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DOI: 10.1055/s-0030-1249214
© Georg Thieme Verlag KG Stuttgart · New York
Gibt es eine Zukunft für künstliche Blutersatzstoffe?
Artificial blood – coming soon or never reaching clinical maturity?Publikationsverlauf
eingereicht: 8.9.2009
akzeptiert: 5.11.2009
Publikationsdatum:
16. März 2010 (online)
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Zusammenfassung
Künstliche Blutersatzstoffe der früheren Generationen sollten, wie die gebrauchte Abkürzung „artificial oxygen carriers” (AOC) impliziert, die Sauerstofftransportfunktion des Blutes möglichst ohne Nebenwirkungen, ohne Blutgruppeninkompatibilitäten und Übertragungsrisiko für Infektionen ersetzen. Sie nutzten entweder die konventionelle Sauerstoffbindung an Hämoglobin: HBOC- „hemoglobin based oxygen carriers” oder die physikalische Lösung des Sauerstoffs im Plasma in den sogenannten Perfluorkarbon (PFC)-Emulsionen. Heutzutage hat man eingesehen, dass der Sauerstofftransport nicht ohne weiteres von weiteren, physiologisch gekoppelten Aufgaben des Blutes losgelöst werden kann. Heutige Blutersatzstoffe sollen auch die Kapillarperfusion aufrecht erhalten, den Gefäßtonus regulieren bzw. die organspezifische Autoregulationsfähigkeit, die Gerinnung und das Immunsystem aufrechterhalten. Weil dieses Konzept aber gegenüber den früheren Bestrebungen relativ jung ist, gestaltet sich die klinische Einführung dieser neuen Generation von Blutersatzstoffen schwierig.
Nichtsdestotrotz existieren erhebliche Forschungsaktivitäten und neue Produkte. Neuere Generationen von künstlichen Sauerstoffträgern werden heute in der dritten und vierten Generation als Spielarten und Mischformen durch Imitation der Erythrozytenfunktion als Mizellen, Nanokapseln (ABC- artifical blood cells) [43] oder Gasblasen (Microbubbles), oder Zumischung von Hydroxyäthylstärke, Gelatine oder Albumin [42]und hyperbarer Oxigenierung [38]erforscht. Selbst künstliche Thrombozyten sind bereits am Menschen bis in die Phasen der klinischen Erprobung IIa vorgedrungen [12,17]
Diese Übersicht fasst die bisherigen Erkenntnisse der Erforschung der Blutersatzmittel zusammen und betont neue Erkenntnisse und Möglichkeiten, die sich aus der Erforschung der AOC ergeben. Sie schließt mit der Schlussfolgerung – ja, höchstwahrscheinlich wird es eine Zukunft für künstliche Blutersatzstoffe geben. Offen bleibt, welches der Konzepte, Ansätze und Produkte sich klinisch durchsetzen wird und vor allem wann.
Abstract
Formerly developed resuscitation fluids solely imitated the main function of the blood -oxygen transport. A research driven by the army requested an oxygen carrier that does not need cross typing and cooled storage . Artificial oxygen carriers (AOC) use either the molecular oxygen bondage to hemoglobin: HBOC- „hemoglobin based oxygen carriers” or the physical dissolution of oxygen in the blood plasma compartment by hyperbaric pressure in perfluorocarbon emulsions (PFC). Decades of preclinical and clinical research did pass but the results were disappointing- in Russia, a not well designed PFC is available locally and the only approved HBOC in South Africa is not being used much. Other products, just prior to filing for FDA approval, did not achieve convincing study results and research and production was stopped. Some trials have been stopped by the FDA for safety reasons, half of trials with the primary endpoint reduction of allogeneic transfusion requirement were unsuccessful or offset by an increased blood requirement later.
However, some ventures currently are trying to use the knowledge gained so far and are investigating third and fourth generation products of artificial blood components. These imitate the cellular structure of red cells as micells, nanocapsules, (ABC- artifical blood cells) or gas bubbles (microbubbles), admixture of volume substitutes such as starches, gelatin or albumin or use hyperbaric oxygenation [38]. Artificial platelets are in clinical phase IIa, recombinant albumin in phase III.
In this article, a short overview about the current situation on artifical blood products is given. The critical point for the break through for artificial blood products did not come yet but could be ahead-
Schlüsselwörter
künstliche Sauerstoffträger - Hämoglobine - Perfluorkarbone - Blutersatz - Transfusion - Perfusion - Hypertension
Keywords
artificial oxygen carriers - hemoglobin-based - perfluorocarbon - artificial blood - transfusion - perfusion - hypertension
Literatur
- 1 Adamson J G, Moore C. HemolinkTM, an o-raffinose crosslinked hemoglobin-based oxygencarrier. In: Chang TM (Ed) Blood Substitutes: Principles, Methods, Products and Clinical Trials. Basel: Karger Landes Systems; 1998: 62-81
- 2 Carmichael F JL, Biro G P, Cheng D CH. Phase III Clinical Trial of HemolinkTM in Conjunction with intraoperative autologous blood donation (IAD) in cardiac surgical patients. In: Chang TMS (Ed) Eighth International Symposium of Blood Substitutes. New York; Dekker, M Nov 09.-11., 2000: 22
- 3 Conover C, Linberg R, Lejeune L, Gilbert C, Shum K, Shorr R G. Evaluation of the oxygen delivery ability of PEG-hemoglobin in Sprague- Dawley rats during hemodilution. Artif Cells Blood Substit Immobil Biotechnol. 1998; 26 199-212
- 4 Conover C D, Gilbert C W, Shum K L, Shorr R G. The impact of polyethylene glycol conjugation on bovine hemoglobin’s circulatory half-life and renal effects in a rabbit top-loaded transfusion model. Artif Organs. 1997; 21 907-915
- 5 Doyle M P, Armstrong A M, Brucker E A, Fattor T J, Lemon D D. Design of a second generation recombinant hemoglobin: minimizing nitric oxide scavenging and vasoactivity while maintaining efficacy. In: Chang TM (Ed) Eighth International Symposium of Blood Substitutes. New York; Dekker, M 2000
- 6 Frietsch T, Gassmann M, Groth G. et al . Excessive erythrocytosis does not elevate capillary oxygen delivery in subcutaneous mouse tissue. Microcirculation. 2007; 14 111-123
- 7 Frietsch T, Lenz C, Waschke K F. Artificial Blood. In: Adams AP, Cashman JN (Ed) Recent advances in anaesthesia and analgesia. London: Churchill Livingstone; 2000: 103-126
- 8 Frietsch T, Lenz C, Waschke K F. Künstliche Sauerstoffträger: Ein Update. Anaesth Intensivmed. 2002; 3 138-146
- 9 Gonzalez P, Hackney A C, Jones S. et al . A phase I/II study of polymerized bovine hemoglobin in adult patients with sickle cell disease not in crisis at the time of study. J Investig Med. 1997; 45 258-264
- 10 Greenburg A G, Kim H W. Use of an oxygen therapeutic as an adjunct to intraoperative autologous donation to reduce transfusion requirements in patients undergoing coronary artery bypass graft surgery. J Am Coll Surg. 2004; 198 373-383; discussion 384 – 375
- 11 Harris D R, Palmer A F. Novel strategies for transporting cellular hemoglobin- based oxygen carriers in the systemic circulation. TATM. 2007; 9 237-245
- 12 Hilarius P M, Escolar G, Gendreau M, Verhoeven A J. Mechanism of action of infusible platelet membranes. In: Chang TM (Ed) Eighth International Symposium of Blood Substitutes. New York; Dekker, M Nov 09.-11.: 2000: 34
- 13 Hill S E, Gottschalk L I, Grichnik K. Safety and preliminary efficacy of hemoglobin raffimer for patients undergoing coronary artery bypass surgery. J Cardiothorac Vasc Anesth. 2002; 16 695-702
- 14 Hsia C JC. Polynitroxylated haemoglobin (PNH): A new generation red cell substitute with vasodilatory and antioxidant properties. In: Chang TM (Ed) Eighth International Symposium of Blood Substitutes. New York; Dekker, M 2000
- 15 Intaglietta M. Microcirculatory basis for the design of artificial blood. Microcirculation. 1999; 6 247-258
- 16 Kasper S M, Grune F, Walter M, Amr N, Erasmi H, Buzello W. The effects of increased doses of bovine hemoglobin on hemodynamics and oxygen transport in patients undergoing preoperative hemodilution for elective abdominal aortic surgery. Anesth Analg. 1998; 87 284-291
- 17 Kim H W, Greenburg A G. Toward 21st century blood component replacement therapeutics: artificial oxygen carriers, platelet substitutes, recombinant clotting factors, and others. Artif Cells Blood Substit Immobil Biotechnol. 2006; 34 537-550
- 18 Komatsu H, Furuya T, Sato N. et al . Effect of hemoglobin vesicle, a cellular-type artificial oxygen carrier, on middle cerebral artery occlusion- and arachidonic acid-induced stroke models in rats. Neurosci Lett. 2007; 421 121-125
- 19 Lamuraglia G M, O’hara P J, Baker W H. et al . The reduction of the allogenic transfusion requirement in aortic surgery with a hemoglobin-based solution. J Vasc Surg. 2000; 31 299-308
- 20 Leese P T, Noveck R J, Shorr J S, Woods C M, Flaim K E, Keipert P E. Randomized safety studies of intravenous perflubron emulsion. I. Effects on coagulation function in healthy volunteers. Anesth Analg. 2000; 91 804-811
- 21 Lenz C, Rebel A, Waschke K F, Koehler R C, Frietsch T. Blood viscosity modulates tissue perfusion – sometimes and somewhere. Transfus Altern Transfus Med. 2007; 9 265-272
- 22 Mullon J, Giacoppe G, Clagett C, Mccune D, Dillard T. Transfusions of polymerized bovine hemoglobin in a patient with severe autoimmune hemolytic anemia. N Engl J Med. 2000; 342 1638-1643
- 23 Natanson C, Kern S J, Lurie P, Banks S M, Wolfe S M. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: A Meta-analysis. JAMA. 2008; 299: 2301-2312
- 24 Ning J, Wong L T, Christoff B, Carmichael F J, Biro G P. Haemodynamic response following a 10 % topload infusion of HemolinkTM in conscious, anaesthetized and treated spontaneously hypertensive rats. Transfus Med. 2000; 10 13-22
- 25 Niquille M, Touzet M, Leblanc I, Baron J F. Reversal of intraoperative myocardial ischemia with a hemoglobin-based oxygen carrier. Anesthesiology. 2000; 92 882-885
- 26 Noveck R J, Shannon E J, Leese P T. et al . Randomized safety studies of intravenous perflubron emulsion. II. Effects on immune function in healthy volunteers. Anesth Analg. 2000; 91 812-822
- 27 Panetta G, Arcovito A, Morea V, Bellelli A, Miele A E. Hb(alphaalpha,betabeta): A novel fusion construct for a dimeric, four-domain hemoglobin. Biochim Biophys Acta. 2008; 3 1462-1470
- 28 Pearce L B, Gawryl M S. Overview of preclinical and clinical efficacy of biopure’s HBOCs. In: Chang TM (Ed) Blood Substitutes: Principles, Methods, Products and Clinical Trials. Basel: Karger Landes Systems; 1998: 82-100
- 29 Reynolds P S, Barbee R W, Ward K R. Lactate profiles as a resuscitation assessment tool in a rat model of battlefield hemorrhage resuscitation. Shock. 2008; 30 48-55
- 30 Rousselot M, Tsai A G, Intaglietta M, Zal F. Hemarina-M101 A new generation of blood substitutes coming from sea. In: Chang TM (Ed) Twelfth International Symposium of Blood Substitutes. Parma; Aug 25 – 18., 2009: 52-53
- 31 Sakai H, Sou K, Tsuchida E. Solution to the problems of acellular hemoglobins by encapsulation and the intrinsic issues of hemoglobin vesicles as a molecular assembly. TATM. 2007; 9 226-232
- 32 Sakai H, Yuasa M, Onuma H, Takeoka S, Tsuchida E. Synthesis and physicochemical characterization of a series of hemoglobin-based oxygen carriers: objective comparison between cellular and acellular types. Bioconjug Chem. 2000; 11 56-64
- 33 Saxena R, Wijnhoud A D, Carton H. et al . Controlled safety study of a hemoglobin-based oxygen carrier, DCLHb, in acute ischemic stroke. Stroke. 1999; 30 993-996
- 34 Sielenkamper A W, Eichelbronner O, Martin C M, Madorin S W, Chin-Yee I H, Sibbald W J. Diaspirin cross-linked hemoglobin improves mucosal perfusion in the ileum of septic rats. Crit Care Med. 2000; 28 782-787
- 35 Sloan E P, Koenigsberg M, Gens D. et al . Diaspirin cross-linked hemoglobin (DCLHb) in the treatment of severe traumatic hemorrhagic shock: a randomized controlled efficacy trial. Jama. 1999; 282 1857-1864
- 36 Spahn D R, Van Brempt R, Theilmeier G. et al . Perflubron emulsion delays blood transfusions in orthopedic surgery. European Perflubron Emulsion Study Group. Anesthesiology. 1999; 91 1195-1208
- 37 Spahn D R, Waschke R, Standl T. et al . Use of perflurbron emulsion to decrease allogeneic blood transfusion in high-blood-loss non cardiac surgery: results of a European phase 3 study. Anesthesiology. 2002; 97 338-349
- 38 Spears J R, Wang B, Wu X. et al . Aqueous oxygen: a highly O2-supersaturated infusate for regional correction of hypoxemia and production of hyperoxemia. Circulation. 1997; 96 4385-4391
- 39 Sprung J, Kindscher J D, Wahr J A. et al . The use of bovine hemoglobin glutamer-250 (Hemopure) in surgical patients: results of a multicenter, randomized, single-blinded trial. Anesth Analg. 2002; 94 799-808
- 40 Standl T, Horn P, Wilhelm S. et al . Bovine haemoglobin is more potent than autologous red blood cells in restoring muscular tissue oxygenation after profound isovolaemic haemodilution in dogs. Can J Anaesth. 1996; 43 714-723
- 41 Tsai A, Cabrales P, Acharya A S, Intaglietta M. Resuscitation from hemorrhagic shock: recovery of oxygen carrying capacity of perfusion? Efficacy of new plasma expanders. Transfusion Alternatives in Transfusion Medicine. 2007; 9 246-253
- 42 Tsuchida E. Properties of and oxygen binding by albumin- tetraphenylporphyrinatoiron(II) derivative complexes. Bioconjug Chem. 2000; 11 56-64
- 43 Tsuchida E. Recent progress of artificial blood project and novel product. In: Chang TM (Ed) Eighth International Symposium of Blood Substitutes. New York ; Dekker, M Nov 09.-11., 2000: 28
- 44 Tsuchida E, Komatsu T, Hamamatsu K. et al . Exchange transfusion with albumin-heme as an artificial O2-infusion into anesthetized rats: physiological responses, O2-delivery, and reduction of the oxidized hemin sites by red blood cells. Bioconjug Chem. 2000; 11 46-50
- 45 Tyssebotn I, Bergoe G, Lundgren C. Intravascular perfluorocarbon-stabilized microbubbles for treatment of hypocemia due to an experimental intrapulmonary shunt. In: Chang TM (Ed) Eighth International Symposium of Blood Substitutes. San Diego; 2000: 102
- 46 Vandegriff K, Young M A, Keipert P, Winslow N. The safety profile of Hemospan: a new oxygewn therapeutic designed using maleimide poly(ethylene) glycol conjugation to human hemoglobin. TATM. 2007; 9 213-225
- 47 Von Dobschuetz E, Hoffmann T, Messmer K. Diaspirin cross-linked hemoglobin effectively restores pancreatic microcirculatory failure in hemorrhagic shock. Anesthesiology. 1999; 91 1754-1762
- 48 Wahr J A, Trouwborst A, Spence R K. et al . A pilot study of the effects of a perflubron emulsion, AF 0104, on mixed venous oxygen tension in anesthetized surgical patients. Anesth Analg. 1996; 82 103-107
- 49 Winslow R M, Gonzales A, Gonzales M l. et al . Vascular resistance and the efficacy of red cell substitutes in a rat hemorrhage model. J Appl Physiol. 1998; 85 993-1003
Prof. Dr. med. Thomas Frietsch
Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum
Marburg/Giessen, Standort Marburg, Philips Universität
Marburg
Telefon: 06421/58 65991
Fax: 06421/58 65495
eMail: thomas.frietsch@urz.uni-heidelberg.de