Abstract
Haemoglobin solutions have been tried as blood substitutes for decades with little success. Problems with early haemoglobin solutions include instability of the haemoglobin tetramer in the plasma, resulting in dissociation of the protein into dimers, as well as excessively high oxygen affinity for clinical oxygen transport capabilities. Newer haemoglobin solutions are currently under development and may prove adequate to transport oxygen while avoiding excessive toxicity However, these compounds pose other difficulties, including a short plasma half-life and the potential for systemic hypertension due to nitric oxide binding.
Several haemoglobin solutions are now undergoing human testing for potential clinical use. Haemoglobin can be harvested from outdated packed red blood cell units and chemically altered for use in clinical scenarios. Likewise, bovine haemoglobin may be obtained and modified for use as a blood substitute. While both these approaches may yield clinically useful oxygen carrying solutions, neither is completely free from infectious risk. The use of recombinant technology to produce a genetically altered haemoglobin from Escherichia coli allows avoidance of infectious risks and a functional haemoglobin which does not need further chemical modification. Use of this first generation of recombinant human haemoglobin as a blood substitute may be limited due to its short half-life of <12 hours, but clinical uses such as replacement fluid for acute normovolaemic haemodilution during the perioperative period may allow significant blood savings for patients and the potential to avoid patient exposure to allogeneic transfusions.
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References
Winslow RM. Hemoglobin-based red cell substitutes. Baltimore (MD): The Johns Hopkins University Press, 1992
Amberson WR, Jennings JJ, Rhode CM. Clinical experience with hemoglobin-saline solutions. Am J Physiol 1949; 1: 469–89
Newman RJ, Podolsky D. Bad blood. U.S. News & World Report 1994 Jun 27: 68–78
Williams AE, Thomson RA, Schreiber GB, et al. Estimates of infectious disease risk factors in US blood donors. JAMA 1997; 277: 967–72
Valeri CR, Hirsch NM. Restoration in vivo of erthyrocyte aden-osine triphosphate, 2,3-diphosphoglycerate, potassium ion, and sodium ion concentrations following the transfusion of acid-citrate-dextrose-stored human red blood cells. J Lab Clin Med 1969; 73: 722–33
Howland WS, Schweizer O. Physiologic compensation for storage lesion of bank blood. Anesth Analg 1965; 44: 8–16
Myhre BA. Fatalities from blood transfusion. JAMA 1980; 244: 1333–5
Lackritz EM, Satten GA, Aberle-Grasse J, et al. Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med 1995; 333: 1721–5
Landers DF, Hill GE, Wong KC, et al. Blood transfusion-induced immunomodulation. Anesth Analg 1996; 82: 187–204
Gascon P, Zoumbos NC, Young NS. Immunologic abnormalities in patients receiving multiple blood transfusions. Ann Int Med 1984; 100: 173–7
Murphy P, Heal JM, Blumberg N. Infection or suspected infection after hip replacement surgery with autologous or homologous blood transfusions. Transfusion 1991; 31: 212–7
Schriemer PA, Longnecker DE, Mintz PD. The possible immunosuppressive effects of perioperative blood transfusion in cancer patients. Anesthesiology 1988; 68: 422–8
Waymack JP, Warden GD, Alexander JW, et al. Effect of blood transfusion and anesthesia on resistance to bacterial peritonitis. J Surg Res 1987; 42: 528–35
Wu HS, Little AG. Perioperative blood transfusions and cancer recurrence. J Clin Oncol 1988; 6: 1348–54
Blumberg N, Heal JM, Murphy P, et al. Association between transfusion of whole blood and recurrence of cancer. BMJ [Clin Res] 1986; 293: 530–3
Blumberg N, Heal JM. Transfusion and recipient immune function. Arch Pathol Lab Med 1989; 113: 246–53
Bradley JA. The blood transfusion effect: experimental aspects. Immunol Lett 1991; 29: 127–32
MacFarlane BJ, Marx L, Anquist K, et al. Analysis of a protocol for an autologous blood transfusion program for total joint replacement surgery. Can J Surg 1988; 31: 126–9
Kruskall MS, Popovsky MA, Pacini DG, et al. Autologous versus homologous donors: evaluation of markers for infectious disease. Transfusion 1988; 28: 286–8
Etchason J, Petz L, Keeler E, et al. The cost effectiveness of preoperative autologous blood donations. N Engl J Med 1995; 332: 719–24
Casthely PA, Yoganathan T, Salem M, et al. Phlebotomy via the pulmonary artery catheter introducer for intraoperative autotransfusion. J Cardiothorac Anesth 1990; 4: 43–5
Whitten CW, Allison PM, Latson TW, et al. Evaluation of laboratory coagulation and lytic parameters resulting from autologous whole blood transfusion during primary aortocoronary artery bypass grafting. J Clin Anesth 1996; 8: 229–35
Landow L. Perioperative hemodilution. Can J Surg 1987; 30: 321–5
Feldman JM, Roth JV, Bjoraker DG. Maximum blood savings by acute normovolemic hemodilution. Anesth Analg 1995; 80: 108–13
Weiskopf RB. Mathematical analysis of isovolemic hemodilution indicates that it can decrease the need for allogeneic blood transfusion. Transfusion 1995; 35: 37–41
Ness PM, Bourke DL, Walsh PC. A randomized trial of perioperative hemodilution versus transfusion of preoperatively deposited autologous blood in elective surgery. Transfusion 1992; 32: 226–30
Klimberg IW. Autotransfusion and blood conservation in urologic oncology. Semin Surg Oncol 1989; 5: 286–92
Jones JW, Rawitscher RE, McLean TR, et al. Benefit from combining blood conservation measures in cardiac operations. Ann Thorac Surg 1991; 51: 541–4
Bland LA, Villarino ME, Arduino MJ, et al. Bactëriologic and endotoxin analysis of salvaged blood used in autologous transfusions during cardiac operations. J Thorac Cardiovasc Surg 1992; 103: 582–8
Rabiner SF, Helbert SR, Lopas H. Evaluation of stroma-free hemoglobin for use as a plasma expander. J Exp Med 1967; 126: 1127–42
Amberson W, Flexner J, Steggerda FR, et al. On the use of Ringer-Locke solutions containing hemoglobin as a substitute for normal blood in mammals. J Cell Comp Physiol 1937; 5: 359–82
Hoffman SJ, Looker DL, Roehrich JM, et al. Expression of fully functional tetrameric human hemoglobin in Escherichia coli. Proc Natl Acad Sci 1990; 87: 8521–5
Klocke RA. Effect of alterations in oxygen binding to hemoglobin on oxygen delivery. Pulm Crit Care Update 1990; 6: 1–7
Klocke RA. Oxygen transport and 2, 3-diphosphoglycerate (DPG). Chest 1972; 62Suppl. 2: 79S–85S
Bunn HF. Differences in the interaction of 2,3-diphosphoglycerate with certain mammalian hemoglobins. Science 1971; 172: 1049–50
Anonymous. BSE-bovine spongiform encephalopathy (’mad cow disease’). J R Soc Health 1996; 116: 322-33
Cullen M, Bellis M, Tocque K. Bovine spongiform encephalopathy. Public health officials are confused over whether to eat beef [letter; comment]. BMJ 1996; 313: 1146
Dealler S. A matter for debate: the risk of bovine spongiform encephalopathy to humans posed by blood transfusion in the UK [see comments]. Transfus Med 1996; 6: 217–22
Looker D, Abbott-Brown D, Cozart P, et al. A human recombinant haemoglobin designed for use as a blood substitute. Nature 1992; 356: 258–60
Viele MK, Weiskopf RB, Fisher D. Recombinant human hemoglobin does not affect renal function in humans: analysis of safety and pharmacokinetics. Anesthesiology 1997; 86: 848–58
Lessen R, Williams MJ, Seltzer JL, et al. A safety study of recombinant human hemoglobin for intraoperative transfusion therapy. Anesth Analg 1996; 81: S–275
Leone BJ, Chuey C, Gleason D, et al. Can recombinant human hemoglobin make ANH more effective? An initial feasibility and safety study. Anesth Analg 1996; 81: S–274
Rand PW, Lacombe E, Hunt HE, et al. Viscosity of normal human blood under normothermic and hypothermic conditions. J Appl Physiol 1964; 19: 117–22
Hint H. The pharmacology of dextran and the physiological background for the clinical use of Rheomacrodex and Macrodex. Acta Anaesth Belgica 1968; 2: 119–38
Messmer KFW. Acceptable hematocrit levels in surgical patients. World J Surg 1987; 11: 41–6
Nelson AH, Fleisher LA, Rosenbaum SH. Relationship between postoperative anemia and cardiac morbidity in highrisk vascular patients in the intensive care unit. Crit Care Med 1993; 21: 860–6
Spahn DR, Smith LR, McRae RL, et al. Effects of acute isovolemic hemodilution and anesthesia on regional function in left ventricular myocardium with compromised coronary blood flow. Acta Anaesth Scand 1992; 36: 628–36
Spahn DR, Smith LR, Veronee CD, et al. Acute isovolemic hemodilution and blood transfusion: effects on regional function and metabolism in myocardium with compromised coronary blood flow. J Thorac Cardiovasc Surg 1993; 105: 694–704
Spahn DR, Smith LR, Schell RM, et al. Importance of severity of coronary artery disease for the tolerance to normovolemic hemodilution: comparison of single versus multivessel stenoses in a canine model. J Thorac Cardiovasc Surg 1994; 108: 231–9
Spahn DR, Fielding RM, Gillespie R, et al. Cardiovascular effects of recombinant human hemoglobin (rHbl.l) in a normovolemic canine model of hemodilution [abstract]. Br J Anaesth 1993; 71: 761P
Cole DJ, Schell RM, Drummond JC, et al. Focal cerebral ischemia in rats: effect of hemodilution with alpha-alpha cross-linked hemoglobin on brain injury and edema. Can J Neurol Sei 1993; 20: 30–6
Cole DJ, Schell RM, Drummond JC, et al. Focal cerebral ischemia in rats. Effect of hypervolemic hemodilution with diaspirin cross-linked hemoglobin versus albumin on brain injury and edema. Anesthesiology 1993; 78: 335–42
Cole DJ, Schell RM, Drummond JC. Diaspirin crosslinked hemoglobin (DCLHb): effect of hemodilution during focal cerebral ischemia in rats. Artif Cells Blood Substit Immobil Biotechnol 1994; 22: 813–8
Schreiber GB, Busch MP, Kleinman SH, et al. The risk of tranfusion-transmitted viral infections. N Engl J Med 1996; 334: 1685–90
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Leone, B.J. Potential Clinical Applications of Recombinant Human Haemoglobin in Blood Conservation. BioDrugs 11, 211–221 (1999). https://doi.org/10.2165/00063030-199911030-00007
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DOI: https://doi.org/10.2165/00063030-199911030-00007