Biomaterials, Artificial Cells and Immobilization Biotechnology

ISSN: 1055-7172 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ianb18

Potential Clinical Applications for Blood Substitutes Robert M. Winslow To cite this article: Robert M. Winslow (1992) Potential Clinical Applications for Blood Substitutes, Biomaterials, Artificial Cells and Immobilization Biotechnology, 20:2-4, 205-217, DOI: 10.3109/10731199209119636 To link to this article: http://dx.doi.org/10.3109/10731199209119636

Published online: 11 Jul 2009.

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BIOMAT.,

ART. C E L L S EL IHMOB. BIOTECH.,

20(2-4), 2 0 5 - 2 1 7 ( 1 9 9 2 )

POTENTIAL CLINICAL APPLICATIONS FOR BLOOD SUBSTITUTES

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Robert M. Winslow, MD.

Depatiment of Medicine, Universiiy of Calgomia, San Diego, 92093

Abstract: In the coming decade, it is likely that oxygen-carrying alternatives to red blood cells will become available for clinical use. The driving force behind their development is the risk of transfusion of homologous blood, which includes transmission of viral disease (HIV and hepatitis) and transfusion reactions as well as the expense of collecting and storing human blood. A number of clinical applicationsfor these products can be anticipated now, but when available, it is likely that the list will grow. How widely these products will be used depends on their safety. In addition to these clinical applications, blood substitutes will be useful in furthering our understanding of basic oxygen transport physiology. The Impact of Red Cell Substitutes on Transfusion Medicine

Red cell transfusion is big business. More than 13 million units are collected each year in the United States alone, and about 10 million units are transfused into 4 million recipients. Of these units, about two-thirds are used during surgery, and the rest are used either for medical or trauma indications. The use of blood and blood products in other parts of the world are not as well known, but represents a significant amount of blood also (Winslow 1991). "he AIDS epidemic has forced careful attention to the clinical indications for transfusion. All units transfused in the United States in the past five years have been screened for HIV, but still about 1 out of 40,000 units can transmit the disease (Busch et af. 1990). Based on 10 million total transfusions, this represents about 250 new cases of AIDS per year transmitted by blood screened as negative. About thirty-five transfusion-related deaths are reported to the Food and Drug Administration(FDA) each year, most of which are attributed to clerical error (ABO incompatibility) and bacterial infection. Hepatitis-related morbidity and mortality may result from as much as 5 percent of all units transfused (Klein 1989). Although 205 Copyright 0 1992 by Marcel Dckker, Inc.

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Table I. Possible Applications for Blood Substitutes Reeusdtation (trauma) E l d v e surgery (hernodilution) Red CCU incompatiity Ischemic distasc

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owaa w m cell fultun

Hematopokb Cardioplegia Sickle-cell anemia Tumor therapy Chronic anemia Imaging Respiratory distress syndrome Decompression sickness RC8Carcb

efforts at ridding the blood supply of all viral contamination have been impressive (Chernoff et al. 1989), no methods of sterilizing cellular components are available currently. It is quite likely that if a sterile, stable, safe alternative to red cells were available, the usage would surely be even higher than the usage of red cells is today. Clinical Indications for Blood Substitutes The clinical indications for which red cell substitutes would be used are still not defined because the products are not available and their properties and formulations are not determined. In any clinical use the benefit of a new agent must be weighed against its risk and against the benefit/risk of existing therapy. In spite of the lack of products for testing, it is nevertheless useful to consider the clinical applications for which these solutions might be developed. This exercise is necessary to plan specific formulations (Table 1). 1. Resuscitation after Trauma One of the most obvious clinical applications for blood substitutes is in emergenciessuch as trauma. Among the factors that determinethe long-term survival after resuscitation from hypovolemic shock is the duration of the shock state (Baker el al. 1985). Messmer and his colleagues (Messmer 1988) have conducted extensive studies of the microcirculation in shock and have pointed out that under the influence of the sympathetic nervous system, blood flow is redirected to protect vital organs. Traumatized tissue can be excluded from this control, however, and blood actually may be directed preferentially to sites of bleeding, with consequent

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hematoma formation.This redistributionof blood flow may protect systemic pressure so that in some instances the degree of shock may not be clinically apparent. Thus, the survival after hemorrhage from severe trauma declines dramaticallyafter the first hour. This critical period has become known as the Go& Hour (Belzberg 1989). Experience during the Korean and Vietnamese conflicts has convinced military physicians that this period is also critical on the battlefield (Mosebar 1989). The objectivesof posthemorrhagefluid therapy are first to reestablish cardiac output by volume expansion and then to reestablish the flow of oxygen to ischemic tissue. Trauma specialists have disagreed for years on whether crystalloid or colloid is preferred in blood-loss shock (Messmer 1988). but it seems that most patients are eventually given electrolytes, colloids, blood, red cells, and clotting factors at some time during their treatment. Since selection of patients for specific parented fluid treatment is controversial it is premature to speculate on which would be candidates to receive blood substitutes if they were available. In routine clinical practice, Ringer's lactate is the most widely used volume expander. In order to restore the cardiac output with this solution, three to four times the volume of lost blood must be given. Some of this hypooncotic material is lost into the interstitial space, and tissue edema can result. The considerable amounts of oncotically active molecules lost in blood-loss shock must be replaced eventually. Prospective, randomized studies have shown that in fact, hernodynamics were restored faster, with less tissue edema, when dextran-70 was the first fluid used instead of Ringer's acetate (Modig 1983; 1986). Recently, interest in the use of hypertonic-hyperoncoticsolutions has been revived. These contain approximately7.5 g/dl NaC1, usually with a colloid such as dextran-70. A number of investigatorshave shown that when small volumes of such solutions are given to animals after the induction of hypovolemic shock, the cardiac output is restored almost immediately (Smith, Kramer et al. 1985; Maningas et ul. 1986, Kramer er al. 1986; Kreimeier and Messmer 1987). In addition to the volume expansion properties, lower molecular weight dextran-40 also has antithrombotic properties, which makes it attractive in vascular obstructive disease, hyperviscosity syndromes, and cerebral vascular insufficiency (Messmer 1988; Goslinga 1981). Hemoglobin solutions have the potential to both provide volume and O2delivery. It would seem that most of the desired properties of hypertonicsaline-dextran,albumin, and whole blood could be combined in a single solution of hemoglobin and electrolytesbut with the added advantage of low viscosity. However, specificationof the properties of this "ideal" solution would be controversial. Add the considerations of oncotic pressure, electrolyte composition and coagulation effects, plasma persistence time, shelf life, and possible toxic effects associated with hemoglobin, and it seems apparent that final formulationof a hemoglobin-containingsolution is a long way off. Perfluorocarbon emulsions have been administered to many recipients as temporary blood substitutes. However, since these materials are selectively taken up by the

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reticuloendothelialsystem, concern has been raised that spleen and liver enlargement might limit their large-scale use. At this time it appears that perfluorocarbon emulsions might not be appropriate for largedose usage such as shock, but newer preparations with shorter retention times might lead to a reevaluation of this of this position. Moreover, low-dose peffluorocarbons in conjunction with a crystalloid volume expander could be very useful.

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2. Elective Surgery (Acute Normovolumic Hemodilution)

In the United States it is during the perioperative period that most blood and red cells are used. Indications for transfusion have included a hemoglobin concentration less than 10 g/dl (Mollison 1983), but this rule is being reevaluated at present in view of the diminishing blood supply and the recognition of the complications of transfusion (National Institutes of Health Consensus Conference 1988). However, surgical studies suggest that the postoperative period can be shortened and, perhaps, made safer if hemoglobin concentrations are not allowed to fall to less than 10 g/dl. Although animal studies have shown that the hemoglobin concentration could be safely reduced to about 25 percent of its normal value (Wright 1975) clinical experience, however, suggests that the hemoglobin concentration should not be allowed to drop below 8 g/dl (Carson er al. 1988). In addition to the prevention of anemia, the outcome of some surgical procedures is improved if blood viscosity can be reduced (Mandel 1986). In these procedures, the combination of low viscosity and maintained oxygen-carrying capacity might optimize transport of oxygen. The use of an oxygen-carrying red cell substitute could be invaluable in managing elective surgical procedures. Blood could be collected at the start of the operation and replaced by the oxygen carrier. The removed autologous blood could then be used as needed, either during or after the operation, avoiding the use of homologous blood. Traditional thinking has been that a red cell substitute, used as a hemodiluent, would be given in relatively large volumes, as blood would be used. However, theoretical calculations (unpublished) have suggested that in addition to increasing the bulk 0, transport in the plasma, small amounts of perfluorocarbon emulsions might also provide facilitation of O2diffusion to tissues. Experimental evidence is beginning to accumulate to support this possibility, and several abstracts in this symposium will discuss this point. Thus, peffluorocarbon emulsions might be used as an adjunct in acute normovolemic hemodilution to reduce or eliminate the need for homologous blood transfusion.

3. Red Cell Incompatibility Certain patients develop antibodies to many red cell surface antigens either because they have received multiple transfusions, sometimes over an entire lifetime, or because the existence of unusual antigens has led to minor incompatibilities in the

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past, with resultant elaboration of antibodies. Some patients simply cannot receive red cell transfusions without undue risk of a fatal reaction. Perhaps blood substitutes could play a role in some of these instances. However, it must be kept in mind that the products being developed now are only oxygen-carrying solutions; they cannot, at present, substitute for other important functions of blood, namely hemostasis and immunity.

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4. Ischemic Disease and Angioplasty

Tissues that are poorly perfused with blood and therefore receive a marginal supply of oxygen may benefit from increased perfusion with cell-free oxygen carriers. Such solutions might be expected to perfuse tissue that is inaccessible to red cells. Examples might be ischemic ulcers seen in diabetic or sickle-cell anemia patients. One report (Iwai et aL 1989) demonstrated improved healing of ischemic ulcers when they were bathed in oxygenated perfluorodecalin. The perfluorocarbonsmay offer the additional advantages of reducing post-ischemic injury because of their inhibitory effect on leukocytes (Bajaj et af. 1989). Perfusion of distal coronary arteries with blood during balloon angioplasty is limited because of blood's high viscosity. Morbidity during and after such procedures may be reduced if the myocardium can be perfused with perfluorocarbon emulsions). These encouraging results formed the basis for the significant recent approval of FluosolDA 20% for coronary angioplasty (Lowe 1991). Solutions of modified hemoglobin have been used also in this clinical setting (Rossen et al. 1987). 5. Extracorporeal Organ Perfusion

The preservation of organs for transplantation is an increasing requirement as graft success improves. Hearts, livers, and kidneys might survive better if they could be perfused with an oxygen-wrying solution. Recent work with isolated perfused rabbit hearts has indicated that much more oxygen can be delivered to the myocardium with a hemoglobin-based blood substitute compared with KrebsHenseleit solution, even if the latter is equilibrated with 100 percent oxygen (Macdonald and Winslow 1990). A variety of organs has been preserved with perfluorocarbon emulsions, also (Lowe 1991). Hemoglobin solutions (Bonhard 1988) and perfluorocarbon emulsions (Smith, van Alphen et af. 1985) may be useful in preserving severed limbs for reattachment. Bonhard discussed the use of pyridoxylated hemoglobin in this regard and suggested post-ischemia syndrome can be prevented (Bonhard 1988). Steinau and Elert (1980) showed that adenosine triphosphate (Am) levels were higher and lactate concentrations lower in limbs perfused with hemoglobin solutions rather than with Ringer's lactate. 6. Cell Culture Media

The recent explosion in cell-cloning technology has increased dramaticallythe use of cultured mammah'an cells for commercial as well as therapeutic and research

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purposes. It is possible that the quality of these cells and their yield of recombinant gene products can be increased by the use of oxygen-canying culture media. Work has already been done using perfluorocarbon emulsions (King el aL 1989; 1990) to show the utility of this approach.

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7. Hematopoietic Stimulation

Amberson el d.(1949), Hawkins and Johnson (1939) and others have noted stimulation of erythropoiesis after administrationof cell-free hemoglobin. It is likely that this is a result of the ready availability of heme iron when administered as hemoglobin. Recombinant human erythropoietin also stimulates red cell production in the preoperative period. Goodnough and his colleagues (1989) showed that 41 percent more autologous blood could be collected from surgical candidates when erythropoietin was administered. Their patients were all given oral iron sulfate during the twenty-one days before surgery. The combined use of erythropoietinand cell-free hemoglobin solution could provide a potent stimulus to endogenous red cell production. 8. Cardioplegia

During certain surgical procedures such as cardiac valve replacement, repair of congenital anomalies, or aneurysm resection, it is necessary to slow or stop the normal heart action. This is done by perfusing the myocardium with various electrolyte solutionsand lowering the temperature. Obviously, solutions that transport oxygen to tissues would be desirable since they could both prolong the time allowed the surgeons to operate and speed recovery of function after the procedure. Elert and Otterman (1979) perfused dog hearts with a solution of pyridoxylated hemoglobin and electrolytes. They induced cardiac arrest with this solution and measured ATP and phosphocreatine concentrations. They were able to show a twenty-minute gain in the time hearts could be stopped, and they had no difficulty in restarting them. On histologic examination, they found less endothelial swelling than in those hearts perfused without hemoglobin. 9. Siclde-Cell Anemia

Therapy of sickle cell anemia has a long and controversial history. In this chronic hemolytic anemia, patients "adapt" to a low hemoglobin concentration, and anemia per se is not the main problem. Rather, the rheologic consequences of deformed red blood cells cause morbidity and mortality. The degree of pathologic damage in sickle cell anemia, moreover, is highly variable from patient to patient, and the clinical course in an individual is completely unpredictable. Some patients may be almost asymptomatic throughout their lives, while others can be severely debilitated. This unpredictability makes the design of clinical trials difficult.

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The red cells of patients with sickle cell anemia deform ("sickle") when they are deoxygenated,when the pH drops, or when they are dehydrated. When any of these occur, the viscosity rises dramatically, and circulation slows. Thus, at a given hematocrit, sickle cell blood has a higher viscosity than normal blood (Charache and Conley 1964). Oxygen transport can be improved in sickle-cell anemia patients by exchange transfusion with normal red cells (Miller et al. 1980) because a lower viscosity can be achieved without reducing the hemoglobin concentration. Dilution with an acellular oxygen carrier may be even more effective than exchange transfusion with whole blood. The idea is especially attractive since one of the contraindications to exchange with normal blood is membrane antigen sensitization that eventually occurs after multiple transfusions. In addition, blood substitutes might be effective in perfusing obstructed capillary beds. Although Oxypherol ( ~ u o s o l ~increases 3) rigidity of red cells by adherence to their surfaces (Tuliani er aL 1988). it improves the rheological properties of sickle erythrocytes at the low shear rates found in capillary beds (Reindorf er al. 1985). In this instance, perfluorocarbon emulsions may not only improve oxygenation of sickle cells, but might also decrease their endothelial adherence (Smith, Hebbel er al. 1987). In v i m observations suggest that a hemoglobin-polyoxyethyleneconjugate may also reverse capillary occlusion with sickled cells (Iwasaki ef al. 1989). One difficulty with this application is that the sickle-cell patients who are in most need of therapy are those with the poorest venous access; thus, hemodilution with cell-free solutions might still be difficult. An additional limiting factor to this application is that although each individual sickle-cell patient is very dependent on the health care system, the total number of patients may not justify the development of commercial products. 10. Tumor therapy

Solid tumors tend to outgrow their blood supply, and therefore may become poorly vascularized and hypoxic, decreasing their sensitivity to antitumor agents and ionizing radiation. The mode of action of antitumor therapies may involve local destruction of malignant tissue by activated oxygen. Thus, any method for increasing tissue oxygen tension could be viewed as an adjunct. Perfluorocarbon emulsions have been used to increase oxygenation of these tumors and to increase their sensitivity to both chemotherapy and radiation (Rockwell 1989; Lustig er al. 1989). Hemoglobin could also be useful; in this case, the optimal product would have the highest Ps possible since the solution could be oxygenated outside of the body and infused directly into the circulation of the tumor. An alternative approach has already been shown to be effective in animals. Drugs

that reduce oxygen affinity dramatically (clofibrate, bezafibrate, and gemfibrozil) were administered to tumor-bearing mice to effect a rise of from 10 to 20 torr in the Ps value. Marked sensitization to irradiation was observed when these animals were

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given supplemental oxygen to breathe (Hirst et al. 1987). If a high "arterial" oxygen tension is achievable, then perfluorocarbons might be the perfusion medium of choice since photoactivation of heme-containing drugs also could be used (hemoglobin would absorb much of the delivered light energy).

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11. Chronic Anemia

Chronic anemia would not seem to be a good indication for blood substitutes. First, patients usually adapt to chronic anemia just as high altitude natives seem to become acclimatized to chronic hypoxia The inability of the currently developed blood substitutes to provide coagulation factors, platelets, or leukocytes would not seem to be a major drawback, especially in patients with chronic hemolysis, red cell aplasia, cancer, or other types of chronic disease. If a red cell substitute were developed for chronic anemia it would need to have the longest possible plasma retention to eliminate the need for excessively frequent infusions. The products that might be candidates to fill this need would be encapsulated or conjugated hemoglobin or derivatives with a very high molecular weight. Most efforts have been directed toward development of perfluorocarbons with short retention times and of hemoglobin solutions with longer times. 12. Contrast agents and diagnostic imaging

Perfluorocarbon emulsions are radioopaque and dense, making them easily visualized by ultrasound,x-ray, and magnetic resonance techniques (Long el al. 1989). Pefflubron emulsions have been particularly successful in diagnostic imaging of the GI tract, liver, and reticuloendothelial systems (Mattrey 1988). Their usefulness in delineating the progress of metastatic disease is particularly impressive. 13. Respiratory distress syndromes

The respiratory distress syndrome is a condition in which alveolar surfactant becomes deficient, very high respirator pressures are required, and arterial oxygenation declines. Approximately 100,OOO cases occur each year in the US,and the mortality is approximately 50%. Recent animal studies (Bhutani and Shaffer 1983; Widjaja et uf. 1988) have shown that ventilation with perfluorocarbons can dramatically increase arterial oxygen tension. This technique has great promise in treating newborn respiratory distress syndrome as well (Greenspan et uf. 1990). In this instance, the perfluorocarbon acts not only as an oxygen carrier, but its low surface tension also reduces the respirator pressures required. 14. Decompression sickness

Decompression sickness is caused by N2 bubbles formed in the blood and tissues when the ambient pressure is suddenly reduced. Since the solubility of N2in perfluorocarbon emulsions is very high, they may have utility in treating this debilitating disorder. Studies in animals have shown improved survival after

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experimental decompression,especially when the perfluorocarbon is pre- oxygenated (Lutz and Henmann 1984; Spiess, er al. 1988). This application would not involve a large number of patients, but decompressionsicknesscan be devastating,and perhaps pretreatment before exposure to great pressures would decrease the morbidity associated with decompression.

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In a related application, perfluorocarbons could be used to treat intraoperative air embolism. Spiess er al. (1986) showed a significantprolongation of survival of rabbits pretreated with Oxypherol ( F ~ u o s o ~who ~ ~ )were , then given a controlled air embolus. 15. Research

Sixteen years ago, Geyer (1975) reviewed the potential uses of blood substitutes. The list of anticipated clinical applications is much like the one above and is the driving force behind commercialization and therefore availability of products. But Geyer also listed prominently a number of research areas that will benefit from the availabilityof these products: they will be extremely useful in basic studies of hematopoiesis, protein metabolism, all aspects of oxygen transport, including the microcirculation,utilization of oxygen by tissues, particularlydifferences between specific organs. This research will not only advance basic knowledge of biochemistry and physiology but will doubtless give rise to new clinical uses that are not appreciated now. Requirements for a Blood Substitute

Some of the required properties of red cell substitutes are obvious. They must be sterile, free of endotoxin and viruses, nontoxic, and efficacious, and it must be possible to store them for reasonable periods. The methods used to produce them must be tractable for industrial scale-up, and not too expensive. Lot-to-lot variation and immunogenicity must be minimal. These requirements can pose serious industrial problems, particularly when large batches must be prepared in a routine fashion. Some of the other properties would be tailored to the individual productsunder development, and their specificationsare more controversial. It is clear that the properties of a blood substitute should be matched to the clinical indication. For example,administrationin a case of chronic, refractory anemia would require a long plasma retention and normal colloid oncotic pressure. A solution for resuscitation from acute blood loss should have an increased colloid oncotic pressure but short plasma retention because blood would be available to the patient within several hours of injury in most cases. The patient who is unable to maintain a normal alveolar oxygen tension might do better with a hemoglobin solution with a reduced ,P but when arterial oxygen tension can be elevated, a high Ps would favor tissue oxygen delivery. In some applications, such as organ preservation for transplantation, the properties are probably less critical because more control of oxygenation and temperature, for example, is possible.

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Potential clinical applications for blood substitutes.

In the coming decade, it is likely that oxygen-carrying alternatives to red blood cells will become available for clinical use. The driving force behi...
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