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Journal of Veterinary Internal Medicine 2003Oxygen (O2) delivery to tissues plays an important role in determining microcirulatory autoregulatory responses. The balance between O2 delivery by whole blood and... (Review)
Review
Oxygen (O2) delivery to tissues plays an important role in determining microcirulatory autoregulatory responses. The balance between O2 delivery by whole blood and tissue O2 consumption likely has evolved based on regulatory processes designed to accommodate the encapsulation of hemoglobin (Hb) within red blood cells (RBCs). The hemodynamic, rheologic, and physical properties of blood, or an alternate O2-carrying solution, can have important consequences for O2 delivery to tissue. The development of acellular hemoglobin-based oxygen carriers (HBOC) requires reassessment of the O2 loading and unloading charactistics of Hb. the effects of altering the rheologic properties of blood, and the impact of these changes on microcirculatory autoregulation and tissue oxygenation. A variety of experimental and clinical studies have demonstrated beneficial effects of HBOCs. However, mechanisms responsible for HBOC-facilitated, O2-dependent autoregulatory changes in the microcirculation have not been completely elucidated.
Topics: Animals; Blood Pressure; Blood Substitutes; Hemoglobins; Microcirculation; Nitric Oxide; Oxygen; Oxygen Consumption; Solutions
PubMed: 12683610
DOI: 10.1111/j.1939-1676.2003.tb02423.x -
Journal of Internal Medicine May 2003Blood transfusion is a remarkably safe, routine procedure in clinical medicine. However, little attention has focused on the perceptions of risk associated with the... (Review)
Review
Blood transfusion is a remarkably safe, routine procedure in clinical medicine. However, little attention has focused on the perceptions of risk associated with the receipt of blood, blood products or 'blood substitutes'. It is pertinent to ask (i) what key stakeholder groups know about transfusion, (ii) how safe they perceive blood/blood products to be, (iii) how the latter information might influence their own and others' perceptions of risk linked to transfusion, and (iv) the extent to which approved blood substitutes might be preferred over autologous or donor blood. An appreciation of what stakeholders perceive to be the benefits and risks of the receipt of blood and blood substitutes will inform future transfusion strategies. To obtain such information, a programme of research has been initiated at Nottingham. Surveys have targeted key stakeholder groups, namely, UK adult blood donors and nondonors, anaesthetists, general practitioners and health care journalists. Experimental studies examining message framing and cueing have also been conducted with undergraduate students. Such research will improve misunderstandings about current issues associated with blood donation and transfusion against the backdrop of changing public trust of health care professionals and attitudes and expectations on blood safety and benefits of blood substitutes.
Topics: Attitude; Blood Donors; Blood Substitutes; Humans; Risk Factors; Transfusion Reaction; Truth Disclosure
PubMed: 12702027
DOI: 10.1046/j.1365-2796.2003.01149.x -
Antioxidants & Redox Signaling Jun 2013The worldwide blood shortage has generated a significant demand for alternatives to whole blood and packed red blood cells for use in transfusion therapy. One such... (Review)
Review
SIGNIFICANCE
The worldwide blood shortage has generated a significant demand for alternatives to whole blood and packed red blood cells for use in transfusion therapy. One such alternative involves the use of acellular recombinant hemoglobin (Hb) as an oxygen carrier.
RECENT ADVANCES
Large amounts of recombinant human Hb can be expressed and purified from transgenic Escherichia coli. The physiological suitability of this material can be enhanced using protein-engineering strategies to address specific efficacy and toxicity issues. Mutagenesis of Hb can (i) adjust dioxygen affinity over a 100-fold range, (ii) reduce nitric oxide (NO) scavenging over 30-fold without compromising dioxygen binding, (iii) slow the rate of autooxidation, (iv) slow the rate of hemin loss, (v) impede subunit dissociation, and (vi) diminish irreversible subunit denaturation. Recombinant Hb production is potentially unlimited and readily subjected to current good manufacturing practices, but may be restricted by cost. Acellular Hb-based O(2) carriers have superior shelf-life compared to red blood cells, are universally compatible, and provide an alternative for patients for whom no other alternative blood products are available or acceptable.
CRITICAL ISSUES
Remaining objectives include increasing Hb stability, mitigating iron-catalyzed and iron-centered oxidative reactivity, lowering the rate of hemin loss, and lowering the costs of expression and purification. Although many mutations and chemical modifications have been proposed to address these issues, the precise ensemble of mutations has not yet been identified.
FUTURE DIRECTIONS
Future studies are aimed at selecting various combinations of mutations that can reduce NO scavenging, autooxidation, oxidative degradation, and denaturation without compromising O(2) delivery, and then investigating their suitability and safety in vivo.
Topics: Animals; Biological Transport; Blood Substitutes; Heme; Hemoglobins; Humans; Nitric Oxide; Oxidation-Reduction; Oxygen; Protein Binding; Protein Stability; Recombinant Proteins
PubMed: 23025383
DOI: 10.1089/ars.2012.4917 -
Critical Care (London, England) Feb 2018
Topics: Blood Substitutes; Humans; Oxygen
PubMed: 29471841
DOI: 10.1186/s13054-018-1949-5 -
European Spine Journal : Official... Oct 2004Orthopaedic patients frequently require blood transfusions to treat peri-operative anemia. Research in the area of hemoglobin substitutes has been of great interest... (Review)
Review
Orthopaedic patients frequently require blood transfusions to treat peri-operative anemia. Research in the area of hemoglobin substitutes has been of great interest since it holds the promise of reducing the reliance on allogeneic blood transfusions. The three categories of hemoglobin substitutes are (1) cell-free, extracellular hemoglobin preparations made from human or bovine hemoglobin (hemoglobin-based oxygen carriers or HBOCs); (2) fluorine-substituted linear or cyclic carbon chains with a high oxygen-carrying capacity (perfluorocarbons); and (3) liposome-encapsulated hemoglobin. Of the three, HBOCs have been the most extensively studied and tested in preclinical and clinical trials that have shown success in diminishing the number of blood transfusions as well as an overall favorable side-effect profile. This has been demonstrated in vascular, cardiothoracic, and orthopaedic patients. HBOC-201, which is a preparation of cell-free bovine hemoglobin, has been approved for clinical use in South Africa. These products may well become an important tool for physicians treating peri-operative anemia in orthopaedic patients.
Topics: Anemia; Animals; Blood Substitutes; Blood Transfusion; Calmodulin; Erythrocytes; Hemoglobins; Humans; Orthopedic Procedures; Perioperative Care; Randomized Controlled Trials as Topic
PubMed: 15168238
DOI: 10.1007/s00586-004-0737-x -
British Journal of Anaesthesia Jul 1977
Topics: Anaphylaxis; Blood; Blood Transfusion; Humans; Hydrogen-Ion Concentration; Plasma Substitutes; Transfusion Reaction
PubMed: 18160
DOI: 10.1093/bja/49.7.681 -
PloS One 2017Nearly 21 million components of blood and whole blood and transfused annually in the United States, while on average only 13.6 million units of blood are donated. As the...
Nearly 21 million components of blood and whole blood and transfused annually in the United States, while on average only 13.6 million units of blood are donated. As the demand for Red Blood Cells (RBCs) continues to increase due to the aging population, this deficit will be more significant. Despite decades of research to develop hemoglobin (Hb) based oxygen (O2) carriers (HBOCs) as RBC substitutes, there are no products approved for clinical use. Lumbricus terrestris erythrocruorin (LtEc) is the large acellular O2 carrying protein complex found in the earthworm Lumbricus terrestris. LtEc is an extremely stable protein complex, resistant to autoxidation, and capable of transporting O2 to tissue when transfused into mammals. These characteristics render LtEc a promising candidate for the development of the next generation HBOCs. LtEc has a short half-life in circulation, limiting its application as a bridge over days, until blood became available. Conjugation with polyethylene glycol (PEG-LtEc) can extend LtEc circulation time. This study explores PEG-LtEc pharmacokinetics and pharmacodynamics. To study PEG-LtEc pharmacokinetics, hamsters instrumented with the dorsal window chamber were subjected to a 40% exchange transfusion with 10 g/dL PEG-LtEc or LtEc and followed for 48 hours. To study the vascular response of PEG-LtEc, hamsters instrumented with the dorsal window chamber received multiple infusions of 10 g/dL PEG-LtEc or LtEc solution to increase plasma LtEc concentration to 0.5, then 1.0, and 1.5 g/dL, while monitoring the animals' systemic and microcirculatory parameters. Results confirm that PEGylation of LtEc increases its circulation time, extending the half-life to 70 hours, 4 times longer than that of unPEGylated LtEc. However, PEGylation increased the rate of LtEc oxidation in vivo. Vascular analysis verified that PEG-LtEc showed the absence of microvascular vasoconstriction or systemic hypertension. The molecular size of PEG-LtEc did not change the colloid osmotic pressure or blood volume expansion capacity compared to LtEc, due to LtEc's already large molecular size. Taken together, these results further encourage the development of PEG-LtEc as an O2 carrying therapeutic.
Topics: Animals; Arterioles; Blood Flow Velocity; Blood Substitutes; Capillaries; Half-Life; Hemoglobins; Infusions, Intravenous; Male; Mesocricetus; Nitrite Reductases; Oligochaeta; Oxygen; Polyethylene Glycols; Venules
PubMed: 28099525
DOI: 10.1371/journal.pone.0170041 -
Transfusion Clinique Et Biologique :... Nov 2005Concerns about the safety and adequacy of the blood supply have fostered twenty years of research into the so-called "blood substitutes" among them the oxygen carriers... (Review)
Review
Concerns about the safety and adequacy of the blood supply have fostered twenty years of research into the so-called "blood substitutes" among them the oxygen carriers based on modified hemoglobin. Although none of these materials has yet been licensed for use in North America or Europe, the results of research and clinical trials have increased our understanding of oxygen delivery and its regulation. In particular, the examination of the basis for the vasoactivity observed with some of the hemoglobin based oxygen carriers has led to the insight that several colligative properties of hemoglobin solutions, such as their diffusion coefficient for oxygen, viscosity and colloid oncotic pressure, are important determinants of efficacy.
Topics: Animals; Blood Substitutes; Erythrocyte Transfusion; Erythrocytes; Hemoglobins; Humans; Models, Animal; Oxyhemoglobins; Stress, Mechanical
PubMed: 16326128
DOI: 10.1016/j.tracli.2005.10.002 -
Scientific Reports Nov 2022For the past thirty years, hemoglobin-based oxygen carriers (HBOCs) have been under development as a red blood cell substitute. Side-effects such as vasoconstriction,...
For the past thirty years, hemoglobin-based oxygen carriers (HBOCs) have been under development as a red blood cell substitute. Side-effects such as vasoconstriction, oxidative injury, and cardiac toxicity have prevented clinical approval of HBOCs. Recently, high molecular weight (MW) polymerized human hemoglobin (PolyhHb) has shown positive results in rats. Studies have demonstrated that high MW PolyhHb increased O delivery, with minimal effects on blood pressure, without vasoconstriction, and devoid of toxicity. In this study, we used guinea pigs to evaluate the efficacy and safety of high MW PolyhHb, since like humans guinea pigs cannot produce endogenous ascorbic acid, which limits the capacity of both species to deal with oxidative stress. Hence, this study evaluated the efficacy and safety of resuscitation from severe hemorrhagic shock with high MW PolyhHb, fresh blood, and blood stored for 2 weeks. Animals were randomly assigned to each experimental group, and hemorrhage was induced by the withdrawal of 40% of the blood volume (BV, estimated as 7.5% of body weight) from the carotid artery catheter. Hypovolemic shock was maintained for 50 min. Resuscitation was implemented by infusing 25% of the animal's BV with the different treatments. Hemodynamics, blood gases, total hemoglobin, and lactate were not different before hemorrhage and during shock between groups. The hematocrit was lower for the PolyhHb group compared to the fresh and stored blood groups after resuscitation. Resuscitation with stored blood had lower blood pressure compared to fresh blood at 2 h. There was no difference in mean arterial pressure between groups at 24 h. Resuscitation with PolyhHb was not different from fresh blood for most parameters. Resuscitation with PolyhHb did not show any remarkable change in liver injury, inflammation, or cardiac damage. Resuscitation with stored blood showed changes in liver function and inflammation, but no kidney injury or systemic inflammation. Resuscitation with stored blood after 24 h displayed sympathetic hyper-activation and signs of cardiac injury. These results suggest that PolyhHb is an effective resuscitation alternative to blood. The decreased toxicities in terms of cardiac injury markers, vital organ function, and inflammation following PolyhHb resuscitation in guinea pigs indicate a favorable safety profile. These results are promising and support future studies with this new generation of PolyhHb as alternative to blood when blood is unavailable.
Topics: Humans; Guinea Pigs; Animals; Rats; Shock, Hemorrhagic; Resuscitation; Blood Substitutes; Polymerization; Inflammation; Oxygen
PubMed: 36443351
DOI: 10.1038/s41598-022-23926-y -
Postgraduate Medical Journal Sep 1967
Review
Topics: Blood Circulation; Blood Volume; Emergencies; Humans; Infusions, Parenteral; Plasma Substitutes; Resuscitation; Shock; Water-Electrolyte Balance
PubMed: 4863457
DOI: 10.1136/pgmj.43.503.592