[en] Anoxia-reoxygenation leads to severe metabolic alterations, which result in a generalized inflammatory reaction and multiple organ dysfunction. Direct blood transfusion limits these alterations, but is accompanied by risk of transmission of infections or viral diseases. To avoid these risks, "blood substitutes" have been designed. The modified hemoglobins are not true blood substitutes because they do not possess the complex functions of erythrocytes. They are only oxygen carriers, with a short intravascular life, adapted for temporary use. They are stable, devoid of toxicity and antigenicity, and are able to carry and deliver O2 without regulation of this oxygen transport and without chemical reaction with O2. They possess rheologic properties and an oncotic pressure like those of blood. The use of natural hemoglobin solutions, obtained after lysis of erythrocytes, remains "at risk" because these solutions easily form methemoglobin, increase the oncotic pressure, present renal toxicity, and possess a too high affinity for O2. For these reasons, 5 types of modified hemoglobin solutions have been designed, prepared from human or bovine hemoglobin or by genetic engineering. These hemoglobins are highly purified to eliminate trace amounts of stroma, lipids and endotoxins, which are responsible for acute toxicity. They are modified by internal cross-linking between the monomers, or by binding to macromolecules. Afterwards, they can be polymerized or encapsulated in liposomes. The purpose of these modifications is to modulate the affinity for O2 (by decreasing the binding of O2 and increasing its delivery to tissue), to reduce the dissociation into monomers and to guard against oxidation into methemoglobin. Encapsulation in liposomes allows co-encapsulation of effector molecules and protective substances. Genetic engineering allows the production of recombinant hemoglobin with selective modifications. The modified hemoglobin solutions are essentially used in hemorrhagic shock and perioperative hemodilution. Experimental work in animals has afforded good results: restoration of normal O2 pressure and no toxicity. These assays allow frequent observation of an unexpected rapid hypertensive effect, transient, reversible, and that could be controlled by antihypertensive drugs. The mechanisms of this hypertensive effect remain controverted (stimulation of endothelin production, inhibition of nitric oxide effects, etc.). In humans, studies with healthy volunteers have been completed, while phase II clinical studies are under way in hypovolemic shock, in major abdominal, orthopedic and cardiac surgery, in stroke and in intensive care patients after surgery. The detailed results are awaited, but the modified hemoglobin solutions already appear to be without toxicity and present the same hypertensive effect as observed in animals. However, until now only low doses have been used, and the catabolism of these solutions remains largely unknown.
Disciplines :
Anesthesia & intensive care
Author, co-author :
Remy, Bernadette ; Centre Hospitalier Universitaire de Liège - CHU > Anesthésie et réanimation
Deby, Ginette ; Université de Liège - ULiège > Centre de l'oxygène : Recherche et développement (C.O.R.D.)
Lamy, Maurice ; Université de Liège - ULiège > Département des sciences cliniques > Anesthésie et réanimation
Language :
French
Title :
Apports et perspectives des dérivés de l'hémoglobine
Alternative titles :
[en] Contributions and Prospects of Hemoglobin Derivatives
Russell, R.C., Roth, A.C., Kucan, J.O., Zook, E.G., Reperfusion injury and oxygen free radicals: A review (1989) J Reconstr Microsurg, 5, pp. 79-84
Pincemail, J., Deby-Dupont, G., Lamy, M., Biochemical alterations in ischemia-reperfusion (1992) Yearbook of Intensive Care and Emergency Medicine, pp. 104-114. , Vincent JL (éd): Berlin: Springer
Faithfull, N.S., The role of perfluorochemicals in surgery and the ICU (1994) Yearbook of Intensive Care and Emergency Medicine, pp. 264-275. , Vincent JL (éd): Berlin: Springer
Riess, J.G., The design and development of improved fluorocarbon-based products for use in medicine and biology (1994) Artif Cells, Blood Substit, Immob Biotech, 22, pp. 215-234
Spahn, D.R., Leone, B.J., Reves, J.G., Pasch, T., Cardiovascular and coronary physiology of acute isovolemic hemodilution: A review of nonoxygen-carrying and oxygen-carrying solutions (1994) Anesth Analg, 78, pp. 1000-1021
Zuck, T.F., Riess, J.G., Current status of injectable oxygen carries (1994) Crit Rev Clin Lab Sci, 31, pp. 295-324
Dracker, R.A., The development and use of oxygen-carrying blood substitutes (1995) Immunol Invest, 24, pp. 403-410
Kaufman, J.R., Clinical development of perfluorocarbon-based emulsions as red cell substitutes (1995) Blood Substitutes: Physiological Basis of Efficacy, pp. 53-74. , Winslow RM, Vandegriff KD, Intaglietta M (éds): Boston: Birkhäuser
Spiess, B.D., Perfluorocarbon emulsions: One approach to intravenous artificial respiratory gas transport (1995) Int Anesth Clin, 33, pp. 103-113
Tomasulo, P., Transfusion alternatives: Impact on blood banking worldwide Blood Substitutes: Physiological Basis of Efficacy, , Winslow RM, Vandegriff KD, Intaglietta M (éds)
Winslow, R.M., Potential clinical applications for blood substitutes (1992) Biomat, Artif Cells, Immob Biotech, 20, pp. 205-217
Deby-Dupont, G., Pincemail, J., Lamy, M., Hemoglobin-based red cell substitutes: Preliminary human studies (1994) Yearbook of Intensive Care and Emergency Medicine, pp. 264-275. , Vincent JL (éd): Berlin: Springer
Lestavel, P., Substituts du sang: Transporteurs artificiels d'oxygène (1992) Réan Urg, 1, pp. 927-946
Tremper, K.K., Wahr, J.A., Blood use and non-blood use: Designing blood substitutes (1995) Soc Crit Care Med, 15, pp. 143-162. , Parker MM, Shapiro JM, Porembka DT (éds): Critical care. State of the art
Misra, H.P., Fridovich, I., The generation of superoxide radical during the autoxidation of hemoglobin (1972) J Biol Chem, 247, pp. 6960-6962
Szebeny, J., Winterbourn, C.C., Carrell, R.W., Oxidative interactions between haemoglobin and membrane lipids (1984) Biochem J, 220, pp. 685-692
Rifkind, J.M., Zhang, L., Heim, J.M., Levy, A., The role of hemoglobin in generating oxyradicals (1987) Oxygen Radicals in Biology and Medicine, pp. 157-162. , Simic MG, Taylor KM, Ward JF, von Sonntag C (éds): New York: Plenum Press
Sadrazadeh, S.M.H., Anderson, D.K., Panter, S.S., Hallaway, P.E., Eaton, J.W., Hemoglobin potentiates central nervous system damage (1987) J Clin Invest, 79, pp. 662-664
Winterbourn, C.C., Oxidative reactions of hemoglobin (1990) Methods Enzymol, 186, pp. 265-272
Balla, G., Vercellotti, G.M., Muller-Eberhard, U., Eaton, J., Jacob, H.S., Exposure of endothelial cells to free heme potentiates damage mediated by granulocytes and toxic oxygen species (1991) Lab Invest, 64, pp. 648-655
Amberson, W.R., Jennings, J.J., Rhode, C.M., Clinical experience with hemoglobin-saline solution (1949) J Appl Physiol, 1, pp. 469-489
Rabiner, S.F., O'Brien, K., Peskin, G.W., Friedman, L.H., Further studies with stroma-free hemoglobin (1970) Ann Surg, 171, pp. 615-622
Savitsky, J.P., Doczi, J., Black, J., Arnold, J.D., A clinical safety trial of stroma-free hemoglobin (1978) Clin Pharmacol Ther, 23, pp. 73-80
Chang, T.M.S., Blood substitutes based on modified hemoglobin prepared by encapsulation or crosslinking: An overview (1992) Biomat Artif Cells Immob Biotech, 20, pp. 159-179
Manning, J.M., Design of chemically modified and recombinant hemoglobins as potential red cell substitutes (1995) Blood Substitutes: Physiological Basis of Efficacy, pp. 76-89. , Winslow RM, Vandegriff KD, Intaglietta M (éds): Boston: Birkäuser
Ogden, J.E., Parry, E.S., The development of hemoglobin solutions as red cell substitutes (1995) Int Anesthesiol Clin, 33, pp. 115-129
Tobias, M.D., Longnecker, D.E., Recombinant haemoglobin and other blood substitutes (1995) Ballière's Clin Anaesthesiol, 9, pp. 165-179
Chatterjee, R., Welty, E.V., Walder, R.Y., Pruitt, S.L., Rogers, P.H., Isolation and characterization of a new hemoglobin derivate cross-linked between the α chains (Lysine 99α1 >
Lysine 99α2) (1986) J Biol Chem, 261, pp. 9929-9937
Benesch, R.E., Kwong, S., Bis-pyridoxal poly-phosphates: A new class of specific intramolecular cross-linking agents for hemoglobin (1988) Biochem Biophys Res Comm, 156, pp. 9-14
Feola, M., Simoni, J., Angelillo, R., Luhruma, Z., Kakabele, M., Clinical trial of hemoglobin based blood substitute in patients with sickle cell anemia (1992) Surg Gynecol Obstet, 174, pp. 379-386
Satoh, T., Kobayashi, K., Sekiguchi, S., Tsuchida, E., Characteristics of artificial red cells. Hemoglobin encapsulated in polylipid vesicles (1992) ASAIO Journal, 38, pp. M580-M584
Usuba, A., Motoki, R., Suzuki, K., Sakaguchi, K., Takahashi, A., Study of effect of the newly developed artifical blood "neo red cells" (NCR) on hemodynamics and blood gas transport in canine hemorragic shock (1992) Biomat Artif Cell Immob Biotech, 20, pp. 531-535
Rabinovici, R., Rudolph, A.S., Vernick, J., Feuerstein, G., Lyophilized liposome encapsulated hemoglobin: Evaluation of hemodynamic, biochemical, and hematologic responses (1994) Crit Care Med, 22, pp. 480-485
Rudolph, A.S., Cliff, R.O., Klipper, R., Goins, B., Phillips, W.T., Circulation persistence and biodistribution of lyophilized liposome-encapsulated hemoglobin: An oxygen-carrying resuscitative fluid (1994) Crit Care Med, 22, pp. 142-148
Rudolph, A.S., Encapsulation of hemoglobin in liposomes (1995) Blood Substitutes: Physiological Basis of Efficacy, pp. 90-104. , Winslow RM, Vandegriff KD, Itaglietta M (éds): Boston: Birkhäuser
Przybelski, R.J., Malcom, D.S., Burris, D.G., Winslow, R.M., Cross-linked hemoglobin solution as a resuscitative fluid after hemorrhage in the rat (1991) J Lab Clin Med, 117, pp. 143-151
Hess, J.R., MacDonald, V.W., Brinkley, W.W., Systemic and pulmonary hypertension after resuscitation with cell-free hemoglobin (1993) J Appl Physiol, 74, pp. 1769-1778
Schultz, S.C., Powell, C.C., Burris, D.G., Nguyen, H., Jaffin, J., Malcolm, D.S., The efficacy of diaspirin crosslinked hemoglobin solution resuscitation in a model of uncontrolled hemorrhage (1994) J Trauma, 37, pp. 408-412
Sharma, A.C., Rebello, S., Gulati, A., Regional circulatory and systemic hemodynamic effects of diaspirin cross-linked hemoglobin in the rat (1994) Artif Cells, Blood Substit, Immob Biotech, 22, pp. 593-602
Dunlap, E., Farrell, L., Nigro, C., Estep, T., Marchand, G., Burhop, K., Resuscitation with diaspirin crosslinked hemoglobin in a pig model of hemorrhagic shock (1995) Artif Cells, Blood Substit, Immob Biotech, 23, pp. 39-61
Sprung, J., Mackenzie, C.F., Barnas, G.M., Williams, J.E., Parr, M., Oxygen transport and cardiovascular effects of resuscitation from severe hemorrhagic shock using hemoglobin solutions (1995) Crit Care Med, 23, pp. 1540-1553
Winslow, R.M., Vasoconstriction and the efficacy of hemoglobin-based blood substitutes (1994) Transfusion Clin Biol, 1, pp. 9-14
Schultz, S.C., Grady, B., Cole, F., Hamilton, J., Burhop, K., Malcolm, D., A role of endothelin and nitric oxide in the pressor response to DCLHb (1993) J Lab Clin Med, 122, pp. 301-308
Gulati, A., Rebello, S., Diaspirin cross-linked hemoglobin: Involvement of adrenergic mechanisms in the pressor effect (1994) Artif Cells, Blood Substit, Immob Biotech, 22, pp. 603-612
Bone, H.G., Traber, L.D., Schenarts, P.J., Spaulding, T., Traber, D.L., Hemodynamic effects of pyridoxylated hemoglobin polyethylene conjugate (PHP) in conscious sheep during septic shock (1995) Anesthesiology, 83, pp. A232
Cole, D.J., Schell, R.M., Drummond, J.C., Przybelski, R.J., Marcantonio, S., Focal cerebral ischemia in rats. Effects of hemodilution with α-α cross-linked hemoglobin on brain injury and edema (1993) Can J Neurol Sci, 20, pp. 30-36
Shoemaker, S., Gerber, M., Evans, G., Paik, L., Scoggin, C., Initial clinical experience with recombinant human hemoglobin (1993) Vth International Symposium on Blood Substitutes, pp. H14. , march 17-20, San Diego, California, USA
Hughes, G.S., Franconi, S.F., Antal, E.J., Adams, W.J., Locker, P.K., Hematologic effects of a novel hemoglobin-based oxygen carrier in normal male and female subjects (1995) J Lab Clin Med, 126, pp. 444-451
Przybelski, R.J., Kisicki, J., Daily, E., Bounds, M., Mattia-Goldberg, C., Diaspirin cross-linked hemoglobin (DCLHb): Phase I clinical safety assessment in normal healthy volunteers (1994) Crit Care Med, 22, pp. A231
Glanz, J., Hemoglobin reveals new role as blood pressure regulator (1996) Science, 271, p. 1670
Varcelotti, G.M., Balla, J., Nath, K., Eaton, J.W., Jacob, H.S., Heme and the vasculature: An oxidative hazard that induces antioxidant defenses in the endothelium (1994) Artif Cells, Blood Substit, Immob Biotech, 22, pp. 207-213
Vandegriff, K.D., Stability and toxicity of hemoglobin solutions (1995) Blood Substitutes: Physiological Basis of Efficacy, pp. 105-131. , Winslow RM, Vandegriff KD, Intaglietta M (éds): Boston: Birkhäuser
Alayash, A.J., Ryan, B.A., Fratantoni, J.C., Cashon, R.E., Redox reactivity of modified hemoglobin with hydrogen peroxide and nitric oxide: Toxicological implications (1994) Artif Cells, Blood Substit, Immob Biotech, 22, pp. 2373-2386
Rogers, M.S., Patel, R.P., Reeder, B.J., Sarti, P., Wilson, M.T., Alayash, A.I., Pro-oxidants effects of cross-linked haemoglobins explored using liposome and cytochrome C oxidase vesicle model membranes (1995) Biochem J, 310, pp. 827-833
Simonis, J., Simonis, G., Garcia, E.L., Prien, S.D., Tran, R.M., Protective effect of selenium on hemoglobin mediated lipid peroxidation in vivo (1995) Artif Cells, Blood Substit, Immob Biotech, 23, pp. 469-1186
Biro, G.P., Ou, C., Ryan-Mac Farlane, C., Anderson, P.J., Oxyradical generation after resuscitation of hemorrhagic shock with blood or stroma-free hemoglobin solution (1995) Artif Cells, Blood Substit, Immob Biotechn, 23, pp. 631-645
Roth, R.I., Kaca, W., Toxicity of hemoglobin solutions: Hemoglobin is a lipopolysaccharide (LPS) binding protein which enhances LPS biological activity (1994) Artif Cells, Blood Substit, Immob Biotech, 22, pp. 387-398