An approach to prevent the severe adverse events associated with transfusion of FDA-approved blood products.

There have been several retrospective studies reporting severe adverse events of mortality and morbidity associated with blood transfusions. Mortality and morbidity associated with posttransfusion infection, transfusion related acute lung injury (TRALI), and systemic inflammatory response syndrome (SIRS) have been reported in patients undergoing cardiac surgery, after massive transfusions for severe traumatic injuries, and after transfusions for elective and emergency indications. After 35 days of storage at 4 degrees C in additive solutions, RBC have 24-h posttransfusion survival values of 75% but do not function satisfactorily. For RBC to function satisfactorily shortly after transfusion, they should be stored at 4 degrees C for no more than 2 weeks. Yet while the FDA requires a 24-h posttransfusion survival value of 75%, there is no requirement for the function of the transfused RBC. It has been shown that red blood cells that circulate and function immediately or shortly after transfusion exert a very important hemostatic effect to reduce the bleeding time and nonsurgical blood loss in anemic and thrombocytopenic patients. Greater restoration of hemostasis is seen with viable and functional RBC transfusions than with platelets or plasma even though the platelets and plasma proteins may have satisfactory viability and function. The length of storage of the blood products affects their survival and function and the transfusion of nonviable compatible RBC, antibodies to granulocytes and WBC HLA antigens and biologically active substances affects the patient's clinical outcome. One of the easiest ways to prevent the severe adverse events that have been observed is to ensure that the transfused blood products survive and function at an optimum level and that the levels of antibodies to granulocytes and WBC HLA antigens and biologically active substances are eliminated or reduced. The best way to ensure this is to store liquid-preserved leukoreduced human red blood cells at 4 degrees C in additive solutions for no more than 2 weeks and leukoreduced platelets at room temperature for no more than 2 days. These liquid-preserved blood products can be used in conjunction with frozen RBC, platelets, and plasma stored in -80 degrees C mechanical freezers and will avoid the need for fresh whole blood and prevent the severe adverse events associated with the transfusion of blood products.

Substâncias carreadoras de oxigênio à base de hemoglobina: situação atual e perspectivas / Hemoglobin-based blood substitutes: current status and perspectives

JUSTIFICATIVA E OBJETIVOS: Soluções alternativas à transfusäo de sangue têm sido estudadas desde a década de 50. O objetivo deste estudo é apresentar a situaçäo atual e as perspectivas futuras das substâncias carreadoras de oxigênio à base de hemoglobina. CONTEUDO: São apresentadas as potenciais áreas de aplicaçäo, bem como estudos clínicos envolvendo as principais moléculas de hemoglobina desenvolvidas, suas vantagens e limitações. CONCLUSÕES: Vários estudos aleatórios demonstraram eficácia com o propósito de evitar ou reduzir a transfusäo sangüínea; entretanto, algumas limitações existem, sendo que o futuro substituto sangüíneo deverá, no mínimo, retratar a segurança e a eficácia do sangue em si

Blood substitutes in surgery.

BACKGROUND: Despite increasing safety of blood supplies, and blood conservation strategies, the need for blood transfusion is increasing. Due to storage characteristics, blood is not always available when it is needed. AIMS: Review the necessity for an oxygen carrying blood substitute. Review the history of the compounds that may become blood substitutes, and briefly describe those in clinical trials. MATERIAL AND METHODS: Review of literature in the area of blood substitutes. RESULTS AND CONCLUSIONS: There is a need for oxygen carrying blood substitutes. Despite disappointments in recent clinical trials leading to withdraw of some compounds, there are several promising products nearing clinical approval.

A system establishment compatibility profiles for artificial oxygen carriers and other substances.

Worldwide, great efforts are being made to develop a clinically useful artificial oxygen carrier. Toxicological and immunological compatibility is generally tested using animal experiments but inflammatory parameters in particular show large species-specific differences. Therefore, we developed an in vitro system using human components to establish a compatibility profile of unknown compounds. The test system comprises induction of hemolysis, activation of complement (C3a), induction/suppression of cytokine production, influence on cell proliferation, direct toxicity on peripheral leukocytes, and phagocytosis of the material under test and of microbes. The test system will be described, along with results of various perfluorocarbon emulsions. When testing lecithin-based perfluorodecalin (PFD) emulsions, and comparing them to Pluronic-based PFD emulsions, we could show that Pluronic-based emulsions were virtually untoxic to peripheral human leukocytes. They neither inhibited cell proliferation nor caused any hemolysis, but caused mild to moderate inhibition of endotoxin-induced cytokine production. At the same time, lecithin-based PFD emulsion caused substantial cytotoxicity in phagocytic cells like monocytes (60-100% after 24 h incubation) and granulocytes (10-20% after 24 h incubation). They also suppressed endotoxin-induced cytokine production in monocytes to more than 98% and inhibited cell proliferation of an endothelial (ECV 304) and a monocytic cell line (MonoMac6) to more than 95%.

[Problems of development, production and clinical use of highly effective blood substitutes]. / Problemy razrabotki, proizvodstva i klinicheskogo primeneniia vysokoéffektivnykh krovezamenitelei.

An analysis of biological properties of blood substitutes has shown the expedience of wider clinical use instead of polyglucin of such substitutes as polyglucol, polifer, rondex, neorondex, polyoxidin, volecam; instead of rheopolyglucin--the rheopolyglucin with glucose, rheogluman and rheoglusol prepared for clinical tests; instead of haemodesin--haemodesin-H, neohaemodesin, gluconeodesin; instead of protein hydrolysates--polyamine and purified from peptides infusamine, hydromine, amicin; instead of 0.9% solution of sodium chloride--disol, quintasol, lactasol, mafusol. They have polyfunctional properties and considerably increase the effectiveness of the infusion--transfusion therapy.

Perfluorinated blood substitutes and artificial oxygen carriers.

Blood transfusion is a remarkably safe, routine clinical procedure. However, the need for sophisticated blood processing, storage and cross-matching, coupled with increasing concerns about the safety of blood products, has fuelled the search for safe and efficacious substitutes. Candidate materials based on modified haemoglobin (including recombinant molecules) or highly inert, respiratory gas-dissolving perfluorinated liquids (perfluorochemicals) have been developed. The latter are immiscible in aqueous systems and must, therefore, be injected as emulsions. Second-generation perfluorochemical emulsions are available and in clinical trials as temporary intravascular oxygen carriers during surgery, thereby reducing patient exposure to donor blood. One commercial product is currently under Phase III clinical evaluation, with regulatory approval expected within 1 2 years. Other biomedical applications for perfluorochemicals and their emulsions include their use as pump-priming fluids for cardiopulmonary bypass, lung ventilation fluids, anti-cancer agents, organ perfusates and cell culture media supplements, diagnostic imaging agents and ophthalmologic tools. Novel applications for perfluorochemicals as immunomodulating agents are also being explored.

A liquid-liquid blood-gas exchange for the treatment of acute respiratory failure. A new blood gas exchange using artificial blood as an oxygen carrier.

A new liquid-liquid blood gas exchange system was investigated using a venovenous low flow extracorporeal circuit. A 2 m2 hollow fiber dialyzer served as the interface of the blood and oxygen carrier (a 38 percent FC-43, perfluorocarbon emulsion in a buffered electrolyte solution), which was continuously recycled through a bubble oxygenator. Experiments were performed on five mongrel dogs under general anesthesia. Upon the arrest of spontaneous ventilation, the dogs' lungs were inflated with 50% oxygen gas under a positive pressure of 10 cmH2O. After 10 min of apnea the dogs' PaO2 decreased to 37 +/- 14 mmHg, and the extracorporeal circulation was started at 10 ml/min/kg b./w. At 15 min the PaO2 had risen to 80 +/- 41 mmHg and at 30 min to 121 +/- 17 mmHg. The oxygen transfer was 8.3 +/- 2.3 ml/min. The extracorporeal circulation was continued 5h, when PaO2 reached 156 +/- 90 mmHg, and PaCO2 148 +/- 43 mmHg, then stopped. Fifteen minutes later, the PaO2 had returned to 32 +/- 10 mmHg. These findings indicate that our blood gas exchange system can supply a sufficient amount of oxygen to the body under apnea with continuous positive airway pressure.

Quality control of hemoglobin-based blood substitutes.

Preparation and use of hemoglobin-based blood substitutes, from stroma-free hemoglobin (SFH or Hb) and its DPG analogue-modified derivatives (PLP-Hb, ATP-Hb etc.) without thorough characterization and quality control in animal or human testing have produced, and may continue to produce, artifacts in the finished product. Thus the development of such a natural substitute for the volume expansion and oxygen delivery functions of the blood will be impeded. A case is made for the use of affinity purified hemoglobin and modified hemoglobin as standard starting materials for the preparation of Hb-based blood substitute(s) in general, and in particular poly PLP-Hb. Development of a commercial scale blood-substitute is only possible after the safety and toxicity issues of substitutes have been resolved by applying rigorous quality control.

Blood substitutes: where are we?

Plasma volume expanders exist and are available. Balance salt solutions are preferred for initial resuscitation. Albumin should be avoided. Synthetic coagulation factors are not available. They exist because proper component therapy creates them to be stored for selective use. A substitute for the prime function of blood--oxygen delivery by the red cell--does not yet exist. Its clear that one is needed; the form is not yet identified. Fluorocarbon emulsions have a certain chemical cleanliness that makes them appealing, yet there are many unanswered questions, especially as to oxygen-carrying capacity and toxicity. Fluorocarbons have been pushed to clinical testing before their time. Chemically modified stroma-free hemoglobin continues to evolve and develop as a useful blood substitute. Most of the early problems seem to have been resolved and a third generation of molecules, the second set of modifications, is promising.