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Ivox : a new alternative method for augmenting blood gas transfer in patients with acute respiratory failure
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Approches thdrapeutiques de I'hypoxemie
v e n t i l a t i o n a l v ~ o l a i r e ~ t a n t ici a r e m p l a c e r p a r c e l u i de renouvellement alv~olaire). Les indications
Les indications actuelles de l'~puration extracorpor e l l e d e CO2 c o u p l ~ e ~ l a v e n t i l a t i o n p s e u d o - a p n ~ i q u e sent encore impr~cises en l'absence d'dtude randomis~e c o n t r S l ~ e p e r m e t t a n t d ' ~ t a b l i r f o r m e l l e m e n t s a sup~riorith sur la ventilation m~canique, elle-m~me v a r i a b l e d a n s s e s m o d e s d ' a d m i n i s t r a t i o n [20]. L ' e x i s t e n c e , n o n e n c o r e r ~ s o l u e , d e c o m p l i c a t i o n s h6morragiques pouvant ~tre source de mortalith et de morbidit6 pulmonaire, doivent faire discuter son indication. L a p r e m i e r e i n d i c a t i o n q u i s e m b l e i n d i s c u t a b l e r6suite de l'am~lioration de l'oxyg~nation constat~e sur les 6 t u d e s p r ~ l i m i n a i r e s e t c o n c e r n e les m a l a d e s atteints de SDRA pour lesquels la ventilation traditionn e l l e n e p e r m e t p a s d ' a t t e i n d r e ce b u t . P l u s difficile e s t d e p r ~ c i s e r l ' a t t i t u d e a a v o i r d e v a n t un malade qui n'~volue pas favorablement sous ventil a t i o n m ~ c a n i q u e t r a d i t i o n n e l l e . E n l ' a b s e n c e d e crit ~ r e ~ v o l u t i f o u p r o n o s t i q u e v a l i d ~ , il s e m b l e licite d e proposer cette m~thode lorsque la ventilation m~caniq u e e s t i m p o s s i b l e s a n s a t t e i n d r e d e s n i v e a u x d61~t~res en terme de Fie2 et/ou de barotraumatisme. En effet l'am~lioration des ~changes gazeux obtenus par cette m~thode r~sulterait d'une r~duction des in~galitds rdgionales des rapports ventilation-perfusion perm e t t a n t u n m o d e m o i n s a g r e s s i f d ' a s s i s t a n c e p o u r le p o u m o n [21-23]. les m~thodes d'assistance respiratoire extracorporelles sent encore des techniques d'exception qui n~cessitent des investigations suppl~mentaires pour ~tablir clairement leur sup6riorit6 sur la ventilation m~canique classique et r~duire leurs c o m p l i c a t i o n s p r o p r e s . C e p e n d a n t les p r e m i e r s r ~ s u l tats semblent prouver qu'elles peuvent assurer des ~changes gazeux plus efficacement que ceux obtenus par la ventilation du parenchyme pulmonaire malade e t m e t t r e celui-ci a u r e p o s e n a t t e n d a n t s a g u ~ r i s o n . En conclusion,
I~F]~RENCES [1] Hill J.D_, O'Brien T.G., Murray J.D. et al. - - Prolonged extracorporeal oxygenation for acute post traumatic respiratory failure (shock-lung syndrome). N. Engl. J. M~d,, 1972, 286, 629634. [2] Gattinoni L_, Pesenti A., Caspani M.L_ et al. - - The role of total static lung compliance in the management of severe ARDS unresponsive to conventional treatment. Intensive Care Med., 1984, 10, 121-126. [3] Chevalier J.Y., Durandy Y., Batisse A., Mathe J.C., Costil J.C. - - Preliminary reports : Extracorporeal lung support for neonatal acute respiratory failure. Lancet, 1990, 335, 1364-1366, [4] Zapol W.M., Snider M.T., Hill J.D. et al. - - Extracorporeal membrane oxygenation in severe acute respiratory failure. JAMA, 1979, 242, 2193-2196. [5] Kolobow T., Gattinoni L_, Tomiinson T., Pierce J.E. - - An alternative to breathing. J_ Thorae_ Cardiovasc. Surg., 1978, 75, 261-266. [6] Gattinoni L., Kolobow T., Tomiinson T. et al. - - Low positive pressure ventilation with extracorporeal carbon dioxide removal (LFPPV-ECCO2R)_ Anesth_ Analg., 1978, 57, 470-477. [7] Gattinoni L., Pesenti A., Mascheroni D. et al. - - Low-frequency pesitive-pressure ventilation with extracorporeal CO2 removal [8]
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H. - - Extrakorporale CO2-elimination_ Dtsch_ Med. Wschr., 1989, 114, 796-799_ [9] Baumann W.R., Jung P~C., Koss M. et al. - - Incidence and mortality of adult respiratory distress syndrome : A prospective analysis from a large metropolitan hospital. Crit. Care Med., 1986, 14, 1-4.
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[10] Montgomery A.B_, Stager M.A., Carrico C.J., Hudson L.D. -Causes of mortality in patmnts with the adult respiratory distress syndrome. Am. Rev. Respir. Dis., 1985, 132, 485-489_
[11] McCoy-Pardington D., Judd W.J., Knafl P., Abruzzo L.V., Coombes K.R., Butch S.H., Oberman H.A. - - Blood use during extracorporeal membrane oxygenation. Transfus/on, 1990, 30, 3O7-309. [12] Uziel L., Agostini A., Pirovano E. - - Haematologic survey during low frequency positive pressure ventilation with extracorporeal'CO2 removal. Trans. Am. Soc. Artif. Intern. Organs, 1982, 28, 359-364. [13] Gattinoni L., Agostini A., Damia G. et al. - - Hemodynamics and renal function during low frequency positive pressure ventilation with extracorporeal CO2 removal_ Intensive Care Med., 1980, 6, 155-161. [14] Gattinoni L, Pesenti A., Avalli L., Rossi F_, Bombino M. - -
Pressure-volume curve of total respiratory system in acute respiratery failure.Am. Rev. Respir. Dis., 1987, 136, 730-736. [15] Dall'ava-Santucci J., Armaganidis A., Brunet F., Dhainaut J.F., Chelucci G.L., Monsallier J.F., Lockhart A. -- Causes of error of respiratory pressure volume curves in paralyzed subjects. J. AppL Physiol., 1988, 64, 42-49. [16] Dall'ava-Santucci J., Armaganidis A., Brunet F_ et aL -- Mechanical effects of P E E P in patients with adult respiratory distress syndrome. J. AppL Physiol., 1990, 68, 843-848. [17] Hurewitz A_N., Bergofsky E.H_, Vomero E. -- Airway insufflation. Increasing flow rates progressively reduce dead space in respiratory failure.Am. Rev. Respir_ Dis., 1991, 144, 1229-1233. [18] Venegas J.G., Y a m a d a Y., Hales C.A. -- Contribution of diffusion jet flow and cardiac activity to regional ventilation in CFV. J. Appl. Physiol_, 1991, 71, 1540-1553. [19] Smith R.B. -- Continuous flow apneic ventilation. Resp. Care, 1987, 32, 458-465. [20] Slutsky A.S. -- N o n conventional methods of ventilation. Am. Rev. Respir. Dis_, 1988, 138, 175-183.
[21] Borelli M., Kolobow T_, Spatola R., Prate P., Tsuno K. - - Severe
acute respiratory failure managed with continuous positive airway pressure and partial extracorporeal carbon dioxide removal by an artificial membrane lung. A controlled, randomized animal study. Am. Rev_ Resp. Dis_, 1988, 138, 1480-1487. [22] Dorrington K.L., McRae K.M., Gardaz J.P., Dunnfll M_S., Sykes M.K., Wilkinson A.R. - - A randomized comparison of total extracorporeal C02 removal with conventionalmechanical ventilation in experimental hyaline membrane disease. Intensive Care Med., 1989, 15, 184-191. [23] Pesenti A., Kolobow T., Buckhold D.K. - - Prevention of hyaline membrane disease in premature lambs by apneic oxygenation and extracorporeal carbon dioxyde removal. Crit, Care Med., 1982, 8, 11-17.
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Ivox • a new alternative method for augmenting blood gas transfer in patients with acute respiratory failure
Mortensen
J.D.
Cardio-Pulrnonics, University of Utah, Salt Lake City, UTAH 84116, USA
A u g m e n t a t i o n of d e f i c i e n t b l o o d g a s t r a n s f e r of p a tients with potentially reversible acute respiratory f a i l u r e is n e c e s s a r y t o a v o i d d e a t h f r o m p r o g r e s s i v e hypoxemia and/or hypercarbia. In most cases, mechanical ventilation with oxygen-enriched inspiratory air successfully reverses the unacceptable blood gases, t h u s <
Approches thCrapeutiques de I'hypox~mie- 7 9 3 to introduce to you t h i s n e w intracorporeal, i n t r a v a s c u l a r blood gas t r a n s f e r technology, k n o w n as IVOX.
IVOX Design Concepts and Performance Characteristics IVOX is a n a c r o n y m for I n t r a V a s c u l a r Oxygenator. The device is a small, elongated, hollow fiber m e m b r a n e o x y g e n a t o r designed to lie w i t h i n the subject's v e n a cavae so t h a t circulating venous blood c a n flow freely over a n d a r o u n d t h e e x t e r n a l surfaces of t h e hollow fibers. Oxygen, u n d e r s u b a t m o s p h e r i c pressure, flows w i t h i n t h e l u m e n s of t h e hollow fibers, t h e walls of which are covered w i t h a n u l t r a t h i n , selectively gas p e r m e a b l e , siloxane m e m b r a n e which perm i t s t r a n s f e r of oxygen a n d carbon dioxide ( b u t n o t w a t e r , p l a s m a , solutes, or formed e l e m e n t s of t h e blood) across t h e m e m b r a n e [1, 2]. The IVOX device is placed in t h e v e n a cavae t h r o u g h a surgical v e n o t o m y in t h e r i g h t femoral or r i g h t j u g u l a r vein. E x t e n s i v e engineering, in vitro, ex vivo, and in vivo e x p e r i m e n t a l a n i m a l l a b o r a t o r y [3] t e s t i n g of IVOX h a s b e e n c a r r i e d out over a nine y e a r d e v e l o p m e n t period. P e r f o r m a n c e c h a r a c t e r i s t i c s of IVOX, d e r i v e d from d a t a p r o d u c e d by its acute a n d chronic ex vivo a n d in vivo e x p e r i m e n t a l a n i m a l t e s t i n g i n d i c a t e t h a t t h e device does t r a n s f e r significant q u a n t i t i e s of oxygen into a n d c a r b o n dioxide out of circulating venous blood for u p to t h r e e weeks in awake, s t a n d i n g , sheep w i t h o u t significant risks, h a z a r d s , or complications [2, 4].
Perceived Clinical Appfication of IVOX
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IVOX is i n t e n d e d for t e m p o r a r y (up to 21 days) augm e n t a t i o n of deficient blood gas t r a n s f e r in p a t i e n t s w i t h m o d e r a t e to severe, p o t e n t i a l l y reversible, acute r e s p i r a t o r y f a i l u r e who h a v e h y p o x e m i a and/or h y p e r c a r b i a which is refractory to conventional r e s p i r a t o r y t h e r a p y . T h e objectives of its clinical a p p l i c a t i o n a r e to : 1) p e r m i t r e d u c t i o n in t h e i n t e n s i t y ( a n d e a r l y wit h d r a w a l or avoidance) of m e c h a n i c a l v e n t i l a t o r supp o r t ; 2) i m p r o v e t h e d e r a n g e d blood gases in t h e patient's c i r c u l a t i n g blood w i t h o u t involving t h e i n j u r e d a n d i n a d e q u a t e l y functioning n a t u r a l lungs ; a n d 3) <
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change with circulating blood (50 to 150 cm3/min, constituting 1/4 to 1/3 t h e t o t a l metabolic requirem e n t s of a d u l t A R F p a t i e n t s ) , t h e t i m e the device can safely r e m a i n i n d w e l l i n g in t h e v e n a cavae ( c u r r e n t l y l i m i t e d to 3 weeks), a n d t h e n e c e s s i t y for t h e p a t i e n t to receive m i l d to m o d e r a t e s y s t e m i c a n t i c o a g u l a t i o n d u r i n g IVOX u t i l i z a t i o n ( a c t i v a t e d clotting t i m e m a i n t e n e d at a b o u t 180 seconds).
Current Status of IVOX Clinical Trials Clinical t r i a l s of IVOX u t i l i z a t i o n to a u g m e n t blood gas t r a n s f e r in p a t i e n t s in a d v a n c e d acute r e s p i r a t o r y failure are c u r r e n t l y being c o n d u c t e d u n d e r F D A supervision. P h a s e I h a s b e e n completed, d e m o n s t r a t i n g safety of IVOX. P h a s e II is in progress, a s s e s s i n g t h e efficacy of the device. E i g h t e e n clinical centers h a v e c o n t r i b u t e d cases as a p a r t of t h e s e trials. T h e expertise, experience, a n d significant c o n t r i b u t i o n of t h e p a r t i c i p a t i n g p r i n c i p a l i n v e s t i g a t o r s a n d t h e i r associates a r e acknowledged a n d a p p r e c i a t e d . To d a t e (March 10, 1992) IVOX h a s b e e n u t i l i z e d in t h e m a n a g e m e n t of 101 p a t i e n t s . Complete d a t a a r e b e i n g collected a n d a n a l y z e d for t h e s e p a t i e n t s , a n d will become t h e b a s i s for a d e t a i l e d r e p o r t being prep a r e d b y t h e i n v e s t i g a t o r s of t h e s e clinical trials. My r e p o r t t o d a y c o n t a i n s only g e n e r a l information glean e d from p r e l i m i n a r y r e v i e w of t h e l i m i t e d a n d incomplete d a t a a v a i l a b l e a t t h i s time. Therefore, t h e findings and t r e n d s n o t e d a r e t e n t a t i v e in n a t u r e . C a u s e s of t h e acute r e s p i r a t o r y failure (ARF) encount e r e d in t h e clinical t r i a l s p a t i e n t s are t y p i c a l for ARDS, p n e u m o n i a s of v a r i o u s t y p e s a n d post-shock lung i n j u r y accounting for m o s t of t h e p a t i e n t s . The severity of t h e A R F in t h e s e v e r y sick p a t i e n t s h a s b e e n classified according to M u r r a y ' s lung injury sev e r i t y scoring m e t h o d [7]. T h e scores indicate t h a t all p a t i e n t s in t h e clinical t r i a l s to d a t e have b e e n in severe to e n d - s t a g e ARDS, w i t h e x p e c t e d s u r v i v a l r a t e s of less t h a n 20 p e r cent. Protocols for conducting t h e IVOX clinical t r i a l s first called for d e t e r m i n i n g t h e incidence of m a j o r safety concerns which h a d p r e v i o u s l y b e e n identified. Safety d a t a came from two sources : o b s e r v a t i o n s m a d e b y t h e a t t e n d i n g clinician, consisting of clinical a n d labor a t e r y findings observed d u r i n g IVOX u t i l i z a t i o n ; a n d observations m a d e b y t h e p a t h o l o g i s t s perform i n g t h e necropsies on p a t i e n t s who died d u r i n g or after IVOX utilization. The incidence of significant complications n o t e d by t h e a t t e n d i n g p h y s i c i a n r e l a t i v e to t h e m a j o r anticip a t e d safety concerns was nil. Similarly, l a b o r a t o r y d a t a received a n d a n a l y z e d to d a t e indicate no signific a n t or c o n s i s t e n t IVOX-related changes in hemoglobin, h e m a t e c r i t , WBC, fibrinogen, fibrin split products, p l a s m a free h e m o g l o b i n or c o m p l e m e n t acti vation. P l a t e l e t count d e c r e a s e d s o m e w h a t in app r o x i m a t e l y h a l f of t h e IVOX p a t i e n t s , b u t fell to significantly low levels in only 2 cases. T r a n s i e n t edem a of t h e r i g h t leg occurred in 3 cases while IVOX was indwelling in t h e femoral or iliac vein, or in t h e e a r l y p o s t e x p l a n t a t i o n p e r i o d after t h e device h a d been removed and the venotomy had been repaired. In each case t h e e d e m a r e s o l v e d s p o n t a n e o u s l y or was controlled b y conservative m e a s u r e s such as t h e a p p l i c a t i o n of elastic hose. Pathologists r e p o r t i n g t h e i r o b s e r v a t i o n s at n e c r o p s y of t h e p a t i e n t s who died d u r i n g or after IVOX utilization found no evidence t h a t IVOX u t i l i z a t i o n caused
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or c o n t r i b u t e d to t h e d e a t h of a n y of t h e IVOX-imp l a n t e d p a t i e n t s . No s i g n i f i c a n t t h r o m b o e m b o l i were found in t h e v e n a cavae, r i g h t h e a r t , or p u l m o n a r y art e r i e s a n d no p u l m o n a r y infarctions were encountered. No bubbles, foam, or collections of gas were observed in t h e blood e x p o s e d to IVOX. T h e r e were no lacerations, d i s r u p t i o n s or l e a k a g e of blood from t h e v e n a cavae or r i g h t a t r i u m in w h i c h IVOX h a d b e e n indwelling. T h e r e h a s b e e n no l a b o r a t o r y d e m o n s t r a tion of I V O X - r e l a t e d sepsis, b a c t e r e m i a , or localized infections. L i k e w i s e t h e r e w a s no evidence of mechanical obstruction to blood flowing in t h e v e n a cavae en r o u t e to the r i g h t h e a r t . At autopsy, five of t h e access femoral veins c o n t a i n e d t h r o m b u s . T h r e e were non-occlusive a n d two w e r e occlusive. However, one of t h e occluded f e m o r a l v e i n s h a d b e e n ligated, accounting for t h e occlusion. All p a t i e n t s receiving a n IVOX i m p l a n t a t i o n were a n t i c o a g u l a t e d j u s t p r i o r to i m p l a n t a t i o n , utilizing an i n t r a v e n o u s b o l u s of h e p a r i n , followed b y a continuous h e p a r i n d r i p to m a i n t a i n a c t i v a t e d clotting t i m e s at a p p r o x i m a t i v e l y 180 seconds. We h a v e b e e n gratified to note t h a t no s i g n i f i c a n t b l e e d i n g was not e d in 75 % of t h e I V O X - i m p l a n t e d p a t i e n t s . More t h a n 100 cm a blood loss a c c o m p a n y i n g IVOX i n s e r t i o n was r e p o r t e d in five cases, due p r i m a r i l y to h i g h venous p r e s s u r e a n d t h e s u r g e o n ' s inexperience in act u a t i n g or m a n i p u l a t i n g t h e r e f l u x valve in t h e introducer sheath. I n only two of t h e s e cases were t r a n s f u s i o n s r e q u i r e d . T h r e e p a t i e n t s receiving IVOX experienced some p o s t o p e r a t i v e oozing at t h e e n t r y site. Two of t h e s e r e q u i r e d blood r e p l a c e m e n t t h e r a p y and in one case t h e b l e e d i n g w a s p e r s i s t e n t enough to r e q u i r e a surgical e x p l o r a t i o n to control it. Five of t h e s e chronically h e p a r i m z e d p a t i e n t s experienced b l e e d i n g at sites r e m o t e from t h e IVOX. T h e s e were sites of r e c e n t s u r g e r y in four cases, a n d b l e e d i n g into t h e left r e t r o p e r i t o n e a l space (not associated w i t h t h e v e n a cavae) in one case. E a c h w a s considered m i l d to m o d e r a t e , w i t h control r e q u i r i n g t r a n s f u s i o n only. None r e q u i r e d surgical i n t e r v e n t i o n . The possibility of significant t h r o m b u s a c c u m u l a t i o n on a n i m p l a n t e d IVOX device is a m a j o r concern. As a consequence of active, d i s t u r b e d blood flow over t h e fibers (achieved b y d e p l o y m e n t of t h e c r i m p e d fibers w i t h i n t h e v e n a cavae), t h e t h r o m b o - r e s i s t a n t coating a p p l i e d to t h e device, a n d m i l d s y s t e m i c h e p a r i n i z a tion, we are p l e a s e d to r e p o r t t h a t t h r o m b u s accumul a t i o n on IVOX h a s not b e e n a significant p r o b l e m in t h e s e I V O X - i m p l a n t e d p a t i e n t s , t h e e x p l a n t e d IVOX devices showing r e m a r k a b l y s m a l l a m o u n t s of visible t h r o m b u s on or a m o n g t h e hollow fibers. While our first a n d m a j o r concern during t h e s e e a r l y IVOX i m p l a n t a t i o n s h a s b e e n a s s e s s m e n t of t h e risks a n d h a z a r d s of IVOX U t i l i z a t i o n , t h e s e first 101 imp l a n t a t i o n s h a v e d e m o n s t r a t e d some i m p o r t a n t t r e n d s concerning IVOX efficacy. The q u a n t i t y of gas t r a n s f e r achieved d u r i n g IVOX i m p l a n t a t i o n h a s b e e n significant in every p a t i e n t receiving an IVOX device [8]. G a s t r a n s f e r achieved t h r o u g h IVOX v a r i e d c o n s i d e r a b l y w i t h size of t h e device u t i l i z e d a n d w i t h t h e s e v e r i t y of t h e h y p o x e m i a or h y p e r c a r b i a , sicker p a t i e n t s a n d l a r g e r devices providing h i g h e r a m o u n t s of g a s t r a n s f e r . A v e r a g e r a t e s of 02 t r a n s f e r a n d CO2 r e m o v a l by IVOX were 66.4 cm 3Ymin a n d 74.0 cm ~ym m ' r e s p e c t i"v e l y . Of significance is t h e o b s e r v a t i o n t h a t each IVOX's gas t r a n s fer p e r f o r m a n c e c o n t i n u e d r e l i a b l y a n d w i t h o u t significant d e g r a d a t i o n d u r i n g t h e t i m e it r e m a i n e d
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i n d w e l l i n g (which in t h e s e cases a v e r a g e d 6.5 days, w i t h a m a x i m u m of 29 days). The m o s t c o m m o n course observed in p a t i e n t s w i t h severe A R F who receive a n IVOX i m p l a n t a t i o n dem o n s t r a t e s a favorable r e s p o n s e to IVOX, w i t h control of t h e h y p o x e m i a a n d h y p e r c a r b i a while ventil a t o r p a r a m e t e r s were a d j u s t e d to safe levels. D e s p i t e t h i s f a v o r a b l e course a n d significant t i m e b o u g h t b y IVOX for r e s o l u t i o n of the lung injury, all p a t i e n t s in t h i s group u l t i m a t e l y died of other, n o n - r e s p i r a t o r y causes. F i f t y eight p e r cent of t h e clinical t r i a l s pat i e n t s fell in t h e group. T h e d e s i r e d ( h o p e d for) outcome w h e n e v e r IVOX is u t i l i z e d to s u p p o r t p a t i e n t s in A R F d e m o n s t r a t e s t h a t t h e severe h y p o x e m i a a n d h y p e r c a r b i a which were refractory to m a x i m u m m e c h a n i c a l v e n t i l a t o r y s u p p o r t prior to IVOX u t i l i z a t i o n resolve quickly a n d improved blood g a s e s occur w h e n IVOX is i m p l a n t e d , while t h e i n t e n s i t y of t h e m e c h a n i c a l v e n t i l a t o r s u p p o r t could be r e d u c e d to safe levels. IVOX could t h e n be r e m o v e d a n d l a t e r t h e e n d o t r a c h e a l t u b e removed. This group of p a t i e n t s s u r v i v e d ICU care a n d h o s p i t a lization, u l t i m a t e l y r e t u r n i n g to n o r m a l activities. The s u r v i v o r s among t h e I V O X - i m p l a n t e d p a t i e n t s (30 %) fall into t h i s group. The course of t h e occasional p a t i e n t who r e c e i v e d no a p p a r e n t h e l p from IVOX d e m o n s t r a t e s t h a t a f t e r IVOX i m p l a n t a t i o n t h e p a t i e n t still r e q u i r e s maxim u m v e n t i l a t o r s u p p o r t a n d t h e blood gases p e r s i s t at u n s a t i s f a c t o r y levels. P a t i e n t s in t h i s group all w e n t on to die in uncontrolled r e s p i r a t o r y failure. F o u r t e e n p e r cent of I V O X - i m p l a n t e d p a t i e n t s to d a t e following t h i s course. D a t a c u r r e n t l y a v a i l a b l e from t h e clinical t r i a l s pat i e n t s i n d i c a t e t h a t IVOX a p p e a r s to provide significant b e n e f i t to m o s t p a t i e n t s in w h o m it is utilized. Blood gases h a v e b e e n improved. M e c h a n i c a l v e n t i l a tor p a r a m e t e r s h a v e b e e n reduced. I m p r o v e d l u n g inj u r y scores h a v e b e e n d e m o n s t r a t e d . I m p r o v e d hemod y n a m i c s h a v e b e e n observed. D e c r e a s e d b a r o t r a u m a was observed. Survival r a t e s h a v e b e e n h i g h e r t h a n expected for t h e p a t i e n t groups i n c l u d e d t h u s f a r in t h e study. I n only (14 %) of t h e s e clinical t r i a l s pat i e n t s did i m p l a n t a t i o n of a n IVOX device h a v e no app a r e n t benefit. Preliminary trends noted to date C o n s i d e r i n g t h e d a t a p r e s e n t e d , a l t h o u g h soft a n d p r e l i m i n a r y due to t h e s m a l l n u m b e r of p a t i e n t s assessed to date, p r e l i m i n a r y observations a n d t r e n d s r e l a t i v e to s a f e t y (risks a n d h a z a r d s ) as well as efficacy of IVOX a r e as follows : 1. No serious significant complications, p r o b l e m s , or u n f a v o r a b l e sequelae a t t r i b u t a b l e to IVOX u t i l i z a t i o n have b e e n recognized clinically or b y clinical l a b o r a t o r y t e s t s in a n y of the p a t i e n t s receiving a n IVOX imp l a n t a t i o n to date. 2. No significant gross or histologic pathologic findings a t t r i b u t a b l e to IVOX u t i l i z a t i o n h a v e b e e n observed a t t h e necropsy e x a m i n a t i o n s of A R F p a t i e n t s dying after IVOX utilization. 3. Clinical evidence of significant b e n e f i t to t h e pat i e n t h a s b e e n observed in 86 % of p a t i e n t s in severe acute r e s p i r a t o r y failure receiving a n IVOX i m p l a n t a tion.
Approches therapeutiques de I'hypoxemieCaution The observations made to date concerning IVOX safety and efficacy are preliminary and tentative. At this point in time, the IVOX project must be considered investigational in nature, the primary objective being collection of sufficient sound, reliable, meaningful data on which definitive conclusions Concerning the safety and efficacy of this new method of gas transfer augmentation can be based. The precise indications for IVOX utilization and the most appropriate niche f o r i t s c l i n i c a l a p p l i c a t i o n will b e d e t e r m i n e d b y a c a r e ful analysis of the data now being collected from its clinical trials. REFERENCES J . D . - - A n Intravenacaval Blood Gas Exchange (IVCBGE) Device Preliminary Report. Trans. Am. Soc. Artif. Intern. Organs, 1987, 33, 570-3.
[1] M o r t e n s e n
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[2] Mortensen J.D., Berry G. - - Conceptual and Design Features of a Practical, Clinically Effective, Intravenous, Mechanical Blood Oxygen/Carbon Dioxide Exchange Device (IVOX). Int. J. Artif. Organs, 1989, 12, 384-9. [3] Cox C_S., Zwischenberger J.B., Traber L_D., Traber D.L. - - Use of an Intravenacaval Membrane Oxygenator (IVOX) in an Ovine Model (abstract), ASAIO, 1991, 20-63. [4] Mortensen M.D_ - - Augmentation of Blood Gas Transfer by Means of an Intravascular Blood Gas Exchanger (IVOX). In : Vincent J.L., Marini J_ Ventilatory Failure. Berlin, Springer-Verlag, Update in Int. Care Emer_ Med_, 15, 318-46. [5] Kallis P., A1-Saady N.M., Bennett D., Treasure T. - - Clinical Use of Intravascular Oxygenation (letter to the editor). Lancet, 1991, 337, 549. [6] Morioka T. - - A method for Intravenous Blood Gas Exchange (Japanese)_ Clin. Anesth., 1990, 14, 1149-56. [7] Murray J_F_, Matthey M.A., Luce J.M_, Flick M_R. - - An Expanded Definition of the Adult Respiratory Distress Syndrome_ Am. Rev. Resp. Dis., 1988; 120, 720. [8] Bagley B., Bagley A., Henrie J_, Froerer Cl_, Brohamer J., Burkart J., Mortensen J.D. - - Quantitative Gas Transfer Into and Out of Circulating Blood by Means of an Intravenacaval Oxygenator (IVOX) (Abstract). A S A I O , 1991, 20:60 ; full paper, Trans. Soc. Artif. Intern_ Organs, 1991, 37, 413-5.
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v e n t i l a t i o n a l v ~ o l a i r e ~ t a n t ici a r e m p l a c e r p a r c e l u i de renouvellement alv~olaire). Les indications
Les indications actuelles de l'~puration extracorpor e l l e d e CO2 c o u p l ~ e ~ l a v e n t i l a t i o n p s e u d o - a p n ~ i q u e sent encore impr~cises en l'absence d'dtude randomis~e c o n t r S l ~ e p e r m e t t a n t d ' ~ t a b l i r f o r m e l l e m e n t s a sup~riorith sur la ventilation m~canique, elle-m~me v a r i a b l e d a n s s e s m o d e s d ' a d m i n i s t r a t i o n [20]. L ' e x i s t e n c e , n o n e n c o r e r ~ s o l u e , d e c o m p l i c a t i o n s h6morragiques pouvant ~tre source de mortalith et de morbidit6 pulmonaire, doivent faire discuter son indication. L a p r e m i e r e i n d i c a t i o n q u i s e m b l e i n d i s c u t a b l e r6suite de l'am~lioration de l'oxyg~nation constat~e sur les 6 t u d e s p r ~ l i m i n a i r e s e t c o n c e r n e les m a l a d e s atteints de SDRA pour lesquels la ventilation traditionn e l l e n e p e r m e t p a s d ' a t t e i n d r e ce b u t . P l u s difficile e s t d e p r ~ c i s e r l ' a t t i t u d e a a v o i r d e v a n t un malade qui n'~volue pas favorablement sous ventil a t i o n m ~ c a n i q u e t r a d i t i o n n e l l e . E n l ' a b s e n c e d e crit ~ r e ~ v o l u t i f o u p r o n o s t i q u e v a l i d ~ , il s e m b l e licite d e proposer cette m~thode lorsque la ventilation m~caniq u e e s t i m p o s s i b l e s a n s a t t e i n d r e d e s n i v e a u x d61~t~res en terme de Fie2 et/ou de barotraumatisme. En effet l'am~lioration des ~changes gazeux obtenus par cette m~thode r~sulterait d'une r~duction des in~galitds rdgionales des rapports ventilation-perfusion perm e t t a n t u n m o d e m o i n s a g r e s s i f d ' a s s i s t a n c e p o u r le p o u m o n [21-23]. les m~thodes d'assistance respiratoire extracorporelles sent encore des techniques d'exception qui n~cessitent des investigations suppl~mentaires pour ~tablir clairement leur sup6riorit6 sur la ventilation m~canique classique et r~duire leurs c o m p l i c a t i o n s p r o p r e s . C e p e n d a n t les p r e m i e r s r ~ s u l tats semblent prouver qu'elles peuvent assurer des ~changes gazeux plus efficacement que ceux obtenus par la ventilation du parenchyme pulmonaire malade e t m e t t r e celui-ci a u r e p o s e n a t t e n d a n t s a g u ~ r i s o n . En conclusion,
I~F]~RENCES [1] Hill J.D_, O'Brien T.G., Murray J.D. et al. - - Prolonged extracorporeal oxygenation for acute post traumatic respiratory failure (shock-lung syndrome). N. Engl. J. M~d,, 1972, 286, 629634. [2] Gattinoni L_, Pesenti A., Caspani M.L_ et al. - - The role of total static lung compliance in the management of severe ARDS unresponsive to conventional treatment. Intensive Care Med., 1984, 10, 121-126. [3] Chevalier J.Y., Durandy Y., Batisse A., Mathe J.C., Costil J.C. - - Preliminary reports : Extracorporeal lung support for neonatal acute respiratory failure. Lancet, 1990, 335, 1364-1366, [4] Zapol W.M., Snider M.T., Hill J.D. et al. - - Extracorporeal membrane oxygenation in severe acute respiratory failure. JAMA, 1979, 242, 2193-2196. [5] Kolobow T., Gattinoni L_, Tomiinson T., Pierce J.E. - - An alternative to breathing. J_ Thorae_ Cardiovasc. Surg., 1978, 75, 261-266. [6] Gattinoni L., Kolobow T., Tomiinson T. et al. - - Low positive pressure ventilation with extracorporeal carbon dioxide removal (LFPPV-ECCO2R)_ Anesth_ Analg., 1978, 57, 470-477. [7] Gattinoni L., Pesenti A., Mascheroni D. et al. - - Low-frequency pesitive-pressure ventilation with extracorporeal CO2 removal [8]
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H. - - Extrakorporale CO2-elimination_ Dtsch_ Med. Wschr., 1989, 114, 796-799_ [9] Baumann W.R., Jung P~C., Koss M. et al. - - Incidence and mortality of adult respiratory distress syndrome : A prospective analysis from a large metropolitan hospital. Crit. Care Med., 1986, 14, 1-4.
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[10] Montgomery A.B_, Stager M.A., Carrico C.J., Hudson L.D. -Causes of mortality in patmnts with the adult respiratory distress syndrome. Am. Rev. Respir. Dis., 1985, 132, 485-489_
[11] McCoy-Pardington D., Judd W.J., Knafl P., Abruzzo L.V., Coombes K.R., Butch S.H., Oberman H.A. - - Blood use during extracorporeal membrane oxygenation. Transfus/on, 1990, 30, 3O7-309. [12] Uziel L., Agostini A., Pirovano E. - - Haematologic survey during low frequency positive pressure ventilation with extracorporeal'CO2 removal. Trans. Am. Soc. Artif. Intern. Organs, 1982, 28, 359-364. [13] Gattinoni L., Agostini A., Damia G. et al. - - Hemodynamics and renal function during low frequency positive pressure ventilation with extracorporeal CO2 removal_ Intensive Care Med., 1980, 6, 155-161. [14] Gattinoni L, Pesenti A., Avalli L., Rossi F_, Bombino M. - -
Pressure-volume curve of total respiratory system in acute respiratery failure.Am. Rev. Respir. Dis., 1987, 136, 730-736. [15] Dall'ava-Santucci J., Armaganidis A., Brunet F., Dhainaut J.F., Chelucci G.L., Monsallier J.F., Lockhart A. -- Causes of error of respiratory pressure volume curves in paralyzed subjects. J. AppL Physiol., 1988, 64, 42-49. [16] Dall'ava-Santucci J., Armaganidis A., Brunet F_ et aL -- Mechanical effects of P E E P in patients with adult respiratory distress syndrome. J. AppL Physiol., 1990, 68, 843-848. [17] Hurewitz A_N., Bergofsky E.H_, Vomero E. -- Airway insufflation. Increasing flow rates progressively reduce dead space in respiratory failure.Am. Rev. Respir_ Dis., 1991, 144, 1229-1233. [18] Venegas J.G., Y a m a d a Y., Hales C.A. -- Contribution of diffusion jet flow and cardiac activity to regional ventilation in CFV. J. Appl. Physiol_, 1991, 71, 1540-1553. [19] Smith R.B. -- Continuous flow apneic ventilation. Resp. Care, 1987, 32, 458-465. [20] Slutsky A.S. -- N o n conventional methods of ventilation. Am. Rev. Respir. Dis_, 1988, 138, 175-183.
[21] Borelli M., Kolobow T_, Spatola R., Prate P., Tsuno K. - - Severe
acute respiratory failure managed with continuous positive airway pressure and partial extracorporeal carbon dioxide removal by an artificial membrane lung. A controlled, randomized animal study. Am. Rev_ Resp. Dis_, 1988, 138, 1480-1487. [22] Dorrington K.L., McRae K.M., Gardaz J.P., Dunnfll M_S., Sykes M.K., Wilkinson A.R. - - A randomized comparison of total extracorporeal C02 removal with conventionalmechanical ventilation in experimental hyaline membrane disease. Intensive Care Med., 1989, 15, 184-191. [23] Pesenti A., Kolobow T., Buckhold D.K. - - Prevention of hyaline membrane disease in premature lambs by apneic oxygenation and extracorporeal carbon dioxyde removal. Crit, Care Med., 1982, 8, 11-17.
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Ivox • a new alternative method for augmenting blood gas transfer in patients with acute respiratory failure
Mortensen
J.D.
Cardio-Pulrnonics, University of Utah, Salt Lake City, UTAH 84116, USA
A u g m e n t a t i o n of d e f i c i e n t b l o o d g a s t r a n s f e r of p a tients with potentially reversible acute respiratory f a i l u r e is n e c e s s a r y t o a v o i d d e a t h f r o m p r o g r e s s i v e hypoxemia and/or hypercarbia. In most cases, mechanical ventilation with oxygen-enriched inspiratory air successfully reverses the unacceptable blood gases, t h u s <
Approches thCrapeutiques de I'hypox~mie- 7 9 3 to introduce to you t h i s n e w intracorporeal, i n t r a v a s c u l a r blood gas t r a n s f e r technology, k n o w n as IVOX.
IVOX Design Concepts and Performance Characteristics IVOX is a n a c r o n y m for I n t r a V a s c u l a r Oxygenator. The device is a small, elongated, hollow fiber m e m b r a n e o x y g e n a t o r designed to lie w i t h i n the subject's v e n a cavae so t h a t circulating venous blood c a n flow freely over a n d a r o u n d t h e e x t e r n a l surfaces of t h e hollow fibers. Oxygen, u n d e r s u b a t m o s p h e r i c pressure, flows w i t h i n t h e l u m e n s of t h e hollow fibers, t h e walls of which are covered w i t h a n u l t r a t h i n , selectively gas p e r m e a b l e , siloxane m e m b r a n e which perm i t s t r a n s f e r of oxygen a n d carbon dioxide ( b u t n o t w a t e r , p l a s m a , solutes, or formed e l e m e n t s of t h e blood) across t h e m e m b r a n e [1, 2]. The IVOX device is placed in t h e v e n a cavae t h r o u g h a surgical v e n o t o m y in t h e r i g h t femoral or r i g h t j u g u l a r vein. E x t e n s i v e engineering, in vitro, ex vivo, and in vivo e x p e r i m e n t a l a n i m a l l a b o r a t o r y [3] t e s t i n g of IVOX h a s b e e n c a r r i e d out over a nine y e a r d e v e l o p m e n t period. P e r f o r m a n c e c h a r a c t e r i s t i c s of IVOX, d e r i v e d from d a t a p r o d u c e d by its acute a n d chronic ex vivo a n d in vivo e x p e r i m e n t a l a n i m a l t e s t i n g i n d i c a t e t h a t t h e device does t r a n s f e r significant q u a n t i t i e s of oxygen into a n d c a r b o n dioxide out of circulating venous blood for u p to t h r e e weeks in awake, s t a n d i n g , sheep w i t h o u t significant risks, h a z a r d s , or complications [2, 4].
Perceived Clinical Appfication of IVOX
[5-6]
IVOX is i n t e n d e d for t e m p o r a r y (up to 21 days) augm e n t a t i o n of deficient blood gas t r a n s f e r in p a t i e n t s w i t h m o d e r a t e to severe, p o t e n t i a l l y reversible, acute r e s p i r a t o r y f a i l u r e who h a v e h y p o x e m i a and/or h y p e r c a r b i a which is refractory to conventional r e s p i r a t o r y t h e r a p y . T h e objectives of its clinical a p p l i c a t i o n a r e to : 1) p e r m i t r e d u c t i o n in t h e i n t e n s i t y ( a n d e a r l y wit h d r a w a l or avoidance) of m e c h a n i c a l v e n t i l a t o r supp o r t ; 2) i m p r o v e t h e d e r a n g e d blood gases in t h e patient's c i r c u l a t i n g blood w i t h o u t involving t h e i n j u r e d a n d i n a d e q u a t e l y functioning n a t u r a l lungs ; a n d 3) <
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change with circulating blood (50 to 150 cm3/min, constituting 1/4 to 1/3 t h e t o t a l metabolic requirem e n t s of a d u l t A R F p a t i e n t s ) , t h e t i m e the device can safely r e m a i n i n d w e l l i n g in t h e v e n a cavae ( c u r r e n t l y l i m i t e d to 3 weeks), a n d t h e n e c e s s i t y for t h e p a t i e n t to receive m i l d to m o d e r a t e s y s t e m i c a n t i c o a g u l a t i o n d u r i n g IVOX u t i l i z a t i o n ( a c t i v a t e d clotting t i m e m a i n t e n e d at a b o u t 180 seconds).
Current Status of IVOX Clinical Trials Clinical t r i a l s of IVOX u t i l i z a t i o n to a u g m e n t blood gas t r a n s f e r in p a t i e n t s in a d v a n c e d acute r e s p i r a t o r y failure are c u r r e n t l y being c o n d u c t e d u n d e r F D A supervision. P h a s e I h a s b e e n completed, d e m o n s t r a t i n g safety of IVOX. P h a s e II is in progress, a s s e s s i n g t h e efficacy of the device. E i g h t e e n clinical centers h a v e c o n t r i b u t e d cases as a p a r t of t h e s e trials. T h e expertise, experience, a n d significant c o n t r i b u t i o n of t h e p a r t i c i p a t i n g p r i n c i p a l i n v e s t i g a t o r s a n d t h e i r associates a r e acknowledged a n d a p p r e c i a t e d . To d a t e (March 10, 1992) IVOX h a s b e e n u t i l i z e d in t h e m a n a g e m e n t of 101 p a t i e n t s . Complete d a t a a r e b e i n g collected a n d a n a l y z e d for t h e s e p a t i e n t s , a n d will become t h e b a s i s for a d e t a i l e d r e p o r t being prep a r e d b y t h e i n v e s t i g a t o r s of t h e s e clinical trials. My r e p o r t t o d a y c o n t a i n s only g e n e r a l information glean e d from p r e l i m i n a r y r e v i e w of t h e l i m i t e d a n d incomplete d a t a a v a i l a b l e a t t h i s time. Therefore, t h e findings and t r e n d s n o t e d a r e t e n t a t i v e in n a t u r e . C a u s e s of t h e acute r e s p i r a t o r y failure (ARF) encount e r e d in t h e clinical t r i a l s p a t i e n t s are t y p i c a l for ARDS, p n e u m o n i a s of v a r i o u s t y p e s a n d post-shock lung i n j u r y accounting for m o s t of t h e p a t i e n t s . The severity of t h e A R F in t h e s e v e r y sick p a t i e n t s h a s b e e n classified according to M u r r a y ' s lung injury sev e r i t y scoring m e t h o d [7]. T h e scores indicate t h a t all p a t i e n t s in t h e clinical t r i a l s to d a t e have b e e n in severe to e n d - s t a g e ARDS, w i t h e x p e c t e d s u r v i v a l r a t e s of less t h a n 20 p e r cent. Protocols for conducting t h e IVOX clinical t r i a l s first called for d e t e r m i n i n g t h e incidence of m a j o r safety concerns which h a d p r e v i o u s l y b e e n identified. Safety d a t a came from two sources : o b s e r v a t i o n s m a d e b y t h e a t t e n d i n g clinician, consisting of clinical a n d labor a t e r y findings observed d u r i n g IVOX u t i l i z a t i o n ; a n d observations m a d e b y t h e p a t h o l o g i s t s perform i n g t h e necropsies on p a t i e n t s who died d u r i n g or after IVOX utilization. The incidence of significant complications n o t e d by t h e a t t e n d i n g p h y s i c i a n r e l a t i v e to t h e m a j o r anticip a t e d safety concerns was nil. Similarly, l a b o r a t o r y d a t a received a n d a n a l y z e d to d a t e indicate no signific a n t or c o n s i s t e n t IVOX-related changes in hemoglobin, h e m a t e c r i t , WBC, fibrinogen, fibrin split products, p l a s m a free h e m o g l o b i n or c o m p l e m e n t acti vation. P l a t e l e t count d e c r e a s e d s o m e w h a t in app r o x i m a t e l y h a l f of t h e IVOX p a t i e n t s , b u t fell to significantly low levels in only 2 cases. T r a n s i e n t edem a of t h e r i g h t leg occurred in 3 cases while IVOX was indwelling in t h e femoral or iliac vein, or in t h e e a r l y p o s t e x p l a n t a t i o n p e r i o d after t h e device h a d been removed and the venotomy had been repaired. In each case t h e e d e m a r e s o l v e d s p o n t a n e o u s l y or was controlled b y conservative m e a s u r e s such as t h e a p p l i c a t i o n of elastic hose. Pathologists r e p o r t i n g t h e i r o b s e r v a t i o n s at n e c r o p s y of t h e p a t i e n t s who died d u r i n g or after IVOX utilization found no evidence t h a t IVOX u t i l i z a t i o n caused
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Approches thCrapeutiques de I'hypoxemie
or c o n t r i b u t e d to t h e d e a t h of a n y of t h e IVOX-imp l a n t e d p a t i e n t s . No s i g n i f i c a n t t h r o m b o e m b o l i were found in t h e v e n a cavae, r i g h t h e a r t , or p u l m o n a r y art e r i e s a n d no p u l m o n a r y infarctions were encountered. No bubbles, foam, or collections of gas were observed in t h e blood e x p o s e d to IVOX. T h e r e were no lacerations, d i s r u p t i o n s or l e a k a g e of blood from t h e v e n a cavae or r i g h t a t r i u m in w h i c h IVOX h a d b e e n indwelling. T h e r e h a s b e e n no l a b o r a t o r y d e m o n s t r a tion of I V O X - r e l a t e d sepsis, b a c t e r e m i a , or localized infections. L i k e w i s e t h e r e w a s no evidence of mechanical obstruction to blood flowing in t h e v e n a cavae en r o u t e to the r i g h t h e a r t . At autopsy, five of t h e access femoral veins c o n t a i n e d t h r o m b u s . T h r e e were non-occlusive a n d two w e r e occlusive. However, one of t h e occluded f e m o r a l v e i n s h a d b e e n ligated, accounting for t h e occlusion. All p a t i e n t s receiving a n IVOX i m p l a n t a t i o n were a n t i c o a g u l a t e d j u s t p r i o r to i m p l a n t a t i o n , utilizing an i n t r a v e n o u s b o l u s of h e p a r i n , followed b y a continuous h e p a r i n d r i p to m a i n t a i n a c t i v a t e d clotting t i m e s at a p p r o x i m a t i v e l y 180 seconds. We h a v e b e e n gratified to note t h a t no s i g n i f i c a n t b l e e d i n g was not e d in 75 % of t h e I V O X - i m p l a n t e d p a t i e n t s . More t h a n 100 cm a blood loss a c c o m p a n y i n g IVOX i n s e r t i o n was r e p o r t e d in five cases, due p r i m a r i l y to h i g h venous p r e s s u r e a n d t h e s u r g e o n ' s inexperience in act u a t i n g or m a n i p u l a t i n g t h e r e f l u x valve in t h e introducer sheath. I n only two of t h e s e cases were t r a n s f u s i o n s r e q u i r e d . T h r e e p a t i e n t s receiving IVOX experienced some p o s t o p e r a t i v e oozing at t h e e n t r y site. Two of t h e s e r e q u i r e d blood r e p l a c e m e n t t h e r a p y and in one case t h e b l e e d i n g w a s p e r s i s t e n t enough to r e q u i r e a surgical e x p l o r a t i o n to control it. Five of t h e s e chronically h e p a r i m z e d p a t i e n t s experienced b l e e d i n g at sites r e m o t e from t h e IVOX. T h e s e were sites of r e c e n t s u r g e r y in four cases, a n d b l e e d i n g into t h e left r e t r o p e r i t o n e a l space (not associated w i t h t h e v e n a cavae) in one case. E a c h w a s considered m i l d to m o d e r a t e , w i t h control r e q u i r i n g t r a n s f u s i o n only. None r e q u i r e d surgical i n t e r v e n t i o n . The possibility of significant t h r o m b u s a c c u m u l a t i o n on a n i m p l a n t e d IVOX device is a m a j o r concern. As a consequence of active, d i s t u r b e d blood flow over t h e fibers (achieved b y d e p l o y m e n t of t h e c r i m p e d fibers w i t h i n t h e v e n a cavae), t h e t h r o m b o - r e s i s t a n t coating a p p l i e d to t h e device, a n d m i l d s y s t e m i c h e p a r i n i z a tion, we are p l e a s e d to r e p o r t t h a t t h r o m b u s accumul a t i o n on IVOX h a s not b e e n a significant p r o b l e m in t h e s e I V O X - i m p l a n t e d p a t i e n t s , t h e e x p l a n t e d IVOX devices showing r e m a r k a b l y s m a l l a m o u n t s of visible t h r o m b u s on or a m o n g t h e hollow fibers. While our first a n d m a j o r concern during t h e s e e a r l y IVOX i m p l a n t a t i o n s h a s b e e n a s s e s s m e n t of t h e risks a n d h a z a r d s of IVOX U t i l i z a t i o n , t h e s e first 101 imp l a n t a t i o n s h a v e d e m o n s t r a t e d some i m p o r t a n t t r e n d s concerning IVOX efficacy. The q u a n t i t y of gas t r a n s f e r achieved d u r i n g IVOX i m p l a n t a t i o n h a s b e e n significant in every p a t i e n t receiving an IVOX device [8]. G a s t r a n s f e r achieved t h r o u g h IVOX v a r i e d c o n s i d e r a b l y w i t h size of t h e device u t i l i z e d a n d w i t h t h e s e v e r i t y of t h e h y p o x e m i a or h y p e r c a r b i a , sicker p a t i e n t s a n d l a r g e r devices providing h i g h e r a m o u n t s of g a s t r a n s f e r . A v e r a g e r a t e s of 02 t r a n s f e r a n d CO2 r e m o v a l by IVOX were 66.4 cm 3Ymin a n d 74.0 cm ~ym m ' r e s p e c t i"v e l y . Of significance is t h e o b s e r v a t i o n t h a t each IVOX's gas t r a n s fer p e r f o r m a n c e c o n t i n u e d r e l i a b l y a n d w i t h o u t significant d e g r a d a t i o n d u r i n g t h e t i m e it r e m a i n e d
R#an.Urg.,1 9 9 2 ,
1 (5), 7 7 3 - 7 9 5
i n d w e l l i n g (which in t h e s e cases a v e r a g e d 6.5 days, w i t h a m a x i m u m of 29 days). The m o s t c o m m o n course observed in p a t i e n t s w i t h severe A R F who receive a n IVOX i m p l a n t a t i o n dem o n s t r a t e s a favorable r e s p o n s e to IVOX, w i t h control of t h e h y p o x e m i a a n d h y p e r c a r b i a while ventil a t o r p a r a m e t e r s were a d j u s t e d to safe levels. D e s p i t e t h i s f a v o r a b l e course a n d significant t i m e b o u g h t b y IVOX for r e s o l u t i o n of the lung injury, all p a t i e n t s in t h i s group u l t i m a t e l y died of other, n o n - r e s p i r a t o r y causes. F i f t y eight p e r cent of t h e clinical t r i a l s pat i e n t s fell in t h e group. T h e d e s i r e d ( h o p e d for) outcome w h e n e v e r IVOX is u t i l i z e d to s u p p o r t p a t i e n t s in A R F d e m o n s t r a t e s t h a t t h e severe h y p o x e m i a a n d h y p e r c a r b i a which were refractory to m a x i m u m m e c h a n i c a l v e n t i l a t o r y s u p p o r t prior to IVOX u t i l i z a t i o n resolve quickly a n d improved blood g a s e s occur w h e n IVOX is i m p l a n t e d , while t h e i n t e n s i t y of t h e m e c h a n i c a l v e n t i l a t o r s u p p o r t could be r e d u c e d to safe levels. IVOX could t h e n be r e m o v e d a n d l a t e r t h e e n d o t r a c h e a l t u b e removed. This group of p a t i e n t s s u r v i v e d ICU care a n d h o s p i t a lization, u l t i m a t e l y r e t u r n i n g to n o r m a l activities. The s u r v i v o r s among t h e I V O X - i m p l a n t e d p a t i e n t s (30 %) fall into t h i s group. The course of t h e occasional p a t i e n t who r e c e i v e d no a p p a r e n t h e l p from IVOX d e m o n s t r a t e s t h a t a f t e r IVOX i m p l a n t a t i o n t h e p a t i e n t still r e q u i r e s maxim u m v e n t i l a t o r s u p p o r t a n d t h e blood gases p e r s i s t at u n s a t i s f a c t o r y levels. P a t i e n t s in t h i s group all w e n t on to die in uncontrolled r e s p i r a t o r y failure. F o u r t e e n p e r cent of I V O X - i m p l a n t e d p a t i e n t s to d a t e following t h i s course. D a t a c u r r e n t l y a v a i l a b l e from t h e clinical t r i a l s pat i e n t s i n d i c a t e t h a t IVOX a p p e a r s to provide significant b e n e f i t to m o s t p a t i e n t s in w h o m it is utilized. Blood gases h a v e b e e n improved. M e c h a n i c a l v e n t i l a tor p a r a m e t e r s h a v e b e e n reduced. I m p r o v e d l u n g inj u r y scores h a v e b e e n d e m o n s t r a t e d . I m p r o v e d hemod y n a m i c s h a v e b e e n observed. D e c r e a s e d b a r o t r a u m a was observed. Survival r a t e s h a v e b e e n h i g h e r t h a n expected for t h e p a t i e n t groups i n c l u d e d t h u s f a r in t h e study. I n only (14 %) of t h e s e clinical t r i a l s pat i e n t s did i m p l a n t a t i o n of a n IVOX device h a v e no app a r e n t benefit. Preliminary trends noted to date C o n s i d e r i n g t h e d a t a p r e s e n t e d , a l t h o u g h soft a n d p r e l i m i n a r y due to t h e s m a l l n u m b e r of p a t i e n t s assessed to date, p r e l i m i n a r y observations a n d t r e n d s r e l a t i v e to s a f e t y (risks a n d h a z a r d s ) as well as efficacy of IVOX a r e as follows : 1. No serious significant complications, p r o b l e m s , or u n f a v o r a b l e sequelae a t t r i b u t a b l e to IVOX u t i l i z a t i o n have b e e n recognized clinically or b y clinical l a b o r a t o r y t e s t s in a n y of the p a t i e n t s receiving a n IVOX imp l a n t a t i o n to date. 2. No significant gross or histologic pathologic findings a t t r i b u t a b l e to IVOX u t i l i z a t i o n h a v e b e e n observed a t t h e necropsy e x a m i n a t i o n s of A R F p a t i e n t s dying after IVOX utilization. 3. Clinical evidence of significant b e n e f i t to t h e pat i e n t h a s b e e n observed in 86 % of p a t i e n t s in severe acute r e s p i r a t o r y failure receiving a n IVOX i m p l a n t a tion.
Approches therapeutiques de I'hypoxemieCaution The observations made to date concerning IVOX safety and efficacy are preliminary and tentative. At this point in time, the IVOX project must be considered investigational in nature, the primary objective being collection of sufficient sound, reliable, meaningful data on which definitive conclusions Concerning the safety and efficacy of this new method of gas transfer augmentation can be based. The precise indications for IVOX utilization and the most appropriate niche f o r i t s c l i n i c a l a p p l i c a t i o n will b e d e t e r m i n e d b y a c a r e ful analysis of the data now being collected from its clinical trials. REFERENCES J . D . - - A n Intravenacaval Blood Gas Exchange (IVCBGE) Device Preliminary Report. Trans. Am. Soc. Artif. Intern. Organs, 1987, 33, 570-3.
[1] M o r t e n s e n
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[2] Mortensen J.D., Berry G. - - Conceptual and Design Features of a Practical, Clinically Effective, Intravenous, Mechanical Blood Oxygen/Carbon Dioxide Exchange Device (IVOX). Int. J. Artif. Organs, 1989, 12, 384-9. [3] Cox C_S., Zwischenberger J.B., Traber L_D., Traber D.L. - - Use of an Intravenacaval Membrane Oxygenator (IVOX) in an Ovine Model (abstract), ASAIO, 1991, 20-63. [4] Mortensen M.D_ - - Augmentation of Blood Gas Transfer by Means of an Intravascular Blood Gas Exchanger (IVOX). In : Vincent J.L., Marini J_ Ventilatory Failure. Berlin, Springer-Verlag, Update in Int. Care Emer_ Med_, 15, 318-46. [5] Kallis P., A1-Saady N.M., Bennett D., Treasure T. - - Clinical Use of Intravascular Oxygenation (letter to the editor). Lancet, 1991, 337, 549. [6] Morioka T. - - A method for Intravenous Blood Gas Exchange (Japanese)_ Clin. Anesth., 1990, 14, 1149-56. [7] Murray J_F_, Matthey M.A., Luce J.M_, Flick M_R. - - An Expanded Definition of the Adult Respiratory Distress Syndrome_ Am. Rev. Resp. Dis., 1988; 120, 720. [8] Bagley B., Bagley A., Henrie J_, Froerer Cl_, Brohamer J., Burkart J., Mortensen J.D. - - Quantitative Gas Transfer Into and Out of Circulating Blood by Means of an Intravenacaval Oxygenator (IVOX) (Abstract). A S A I O , 1991, 20:60 ; full paper, Trans. Soc. Artif. Intern_ Organs, 1991, 37, 413-5.
mmu
R#an. Urg., 1992, 1 (5), 773-795