Synthetic Membranes: Volume II - American Chemical Society

6

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on June 2, 2015 | http://pubs.acs.org Publication Date: May 27, 1981 | doi: 10.1021/bk-1981-0154.ch006

Pressure Control of the Ultrafiltration Rate During Hemodialysis with High-Flux Dialyzers and the Time Dependence of Membrane Transport Parameters A L L E N ZELMAN, DAVID GISSER, GARY STRAIT, and VICTOR BASTIDAS Center for Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY

12181

ROBERT STEPHEN, C A R L KABLITZ, JEFFREY HARROW, BARRY DEETER, and W. J. K O L F F Division of Artificial Organs, University of Utah, Salt Lake City, UT

74112

Recent hemodialysis research has focused a t t e n t i o n on the "middle molecule hypothesis" (1, 2) which suggests that s o l u t e s i n the "middle molecular weight" spectrum of 500-3000 daltons i n c l u d e important uremic t o x i n s . I t appears that a s i g n i f i c a n t f r a c t i o n of the d i a l y s i s p o p u l a t i o n could b e n e f i t from hemodialysis using a membrane w i t h a l a r g e r pore s i z e . However, if the diameter of the pore is doubled, the water l o s s will increase s i x t e e n times. Thus, accurate and r e l i a b l e ultrafiltration c o n t r o l i s necessary when using so c a l l e d "high f l u x membranes". The three e x t r a c o r p o r e a l techniques used to remove middle molecules while controlling ultrafiltration are: 1) hemoperfusion (3, 4); 2) h e m o f i l t r a t i o n (5, 6, 7); and 3) d i a l y s i s with a d i a l y z e r which contains a h i g h l y porous membrane capable of removing middle mole c u l e s , such as the Hospal RP-6 d i a l y z e r (8, 9). Nevertheless, there are problems with all three techniques. P r e d i l u t i o n hemo filtration o f f e r s small molecule clearance comparable to hemodialysis and e x c e l l e n t (~ 100 ml/min) middle molecule c l e a r ance. I t is, however, q u i t e expensive and t e c h n i c a l l y complicated. P o s t d i l u t i o n a l h e m o f i l t r a t i o n o f f e r s good middle molecule c l e a r ance, but the small molecule clearance of 60-70 ml/min i s margin al. Hemoperfusion has no capability f o r fluid removal and little c a p a c i t y f o r urea removal; t h e r e f o r e , it fulfills only a supple mentary r o l e i n the treatment of End Stage Renal Disease. Hemodialysis with a high f l u x membrane used i n the standard counter-current mode r e q u i r e s e i t h e r an expensive (~ $4,500) ultrafiltration c o n t r o l system ( i n a d d i t i o n to the u s u a l $6,000 d i a l y s a t e d e l i v e r y system) or a closed circuit 70 liter d i a l y s a t e tank wherein the adequacy of urea removal i s debatable: p a t i e n t s using the tank system average 22% higher BUNs than p a t i e n t s on standard s i n g l e pass systems (10). The mean transmembrane h y d r o s t a t i c pressure drop,

ΔP , m

pri

m a r i l y determines the r a t e of u l t r a f i l t r a t i o n and i s given by 0097-6156/81/0154-0061$05.00/0 © 1981 American Chemical Society

In Synthetic Membranes: Volume II; Turbak, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

62

SYNTHETIC MEMBRANES:

3p

-

P

Bl

m AP

+

P

Bo _

I

P

DI

+

P

Do

H F AND U F

USES

m

1

i s r e l a t e d t o the u l t r a f i l t r a t i o n r a t e , Q , by Q

= L

v

where L

p

(AP

m

- TT )

(2)

p

i s the u l t r a f i l t r a t i o n index, TT

P

i s the osmotic

pressure

P

of the plasma p r o t e i n s , P ^ and P ^ are the h y d r o s t a t i c pressures of the blood i n and the blood out l i n e r e s p e c t i v e l y , P and P q


D

I

D

O

are the h y d r o s t a t i c pressures of the d i a l y s a t e i n and d i a l y s a t e out l i n e r e s p e c t i v e l y . C o n t r o l of A P o b v i o u s l y allows c o n t r o l of Q . v Consider F i g u r e 1, which d e p i c t s the conventional hemodialys i s system i n counter-current mode. This d i a l y z e r set-up maximizes the c o n c e n t r a t i o n d i f f e r e n c e across the membrane and thus ensures maximum s o l u t e t r a n s f e r . However t h i s c o n f i g u r a t i o n a l s o maximizes the transmembrane h y d r o s t a t i c pressure d i f f e r e n c e and thus, maximizes the water f l u x . During hemodialysis the h y d r o s t a t i c pressure of the blood must always be higher than the pressure of the d i a l y s a t e to ensure s t e r i l i t y i n the event of a membrane rupture. One has the f o l l o w i n g c o n s t r a i n t s during counter-current f l o w P _ . > P ^ , P ^ . > P ^ , P „ > P - , (everywhere). Bl Bo Di Do B D From these c o n s t r a i n t s i t i s easy to see from Figure 1 that by s e t t i n g d i a l y s a t e and blood pressure a t a r b i t r a r y v a l u e s , a m i n i mum A P can o n l y be generated to equal to ( P , , . - P ) . m DI DO In the counter-current mode the magnitude of t h i s d i f f e r e n c e i s s e t by the c o n s t r u c t i o n of the d i a l y z e r and the d i a l y s a t e pressure c o n t r o l and i s g e n e r a l l y on the order of 50 mm Hg or g r e a t e r . This minimum pressure w i l l induce an absolute minimum u l t r a f i l t r a t i o n r a t e of 350 ml/hr f o r a t y p i c a l high f l u x membrane. Thus, when the p a t i e n t has l o s t s u f f i c i e n t water or perhaps when he does not need to l o s e any water during d i a l y s i s , the p a t i e n t must cont i n u o u s l y be given s t e r i l e s a l i n e to make up f o r the minimum u l t r a f i l t r a t i o n loses. The purpose of t h i s research was to develop a simple and i n expensive hemodialysis p r o t o c o l w i t h the f o l l o w i n g o b j e c t i v e s : (a) to ensure maximum removal of the "middle molecules" by u t i l i z i n g a h i g h l y porous membrane i n c o r p o r a t e d i n t o so c a l l e d "high f l u x d i a l y z e r s " ; (b) to ensure normal removal of low molecular weight s o l u t e s by u t i l i z i n g a s i n g l e pass d i a l y s i s d e l i v e r y system (11); (c) to ensure accurate c o n t r o l of u l t r a f i l t r a t i o n by maint a i n i n g the transmembrane h y d r o s t a t i c pressure, A P ^ , a t a p p r o p r i a t e s m a l l values e a s i l y read on standard d i a l y s i s equipment; and (d) to accomplish the above o b j e c t i v e s without the use of expensive v o l u m e t r i c or other s p e c i a l i z e d equipment. m

N


6.

ZELMAN ET AL.

63

Hemodialysis

D e s c r i p t i o n of a Simple Means of C o n t r o l l i n g U l t r a f i l t r a t i o n . Consider F i g u r e 2 w i t h co-current flows. When the h y d r o s t a t i c pressures have reached a steady s t a t e , the net f o r c e s a c t i n g on the membrane are balanced, i . e . , mechanical e q u i l i b r i u m e x i s t s . In a very s i m p l i f i e d view, the mechanical f o r c e balance can be w r i t t e n a t any d i s t a n c e z along the l e n g t h of the membrane as (3)

P ( z ) = P ( z ) + V(z)


B

where P (z) brane Thus, fi

D

v(z) i s the r e s t o r i n g f o r c e s u p p l i e d by the membrane. I f i n c r e a s e s as a r e s u l t of increased blood f l o w , then the memr e s i s t s bending i n t o the d i a l y s a t e path by an amount v ( z ) . the transmembrane pressure a t z can be expressed by (4)

AP (z) = P (z) - P (z) = v(z) m

B

D

Now consider t h a t i f

. i n c r e a s e s , then P^Cz) i n c r e a s e s and

the membrane w i l l be f o r c e d i n t o the path of the d i a l y s a t e . The r e s t r i c t i o n of d i a l y s a t e cross s e c t i o n w i l l cause the d i a l y s a t e pressure t o i n c r e a s e when i s h e l d constant, so equation 4 w i l l h o l d f o r new values of P _ ( z ) , P^Cz) and v ( z ) .

I t i s apparent

that

when the membrane becomes very d i s t e n s i b l e or f l e x i b l e , i . e . , v ( z ) tends toward z e r o , then P^Cz) - P^Cz) tends toward zero a l s o , i . e . , the membrane cannot support a h y d r o s t a t i c pressure drop. Thus i f the membrane i s f r e e to move, the transmembrane pressure drop w i l l tend toward a minimum value. In the co-current mode (P^ - P_ ) can be made a r b i t r a r i l y Bo Do c l o s e t o zero by a d j u s t i n g 5 t h i s i s a standard adjustment on n e a r l y a l l d i a l y s a t e d e l i v e r y systems. However, the d e l i v e r y system must have the c a p a b i l i t y of p r o v i d i n g a p o s i t i v e d i a l y s a t e pressure equal to the blood venous pressure (~ 80 mm Hg). The pressure drop ~ D p ™m a u t o m a t i c a l l y be adjusted to near zero by the i n t e r a c t i o n of the co-current flows and d i s t e n s i b l e membrane. Therefore by a d j u s t i n g P^ u n t i l AP = if , no matter Do m p how porous the membrane, the u l t r a f i l t r a t i o n r a t e can be brought to zero when the d i a l y z e r i s operated i n the co-current mode. Because our system i s a pressure c o n t r o l of u l t r a f i l t r a t i o n r a t e , i t i s obvious that an accurate i n v i v o value of the u l t r a f i l t r a t i o n index, L^, i s r e q u i r e d . Our f i r s t attempts a t manual determination of (12) produced only a very s m a l l amount of data v

p

D o

P

J

compared to the enormous e f f o r t necessary to c o l l e c t i t . Thus, an automated system was designed and constructed f o r c o l l e c t i n g and e v a l u a t i n g u l t r a f i l t r a t i o n data.



64

SYNTHETIC M E M B R A N E S :

H F A N D U F USES

Counter-Current Flows Figure 1.

r

Q

BO«-

Q

DO«-

Countercurrent dialyzer set-up

r

BOJ

BLOOD

Bi,

Q

Bi

DIALYSATE

Co-Current Flows Figure 2.

Cocurrent dialyzer set-up


6.

ZELMAN ET AL.

65

Hemodialysis

Equipment and Methods. The experimental set-up f o r f i n d i n g the i n v i v o v a l u e of L^ i s shown s c h e m a t i c a l l y i n F i g u r e 3. Blood i s withdrawn from the p a t i e n t a t 225 ml/min. The d i a l y s a t e input i s 500 ml/min. The d i a l y z e r i s operated i n the co-current mode. Two d i f f e r e n t i a l pressure transducers (Model CD 7, Celesco Transducer Products, Canoga Park, CA) monitor ( P -P ) =AP and ( P -P ) = f i ±


AP

B D q

t o ± 1 mm Hg.

D ±

B

D

±

B q

D o

The pressures a r e time v a r y i n g due to p a t i e n t

unrest and the p u l s a t i l e nature of blood r o l l e r pumps. The analog s i g n a l s of each pressure transducer demodulator i s sent to the " u l t r a f i l t r a t i o n monitor" c o n t i n u o u s l y . The d i a l y s a t e i s d e l i v e r e d i n the s i n g l e pass mode, but the d i a l y s a t e tanks a r e arranged to mimic a c l o s e d system. Dialysate r e s e r v o i r s r e s t on a p l a t f o r m , the weight of which i s c o n t i n u o u s l y monitored to ± 2 g by an Aimex e l e c t r o n i c weighing system (Aimex Corp., Boston, MA). Fresh d i a l y s a t e flows from one tank through the d i a l y z e r and r e t u r n s to a d r a i n tank. The t o t a l weight of these tanks may change- only as a r e s u l t of water l o s s by the p a t i e n t or by compliance e f f e c t s of the d i a l y z e r . The Aimex weighing system sends a continuous analog s i g n a l i n d i c a t i n g d i a l y sate weight as a f u n c t i o n of time t o the u l t r a f i l t r a t i o n monitor. The u l t r a f i l t r a t i o n monitor i s a hard-wired, d i g i t a l s i g n a l processor. I t s purpose is_ to average the input s i g n a l s of weight and pressure and compute A P ( t ) , Q ( t ) and L ^ ( t ) . F i g u r e 4 i s a m

y

schematic of the o p e r a t i o n of the u l t r a f i l t r a t i o n monitor. The time averaging systems operate i n the f o l l o w i n g way. About once a sec a short data sample i s c o l l e c t e d from each i n p u t ; a f t e r about 2 min, 128 data p o i n t s a r e averaged and d i s p l a y e d on LED readouts. The average i s updated f o r each sample. Since a l l v a r i a b l e s during d i a l y s i s a r e s l o w l y v a r y i n g compared to 2 min and a l l n o i s e i s f a s t compared t o 2 min, a 2 min time averaging system seemed to be a reasonable f i r s t t r y . The u l t r a f i l t r a t i o n monitor had the f o l lowing ranges and i n v i t r o a c c u r a c i e s as a f u n c t i o n of time: d i a l y s a t e weight changes ± 4 kg to ± 2 g; u l t r a f i l t r a t i o n r a t e ± 4000 ml/hr t o ± 2 ml/hr; mean transmembrane h y d r o s t a t i c pressure ± 250 mm Hg to ± 1 mm Hg; and the membrane h y d r a u l i c p e r m e a b i l i t y ( u l t r a f i l t r a t i o n index) 60 ml hr ^ mm Hg ^ to ± 0.8 ml hr ^ mm Hg . Q and A P ^ were c o n t i n u o u s l y recorded on a 2 pen c h a r t r e corder t o an accuracy of 10 ml/hr and 2 mm Hg per d i v i s i o n (0.2 cm) a t a c h a r t speed o f 30 cm/hr. Data was read from the chart a t 2 min i n t e r v a l s . Data i s excluded from a n a l y s i s whenever changes i n v a r i a b l e s i n v a l i d a t e the averaging of the u l t r a f i l t r a t i o n monitor; approximately 50% of a l l data was excluded. The mass t r a n s f e r of each s o l u t e was computed from the s t a n dard c l e a r a n c e , C, formula V


SYNTHETIC

MEMBRANES:

120 $ dialysate drain

I20.P dialysate

H F AND

UF

USES

LED OUTPUT and recorder ^i - *L (t) >r

v

m


p

AP Ct) BD1

Figure 3. Patient monitoring system. This apparatus was assembled only to determine the dialyzer UF index, L . Knowing L then allows safe high-flux dialysis without specialized equipment p

Dialyzer

j_J Differential Pressure Transducers

AP

BDo

Synthetic Membranes: Volume II - American Chemical Society

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