a c e . 6. T h e b a s i c c o s t o f t h e m a t e r i a l a n d e a s e o f f a b r i c a t i o n must p e r m i t e c o n o m i c a l d i s p o s a b l e d e v i c e s t o be c o n s t r u c t e d . A number o f c o n f i g u r a t i o n s a r e used f o r c o m m e r c i a l membrane l u n g s ; t h o s e b a s e d on f l a t s h e e t s a r e Bramson, G . E . - P i e r c e , Lande-Edwards and T r a v e n o l . A m o d i f i c a t i o n o f the f l a t sheet c o n f i g u r a t i o n i s t h e K o l o b o w / S c i - M e d s p i r a l c o i l membrane l u n g . H o l l o w f i b e r membrane l u n g s a r e r e p r e s e n t e d by t h e Dow and t h e Terumo a r t i f i c i a l l u n g s . B l o o d f l o w i n g p a s t a membrane, a t l e a s t a s t h e f l u i d v e l o c i t i e s p e r m i t t e d i n membrane l u n g s , f o r m s a l a m i n a r b o u n d a r y l a y e r


8

7


9

158


a d j a c e n t t o t h e membrane. T h i s phenomena l i m i t s t h e gas t r a n s f e r p r o p e r t i e s , e x p e c i a l l y oxygen, o f the device. To e x p l o i t t h e t r u e , h i g h p o t e n t i a l 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 membrane m a t e r i a l i n modern membrane l u n g s , B e l l house and c o w o r k e r s have i n v e s t i g a t e d v o r t e x s h e d d i n g , s e c o n d a r y f l o w t e c h n i q u e s t o i n c r e a s e membrane t o b l o o d g a s t r a n s f e r . T h i s i s a c c o m p l i s h e d by i m p r e s s i n g a s e c o n d a r y p u l s i t i l e f l o w on t h e c i r c u l a t o r y f l o w t o d i s t u r b t h e l a m i n a r l a y e r . Examples o f d e v i c e s u s i n g t h i s t e c h n i q u e a r e t h e O x f o r d p u l s e d f l a t s h e e t l u n g and t h e d e v i c e o f f e r ed by E x t r a c o r p o r e a l . T h e s e d e v i c e s t h a t augment m i x i n g and i n c r e a s e gas t r a n s f e r p e r u n i t a r e a have c a u s e d a r e - e v a l u a t i o n o f t h e membrane m a t e r i a l s used i n a r t i f i c i a l lungs. 1 1


1 2

K e t t e r i n g h a m , d e F i l i p p i and B i r k e t t w o r k i n g w i t h a number o f p e r m s e l e c t i v e m a t e r i a l s f a b r i c a t e d i n t o u l t r a t h i n membranes have d e t e r m i n e d t h e CO2/O2 f l u x r a t i o f r o m i n v i t r o measurements u s i n g a s e r i e s o f a r t i f i c i a l l u n g s w i t h i n c r e a s i n g l y more e f f i c i e n t oxygen t r a n s f e r c h a r a c t e r i s t i c s . As c a n be seen f r o m T a b l e 1, f o r t h e p o l y m e r s t h a t a r e s e r i o u s c a n d i d a t e s a s memb r a n e s , t h e c a r b o n d i o x i d e p e r m e a b i l i t y i s much h i g h e r t h a n t h e oxygen p e r m e a b i l i t y . In d e v i c e s w i t h o u t i n d u c e d o r augmented s e c o n d a r y f l o w , t h e membrane a r e a r e q u i r e d t o m a i n t a i n a d e q u a t e oxygen t r a n s f e r t o t h e b l o o d was more t h a n a d e q u a t e f o r c a r b o n dioxide clearance. W i t h more e f f i c i e n t d e v i c e s t h a t e l i m i n a t e o r r e d u c e t h e d e l e t e r i o u s s t a g n a n t b l o o d l a y e r , t h e membrane area required f o r C 0 clearance i s a l s o o f concern. Figure 3 represents a s i m p l i f i e d presentation o f the information reported by K e t t e r i n g h a m . The r a t i o C 0 f l u x / 0 2 f l u x i s p l o t t e d v e r s u s the t o t a l oxygen f l u x . A t a f l u x r a t i o l e s s t h a n 0.82, insuffic i e n t C 0 i s c l e a r e d r e l a t i v e t o oxygen t r a n s f e r . T h e r e f o r e , any f u r t h e r improvement i n t o t a l o x y g e n t r a n s f e r i s o f no p h y s i o l o g i c a l advantage. The i n t e r c e p t o f t h e c u r v e d l i n e s w i t h t h e dotted l i n e y i e l d s the value f o r the highest usable 0 t r a n s f e r f o r a g i v e n m a t e r i a l . BIOBLAND 16 used i n t h e u l t r a t h i n memb r a n e c o n f i g u r a t i o n a p p r o a c h e s t h e gas t r a n s f e r c h a r a c t e r i s t i c s of t h e microporous m a t e r i a l s , but without the problems a s s o c i a t e d w i t h t h e m i c r o p o r o u s m a t e r i a l s . The p r o b l e m s most o f t e n a s s o c i a t e d w i t h t h e m i c r o p o r o u s membranes a r e p o s s i b l e b l o o d damage due t o gas m i c r o b u b b l e i n t r u s i o n , e x c e s s i v e w a t e r f l u x and p o s s i b l e seepage. 2

1 2

2

2

2

S i n c e membrane l u n g s a s e x t r a c o r p o r e a l d e v i c e s a r e i n w i d e u s e , t h o u g h t s have t u r n e d t o an i m p l a n t a b l e a r t i f i c i a l l u n g p r o s t h e s i s based on membrane t e c h n o l o g y . D e v e l o p i n g such a d e v i c e w i t h t h e a d e q u a t e c h a r a c t e r i s t i c s and l o n g - t e r m r e l i a b i l i t y i s a much more d i f f i c u l t t a s k t h a n e n c o u n t e r e d w i t h t h e e x t r a c o r p o r e a l d e v i c e d e v e l o p e d f o r i n t e r m i t t a n t u s e . However, a s m a l l p r o t o t y p e d e v i c e made o f p o r o u s T e f l o n has been f a b r i c a t e d and t e s t e d by R i c h a r d s o n a n d G a l l e t t i . The hopes f o r t h e use o f E x t r a c o r p o r e a l Membrane O x y g e n a t i o n (ECMO) f o r t r e a t i n g a c u t e r e s p i r a t o r y f a i l u r e went t h r o u g h a l o w p o i n t i n t h e mid 1970's a f t e r t h e r e s u l t s o f t h e N a t i o n a l I n s t i 1 3



GRAY


Figure 3 . Membrane e f f i c i e n c i e s . Key: MEM 2 1 3 , p o l y s i l o x a n e / p o l y c a r b o n a t e ; SSR, standard s i l i c o n e rubber UTEFB, u l t r a t h i n e t h y l c e l l u l o s e p e r f l u o r o b u t y r a t e ; UTSR, u l t r a t h i n s i l i c o n e rubber; and BIOBLAND 1 6 , poly(a-hexadecene s u l f o n e ) . (Reproduced w i t h permission from Ref. 1 2 . Copyright 1 9 7 6 , Academic Press.)


160


t u t e s o f H e a l t h - E x t r a c o r p o r e a l Membrane O x y g e n a t i o n s t u d y became known \ T h i s work d e s c r i b e s t h e f i n d i n g s o f a c o o p e r a t i v e study i n v o l v i n g n i n e prominent medical c e n t e r s w e l l versed i n e x p n a c o r p o r e a l p e r f u s i o n . N i n e t y i n d i v i d u a l s were c h o s e n whose c o n d i t i o n ( r e s p i r a t o r y f a i l u r e ) o f f e r e d them o n l y a t e n p e r c e n t c h a n c e o f s u r v i v a l u s i n g s t a n d a r d r e s p i r a t o r y t h e r a p y management. T h i s g r o u p was r a n d o m l y d i v i d e d i n t o two s m a l l e r , e q u a l g r o u p s (45 e a c h ) , one g r o u p b e i n g g i v e n ECMO s t a t e - o f - t h e - a r t s u p p o r t and t h e o t h e r g i v e n s t a n d a r d t h e r a p y . T h e r e were f o u r (4) s u r v i v o r s i n e a c h g r o u p i n d i c a t i n g t h a t t h e more d i f f i c u l t and e x p e n s i v e ECMO t h e r a p y a p p a r e n t l y y i e l d e d no b e n e f i t s . However, t h e gloomy p r o s p e c t has b r i g h t e n e d i n t h e l a s t f i v e years. In 1979 B a r t l e t t r e p o r t e d on t h e s u r v i v a l o f o n e - h a l f o f a g r o u p o f 32 m o r i b u n d i n f a n t s u s i n g ECMO t e c h n i q u e s and s t a t e d as a r e s u l t o f h i s f i n d i n g s t h a t " r e c o v e r y and s u r v i v a l s h o u l d be r o u t i n e i f ECMO i s i n s t i t u t e d i n t h e f i r s t two days o f life". As e a r l y a s 1978, K o l o b o w r e p o r t e d c a r b o n d i o x i d e c o u l d be removed f r o m b l o o d (and hence b l o o d pH c o u l d be p r o p e r l y m a i n t a i n e d ) by s h u n t i n g o n l y 10-30% o f t h e c a r d i a c o u t p u t t h r o u g h a membrane l u n g . T h i s s t u d y has been f o l l o w e d by more c l i n i c a l work by Kolobow and h i s a s s o c i a t e s ' . In one s t u d y a 63% s u r v i v a l r a t e was o b t a i n e d by s i m u l t a n e o u s l y u s i n g ECMO f o r c a r b o n d i o x i d e removal c o u p l e d w i t h c l a s s i c a l v e n t i l a t o r t e c h niques f o r oxygenation. T h e s e s t u d i e s have prompted a r e a p p r a i s a l o f t h e u s e o f ECMO t h e r a p y w i t h renewed e m p h a s i s on p a t i e n t c h o i c e and m o d i f i e d treatment t e c h n i q u e s . It i s e x p e c t e d t h a t w i t h t h e g r e a t e r a v a i l a b i l i t y o f s i m p l e r , more d e p e n d a b l e and l o w e r c o s t d i s p o s a b l e membrane o x y g e n a t o r s i n s u r g i c a l p r o c e d u r e s o f t h e h e a r t , t h e i r u s e w i l l i n c r e a s e . In t h i s c o u n t r y , a b o u t 500 i n d i v i d u a l s e a c h d a y u n d e r g o r o u t i n e heart surgery that requires extracorporeal o x y g e n a t i o n . Bubble o x y g e n a t o r s s t i l l d o m i n a t e , b u t t h e number o f p e r f u s i o n teams t h a t a r e s h i f t i n g t o membrane u n i t s i s i n c r e a s i n g . The t o t a l p o t e n t i a l m a r k e t (U.S.) f a r membrane l u n g s i s a b o u t $20 m i l l i o n / y e a r ( a t t h e p r e s e n t p r i c e o f $ 2 0 0 / u n i t ) making i t a r e l a t i v e l y small market as compared, f o r example, t o t h e a r t i f i c i a l k i d n e y ( d i a l y s i s ) m a r k e t o f $225 m i l l i o n / y e a r . T h e r e f o r e , one w o u l d n o t e x p e c t t o s e e many new "me-too" membrane o x y g e n a t o r d e v i c e s i n t r o d u c e d . Any new p r o d u c t w o u l d have t o o f f e r a c l e a r b e n e f i t o r f i l l a r e c o g n i z e d need t o c a p t u r e m a r k e t s h a r e . 1


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Literature Cited 1. Galletti, P.M., Artificial Lungs for Acute Respiratory Failure, edited by Warren M. Zapol and Jesper Qvist, Academic Press (1976) 2. Lillehei, C.W., DeWall, R.A., Read, R.C., Warden, H.E. and Varco, R.L., Dis. Chest, 29, 1 (1956) 3. Kirklin, J.W., DuShane, J.W., Patrick, R.T., Donald, D.E., Hetzel, P.S., Harshbarger, H.G. and Wood, E.H., Proc. Staff Meet., Mayo Clin, 30, 201 (1955) 4. Kolff, W.J. and Balzer, R., Trans. Am.Soc.Artif. intern. Organs, 1, 39 (1955) 5. Clowes, G.H., Jr., Hopking, A.L. and Neville, W.E., J. Thoracic Surg., 32, 630 (1956) 6. Private Communication - Prof. Sun-Tak Hwang, University of Cincinnati 7. Kammermeyer, Κ., Ind. and Eng. Chem, 49, 1685-1686 (1957) 8. Lande, A.J., Fillmore, S.J., Subramanian, V., Tiedenamm, R.N., Carlson, R.G., Bloch, J.A. and Lillehei, C.W., Trans. Soc. Artif. Intern. Organs, 15, 181 (1969) 9. Kolobow, T. and Zapol, W.M., Adv. Cardiol., 6, 112 (1971) 10. Zapol, W.M. and Ketteringham, J.M., Polymers in Medicine and Surgery, Polymer Science and Technology, Volume 8, Plenum Press, N.Y. (1975) 11. Bellhouse, B.J., Bellhouse, F.M., Curl, C.M., MacMillan, T.I., Gunning, A.J., Spratt, E.M., MacMurray, S.B. and Nelems, J.M., Trans. Am. Soc. Artif. Intern. Organs, 19, 72 (1973) 12. Ketteringham, J.M., DeFillippi, R. and Birkett, J.D., Ultra thin Membranes for Membrane Lungs, in Artificial Lungs for Acute Respiratory Failure, Zapol, W.M. and J. Qvist, ed., Academis Press (1976) 13. Galletti, P.M., Richardson, P.D., Trudell, L.A., Parol, G., Tanishita, K. and Accinelli, D., Trans. Am. Soc. Artif. Intern. Organs, 26, 573 (1980) 14. Zapol, W., Snider, M.T., Hill, J.D., Fallat, R.J., Bartlett, R.H., Edmunds, L.H., Morris, A.H., Pierce, E.C.,II, Thomas, A.N., Drinker, P.Α., Pratt, P.C., Bagiewski, Α., Miller, R.G. Jr., Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA 242, 2193 (1979) 15. Bartlett, R.H., Gazzaniga, A.B., Huxtable, R.H., Rucker, R., Wetmore, N., Haiduc, N. Extracorporeal membrane oxygenation (EMCO) in newborn respiratory failure: Technical considera tions. Trans. Am. Soc. Artif. Intern. Organs, 25, 473 (1979) 16. Kolobow, T. Gattinoni, L., Tomlinson, T., Pierce, J.E., An alternative to breathing. J. Thorac. Cardiovasc. Surg., 75, 261 (1978) 17. Gattinoni, L., Pesenti, Α., Pelizzola, Α., Caspani, M.L., lapichino, G., Agostoni, Α., Damia, G., and Kolobow, T., Reversal of terminal acute respiratory failure by low


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frequency positive pressure ventilation with extracorporeal removal of CO2(LFPPV-ECCO R).Trans. Am. Soc. Artif. Intern. Organs, 27, 289 (1981) Pesenti, Α., Pelizzola, Α., Mascheroni, D., Uziel, L, Pirovani, E., Fox, U., Gattinoni, L. and Kolobow, T., Low frequency positive pressure ventilation with extracorporeal CO removal(LFPPV-ECCO R)in acute respiratory failure (ARF); Technique. Trans. Am. Soc. Artif. Intern. Organs, 27, 263 (1981) Warden, H.E., Cohen, M., DeWall, R.A., Schultz, E.A., Buckley, J.J., Read, R.C., Lillehei, C.W. Experimental closure of intraventricular septal defects and further physiologic studies on controlled cross circulation. Surg. Forum, 5, 22 (1954) Warden, H.E., Cohen, M. Read, R.C., Lillehei, C.W. Controll ed cross circulation for open intracardiac surgery. J. Thorac. Surg., 28, 331 (1954) Campbell, G.S., Crisp, N.W., Brown, E.B. Total cardiac by pass in humans utilizing a pump and heterologous lung oxygen ator (dog lungs). Surgery, 40, 364 (1956) Gott, V.L., Extracorporeal Circulation: 1970-1982, Trans. Am. Soc. Artif. Inter. Organs, 28, 17 (1982) Galletti, P.M., Impact of the artificial lung on medical care, Int. J. of Artif. Organs, 3, 157 (1980) 2

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