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Journal of Fluorine Chemistry 109 (2001) 59±65


Fluorinated blood substitutes and oxygen carriers
Kenneth C. Lowe*
School of Life & Environmental Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK Accepted 16 January 2001

Abstract Per¯uorochemicals (PFCs) are highly ¯uorinated, inert organic compounds that can dissolve large volumes of O2 and other respiratory gases. PFCs are unreactive in the body and excreted primarily as a vapour by exhalation. However, PFC liquids are immiscible with aqueous systems, including blood, but can be injected safely into the bloodstream as emulsions. Such emulsions are currently being assessed clinically as temporary, intravascular respiratory gas-carriers and tissue oxygenating ¯uids (so-called `blood substitutes'). One such emulsion, a commercial per¯ubron-based formulation, OxygentTM, is in advanced clinical trials as an alternative to allogeneic (donor) blood transfusion during surgery. Basic and clinical studies indicate that OxygentTM can support O2 delivery to tissues during acute blood loss with no abnormal haemodynamic changes. # 2001 Elsevier Science B.V. All rights reserved.
Keywords: Per¯uorochemicals; Blood substitutes; Respiratory gas carriers; Tissue oxygenation; Blood transfusion; Fluoro-surfactants; Emulsi®cation

1. Introduction Increasing concerns about the safety of conventional blood transfusion have fuelled the search for effective alternatives, often referred to as so-called `blood substitutes'. One class of such materials are PFCs that can be administered safely into the bloodstream in an emulsi®ed form. Such emulsions are currently in advanced clinical trials for use during surgery as temporary tissue oxygenating ¯uids, thereby reducing patient exposure to donor blood. The focus of this paper is to review the properties of PFCs relevant to their current and predicted uses in medicine, especially as intravascular respiratory gas carriers. 2. General physico-chemical properties of PFCs PFCs are chemically inert, heat stable, ¯uorine-substituted, linear, cyclic or polycyclic anthropogenic hydrocarbons that can dissolve large volumes of O2, CO2 and other non-polar gases. O2 solubility in PFC liquids (STP) is ca. 45 ml per 100 ml, whereas CO2 solubility can be >200 ml per 100 ml [1±3]. This gas solubility decreases in the order CO2 @ O2 > CO > N2 correlating with the decrease in molecular volume of the solute [1±3]. Linear PFCs, such as bromoper¯uoro-n-octane (empirical formula: C8F17Br,
* Tel.: ‡44-115-951-3311; fax: ‡44-115-951-3251. E-mail address: (K.C. Lowe).

more commonly known by the generic name of per¯ubron; Fig. 1), dissolve O2 more readily than cyclic molecules (e.g. per¯uorodecalin, C10F18; Fig. 1). O2 solubility in PFC liquids is ca. 20±25 times greater than in water or blood plasma under identical conditions. In contrast to the chemical binding of O2 to the porphyrin±iron sites of the respiratory pigment, haemoglobin, O2 dissolution in PFCs occurs passively, with gas molecules occupying intermolecular spaces within the PFC liquid. Unlike the characteristic sigmoid binding curve of O2 to haemoglobin, O2 solubility in PFCs and their emulsions increases linearly with partial pressure (pO2) approximating to Henry's Law. In addition, gas solubility in PFC liquids is independent of temperature. Details of the synthesis and other physico-chemical properties of PFCs relevant to their uses in biological systems have been reviewed in detail elsewhere [1±10]. PFC liquids are immiscible with aqueous-based systems, including blood and other body ¯uids, but can be injected intravascularly as emulsions. Such emulsions, typically consisting of submicron PFC droplets (ca. 0.1±0.2 mm diameter) dispersed in a buffered, isotonic aqueous phase, have been evaluated clinically as, for example, temporary respiratory gas-carrying ¯uids for intravascular infusion (including their use to potentiate the tumour-killing effects of ionising radiation or chemotherapeutic drugs) and perfusates for isolated organs [1±14] (Table 1). When administered into the bloodstream, PFC emulsions provide their main bene®t by increasing the O2 solubility in the plasma phase [1±14], as discussed later. As indicated in Table 1, neat PFC liquids

0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 1 1 3 9 ( 0 1 ) 0 0 3 7 4 - 8

including Emulsion No. Perfluorotripropylamine Perfluorodecalin. however.0% (w/v) per¯uorodecalin. 1. for example. II and Perftoran from China and Russia.g. The main limitations of Fluosol1 were:  stem emulsion unstable at room temperature. Fluosol1 did provide a baseline for the subsequent development of improved.C. Perfluorotripropylamine Perfluorotributylamine Perfluorodecalin. .23. It was not. II Fluosol Oxypherol Perftoran Second-generation emulsions Fluxonb Oncosol Oxyfluor Oxygent a b PFC(s) constituents Perfluorodecalin.26]. First generation injectable PFC mulsions The ®rst injectable PFC emulsion to be produced commercially was Fluosol1 (Green Cross. including complement activation and altered white blood cell function. Fluosol1 received regulatory approval in the USA and Europe in 1989±1990 for clinical use as an O2-carrying adjunct to coronary balloon angioplasty in high-risk patients [1±14. and as tools in ophthalmologic surgery.22] (Table 1). Perfluorodimorpholinopropane Perfluorophenanthrene Perfluorodichlorooctane Perflubron.and second-generation PFC emulsions for use as intravascular oxygen carriers and tissue oxygenation fluids (so-called `blood substitutes') Commercial name First-generation emulsions Emulsion No.24]. per¯uoropropane (C3F8) and per¯uoro-n-pentane (C5F12). C5F12). Lowe / Journal of Fluorine Chemistry 109 (2001) 59±65 are currently being evaluated clinically as ultrasound contrast imaging agents [1±10. manufacture of the emulsion ceased in 1994. Provisional commercial name. Perfluorodecyl bromide Country of origin China Japan Japan Russia Europe USA USA USA Clinical trails Yes Yes No Yes No Yes Yes Yes Availabilitya Available Discontinued Discontinued Available Available Available Available Available Based on current information concerning availability for non-clinical studies. Table 1 Some biomedical applications for PFC liquids and their emulsions Biomedical application Tissue oxygenation fluids (`blood substitutes'. C3F8. perfluoro-propane.25].24] a Interest currently focused on PFCs that are gaseous at body temperature (e. `oxygen therapeutics') Anti-cancer agents Perfusates for isolated organs Cell culture media supplements Liquid ventilation fluids Surgical tools in ophthalmology Diagnostic imaging agents PFC liquid (L) or emulsion (E) E E E E/L L L La Reference(s) [1±14] [15] [1±14] [16] [17±20] [21. As with Fluosol1. Perftoran Fig.60 K. Low molecular weight (Mw) PFCs. and perfluoro-pentane. Pluronic1 F-68 (poloxamer 188). ®rst-generation. Perfluoromethylcyclopiperidine Perfluorodecalin. including fermenter systems (Table 1). which consisted of 14. primarily for retinal manipulation [21. Concurrent with the development of Fluosol1 was the production of other. Japan). 6% (w/v) per¯uorotri-n-propylamine [(C3F7)3N] (Table 2) and the surfactants. PFCs have also been used in liquid or emulsi®ed form as respiratory gas-carrying culture media supplements for both prokaryotic and eukaryotic cells. are also being assessed clinically as ventilation ¯uids for the treatment of acute respiratory failure [17±20].22] [23. PFC emulsions. Table 2 First. that are gaseous at body temperature such as. `second-generation' PFC emulsions for intravascular applications. egg yolk phospholipids (EYP) and potassium oleate. 3. mainly because subsequent improvements in angioplasty technology made its use redundant and.  relatively poor efficacy as an O2 carrier. Chemical structures of perfluorodecalin (upper) and perflubron (lower) (from [1±3]). therefore.  unwanted side effects. highlighting the growing interest in the biotechnological applications of these compounds [16]. Despite its shortcomings. attributed mainly to the synthetic Pluronic1 F-68 surfactant component [1±14]. respectively (Table 2) [1±13. widely adopted by cardiologists.

whilst avoiding formulations with viscosities that are too high for use in the blood. This strategy was employed in the production of both Fluosol1. high boiling point oil (HBPO) additive. II has been administered to over 340 patients. to stabilise against Ostwald Ripening [6±8]. Second-generation emulsions based on per¯ubron or per¯uorodecalin have similarly been stabilised against Ostwald Ripening using small quantities of an appropriate HBPO.6% w/v). It is also an attractive compound for clinical use because of its excellent imaging properties [23]. For both emulsions. 50 ml per 100 ml) of any of the PFCs commonly used for biomedical applications. in which emulsi®ed per¯uorodecalin was stabilised with per¯uorotri-n-propylamine. this can be retarded by adding an antioxidant. 4. as described later. and Perftoran. 4.0% (w/v) per¯uoromethylpiperidine (C12F23N] in place of per¯uorotri-n-propylamine [26]. Second-generation injectable PFC emulsions The main objectives of the research and development effort to produce superior PFC emulsions to supersede Fluosol1 and other ®rst-generation emulsions were to:  identify highly purified PFCs with acceptable biocompatibility and excretion properties. 1) are the two compounds most widely evaluated as the principal constituents of injectable PFC emulsions.g. Following clinical evaluation in >500 patients. EYP.1. Both of these PFCs can be manufactured to a very high degree of purity.1±0. Production of stable emulsions As noted already. Emulsion No. OxygentTM. However. a-tocopherol is added routinely (ca. However.3.2. A further commercial emulsion. primarily because of its very high lipophilicity endowed by the presence of a single bromine atom on the terminal carbon (Fig. in PFCbased formulations. The Mw of both compounds are within the range 460±500. In this respect. Germany) that have been used in other PFC emulsions.29]. that are excellent stabilisers of PFC emulsions [28. Perftoran was approved (in 1995±1996) by the Russian health regulatory authorities as a temporary intravascular O2 carrier for haemorrhagic shock patients and perfusate for isolated human organs. II is a 20% (w/v) emulsion based on the same PFCs as Fluosol1.  develop concentrated emulsions having significantly increased PFC content conferring superior O2-carrying capacity [1±14].29]. 4. 1) has also been used as the basis of second-generation injectable PFC emulsions. 1). which has a shelf life at 5±108C of >1 year. as discussed later.K. such as per¯uoroperhydrophenanthrene [30. a poloxamer-type compound is incorporated as sole or major surfactant. Lipoid E100. the primary mechanism by which droplets grow is through a process of molecular diffusion known as Ostwald Ripening.  improve stability characteristics and hence. 4 days [1± 10]. per¯uoro-decyl bromide (C10F21Br) (Table 2). Ostwald Ripening in emulsions of per¯uorodecalin can be retarded by adding a small amount of a per¯uorinated. is stabilised with EYP (3. some of them war casualties [27]. was also manufactured by Green Cross. Lipoid GmbH.31] (C16F26) (Table 2). 0. containing 20% (w/v) of per¯uorotributylamine [(C4F9)3N] (Table 2). This is because its acceptable tissue retention time outweighs its . Lowe / Journal of Fluorine Chemistry 109 (2001) 59±65 61 also consists of 14% (w/v) per¯uorodecalin.C. fluoro-surfactants). but not for clinical use owing to the high Mw (671) of its core PFC giving a prolonged body retention half-time (>500 days) [1±3]. in some PFC-based emulsions. studies in animals have shown that the body retention half-time of per¯ubron is ca. shelf-life. but contains 6.g. where per¯uoromethylpiperidine was used as the HBPO [1±10] (Table 2). Per¯ubron can be readily emulsi®ed with EYP and is rapidly excreted from the body. EYP are sensitive to slow oxidative degradation but. but little information is available about its current clinical status. such as a-tocopherol [32]. Perfluorodecalin emulsions Per¯uorodecalin (Fig. Indeed. which is recognised as that giving acceptable tissue retention times [1±14]. one major objective in the production of second-generation. This occurs when PFC molecules from smaller droplets diffuse through the continuous phase to the larger droplets which progressively increase in size at the expense of the former [28. injectable PFC emulsions was to improve stability and. Table 2) developed by the Alliance Pharmaceutical Corporation in San Diego. it was necessary to achieve a compromise between producing highly concentrated PFC emulsions with increased O2-carrying capacity. consequently. 4. Emulsion No. Perflubron emulsions Per¯ubron has one of the highest respiratory gas-dissolving capacities (ca. Oxypherol1. thereby avoiding unwanted side-effects that have often been attributed to partially-¯uorinated contaminants when used in vivo [1±14]. For the latter point. 4.2% w/v) to some commercial phospholipid formulations (e. through the use of perfluorinated stabilisers and more appropriate surfactants (e. extend shelf life. high Mw. Per¯ubron is the major PFC component in a commercial O2-carrying emulsion (OxygentTM.4. The current OxygentTM formulation (AF0144) consists of 58% (w/v) per¯ubron and 2% (w/v) of its higher homologue. Emulsions are thermodynamically unstable systems and. Biocompatible PFCs Per¯ubron and per¯uorodecalin (Fig.

Oxy¯uor1 consists of 76% (w/v) of a linear compound. a boiling point of 1828C and can dissolve ca. have recently been synthesised for PFC emulsi®cation (Fig. 140 ml per 100 ml of CO2 and has a body clearance half-time of ca. 0. Lowe / Journal of Fluorine Chemistry 109 (2001) 59±65 relatively poor emulsifying properties [1±10]. Chemical structures of novel glycosidic (compounds S2 and S4) and polyol (compounds P1 and P4) fluoro-surfactants (from [40]). derived from glycosides (monosaccharides. `P' series). 2. and as a perfusate for cardiopulmonary bypass (CPB) machines [36]. It has an estimated body clearance half-time of 55 days [34]. poly(oxyethylene) monocarbamate. Per¯uorodecalin dissolves ca.5% (w/v) of lecithin (Lipoid E100) and given the provisional commercial name of Fluxon (Table 2). particularly the polyol compounds. polyethoxylated alcohols and partially protected sugars at anomeric carbon. C 8 F 17 C 2 H 4 NHC(O)(CH 2 CH 2 O) 2 Me (designated as compound P6).C. The resultant compounds were per¯uoroalkylated with hydroxylic ``head'' groups (Fig. 40 ml per 100 ml of O2 and ca. respectively [1±10]. `¯uorophilic' surfactants and/ or co-surfactants [37±40]. Some of the emulsions also contained 1. 6.8-dichlorooctane (C8F16Cl2) (Table 2). The emulsions were steam sterilisable and showed no signi®cant changes in droplet diameter (ca. A novel series of per¯uorodecalin-based emulsions. stabilised with up to 2. routes using highly ¯uorinated isocyanates with amino alcohols.3 mm) during >300 days' storage at room temperature. The novel emulsions are currently being assessed as O2-carrying perfusates of animal organs. `S' series) or polyols (ureas or carbamates. 5. The emulsion has an average droplet diameter of ca. amino acids and lipids.0% (w/v) of per¯uoro-1.2± 0. One promising ¯uoro-surfactant to emerge from this research effort is an amphiphilic.22± 0.5. some of these novel ¯uoro-surfactants. Novel fluoro-surfactants PFC emulsion stability has been markedly improved by adding specially synthesised. Safety and biocompatibility The PFCs are unreactive in the body and excreted primarily as a vapour through the lungs. Such ¯uoro-surfactants were produced via simple.3-dimorpholinopropane (C11F22N2O2) (Table 2) to suppress droplet growth by Ostwald Ripening. yields were 88±95% [41]. 2). including the dog heart and pig liver. A novel series of ¯uoro-surfactants. Interestingly.31]. second-generation PFC emulsion is Oxy¯uor1. Oxy¯uor1 has been evaluated as an intravascular O2 carrier in preclinical studies [35]. but highly selective. developed in the USA by Hemagen-PFC of St. per¯uoro-1.25 mm. suggesting possible applications for these compounds as anti-thrombotic agents which warrant further investigation. The most effective compounds are those derived from sugars. Louis. The novel emulsions were prepared by homogenisation and had a PFC content of 20±40% (w/v). Per¯uorodimorpholinopropane has a Mw of 610. Other concentrated emulsions A further. . analogous with earlier related studies [30. but little further information on its current commercial or clinical status is available. have been produced recently by a European research team [33]. 0. PFC droplets infused into the bloodstream are cleared by phagocytic cells of the Fig.62 K. 43 ml per 100 ml of O2. 7 days [1±10]. inhibited spontaneous platelet aggregation in human blood in vitro [42]. 4. This compares favourably with corresponding values of 60 days for the per¯uorotripropylamine and per¯uoromethylpiperidine constituents of Fluosol1 and Perftoran1. 2). together with saf¯ower oil as stabiliser and EYP as surfactant.

The total amount of O2 dissolved in a PFC emulsion depends on the concentration of PFC and the solubility coef®cient of the compound for the gas. In vessels with rapid ¯ow (e. normal blood (packed cell volume 45%. Such an increased O2 ¯ux was greater for non-uniform dispersions. Further detailed discussion on the fate and effects of PFCs and other emulsion constituents in the body can be found in recent reviews [1±10]. therefore. a typical physiological pO2 gradient between the lungs and tissues during air breathing would be about 60 Torr. if an atmosphere containing 90±100% O2 were breathed. It was also noted that a near-wall excess of PFC droplets was not essential to cause this increase but. the duration and magnitude of such responses are highly species-speci®c and dependent. In the microcirculation. as noted already.51].5 ml per 100 ml of OxygentTM to haemodiluted patients breathing supplementary O2 during surgery would temporarily maintain adequate tissue oxygenation.13] that most of the side-effects attributed to secondgeneration PFC emulsions. in some instances. low shear regions of the vessel [50. a PFC emulsion will make a signi®cant contribution to overall tissue O2 delivery. [56] described computer programme which predicted that the infusion of ca. are ideally only ca. 1. the overall plasma O2 concentration achieved was even greater [50. 7±8 mm). Oxygen delivery by PFCs appears to be more complex than simple `bulk' transport. as measured by the mixed venous O2 tension (pvO2). the corresponding value for a 60% (w/v) per¯ubron emulsion under ambient pO2 would be ca. PFC droplets will occupy the plasma gaps between erythrocytes and thereby perfuse even the smallest capillaries. [55]. vital capacity. 5 ml O2 per 100 ml.C. such as delayed febrile reactions and ¯u-like symptoms. such theoretical analyses assist in predicting the precise mechanisms by which PFCs improve tissue oxygenation and form a baseline for the interpretation of in vivo studies. The programme has subsequently been validated in animal studies and in . 8.51] compared their theoretical ®ndings with experimental observations on PFC-mediated O2 supply [53. delay the indication for transfusion of donor (allogeneic) blood and. therefore. However. in part. thus representing an extraction rate of ca. However. ef®cacy was maximised when patients breathed an O2-enriched atmosphere [11±13]. with transient alterations in cellular enzymes.K. 7.g. Injection of PFCs is often followed by temporary increases in the weights of liver and spleen coupled. PFC emulsions as tissue oxygenation fluids and potential transfusion alternatives Faithfull et al. it has been proposed [46±49] that PFCs may enhance O2 transfer into tissues by acting as `stepping stones' between red cells and blood vessel walls. and then diffuse through both the membranes of the endothelial cells and those of the tissues it is supplying. pass through the plasma. PFC emulsion droplets in the circulation are believed to ¯ow mainly in the plasma layer that forms close to the vessel walls as a result of red cell streaming [11]. 2 ml O2 per 100 ml. mainly liver Kupffer cells and spleen macrophages. Under such conditions. where it occurred. Patel and Mehra [50. under such conditions.51]. in some patients.45]. In this respect. Their modelling approach was based on an earlier study which used engineering mass transfer principles to compare O2 uptake in PFC emulsions and blood [52]. on dose and type of PFC injected [1±5]. It been claimed [11. Alveolar O2 loading in PFCs increases linearly in proportion to the pO2 and is.54]. PFCs subsequently diffuse back into the blood where they are carried in plasma lipids to the lungs and exhaled [43]. arterioles). lung compliance or the dynamic behaviour of the natural lung surfactant [44. Lowe / Journal of Fluorine Chemistry 109 (2001) 59±65 63 monocyte-macrophage system (MMS). especially the cytochromes P-450 complex [1±5]. Additional support for PFC-enhanced increased transfer of O2 from red cells to tissues also comes from the modelling studies described by Perevedentseva et al. thus. For example. O2 delivery by PFC is also much simpler than the release of O2 from haemoglobin. the patients pre-donated (autologous) blood could be kept in reserve until needed. where the red blood cells were predicted to migrate towards the central. This example illustrates why. leading to enhanced tissue oxygenation. Some perfusion by PFCs will be expected to occur in vessels that effectively exclude red cells through local vasoconstriction or ischaemia. enhanced if the recipient breathes supplementary O2. Such use of OxygentTM would. Oxygen transport and delivery by PFCs Oxygen dissolves in PFC droplets as they pass through the lungs. Thus. Animal studies have shown that the pulmonary elimination of per¯ubron does not affect functional residual capacity. about 10 ml O2 per 100 ml would be released. thus raising the arterial pO2 to >400 Torr. 2±3% of the diameter of the normal erythrocyte (ca. 25%. Patel and Mehra [50. where the gas has to cross the red cell membrane. Oxygen extraction from PFCs is signi®cantly increased by the lack of chemical ®xation and by the large surface area provided by the emulsion droplets which. representing an extraction rate of ca.51] studied aspects of O2 transport in mathematical models of both uniform and non-uniform blood-PFC systems focusing on O2 uptake from large (>300 mm diameter) and smaller (<300 mm) vessels into tissues. In contrast. At elevated O2 tensions. can be attributed to the normal activity of the phagocytic cells of the MMS scavenging PFC droplets from the blood. Overall. 90% [46.47]. PFC emulsion signi®cantly increased O2 ¯ux at the vessel wall. haemoglobin 15 g per 100 ml) releases ca. in clinical studies where a PFC emulsion was used to enhance tissue oxygenation.

Waschke. Zuck. Cells.L.G. coupled with autologous blood transfusion. Thus. J. in: T. Leonard. [64] reported that over 250 surgical patients had received OxygentTM during the Phase II clinical trials. [4] T. Eur. Rossi. Waschke. K.K. Faithfull. K. patients were initially subjected to acute normovolaemic haemodilution (ANH) with a colloidal plasma expander to collect ca. Blood Substitutes: Principles. [14] K. Batra and co-workers [57±59] subjected anaesthetised dogs to moderate haemodilution (®nal haemoglobin concentration 8 g per 100 ml) using hydroxyethyl starch solution. Baltimore. animals were then given a single dose of 1.B. Sci. as needed. Crit. in: E. Immob.v. and re-infused into the patient towards the end of surgery. Products and Clinical Trials. Infusion of the emulsion was followed by a 17% increase in mean pvO2. Crucial Phase III studies with OxygentTM were initiated towards the end of 1998. Elsevier. Anaesthesiol. Fluorocarbon emulsions as blood substitutes. Lab.). Keipert. excepting a 17% reduction in the platelet count after 3 days with the higher dose [61]. Lowe / Journal of Fluorine Chemistry 109 (2001) 59±65 ongoing clinical trials [11±13. 101±126. G. at 24 h after receiving the emulsion [62]. Lowe. In this respect. 15 (1998) 571±584. [19] M. Art. [8] J. J. Perfluorocarbons. 23 (1995) 381±394. R. mixed venous O2. Biotechnol. but also allows surgery to be initiated at a lowered packed cell volume. pp. venous drainage pO2. Biotechnol. coupled with increased serum interleukin-6 concentration. Boston.M. Challenges. Riess. 13 (1999) 171±184. Future research should focus on resolving this important issue. J. Gould (Eds. C.E. Spahn et al. Meinhardt. M. 1996. 1997. 16 (1998) 272±277. Biotechnol. T. Riess.A. is a desirable and cost-effective strategy for blood conservation and limiting the use of banked blood [67±69]. Industrial Opportunities and Medical È user. Quintel. persistence compared to transfused red blood cells [66] This raises the question of whether perioperative ANH. [11] P. Blood Rev. Cells. Care 26 (1998) 11±21. 127±156. pp. Fluorocarbon-based oxygen-delivery: basic principles and product development. Keipert subsequently noted that by November 2000.F. 74 (Suppl. 5 (1994) 15±32. Intens. in an extensive study involving 147 orthopaedic patients. Clin.C. Simon. Rev. Following haemodilution. uptake of dissolved O2. were:       increased increased increased increased increased increased plasma O2 concentration. Birkha [13] P. systemic O2 delivery.S. Power.8 g kgÀ1 OxygentTM (60% w/v per¯ubron) which signi®cantly raised the mean pO2 in skeletal muscle. Teicher. [10] N. Lausanne.F. in: R. Anaesth. Such use of relatively low doses of PFC emulsion to maintain tissue oxygenation means that autologous blood can be conserved . More recently. in accord with predictions from the earlier computer modelling [56]. Keipert.F. Anaesthetist 47 (1998) 479±489. Immob. Vasc. Spence. Vandegriff. Gedeit. pp.E.G. Riess.G. [12] S. Biomaterials 19 (1998) 1529±1539. [17] R.C.57±60].G. [9] T. Immob. In one preliminary study. Cells. 327±338. 189±196. 2nd Edition.. Chang (Ed. [18] S. Present and Future Perspectives of Blood Substitutes.13]. Clin.2 or 1. Frietsch. 1998. Basel. tissue oxygenation.G. Intaglietta (Eds. The potential oxygenation bene®ts from a PFC-based O2 carrier (assuming stable O2 consumption). Blood Subs. in: T. Med.). 2) (1998) 243±248. The latter ®ndings were consistent with previous observations of transient alterations in immune system function following intravascular infusion of emulsi®ed PFC [11. 91±132. Blood Substitutes: Principles. In September 1997. Products and Clinical Trials. II. M. Multiple-site Phase IIa ef®cacy trials with OxygentTM in surgical patients began in the USA and Europe during 1995± 1996. J. Perflubron-based emulsion: efficacy as temporary oxygen carrier. [7] J.C. Weers.M. Lowe..R.M.E. infusion of 1. as noted by Keipert [11]. 1998. K.P. References [1] K.P. and during concurrent 100% O2 breathing. Blood Subs.C. [63] reported that.9 g PFC kgÀ1 body weight) was infused into 100% O2-breathing patients as an alternative to blood [60]. con®rming this variable to be a reliable indicator of PFC-induced increased tissue pO2. Lowe. Infusion of OxygentTM also increased the pvO2 by 16%. Rev. Perfluorochemical emulsions: future alternatives to transfusion. whilst in [65].D. Advances in Blood Substitutes.S.. Lowe. Karger Landes.). 1998. [2] K.G. One problem with the perioperative use of current PFCbased O2 carriers is their relatively short i. pp. Riess. Lenz. 2 units of fresh autologous blood from each individual immediately before surgery. Sci. M. Chang (Ed. Trends Biotechnol.8 g of Per¯ubron emulsion per kilogram body weight combined with 100% O2 ventilation was more effective than autologous blood or colloid solution in reversing physiologic transfusion triggers. 25 (1997) 43±52. Day. [6] J.S.). OxygentTM is currently being evaluated in advanced clinical trials as a temporary tissue oxygenation ¯uid for use in patients undergoing potentially high blood loss (typically 3 units or more) surgical procedures. 25 (1998) 711±722. Moss. Art. Tsuchida (Ed. Krafft. Methods. Reports on Phase I safety studies using OxygentTM infused intravascularly into healthy volunteers (1. the use of PFC emulsion in conjunction with ANH not only minimises the need to infuse allogeneic blood. Williams and Watkins. Karger Landes. Vox Sang. Lowe. Art. brain parietal cortex and gut serosa. II. A single bolus dose of a 90% (w/v) per¯ubron emulsion (0.S. M. pp. S.C. Winslow.E. Perinatol. the number had risen to >1300. [5] R. Krafft. 31 (1994) 295±324. Keipert et al. 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