current status of artificial oxygen carriers

LAdvanced Drug Delivery Reviews 40 (2000) 143–151www.elsevier.com/ locate /drugdeliv

Current status of artificial oxygen carriers*Donat R. Spahn

¨ ¨ ¨ ¨ ¨Institut f ur Anasthesiologie, UniversitatsSpital, Ramistrasse 100, CH-8091 Zurich, Switzerland

Received 10 August 1999; accepted 15 October 1999

Abstract

Artificial oxygen carriers may be grouped into modified hemoglobin solutions and fluorocarbon emulsions. In animalexperiments, both have been shown to be efficacious in improving tissue oxygenation and as substitutes for bloodtransfusions. Advantages and disadvantages are being discussed in this article as well as the latest steps in the clinicaldevelopment. 2000 Elsevier Science B.V. All rights reserved.

Keywords: Artificial oxygen carriers; Oxygen transport; Hemoglobin solutions; Fluorocarbon emulsion; Perflubron

1. Introduction to decrease O affinity and to prevent rapid dissocia-2

tion of the native a –b tetramer into a–b dimers.2 2

Artificial oxygen (O ) carriers aim at improving This has been reviewed in detail [2].2

O transport and O unloading to the tissue. Artifi- The O transport characteristics of modified hemo-2 2 2

cial O carriers may thus be used as an alternative to globin solutions and fluorocarbon emulsions are2

allogeneic blood transfusions or to improve tissue fundamentally different (Fig. 1 and Tables 2 and 3).oxygenation and function of organs with marginal O The modified hemoglobin solutions exhibit a sigmoi-2

supply. Such substances have also been named dal O dissociation curve similar to blood. In con-2

‘artificial blood’. This term, however, is a misnomer trast, the fluorocarbon emulsions are characterized bysince these substances are designed to exclusively a linear relationship between O partial pressure and2

carry O and CO while they are devoid of other O content. Modified hemoglobin solutions thus2 2 2

properties of blood such as coagulation and anti- provide an O transport and unloading capacity2

infectious properties [1]. The aim of the presentTable 1article is to describe the currently evaluated artificialArtificial O carriers. The modified hemoglobin solutions are2O carriers, to summarize their efficiency and to2 grouped by the source of the hemoglobin

discuss potential side-effects.Modified hemoglobin solutionsCurrently evaluated artificial O carriers can be2Outdated human bloodgrouped into modified hemoglobin solutions andBovine hemoglobin

fluorocarbon emulsions (Table 1). The native human Human recombinant hemoglobinhemoglobin molecule needs to be modified in order E. coli [50]

Transgenic tobacco [51]Fluorocarbon emulsions

*Tel.: 141-1-255-2696; fax: 141-1-255-4409.Perflubron

E-mail address: [email protected] (D.R. Spahn)

0169-409X/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S0169-409X( 99 )00046-0

144 D.R. Spahn / Advanced Drug Delivery Reviews 40 (2000) 143 –151

Table 2Advantages and disadvantages of hemoglobin solutions

AdvantagesCarries and unloads O2

Sigmoidal O dissociation curve2

100% FiO is not mandatory for maximal potency2

Easy to measure

DisadvantagesSide-effects

VasoconstrictionInterference with colorimetric laboratory methods

Table 3Advantages and disadvantages of fluorocarbon emulsions

AdvantagesCarries and unloads O2

Few and mild side-effectsNo known organ toxicity

Disadvantages100% FiO is mandatory for maximal potency2

Additional colloid often necessary with potential side-effects

maximize the O transport capacity of fluorocarbon2

emulsions. Despite these fundamental differences,the efficiency of both groups of artificial O carriers2

has been demonstrated under a variety of experimen-tal conditions (see below).

2. Hemoglobin solutionsFig. 1. (Top) O dissociation curve of native human blood2

(Blood) and human recombinant hemoglobin version 1.1 (rHb1.1)(modified according to Looker et al. [50]). P is the partial O50 2 The efficiency of hemoglobin solutions to trans-pressure required for 50% O saturation. Note the higher P (4.42 50 port and unload O has been shown in a variety of2kPa) resulting in a greater O unloading capacity (35%) for2 shock models and at extreme hemodilution [2]. In arHb1.1 compared with native blood (P 5 3.5 kPa and an O50 2

whole animal sheep model, Vlahakes et al. showed,unloading capacity of 24%) when assuming a mixed venous PO2

of 5.3 kPa. (Bottom) O carrying capacity of native human blood in awake sheep, that extreme hemodilution to a2

(Blood) and perflubron emulsion (modified according to Keipert et hematocrit of 2.460.5% was only tolerated when aal. [38]). Note that 5 vol% of O can be offloaded by the blood as2 polymerized bovine hemoglobin solution was used,well as by the perflubron emulsion. With the perflubron emulsion,

but not in animals treated with hydroxyethyl starchhowever, higher arterial P values are required. Note also thatO2 devoid of O carrying capacity [3]. All animalsperflubron emulsion transported O is more completely offloaded 22

than blood transported O , resulting in approximate O extraction surviving acute hemodilution also survived the fol-2 2

(O -Ex.) ratios of 90 and 25%. C denotes O content and P2 O 2 O lowing 25 days without evidence of renal or hepatic2 2

denotes O partial pressure.2 dysfunction [3]. Similar results were achieved re-cently when anesthetized dogs were hemodiluted to a

similar to blood. This means that, already at a hematocrit of 2.061.8% using a polymerized bovinerelatively low arterial O partial pressure, substantial hemoglobin [4]. Even at this extremely low hemato-2

amounts of O are transported. In contrast, relatively crit, the dogs were hemodynamically stable, there2

high arterial O partial pressures are necessary to was no evidence of (lactic) acidosis and there were2

D.R. Spahn / Advanced Drug Delivery Reviews 40 (2000) 143 –151 145

no histologic signs of ultrastructural destruction in Thus, modified hemoglobin solutions are indeedliver and kidney. very promising for improving O transport and tissue2

Siegel et al. found, in dogs, that infusion of human oxygenation to a physiologically relevant degree.recombinant hemoglobin (rHb1.1) resulted in a more Without the need of cross matching, these solutionsrapid reversal of O debt after progressive hemor- thus hold great promise as an alternative to al-2

rhage, a more uniform reperfusion and a more logeneic blood transfusions and as O therapeutics2

complete wash-out of acids accumulated during which may also be of great value in the prehospitalbuildup of the O debt during hemorrhage compared resuscitation of trauma victims or in specific situa-2

with treatment with a mixture of autologous blood tions in intensive care medicine.and colloid [5]. Since the breakdown of the native a –b hemo-2 2

In a rat model of hemorrhage and surgical trauma, globin tetramer into a–b dimers is largely preventedXu et al. demonstrated that treatment with a-a- by genetic modification or chemical modification,diaspirin cross-linked hemoglobin improved wound nephrotoxicity is no longer a potential side-effect ofhealing, enhanced hepatic cell proliferation and, most these solutions [12]. Simultaneously, the intravascu-importantly, decreased splanchnic bacterial translo- lar half-life was also prolonged. Interestingly, thecation when compared with transfusion of fresh intravascular half-life increases with increasing doseautologous blood [6]. It is of particular interest that [13] (for a-a-diaspirin cross-linked hemoglobin) andtreatment with a-a-diaspirin cross-linked hemoglo- increases with achieved plasma hemoglobin con-bin induced a more favorable response to trauma and centration [12] (human recombinant hemoglobin,hemorrhage than transfusion of fresh autologous rHb1.1). Although there are no definitive data avail-blood considering the fact that the efficiency of able on the intravascular half-lives of the variousblood transfusions in improving O consumption and modified hemoglobin solutions in man, a dose-re-2

aerobic metabolism is not exactly defined [7]. In fact, lated increase in intravascular half-life could be veryonly fresh blood (3 days old), but not 28 day old advantageous for the clinical use of these substances.blood, was recently shown to partially correct the Vasoconstriction resulting in an increase in sys-decrease in O consumption induced by extreme temic and pulmonary artery pressures has been2

hemodilution [8]. It is therefore particularly notewor- observed with all modified hemoglobin solutionsthy that a-a-diaspirin was even more efficient than evaluated so far. The mechanisms involved includetransfusion of fresh autologous blood, which was not nitric oxide (NO) scavenging [2,14–16], endothelinstored at all [6]. release [17] and a sensitization of peripheral a-

Bovine polymerized hemoglobin was also more adrenergic receptors [18]. NO scavenging has beenefficient in restoring muscle P after extreme the subject of a variety of studies [2,14–16]. NOO2

hemodilution to a hematocrit of 10% in dogs than produced by the endothelial cells reacts with the21fresh (day of experiment) or old (21 days) autolog- Fe in the guanylate cyclase located in the smooth

ous blood [9]. Likewise, muscle P was better muscle cells of the vessel wall to modulate theO2

restored with bovine polymerized hemoglobin than vascular tone towards vasodilatation. It has beenhydroxyethyl starch in a dog model of hemodilution speculated that unpolymerized hemoglobin mole-(hematocrit of 23–27%) and 95% arterial stenosis cules, in particular, may penetrate into the interstitial[10]. space of the subendothelial layers of vessel walls

Hemoglobin solutions have also been used in [19]. Extravascular hemoglobin at this locationresuscitation from hemorrhagic shock [11]. In awake would be perfectly positioned to scavenge NO andsheep bled to a base deficit of 25 to 210 meq/ l, thus to shift vasomotor tone towards vasoconstric-infusion of a-a-diaspirin cross-linked hemoglobin tion. Although, to my knowledge, there are norestored the base deficit at a similar rate as the studies directly demonstrating the presence of ex-infusion of autologous blood. Therefore, blood and ogenous hemoglobin molecules within the interstitiala-a-diaspirin cross-linked hemoglobin were both space of blood vessels, there are studies documentingsignificantly more efficient than hydroxyethyl starch, extravasation of hemoglobin molecules [20,21].a colloid without O carrying capacity. The involvement of NO-scavenging in the vaso-2


pressor effect of many hemoglobin solutions is striction may be used therapeutically in patients withfurthermore suggested by the particular efficiency of septic shock to decrease the vasopressor support withNO donors such as nitroglycerin and L-arginine in norepinephrine [25].decreasing hemoglobin-induced hypertension [22]. Such mild vasoconstriction might also be wellAn increase in mean arterial pressure due to hemo- tolerated or even be beneficial in other states ofglobin infusion can also be prevented with endo- vasodilatation such as in the early period afterthelin receptor antagonists [17]. Thus, there are ways cardiopulmonary bypass. Indeed, Baron et al. haveto prevent or treat hemoglobin-mediated vasocon- recently shown that the incidence of allogeneic bloodstriction. transfusions can be significantly reduced with the use

Hemoglobin-induced vasoconstriction may be re- of a-a-diaspirin cross-linked hemoglobin in patientsgarded as an untoward side-effect. This view may be undergoing cardiac surgery [26]. In this prospectivecorrect when relatively small volumes of hemoglobin randomized multicenter study, 209 patients weresolutions are being given to patients with a reduced allocated to receive either packed allogeneic redcardiac contractility and a normal or elevated mean blood cells or up to 750 ml of a 10% a-a-diaspirinarterial pressure. In such patients a hemoglobin cross-linked hemoglobin solution when reaching ainfusion may induce increases in systemic and predefined transfusion trigger following cardiopul-pulmonary vascular resistances high enough to cause monary bypass. In the a-a-diaspirin cross-linkeda reduction in cardiac output [15]. In contrast, in a hemoglobin group, 59% of patients avoided al-previously healthy trauma victim suffering from logeneic blood transfusions until the first postopera-severe hypovolemia due to massive hemorrhage, the tive day, while, by the study protocol, 100% ofcombined effects of volume replacement, added O patients randomized to the control group had re-2

transport capacity and a certain vasoconstriction due ceived packed allogeneic red blood cells. At hospitalto the infusion of a modified hemoglobin solution discharge, 19% of patients in the a-a-diaspirin cross-may be very beneficial indeed. However, this may be linked hemoglobin group still avoided any allogeneictrue primarily in blunt trauma, while with penetrating transfusion as compared to none in the control group.(torso) injury even a mild vasoconstiction might also This statistically significant result indicates that it isbe deleterious in a relatively healthy young trauma indeed possible to save allogeneic blood transfusionsvictim because any increase in blood pressure may with the use of modified hemoglobin solutions.aggravate blood loss and compromise survival [23]. Besides the use of a-a-diaspirin cross-linked

Also very important regarding the relevance of hemoglobin in patients undergoing cardiac surgery,hemoglobin-induced vasoconstriction is the recent hemoglobin solutions have been used in humansobservation that the vasoconstriction due to a-a- during preoperative hemodilution prior to aortic [15]diaspirin cross-linked hemoglobin is not distributed and liver surgery [27] as well as in trauma andevenly throughout the body. Dietz et al. found that emergency surgery [28]. In both well controlledvasoconstriction was most pronounced in the femoral hemodilution protocols a distinct and statisticallyartery supplying mainly skeletal muscles, but no significant vasoconstriction, as evidenced by anvasoconstriction was observed in the mesenteric increase in mean arterial pressure and systemicvasculature and a distinct vasodilatory effect was vascular resistance and a concomitant decrease inobserved in the coronaries [16]. These findings were cardiac output, was observed when a polymerizedrecently confirmed by Gulati and Sen, who measured bovine hemoglobin solution was being infusedorgan blood flows after hemorrhagic shock in rats [15,27]. In contrast, it is claimed that no vasocon-resuscitated with a-a-diaspirin cross-linked hemo- striction had occurred when a polymerized humanglobin [24]. These authors also found a significant hemoglobin solution was infused in trauma patientsincrease in blood flow to the brain, heart and kidneys and during emergency surgery, respectively [28].after resuscitation with a-a-diaspirin cross-linked However, no cardiac output data are presented andhemoglobin, while blood flow to the splanchnic thus assessment of vasoconstriction due to the infu-organs was restored to the pre-hemorrhage level sion of a hemoglobin solution during concomitant[24]. Furthermore, hemoglobin-mediated vasocon- emergency surgery appears rather difficult. Besides


vasoconstriction, hemoglobin solutions have been characteristics is a great technological challenge,well tolerated in all published studies so far. Par- because only droplets of a very specific size (approx-ticularly important may be the fact that, 3 months imately 0.17 mm diameter) are well tolerated. Theafter administration, no anti-hemoglobin antibodies spectrum of side-effects also critically depends onwere detected [29]. However, clinical experience the size distribution of the droplets; in general, thewith true re-administration of hemoglobin solutions narrower the distribution around the target size, theis lacking at the present time. fewer the side-effects. With the development of a

Other aspects of hemoglobin solutions deserve stable 60% (58% perfluorooctyl bromide and 2%mentioning. Since hemoglobin solutions are colored perfluorodecyl bromide) emulsion there is now asolutions the potential exists that some colorimetric relatively highly concentrated emulsion which islaboratory measurement methods may be disturbed clinically well tolerated [33–35].[30]. The potential also exists that the presence of After intravenous application, the droplets of theplasma hemoglobin could interfere with AB0 and Rh emulsion are taken up by the reticulo-endothelialtyping and cross-match testing. A recent study, system (RES). This uptake into the RES determineshowever, indicated that this concern was unfounded the intravascular half-life [2,33,35]. At the presentso that should a patient require allogeneic blood time no exact data are available on the intravascularproducts in addition to the initially transfused hemo- half-life in humans. After the initial uptake of theglobin solutions, compatibility testing appears undis- fluorocarbon emulsion into the RES, the droplets areturbed [31]. The lack of preexisting antibodies to slowly broken down, and the fluorocarbon moleculesa-a-diaspirin cross-linked hemoglobin was recently are taken up in the blood again (bound to blooddemonstrated in more than 300 patients [32] as well lipids) and transported to the lungs, where theas the absence of immunogenicity of a-a-diaspirin unaltered fluorocarbon molecules are finally excretedcross-linked [32] as well as in a small study in six via exhalation. At the present time, metabolism ofpatients for a polymerized bovine hemoglobin solu- fluorocarbon molecules is unknown in humanstion [29]. There is also one report in dogs, in which [2,33,35].infusion of human recombinant hemoglobin induced The ability of fluorocarbon emulsions to transportan increase in liver enzymes as well as amylase [5]. and efficiently unload O is undisputed. Young et al.2

However, in other studies in which even larger showed, in patients undergoing coronary angioplasty,quantities of bovine hemoglobin were given, no that distal coronary perfusion with oxygenatedhepatic dysfunction was observed during 25 days Fluosol largely blunted myocardial lactate releaseafter near complete exchange transfusion [3]. during balloon inflation and prevented major regional

wall motion abnormalities, resulting in a far betterpreserved left ventricular ejection fraction [36]. The

3. Fluorocarbon emulsions ischemia-preventing effect of distal coronary perfu-sion with Fluosol was confirmed by Kent et al., again

Fluorocarbons are carbon–fluorine compounds demonstrating by echocardiography that wall motioncharacterized by a high gas dissolving capacity (O , was far better preserved during balloon inflation in2

CO and other gases), low viscosity, and chemical transluminal coronary angioplasty and that patients2

and biological inertness [2,33]. Fluorocarbons are experienced significantly less angina [37].virtually immiscible in water. The first generation Perflubron emulsion has been assessed in a variety

fluorocarbons, such as Fluosol (Green Cross Corp., of hemodilution studies. Keipert et al. applied per-Japan), used a poloxamer-type Pluronic F-68 as an flubron emulsion in dogs after acute normovolemicemulsifier, which, however, has the potential to hemodilution at a hematocrit of 10% [38]. Duringcause anaphylaxis [33]. The second generation hemodilution the expected increase in cardiac outputfluorocarbons use egg-yolk phospholipid as emul- was observed [2,38]. With the application of perflub-sifier, which is well tolerated except in patients with ron emulsion, cardiac output tended to increasean egg allergy [2,33]. further and a massive rise in mixed venous O partial2

Manufacturing an emulsion with very specific pressure and mixed venous saturation was observed.


The percentage of metabolized O originating from transport and also unload O where this oxygen was2 2

endogenous hemoglobin decreased dramatically with needed most.the application of perflubron emulsion, indicating Perflubron emulsion has also been used in humansthat the O transported by perflubron emulsion is [34]. Acute normovolemic hemodilution to a hemo-2

preferentially metabolized, most likely due to the globin concentration of approximately 9 g/dl wasexcellent O unloading characteristics of this fluoro- performed preoperatively. During surgery, perflubron2

carbon emulsion [38]. emulsion (0.9 g/kg) was administered when a bloodFurthermore, Holman et al. tested perflubron transfusion was deemed necessary by the anes-

emulsion in severely hemodiluted dogs undergoing thesiologist, which occurred at a hemoglobin con-cardiopulmonary bypass [39]. Without using cat- centration of approximately 8 g/dl. Mixed-venousecholamines, dogs treated with increasing doses of oxygen tension and mixed-venous oxygen saturationperflubron emulsion survived cardiopulmonary by- both increased significantly after perflubron emulsionpass progressively better than control animals. Also, administration and cardiac output was stable. Al-brain tissue oxygenation may be improved by a though only relatively little O was transported by2

combined treatment with Perflubon infusion and the perflubron emulsion (approximately 1%), 5% of100% oxygen ventilation, notably more than with the metabolized O originated from the perflubron2

100% oxygen ventilation alone [40]. emulsion transported O , again indicating that per-2

Perflubron emulsion may also be beneficial as an flubron emulsion transported O is preferentially2

adjunct to resuscitation. In a porcine model of near metabolized [34,38].fatal hemorrhage, perflubron emulsion treatment in Recently, the results of a large prospective ran-addition to standard resuscitation decreased mortality domized multicenter study on the use of perflubronfrom 43 to 13% [41]. Although this difference did emulsion in orthopedic surgery were presented [46].not reach statistical significance due to a small In this study, patients undergoing hip replacementnumber of observations (n 5 15 total) it was felt by and spine surgery were hemodiluted preoperativelythe authors that the added and readily available O to a hemoglobin level of 9 g/dl. After the patients2

provided by perflubron emulsion was beneficial. had reached a predefined transfusion trigger, theyAlso in a dog model of ventricular fibrillation the were randomized into four groups: group A, standardadditional direct infusion of oxygenated perflubron care (retransfusion of 450 ml of autologous blood atemulsion into the aortic arch improved the chances an unchanged FiO of 0.4); groups B and C,2

of spontaneous return of circulation and this was perflubron emulsion (0.9 or 1.8 g /kg) with colloid toachieved earlier as with standard resuscitation [42]. a total of 450 ml with ventilation with an FiO of2

In addition, Habler et al. recently found that the 1.0; group D, infusion of 450 ml of colloid withmixed-venous O partial pressure was higher in ventilation with an FiO of 1.0. Perflubron emulsion2 2

perflubron emulsion treated animals after hemodilu- (1.8 g /kg) was most successful in reversing transfu-tion to a hemoglobin of 7 g/dl than in control sion triggers in 97% of patients as compared to 60%animals [43,44] and also measures of left ventricular in the control group. Transfusion trigger reversalcontractility were found improved after perflubron lasted significantly longer in the perflubron emulsionemulsion administration at a hemoglobin level of 3 1.8 g /kg group (80 min) than in the control andg/dl [45]. This might be explained by augmented O colloid groups (55 and 30 min). Thus, physiologic2

delivery through very narrow capillaries where per- transfusion triggers may be treated at least as suc-flubron emulsion particles (,0.2 mm in diameter), cessfully with perflubron emulsion as with autolog-but less so the relatively larger red blood cells (7–8 ous blood of colloids. This illustrates the remarkablemm in diameter), may penetrate and thereby increase potency of perflubron emulsion to deliver readilylocal tissue oxygenation including the myocardium available O to those areas in the body where the2

[35]. Furthermore, in all of these studies a trend extra O is most needed.2

towards a higher blood pressure was observed after Fluorocarbon emulsions also have side-effects.treatment with perflubron emulsion [44,45]. These Volunteers experienced mild flu-like symptoms withstudies indicate that perflubron emulsion did indeed myalgia and light fever and an approximately 15%


decrease in platelet count 3 days post-dosing return- the sum of endogenous hemoglobin (within reding to normal by day 7 [33,47]. Traditional coagula- blood cells) and exogenous hemoglobin (in thetion tests including bleeding time, however, were plasma), correctly. However, since we should not gounaffected by perflubron emulsion [47]. With a by hemoglobin concentration alone in our decisionmodification of the fluorocarbon emulsion, these regarding blood transfusions [49], the above differ-side-effects were blunted and thus no longer repre- ence may not be relevant. However, daily practice insent a relevant clinical problem. many institutions is still to transfuse blood primarily

based on institutional guidelines in which the hemo-globin concentration may be a crucial parameter.

4. Comparison between hemoglobin solutions Also, the recourse used for the production of theseand fluorocarbon emulsions solutions may matter for certain groups of physicians

and patients, such as Jehovah’s witnesses.A direct comparison between hemoglobin solu- Public knowledge of both categories of artificial

tions and fluorocarbon emulsions is difficult. To a O carriers is not sufficient to favor one over another2

large extent this is related to the fact that there are no at the present time. Hemoglobin solutions as well ascomparative studies between different hemoglobin fluorocarbon emulsions have both been demonstratedsolutions or between hemoglobin solutions and in many situations to transport and unload O2

fluorocarbon emulsions. Despite the lack of such efficiently. Furthermore, it is expected that modifieddirect comparisons, there are several aspects in formulations will be developed which will serve thiswhich these substances can indeed be compared. In purpose even better in the future. Artificial O2

this comparison, qualitatively similar properties of carriers are thus very promising substances whichthe different hemoglobin solutions are assumed, will enter clinical medicine within the next 5 years.knowing that this assumption may not be correct.

Hemoglobin solutions are also isooncotic or evenhyperoncotic colloidal volume expanders. Infusion of Referencesthese solutions thus not only provides additional O2

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Tiede, G.I. Kemming, M.V. Welte, C.O. Corso, S. Batra, P.E.

current status of artificial oxygen carriers

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