Journal of Clinical Apheresis 2:81-90 (1984)

ADVERSE EFFECTS IN DONORS AND PATIENTS SUBJECTED TO HEMAPHERESIS

Douglas W. Huestis, M.D.

University of Arizona Medical Center; Tucson, AZ.

Any type of hemapheresis is an invasive surgical procedure, temporarily modifying the circulating blood of a person. In some cases, it can be likened to an amputation, except that the amputated blood components grows back again. Obviously, such a procedure has many effects on the subject, some immediately apparent, some not.

Vascular Effects

To modify blood, one must have access to it, and this means an interplay of veins and needles. Willy nilly, there is vascular damage. In donors, this is usually minor and temporary, but in patients it can be considerable, and when a patient already has damaged peripheral veins, access may be nearly impossible. In such a case, one may have to resort to the use of various types of intravenous catheters, or even to the insertion of an arteriovenous shunt or fistula if hemapheresis must be performed. The latter expedient, of course, is not lightly undertaken, since it has permanent effects on the patient. Complications have included stroke, and gangrene requiring amputation.

Other problems of vascular access include such things as venous spasm or collapse, preventing adequate outflow of blood to the separator, and infiltration or hematoma, either of which can prevent inflow or outflow. Repeated hemapheresis procedures, like any other repeated vascular insult, can result in venous thrombosis and progressive reduction in the number of available venous sites.

Procedural Reactions

Circulatory effects

Healthy blood donors subjected to cytapheresis for blood components (e.g. for platelets or granulocytes) may experience tiredness and vague malaise, quite apart from the potentially complicating influences of steroids and macromolecular agents. These effects, presumably caused by extracorporeal circulation and shifts in body fluid balance, are more pronounced in sick patients undergoing hemapheresis.

In hemapheresis, including plasma exchange (PE), subjects experience many of the reactions associated with regular blood donation, e.g. hypotension and syncope, at least partly related to the extracorporeal circulatory volume, and presumably aggravated by psychological factors. They are more likely to occur with larger extracorporeal volumes, such as would be the case with intermittent flow centrifugation (IFC) procedures. The operator can usually control these by temporarily stopping the procedure and returning some extra fluid to restore plasma volume.

end of a procedure, when the blood outflow has been stopped but fluid return is still On the other hand, fluid overload may occur, particularly in the elderly, towards the

0 1984 Alan R. Liss, Inc.

82 Huestis

c o n t i n u i n g . Of much g r e a t e r import is t h e o c c a s i o n a l o c c u r r e n c e of c a r d i a c a r r h y t h m i a . Th i s compl i ca t ion may be r e l a t e d i n p a r t t o a c i t r a t e e f f e c t , and i s more o f t e n seen i n t h e r a p e u t i c p rocedures w i t h t h e use of s u b c l a v i a n l i n e s , perhaps because of t h e r a p i d d e l i v e r y of c i t r a t e d plasma t o t h e g r e a t v e i n s n e a r t h e h e a r t .

C i t r a t e e f f e c t s

The adve r se e f f e c t s of c i t r a t e a n t i c o a g u l a n t s are caused by t h e i r c h e l a t i n g e f f e c t s on i o n i z e d ca l c ium, and a f f e c t bo th p a t i e n t s and donors . C i t r a t e c a u s e s m a n i f e s t a t i o n s of neuromuscular h y p e r a c t i v i t y , s p e c i f i c a l l y c i r c u m o r a l p a r e s t h e s i a , i n c r e a s e d muscular t e n s i o n , p a r t i c u l a r l y f e l t a s a f l u t t e r y f e e l i n g i n t h e c h e s t , nausea and sometimes vomi t ing , c h i l l s , and r a r e l y o v e r t t e t a n y . V a r i a b l e s a f f e c t i n g t h e s e m a n i f e s t a t i o n s i n c l u d e t h e c o n c e n t r a t i o n of c i t r a t e i n t h e r e t u r n i n g component, t h e r a t e of r e i n f u s i o n , and t h e i n d i v i d u a l s u s c e p t i b i l i t y of t h e s u b j e c t t o c i t r a t e . G e n e r a l l y , c i t r a t e e f f e c t s can be c o n t r o l l e d by t h e o p e r a t o r by s lowing t h e f low r a t e o r by d e c r e a s i n g t h e p r o p o r t i o n of c i t r a t e i n t h e r e t u r n f l u i d . T h i s i s p robab ly a s a f e r e x p e d i e n t t h a n t r y i n g t o n e u t r a l i z e t h e c i t r a t e e f f e c t by t h e i n j e c t i o n of i o n i z e d ca l c ium, a l t h o u g h t h e l a t t e r has been s u c c e s s f u l l y used. E l e c t r o l y t e imbalances i n p a t i e n t s may be a g g r a v a t e d by PE, and may r e q u i r e i n d i v i d u a l c o r r e c t i o n .

Cold

P a t i e n t s and donors may f e e l c o l d and s h i v e r y d u r i n g hemapheresis because t h e i r b i s going through an e x t r a c o r p o r e a l c i r c u i t a t room t e m p e r a t u r e . The e f f e c t i s more pronounced i f t h e room i t s e l f i s c o l d . The s o l u t i o n s a r e obv ious : a b l a n k e t may be a t h a t i s needed. The r o u t i n e use of a blood w a r m e r on each s e p a r a t o r i n c r e a s e s comfort r educes t h e i n c i d e n c e of c h i l l s .

ood

1 and

Hemolysis

Fo rc ing blood through a narrow o r i f i c e , p a r t i c u l a r l y when t h e blood is c o n c e n t r a t e d t o a high h e m a t o c r i t , i s i n c l i n e d t o cause hemolys i s . T h i s s t a t e of a f f a i r s has been observed e s p e c i a l l y i n IFC hemapheresis when t h e r e i s an u n n o t i c e d k i n k i n some p a r t of t h e t u b i n g . Hemolysis is seldom seen i n con t inuous f low c e n t r i f u g a t i o n (CFC) sys t ems . N e v e r t h e l e s s , t h e plasma l i n e s shou ld be c a r e f u l l y observed f o r t h i s e f f e c t , s i n c e hemolysis i n d i c a t e s g e n e r a l i z e d damage t o t h e r e d c e l l s , and it may be d e s i r a b l e t o s t o p t h e p rocedure t o p reven t t h e r e t u r n of l a r g e numbers of damaged r e d c e l l s t o t h e p a t i e n t o r donor.

Complicat ions s p e c i f i c t o t h e r a p e u t i c p rocedures

Replacement medium

D i f f e r e n t r e a c t i o n s and r i s k s a r e a s s o c i a t e d w i t h t h e u s e of plasma as replacement i n PE i n s t e a d of a lbumin. Plasma i n c l u d e s c i t r a t e i n gene rous amounts, which can cause untoward e f f e c t s . Second, t h e f r equency of a l l e r g i c r e a c t i o n s , i n c l u d i n g a n a p h y l a c t i c , i s r e l a t i v e l y h i g h . T h i r d , h e p a t i t i s may fo l low. A l l e r g i c r e a c t i o n s compl i ca t e t h e use of albumin o r plasma p r o t e i n f r a c t i o n a s w e l l , a l t h o u g h less o f t e n . But h e p a t i t i s does n o t occur w i t h albumin p r e p a r a t i o n s , and c i t r a t e r e a c t i o n s are less l i k e l y , s i n c e t h e on ly c i t r a t e i s i n t h e r e t u r n i n g r e d c e l l s .

Plasma, of c o u r s e , c o n t a i n s a n t i b o d i e s . Because of i t s c o n t e n t of ant i -A and /o r an t i -B , plasma shou ld be s e l e c t e d f o r c o m p a t i b i l i t y w i t h t h e p a t i e n t . However, o t h e r a n t i b o d i e s may be p r e s e n t . r e p o r t e d from France i n c o n n e c t i o n w i t h PE, and have been t e n t a t i v e l y a s c r i b e d t o non-HLA leukocy te a n t i b o d i e s i n donor plasma. Although t h i s c o n c l u s i o n h a s n o t as y e t been confirmed, t h e French workers have seen no such r e a c t i o n s s i n c e t h e y s topped u s i n g t h e

A number of c a s e s of a c u t e r e f r a c t o r y pulmonary edema have been

Adverse Effects of Hemapheresis 83

plasma from women, and from men with a history of having received transfusions (A. Bussel; personal communication, 1982).

Hemorrhage or thrombosis

PE using albumin as the replacement medium significantly depletes those clotting factors that are not rapidly replaced, as well as fibrinogen and antithrombin 111. Depending on the technique used, there may also be some loss of platelets. hemorrhage or thrombosis, however, seems to be a rare occurence.

Complicating

Bacteria 1 infect ions

As with the clotting factors, PE with albumin does deplete immunoglobulins, in addition t o which most procedures are carried out in combination with immunosuppressive drug therapy. progressive glomerulonephritis. In addition, such complicating infections may cause worsening of the underlying disease process. closely spaced series of PE, the prophylactic administration of immune serum globulin may be considered. Admittedly, data to back up this recommendation are not available.

Complicating infections have been reported in patients with rapidly

As a precaution, in some patients receiving a

Viral infections

Hepatitis is a risk whenever plasma is used as the replacement medium. I know of no data on the frequency of this complication. Other than not using plasma for replacement, there seems to be no reliable way to avoid the risk of hepatitis. immune globulin nor hepatitis B vaccine would be likely to be of use, since 90% of posttransfusion hepatitis is of the non-A/non-B type. Viral infections other than hepatitis, such as cytomegalovirus, have not been reported.

Neither hepatitis B

Protein depletion

Regulations established for the protection of normal plasma donors are not particularly helpful as guidelines for PE, where as much as 4 liters or more of plasma may be removed at a single session. The question is, how much protein needs to be replaced? To be cautious and replace all of it with albumin is both unnecessary and unduly expensive. In undergoing three or four 3-liter procedures a week, most patients tolerate a replacement of about half 5% albumin and half crystalloid solution. Of course, such patients must be observed clinically, as well as by evaluation of their serum protein and immunoglobulin levels.

See Table 1 for a summary of complications.

Mor ta 1 i ty

Over the past two years, I have tried to gather worldwide data on mortality and on serious complications or %ear misses" as well, in the hope of bringing to light some factor or factors that may spell danger for a particular patient. Preliminary results were published in a letter to the Lancet, 7 May 1983.

a ruptured berry aneurysm and cerebral hemorrhage. leukapheresis and death followed about a week later (report to the FDA).

Most deaths associated with therapeutic hemapheresis have not been published, and the ones that have appeared in print are presented in no consistent fashion and without comparable details. Another difficulty is whether to classify a given death as related to the procedure itself, as an indirect complication of it, or as primarily related to the

To my knowledge, only 1 donor death has been reported: a middle-aged man who died of The hemorrhage occurred during

84 Huestis

p a t i e n t ' s unde r ly ing d i s e a s e , w i th t h e hemapheresis on ly an u n s u c c e s s f u l t h e r a p e u t i c measure. See Table 2 .

From v a r i o u s s o u r c e s , I e s t i m a t e t h a t about 140,000 t h e r a p e u t i c hemapheresis procedures were done from 1979 through 1982 i n F r a n c e , Great B r i t a i n , Canada, and USA. F o r t y dea ths a r e known i n t h o s e c o u n t r i e s i n t h a t p e r i o d , t h u s a c a s e m o r t a l i t y of about 3 per 10,000 procedures .

The number of d e a t h s r e p o r t e d , wh i l e s o b e r i n g , i s h a r d l y a l a rming i n t h e o v e r a l l c o n t e x t . PE is mos t ly c a r r i e d o u t on p a t i e n t s who a l r e a d y have s e r i o u s a i l m e n t s t h a t a r e no t responding t o a g g r e s s i v e conven t iona l t h e r a p y . S u b j e c t i n g such p a t i e n t s t o PE, w i t h t h e v a r i o u s r i s k s t h a t have been g iven h e r e , is bound t o produce some untoward r e a c t i o n s , a few of which may be f a t a l . The impor t an t t h i n g f o r t h e p r a c t i t i o n e r c o n s i d e r i n g t h e use of t h e r a p e u t i c hemapheresis is t o r e a l i z e n o t on ly t h a t it may be i n e f f e c t i v e o r may even cause an t ibody rebound, bu t a l s o t h a t i t e n t a i l s i n h e r e n t r i s k s . These must be ba l anced a g a i n s t t h e a n t i c i p a t e d b e n e f i t s , and an educated d e c i s i o n made i n t h e b e s t i n t e r e s t s of t h e p a t i e n t .

DISCUSS I O N

Quest i o n

more d e t a i l s on t h a t ? Death from femoral venous punc tu re seems a l i t t l e unusua l . Could you g i v e us a few

Answer

per icardium. I n a n o t h e r c a s e , t h e c a t h e t e r had a p p a r e n t l y been i n s e r t e d s e v e r a l t imes i n t h e f emora l s . I d o n ' t have a l l t h e d e t a i l s w i t h m e . My reason f o r i n c l u d i n g them i s , i f it h a d n ' t been f o r doing t h e p rocedures , t h e c a t h e t e r s wou ldn ' t have been in . Consequent ly , i t ' s an i n d i r e c t compl i ca t ion .

I n one c a s e , a c a t h e t e r was i n s e r t e d through t h e s u b c l a v i a n and was l a t e r found i n t h e

Quest i o n I can s e e s u b c l a v i a n and a t r i a l . Femoral seems a l i t t l e odd.

Answer Femoral is a l i t t l e ha rd t o unde r s t and , b u t it happened.

Quest ion

l e u k a p h e r e s i s and t h e donor was g iven h e p a r i n ? I s t h a t c o r r e c t ? Would I be c o r r e c t i n s a y i n g , t h a t one donor d e a t h occur red a f t e r f i l t r a t i o n

Answer

p a r t s omi t t ed . You may be c o r r e c t . I t h i n k n o t , bu t t h a t p o i n t e l u d e s m e . That was one of t h e FDA r e p o r t s w i t h v a r i o u s

Comment

c a r d i a c a r rhy themia u n t i l t hey d imin i shed t h e amount of c i t r a t e t h e y w e r e u s ing . I d o n ' t know i f t hey d i d any th ing d i f f e r e n t w i th t h e c a t h e t e r s . I t h i n k they s t i l l u se s u b c l a v i a n c a t h e t e r s . A good number of them a r e unques t ionab ly o r d i n a r y p e r i p h e r a l blood a c c e s s .

A group i n Toronto doing exchanges on r e n a l t r a n s p l a n t r e j e c t o r s had a l o t of c a s e s of

Ques t ion I f t h e on ly venous a c c e s s a v a i l a b l e is c e n t r a l , do you t h i n k plasma exchange shou ld be

Adverse Effects of Hemapheresis 85

conducted t h a t way o r shou ld t h e r e t u r n l i n e always be p l aced i n a p e r i p h e r a l v e i n ?

Answer I f e e l a l o t more comfor t ab le w i t h a r e t u r n l i n e i n a c e r t a i n modest d i s t a n c e from t h e

h e a r t . Both t h e c o o l i n g e f f e c t and c i t r a t e e f f e c t obv ious ly are a b i t more hazardous i f t hey go r i g h t i n t o t h e h e a r t . I t h i n k t h e Toronto group, as I remember, swi t ched from ACD- A t o ACD-B. They were u s i n g i n t e r m i t a n t f low p rocedures f o r t h e most p a r t and t h e i r i n c i d e n c e s of c a r d i a c a r rhy themia have dropped d r a m a t i c a l l y . They d i d have one d e a t h i n t h a t group which has been pub l i shed .

Ques t ion One of t h e t h i n g s about plasma exchange is t h a t when we have t o d i s t i n g u i s h between -

c i t r a t e e f f e c t and ca l c ium e f f e c t ( i f i t ' s be ing done i n a r e a s o n a b l e way and t h e h e m a t o c r i t of t h e r e t u r n i n g blood is around 7 0 - 7 5 4 ) most of t h e c i t r a t e shou ld be going o f f i n t o t h e waste plasma. We have measured c i t r a t e c o n c e n t r a t i o n s i n exchange p a t i e n t s and found t h a t t h e i r l e v e l s w i l l rise from 2 t o 7 o r 8 mg/dl, i n comparison t o normal donor s whose l e v e l s a r e 25-30 mg/dl. Th i s documents t h a t t h e c i t r a t e is no t going back i n an e x c e s s i v e f a s h i o n t o t h e p a t i e n t . It is going ou t i n t h e plasma. However, i t ' s t h e replacement f l u i d t h a t may be ca l c ium d e f i c i e n t and my concern is t h a t i f we look a t t h e e l e c t r o l y t e s t h a t are a s s o c i a t e d w i t h c a r d i a c s t a b i l i t y , po ta s s ium i s , ca l c ium p robab ly is . We have EKG ev idence i n normal donors t h a t a t l eas t something i n t h e c a r d i a c p i c t u r e is changing. Sodium seems t o be no problem, t h e y are g e t t i n g p l e n t y of t h a t . Potassium i s d i f f u s i n g so r a p i d l y , t h e r e d o e s n ' t seem t o be any r e p o r t s of i n t e n s e hypokalemia t o my knowledge. Do you know i f t h a t i s c o r r e c t ? The two c a t i o n s t h a t are l e f t are ca l c ium and magnesium which, perhaps over t h e n e x t few months o r y e a r s , d e s e r v e some a t t e n t i o n f o r a p p r o p r i a t e r ep lacemen t .

Answer

i n plasma exchange may w e l l r e l a t e t o what you were t a l k i n g about e a r l i e r as t h e c h e l a t i n g e f f e c t of t h e albumin because o t h e r w i s e , you would be tempted t o t h i n k t h a t t hey s h o u l d n ' t be g e t t i n g any c i t r a t e e f f e c t s a t a l l . We a l l know d i f f e r e n t l y . They c e r t a i n l y d o , some p a r t i c u l a r l y do. I t h i n k as f a r as e l e c t r o l y t e replacement is concerned, t h a t ' s something t h a t shou ld no t be s u b j e c t e d t o any g e n e r a l r u l e s of thumb b u t shou ld be c l e a r l y i n d i v i d u a l i z e d t o t h e p a t i e n t ' s d i r e c t needs. I d o n ' t b e l i e v e i n u s i n g any e l e c t r o l y t e s supp lemen ta t ion u n l e s s t h e r e is a p o s i t i v e i n d i c a t i o n f o r it.

I d o n ' t have any o b s e r v a t i o n s t o add t o t h a t . I t ' s p robab le t h a t some of t h e problems

Ques t ion

a p a r t i c u l a r t ype of i n s t r u m e n t ? Have you n o t i c e d i n c a s e s of s e v e r e r e a c t i o n s , whether t hey seem t o be a s s o c i a t e d w i t h

Answer That is a loaded a u e s t i o n . In almost a l l c a s e s , I know t h e in s t rumen t t h a t w a s used.

You have t o r e a l i z e t h e v a s t m a j o r i t y of i n s t r u m e n t s ou t i n t h e world a r e i n t e r m i t t a n t f low Haemonetics machines and t h e r e f o r e t h i s i s going t o be ove r - r ep resen ted . Unless we had some way of r e c a l c u l a t i n g t h e f i g u r e s t o a l l o w f o r t h e numbers of p rocedures done w i t h d i f f e r e n t i n s t r u m e n t s , we have no way of knowing t h e t r u e r e a c t i o n ra te . It does n o t appear t h a t any one in s t rumen t i s r e a l l y f avored over a n o t h e r .

Quest i o n I n t h e a n a l y s i s of t h e s e c a s e s , have t h e q u a l i t y of t h e pe r sonne l o r t h e CPRS systems

been ana lyzed?

86 Huestis

Answer

What I d i d is send ou t a s t a n d a r d i z e d form t o everybody t h a t I knew who had had any s o r t of e x p e r i e n c e t h a t was r e v e l e n t . The amount of i n f o r m a t i o n r e c e i v e d was h i g h l y v a r i a b l e . Nobody i s going t o s a y t h a t I have an i n e x p e r i e n c e d team. I mean, some p robab ly d i d no t do many plasma exchanges b u t we have a b s o l u t e l y no way of knowing t h a t . came from f i r s t - c l a s s c e n t e r s .

I would say t h e r e i s a b s o l u t e l y no way of j u d g i n g t h a t from t h e k ind of r e p o r t s I have.

Some of t h e d e a t h s

Comment

complaining about some p a t i e n t s t h a t had h y p o t e n s i v e r e a c t i o n s and t h e y were u s i n g plasma p r o t e i n f r a c t i o n as r ep lacemen t f l u i d . When we assumed c o n t r o l o f t h e a p h e r e s i s , we switched t o 5% albumin because of t h e r e p o r t e d problems w i t h t h e p r e k a l l i k r e i n a c t i v a t o r i n some PPF l o t s . I n t h e c i r c u l a r of i n f o r m a t i o n t h a t comes w i t h t h e PPF, i t i n d i c a t e s i t shou ld no t be i n f u s e d a t a r a t e i n e x c e s s of 10 m l a minu te , which i s r e a l l y n o t c o n s i s t e n t w i t h t h e rates you use d u r i n g a p h e r e s i s . I t h i n k i t is impor t an t t o p o i n t o u t when one t a l k s about t h e c o m p l i c a t i o n s of a p h e r e s i s , t h e problems one can encoun te r w i t h PPF.

Before we took ove r t h e a p h e r e s i s s e r v i c e a t o u t i n s t i t u t i o n , t h e c l i n i c i a n s were

Response

c a s e s , good e x p e r i e n c e w i t h PPF t o o . We o f t e n j u s t use what i s a v a i l a b l e . I can s a y & of t h e r e s p i r a t o r y o r c a r d i a c d e a t h s used plasma a s t h e r e p l a c i n g medium, r a t h e r t han albumin o r PPF. Some of them were p a r t plasma and p a r t a lbumin. Every s i n g l e one of t h e r e s p i r a t o r y and c a r d i a c d e a t h s had r ep lacemen t - a t l e a s t i n p a r t by plasma.

That is a good p o i n t . We g e n e r a l l y have good e x p e r i e n c e w i t h albumin and i n some

Comment I would l i k e t o make a comment abou t PPF. I ' v e been a s s u r e d by peop le c l o s e t o t h e

FDA, i n c l u d i n g t h e pe r son who d e s c r i b e d t h e p r e k a l l i k r e i n a c t i v a t o r and PPF, t h a t i t ' s p robab ly n o t p o s s i b l e f o r t h a t t o occur w i t h t h e c u r r e n t p rocedures i n making PPF i n t h e U.S. The PPF i s t e s t e d f o r a c t i v a t o r s . It is my u n d e r s t a n d i n g , t h a t t h e PPF which can cause h y p e r t e n s i o n i s no t be ing produced i n t h e U.S and h a s n ' t been i n s e v e r a l y e a r s .

Response Perhaps they s imply h a v e n ' t t aken it o f f t h e package i n s e r t

Quest i o n There a r e p robab ly o t h e r mechanisms invo lved . For example,

y e t .

t h e use of a c e t a t e b u f f e r t h a t was popu la r b e f o r e t h e p r e k a l l i k r e i n a c t i v a t o r . We have had two a n a p h y l a c t i c - l i k e r e a c t i o n s f o l l o w i n g i n f u s i o n w i t h i n t h e p a s t yea r and a h a l f . One i n t h e blood c e n t e r and one i n a c l i n i c a l r e s e a r c h c e n t e r . So, c l i n i c a l l y , it s t i l l o c c u r s . What t h e mechanism i s , s t i l l i s n ' t c l e a r .

Answer I t h i n k we a r e a l l r e a s o n a b l y concerned when we r e i n f u s e blood and r ep lacemen t f l u i d

by a c e n t r a l c a t h e t e r . T h i s became an i s s u e f o r conce rn i n a p h e r e s i s f o l l o w i n g t h e r e p o r t s from Toron to . However, i f you r e a l l y c o n s i d e r t h e c o n c e n t r a t i o n of any s u b s t a n c e t h a t ' s p r e s e n t e d t o t h e h e a r t , i t ' s r e a l l y , i n f a c t , r e l a t e d t o t h e c o n c e n t r a t i o n which we i n f u s e and n o t t h e p o i n t a t which we i n f u s e i t . T h i s is because t h e c a r d i a c o u t p u t i s so h i g h , t h a t r a p i d mixing d i l u t e s t h i s o u t . When w e r e i n f u s e t h e s u b s t a n c e w i t h i n a p h e r e s i s , we r a r e l y exceed an i n f u s i o n r a t e of 100 m l pe r minute and y e t t h e c a r d i a c o u t p u t has 5 l i t e r s per minute so t h a t mixing t a k e s p l a c e q u i c k l y .

Adverse Effects of Hemapheresis 87

Quest i on

is even on t h a t b r i e f passage t h a t t h e r e may be some t r i g g e r i n g e f f e c t of a h igh c o n c e n t r a t i o n bu t it is probably more r e l a t e d t o c o n c e n t r a t i o n than any th ing e l s e . know i f t h e Toronto team changed t h e placement of t h e i r c a t h e t e r s , do you?

I t ' s a good p o i n t . You a r e probably r i g h t . What we a r e always a f r a i d o f , I suppose,

I d o n ' t

Answer No, a s a m a t t e r of f a c t , I was c h a i r i n g t h i s s e s s i o n a t t h e Haemonetics Seminar when

t h i s was p r e s e n t e d , and I, a s w e l l a s many people i n t h e aud ience , jumped up and s a i d , "Hey, t h i s is probably r e l a t e d t o t h e p o i n t of i n fus ion . " I went back t o our i n s t i t u t i o n and t a l k e d w i t h one of our expe r i enced trauma surgeons who q u i c k l y po in ted ou t t h a t , i n f a c t , i t ' s probably n o t a major i s s u e , a l though I s h a r e your concern n e v e r t h e l e s s . I n f a c t , t h e d i f f e r e n c e of 100 ml/minute v s . 5 l i t e r s is impressive.

Quest i o n When you use c i t r a t e i n f r e s h f rozen plasma, you will g e t an e l e v a t i o n . May I ask

whether o t h e r people have measured v a s o a c t i v e p e p t i d e s ? u r t i c a r i a bu t no t broncospasm a f t e r albumin and e s p e c i a l l y PPF, bu t i t u s u a l l y occur s a f t e r about 4 l i t e r s of plasma have been exchanged. It has occur red i n p a t i e n t s who have never had any blood p roduc t s at a l l , so I c a n ' t s u s p e c t p r i o r exposure t o blood p roduc t s . anybody e l s e had a concern of whether i t ' s due t o some removal of c o r t i c o s t e r o i d hormones, v a s o a c t i v e p e p t i d e s , o r i n f u s i o n of t h e p r e k a l l i k r e i n ?

We've seen hypotension and

Has

Quest i o n

a r e more l i k e l y t o g e t a c i t r a t e r e a c t i o n and t h a t i s l o g i c a l because you can produce t h e same e f f e c t w i th j u s t h y p e r v e n t i l i z a t i o n . Do you have an o v e r a l l f i g u r e f o r thromboembolic compl i ca t ions and what i s your f e e l i n g about t h e need t o g i v e f r e s h f r o z e n plasma t o r e p l a c e ant i - thrombin I11 or whatever s o r t of i n h i b i t o r s depending upon t h e frequency and i n t e n s i t y of exchange?

It seems t o us t h a t when a p a t i e n t or a donor is anxious and h y p e r v e n t i l a t i n g , t h e y

Answer

of t h e dea ths r e p o r t e d have m a t e r i a l i n lung c a p i l l a r i e s t h a t seems t o be of thrombotic o r i g i n . Forgive me i f I pu t it i n t o such a c a u t i o u s way. I do n o t l i k e t o c a l l i t thromboembolism, a l though it was c a l l e d t h a t i n t h e r e p o r t from Houston. I ' v e looked a t t hose s l i d e s and I have been t r y i n g t o g e t a s many s l i d e s a s p o s s i b l e on t h e o t h e r r e s p i r a t o r y d e a t h s t o s e e i f t h i s k ind of s t u f f has been r e p e a t e d . r e c e i v e d s l i d e s on about a h a l f dozen of them. Some of them do have m a t e r i a l , bu t i n s m a l l e r and less impress ive amounts t han i n t h e one r e p o r t e d from Houston. What t h a t means p r e c i s e l y , I d o n ' t know. I ' d l i k e t o be a b l e t o g e t a l l t h e r e s p i r a t o r y d e a t h s and look a t s l i d e s on a l l of them.

I n answer t o t h e second p a r t of your q u e s t i o n , I d o n ' t p e r s o n a l l y r e p l a c e any plasma i n a plasma exchange u n l e s s t h e r e i s some o v e r r i d i n g r eason t o do s o . We d i d have a couple of people who b led a l i t t l e b i t a f t e r e x t e n s i v e plasma exchanges. They were s m a l l peop le , and on t h o s e , we have used plasma simply because it seemed t o be i n d i c a t e d and it worked. I d o n ' t t h i n k t h e r e a r e any f i g u r e s a v a i l a b l e . We d o n ' t have f i g u r e s on compl i ca t ions . We on ly have f i g u r e s so f a r on d e a t h s , and we d o n ' t even know i f we have a l l of t h o s e . I n f a c t , I know we d o n ' t . There i s no r e g i s t r y on t h e occur rence of compl i ca t ions . There a r e no d a t a a v a i l a b l e . There may have been l o t s of hemorrhagic compl i ca t ions , bu t I d o n ' t know t h a t .

The o v e r a l l occu r rence of thromboembolic phenomema i s n ' t r e a l l y c e r t a i n because some

So f a r , we've only

Comment

t e r r i b l e ep i sode of t h romboph leb i t i s a f f e c t i n g t h e femoral and i l i a c v e s s e l s i n a p a t i e n t I ' l l t e l l you about one which we d i d n ' t r e p o r t because it wasn ' t a dea th . We had a

88 Huestis

w i t h s i c k l e c e l l d i s e a s e . I t h i n k it p o i n t s o u t t h a t many of t h e c o m p l i c a t i o n s , may i n f a c t , be r e l a t e d t o t h e p a t i e n t ' s u n d e r l y i n g d i s e a s e . performed a e r y t h r o c y t e a p h e r e s i s and t h e p a t i e n t had a femoral c a t h e t e r . p h y s i c i a n wanted t o l e a v e t h e c a t h e t e r i n p l a c e f o r 24 hours so she c o u l d i n f u s e some o t h e r f l u i d s . The p a t i e n t developed t e r r i b l e t h r o m b o p h l e b i t i s , b u t d i d s u r v i v e . When we d i s c u s s e d t h i s c a s e w i t h one of our expe r i enced s i c k l e c e l l d i s e a s e p h y s i c i a n s i n Los Angeles , she p o i n t ou t t h a t of c o u r s e , you NEVER l e a v e c a t h e t e r s i n p a t i e n t s w i t h s i c k l e c e l l d i s e a s e because t h e y have a hype rcoagu lab le tendency. I t h i n k it is impor t an t t h a t when d e a l i n g w i t h c e r t a i n c l a s s e s of p a t i e n t s , e s p e c i a l l y t h o s e who may have a tendency toward h y p e r c o a g u l a b i l i t y , w e shou ld c o n s i d e r t h a t t h i s m a n i p u l a t i o n of venous a c c e s s may set t h e p a t i e n t up f o r s e r i o u s c o m p l i c a t i o n s .

T h i s w a s a p a t i e n t on whom we had The p a t i e n t ' s

Comment I would a l s o l i k e t o s u p p o r t t h e o t h e r p o i n t mentioned a moment ago. The worse

c i t r a t e r e a c t i o n s we have e v e r s e e n w e r e on peop le t h a t w e r e u p s e t and concerned. T h i s happened wi th s e v e r a l donors and it w a s f r i g h t e n i n g . H y p e r v e n t i l a t i o n , p l u s c i t r a t e , i s a bad combinat ion.

Comment

w i l l be r e a d i n g more about i n t h e f u t u r e . The c o n s i d e r a t i o n s t o keep i n mind when you are r e a d i n g t h a t l i t e r a t u r e is t h a t among t h e p a t i e n t s w i th c o n g e n i t a l a n t i t h r o m b i n 111 d e f i c i e n c y , t h e th rombot i c e p i s o d e s u s u a l l y occur when t h e l e v e l s a r e less than 70% o r t h e a c t i v i t y is u s u a l l y less than 70% of what it norma l ly would be. There are a number of i n d i v i d u a l s w i t h i n thoe f a m i l i e s who have e q u a l l y low l e v e l s , who w i l l n o t have th rombot i c ep i sodes . The second p o i n t i s , as D r . G o l d f i n g e r ment ioned, t h a t t h e u n d e r l y i n g i l l n e s s of t h e p a t i e n t may a f f e c t t h e l e v e l s of t h e a n t i t h r o m b i n 111. I f you have i n t r a v a s c u l a r c l o t t i n g , i t ' s going t o be low. I f you have l i v e r d i s e a s e , i t ' s go ing t o be low. The l e v e l s of o t h e r r e g u l a t o r y p r o t e i n s i n t h e c o a g u l a t i o n sys t em, such as P r o t e i n C and t h e p r o t e i n s t h a t are invo lved i n t h e P r o t e i n C system a l s o can be a f f e c t e d by l i v e r problems, as i n Alpha I1 macrog lobu l in and some of t h e o t h e r s . I would be v e r y s k e p t i c a l of pape r s s u g g e s t i n g t h a t you do a n y t h i n g abou t a n t i t h r o m b i n I11 u n t i l a l i t t l e more i n f o r m a t i o n is a v a i l a b l e about t h e l e v e l s of p r o t e i n a c t i v i t y i n t h o s e p a r t i c u l a r p a t i e n t s .

L e t m e comment abou t t h e a n t i t h r o m b i n 111 f o r a second. I t h i n k i t ' s something we

Comment

h y p e r c o a g u l a b i l i t y . There was a q u e s t i o n of h y p e r c o a g u l a b i l i t y i n t h r e e p a t i e n t s , a l l of whom were bedr idden and on subcutaneous h e p a r i n . Two p a t i e n t s had G u i l l a i n - B a r r e and one had myasthenia g r a v i s . When we t r i e d t o phe rese them, t h e y would c l o t e v e r y l i n e we p l a c e d i n t o them. seconds s h o r t e r t han t h e c o n t r o l . pulmonary embolism and s u r v i v e d . But i t r e a l l y conce rns us and I d o n ' t know t h e answer. We looked a t a n t i t h r o m b i n I11 a s an a l t e r n a t e and they were n o t p a r t i c u l a r l y abnormal.

I wonder i f I cou ld mention some of our e x p e r i e n c e i n r e l a t i o n t o a q u e s t i o n of

We f i n a l l y phe resed them w i t h h e p a r i n , b u t t h e y a l l had PTT's 6 , 8, o r 10 One of them, t h r e e days a f t e r one p h e r e s i s , had a major

Quest i o n Everyone has t h e i r own formula f o r how o f t e n normal donors ought t o e x p e r i e n c e

mechanical c y t a p h e r e s i s of d i f f e r e n t k i n d s . What i s t h e p o l i c y you f o l l o w a t your p l a c e f o r p l a t e l e t d o n a t i o n and f o r w h i t e c e l l d o n a t i o n and how f r e q u e n t l y w i l l you a l l o w them t o dona te? How would you modify t h a t p o l i c y w i t h t h e c l i n i c a l i n d i c a t i o n s f o r t h e r e c i p i e n t s ?

Answer We, more or l ess , have a s t a n d a r d r u l e . We s t a y w i t h , a s a r u l e , t h e two month

i n t e r v a l . We w i l l make an e x c e p t i o n when we have t o , b u t t h e p h y s i c i a n i n cha rge h a s t o make t h a t d e c i s i o n . For a l i m i t e d p e r i o d of t i m e , i f I need t o u s e a donor two or t h r e e t imes a week, w e w i l l do so. h e a l t h and v i t a l s i g n s .

N a t u r a l l y , you do t h i s w i th knowledge of t h e d o n o r ' s s t a t e of

rl

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8 U

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C 0 .4 4J 0 m al &

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6 -2 P

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90 Huestis

Table 2. DEATHS RELATED TO THERAPEUTIC HEMAPHERES I S

A. Direct ly r e l a t ed t o procedure

1. P r i m a r i l y cardiovascular

2. P r i m a r i l y r e sp i r a to ry

3. Anaphylactic

4. Pulmonary thromboembolism

5. Hemorrhaae, DIC

B. Presumably r e l a t ed t o procedure, but inadequate data t o evaluate

C. I nd i r ec t ly associated

1. Hepat i t is

2. Sepsis

3 . Perforation of hea r t or g rea t vessel by ca the te r

TOTAL

1 3

14

3

2

2

2

2

2

3

4 3

Note: The above t ab le does not include pa t i en t s already moribund a t the

s t a r t of a procedure, deaths caused by b a c t e r i a l i n fec t ions not c l e a r l y

r e l a t ed t o hemapheresis, or i n which PE f a i l e d t o h a l t rapidly progressive

disease.