TRANSFUSION TRIGGER EXTENSION BY PLASMA EXPANDERS
Marcos Intaglietta
Department/ Educational Institution Type:
Grant 5R01HL062354-08 from National Heart, Lung, And Blood Institute
Abstract: Our aim is to determine the application of new PEs that specifically maintain microvascular and heart function, allowing the lowering of the transfusion trigger, which would minimize or delay the use of blood transfusions. Conventional plasma expanders (PEs) lower blood viscosity and their use beyond the transfusion trigger causes 1) Arteriolar vasoconstriction and decreased blood flow; 2) Reduced number of capillaries with red blood cell transit (i.e., functional capillary density, FCD); and, 3) Lowered blood pressure. These effects occur also in the microcirculation of the heart, causing heart function, and cardiac output to decrease. In normal conditions, shear stress on the endothelium generated by blood flow produces sufficient nitric oxide (NO) resulting in normal vascular tone and blood flow, restricting mitochondrial tissue oxygen consumption. Conversely, lowered blood viscosity and decreased heart function obtained with the presently used PEs do not generate the vessel wall shear stress necessary to produce sufficient NO for cardiovascular regulation when used beyond the transfusion trigger. We identified alginate, a high viscosity PE and polyethylene glycol conjugated albumin, a moderate viscosity PE, as fluids that restore FCD, heart function and mean arterial blood pressure in extreme hemodilution. We propose that these effects arise from improvement of heart function by maintaining microvascular perfusion of the myocardium and limiting damage to endothelial function and vessel wall integrity by interaction with the glycocalyx. Our research will test the hypothesis that there is a direct relationship between microvascular recovery and improvement of heart function in extreme hemodilution and shock resuscitation. Studies will use microvascular analysis by direct in vivo measurement of micro-pO2, micro-NO, capillary pressure, microvascular flow, FCD, tissue pH, reactive oxygen species (ROS) formation and cellular necrosis and apoptosis. These studies will be correlated with electrocardiographic measurements aimed at documenting myocardial ischemia. Heart function will also be assessed by measuring contractility (dP/dt) and cardiac output. Blood flow distribution to major organs will be measured using fluorescent tracers. Parallel studies will be made in isolated microvessels to determine the effects of the proposed materials on microvessel reactivity by interaction with the glycocalyx. Glycocalyx studies will also be made in the hamster window chamber model. Blood will be substituted with PEs in the hamster window chamber model which can be studied without complications of anesthesia and for long periods. An extreme hemodilution and a hemorrhagic shock model followed by continuous bleeding will be used to simulate realistic clinical conditions. Strategies for optimal follow up of plasma resuscitation and exchange with blood transfusion will be investigated
Keywords: Abbreviations; Active Follow-up; Active Oxygen; Acute; Albumins; Alginates; Anemia; anesthesia complication; Animals; Apoptosis; Apoptosis Pathway; Autologous; Binding; Binding (Molecular Function); biological signal transduction; Bleeding; Blood; Blood capillaries; blood corpuscles; Blood erythrocyte; Blood flow; blood loss; Blood normocyte; Blood Plasma; Blood Pressure; Blood Pressure, Low; Blood Transfusion; Blood Vessels; Blood Viscosity; Body Tissues; Capillaries; Capillary; capillary; Capillary, Unspecified; Cardiac; cardiac muscle; Cardiac Output; Cardiovascular; Cardiovascular Body System; Cardiovascular system; Cardiovascular system (all sites); Carrying Capacities; Cell Coat; Cell Communication and Signaling; Cell Death; Cell Death, Programmed; Cell Signaling; Circulatory Collapse; circulatory shock; circulatory system; Clinical; clinical investigation; clinical relevance; Clinical Trials; Clinical Trials, Unspecified; clinically relevant; Common Rat Strains; Cricetinae; Critiques; density; design; designing; Drug Formulations; ECG; EKG; Electrocardiogram; Electrocardiography; Emergencies; Emergency Situation; Endogenous Nitrate Vasodilator; endothelial cell derived relaxing factor; Endothelium; Endothelium-Derived Relaxing Factor; Erythrocyte Volume, Packed; Erythrocytes; Erythrocytic; exhaust; experiment; experimental research; experimental study; falls; fluid; follow-up; Formulation; Formulations, Drug; Glycocalyx; Hamsters; Hct; Heart; heart function; heart ischemia; heart muscle; heart output; Hematocrit; Hematocrit procedure; Hemodilution; Hemorrhage; Hemorrhagic Shock; Hypotension; Hypovolemia; improved; in vivo; indexing; Intracellular Communication and Signaling; Investigators; Ischemic Heart; Ischemic Heart Disease; Ischemic myocardium; Knowledge; language translation; liquid; Liquid substance; living system; Macrogols; Maintenance; Maintenances; Mammals, Hamsters; Mammals, Rats; Marrow erythrocyte; Materials Testing; Measurement; Measures; Mechanics; Mediating; Methods and Techniques; Methods, Other; Microbeads; Microcirculation; Microspheres; Mitochondria; mitochondrial; Modeling; Molecular Interaction; Monitor; Mononitrogen Monoxide; Muscle, Cardiac; Muscle, Heart; Myocardial Ischemia; myocardial ischemia/hypoxia; Myocardium; myocardium ischemia; necrocytosis; Necrosis; Necrotic; Nitric Oxide; Nitric Oxide, Endothelium-Derived; Nitrogen Monoxide; Nitrogen oxide; Nitrogen Protoxide; novel; Optics; Organ; Organ System, Cardiovascular; Organism; Outcome; Oxygen Consumption; Oxygen Radicals; Packed Red-Cell Volume; Peer Review; PEG; Perfusion; Plasma; Polyethylene Glycols; Polyethylene Oxide; Polyethyleneoxide; Polyoxyethylenes; pressure; Pressure; Pressure- physical agent; Pro-Oxidants; programs; Programs (PT); Programs [Publication Type]; Publications; Rat; Rattus; Reactive Oxygen Species; Recovery; Red Blood Cells; Red blood corpuscule; Red Cell; Red cell of marrow; Regulation; Relative; Relative (related person); Reporting; Research; Research Personnel; research study; Researchers; response; restoration; Resuscitation; Reticuloendothelial System, Blood; Reticuloendothelial System, Erythrocytes; Reticuloendothelial System, Serum, Plasma; Scientific Publication; Serum, Plasma; shear stress; Shock; Signal Transduction; Signal Transduction Systems; Signaling; Simulate; Solutions; Staging; standard measure; Study Section; Surrogate End Points; Surrogate Endpoint; System; System, LOINC Axis 4; Tag; Techniques; Testing; Therapeutic; Tissue Viability; Tissues; Toxic effect; Toxicities; Tracer; Transfusion; Translating; Translatings; Transmission; transmission process; Trauma; TRNSF; vascular; Vascular constriction (function); Vascular Hypotensive Disorder; Vascular, Heart; Vasoconstriction; Vasodilatation; Vasodilation; Vasorelaxation; Viscosity; WHBLOOD; Whole Blood
Project start date: 2000-09-01
Project end date: 2011-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2011
5R01HL062354-08 (2009): $348589
Sponsored Links Excellgen http://Excellgen.com
Transfusion Trigger Extension By Plasma Expanders
Marcos Intaglietta, Chairman Of Board Of Trustees
Bioengineeringuniversity Of California San Diego
9500 Gilman Dr, Dept 0934
la Jolla, Ca 920930934
Grant 5R01HL062354-07 from National Heart, Lung, And Blood Institute IRG: HM
Abstract: Our aim is to determine the application of new PEs that specifically maintain microvascular and heart function, allowing the lowering of the transfusion trigger, which would minimize or delay the use of blood transfusions. Conventional plasma expanders (PEs) lower blood viscosity and their use beyond the transfusion trigger causes 1) Arteriolar vasoconstriction and decreased blood flow; 2) Reduced number of capillaries with red blood cell transit (i.e., functional capillary density, FCD); and, 3) Lowered blood pressure. These effects occur also in the microcirculation of the heart, causing heart function, and cardiac output to decrease. In normal conditions, shear stress on the endothelium generated by blood flow produces sufficient nitric oxide (NO) resulting in normal vascular tone and blood flow, restricting mitochondrial tissue oxygen consumption. Conversely, lowered blood viscosity and decreased heart function obtained with the presently used PEs do not generate the vessel wall shear stress necessary to produce sufficient NO for cardiovascular regulation when used beyond the transfusion trigger. We identified alginate, a high viscosity PE and polyethylene glycol conjugated albumin, a moderate viscosity PE, as fluids that restore FCD, heart function and mean arterial blood pressure in extreme hemodilution. We propose that these effects arise from improvement of heart function by maintaining microvascular perfusion of the myocardium and limiting damage to endothelial function and vessel wall integrity by interaction with the glycocalyx. Our research will test the hypothesis that there is a direct relationship between microvascular recovery and improvement of heart function in extreme hemodilution and shock resuscitation. Studies will use microvascular analysis by direct in vivo measurement of micro-pO2, micro-NO, capillary pressure, microvascular flow, FCD, tissue pH, reactive oxygen species (ROS) formation and cellular necrosis and apoptosis. These studies will be correlated with electrocardiographic measurements aimed at documenting myocardial ischemia. Heart function will also be assessed by measuring contractility (dP/dt) and cardiac output. Blood flow distribution to major organs will be measured using fluorescent tracers. Parallel studies will be made in isolated microvessels to determine the effects of the proposed materials on microvessel reactivity by interaction with the glycocalyx. Glycocalyx studies will also be made in the hamster window chamber model. Blood will be substituted with PEs in the hamster window chamber model which can be studied without complications of anesthesia and for long periods. An extreme hemodilution and a hemorrhagic shock model followed by continuous bleeding will be used to simulate realistic clinical conditions. Strategies for optimal follow up of plasma resuscitation and exchange with blood transfusion will be investigated
Keywords: alginate, blood /plasma substitute, blood transfusion, blood viscosity, blood volume, hemodynamics, polyethylene glycol, vascular resistance blood circulation, cardiovascular function, electrocardiography, glycoprotein, heart function, hemorrhagic shock, microcirculation, nitric oxide, oxygen consumption, polysaccharide, respiratory oxygenation, vasoconstriction blood flow measurement, hamster, laboratory rat
Project start date: 2000-09-01
Project end date: 2010-07-31
5R01HL062354-07 (2008): $348589
5R01HL062354-06 (2007): $348589
5R01HL062354-04 (2003): $377773
5R01HL062354-03 (2002): $366945
5R01HL062354-02 (2001): $372615
Grants awarded to Marcos Intaglietta
Microvascular Effects Of Surface Decorated Hemoglobins
Marcos Intaglietta, Chairman Of Board Of Trustees
Yeshiva University 500 W 185th St New York, Ny 10033
Grant 5P01HL071064-050005 from National Heart, Lung, And Blood Institute IRG: HLBP
Abstract: We propose to determine the mechanisms that cause vasoconstriction when cell free hemoglobins are introduced into the circulation as the O2 carrier of an O2-carrying plasma expander (OCPE) by studying the vascular effects produced by polyethylene glycol (PEG) surface decorated hemoglobins (HbS) developed in this program. We will study the presser response to top loads of various formulations and quantify the reactions of the microcirculation in the hamster skinfold model, which can be studied without anesthesia, in the awake condition for periods of up to 2 weeks. The principal microvascular parameters to be evaluated in vivo are functional capillary density and intravascular oxygen tension distribution. Tests will analyze different hypothesis on the genesis of vasoactivity due to molecular hemoglobin in the circulation, namely 1) NO scavenging by hemoglobin; 2) lowered viscosity in hemodilution, leading to lowered shear stress and production of endothelial relaxing factors; 3) Increased facilitated diffusion and O2 autoregulation by oxyhemoglobin; and, 4) Extent of hemoglobin surface shielding by PEG molecules. Efficacy of the OCPEs will be determined in conditions of isovolemic hemodilution and hemorrhagic shock. An effective OCPE must also insure sufficiently elevated blood viscosity, which is necessary for the maintenance of adequate microvascular function, and condition that can be obtained with PEG-Hbs. In hemodilution these molecules increase plasma viscosity, causing redistribution of hydraulic pressure in the circulation, decreasing systemic viscosity dependent pressure losses and increasing peripheral resistance. Additionally the O2 dissociation curve for these modified hemoglobins should be left shifted, so O2 release occurs only in anoxic regions and not from arterioles and where tissue oxygenation is adequate. Our goal is to obtain an understanding of vasoactivity in support of OCPE development that prioritizes maintenance of microvascular function in terms of capillary perfusion, which is as critical for tissue survival as adequate oxygenation, by using methods for the analysis at the cellular microscopic level, where blood performs its vital functions.
Keywords: biomaterial development /preparation, biomaterial evaluation, blood /plasma substitute, hemoglobin, microcirculation, oxygen transport, plasma, polyethylene glycol, vasoconstriction, vasomotion, blood viscosity, endothelin, hemodynamics, hemorrhagic shock, nitric oxide, prostacyclin, vascular endothelium, biotechnology, blood chemistry, blood flow measurement, hamster, tissue /cell culture
BIOENGINEERING DESIGN OF ARTIFICIAL BLOOD
Marcos Intaglietta, Chairman Of Board Of Trustees
University Of California San Diego 9500 Gilman Dr, Dept 0934 La Jolla, Ca 920930934
Grant 5R24HL064395-05 from National Heart, Lung, And Blood Institute IRG: ZRG1
Abstract: verbatim) We plan to design, develop, and produce an economic oxygen carrying plasma expander based on modified molecular human hemoglobin engineered with properties that insure the maintenance of microvascular function, leading to improved survival and tissue oxygenation relative to blood, for treatment of trauma victims within 48 hours of injury. The program is vertically integrated, including production of purified hemoglobin from red blood cells by means of a modified, self contained plasma fractionation centrifuge ~at directly produces the necessary molecular modifications and a unit of artificial blood ready for use. This approach eliminates the need for fabrication of large, clean facilities and reduces cost. Furthermore it allows for production in remote areas. Our bioengineering design principle is that when a blood replacement fluid is introduced in the circulation it should cause the resulting blood viscosity to remain sufficiently elevated to insure the adequate generation of shear stress at the-blood/tissue interface, which we have demonstrated to be necessary to provide normal capillary blood flow the key -determinant of tissue survival. According to this principle even small amounts of cell-free hemoglobin (l-2 g/dl) are very effective in improving survival after hemorrhage. Due to this low-dose effect at least two units of product can be obtained from each unit of collected normal blood. The molecular modification to be pursued is surface modification with polyethylene glycol (PEG), and other modifications that will result in molecules with large radius. Different formulations of product are envisioned including a low volume concentrated solution that will restore blood volume by autotransfusion. The program encompasses all aspects of artificial blood production from obtaining the raw materials to the final commercial product and is aimed at; establishing a blood transfusion technology that delivers a-blood replacement biomaterial that is cost effective and as efficacious as blood. The envisioned artificial blood will be universal, requiring no typing, will have long shelf life and will be easy to store.
Keywords: bioengineering /biomedical engineering, biomaterial development /preparation, blood substitute, hemoglobin, polyethylene glycol, biotechnology, hamster, laboratory mouse, laboratory rat
Project start date: 2000-05-05
Project end date: 2007-04-30
5R24HL064395-05 (2004): $1009112
5R24HL064395-04 (2003): $984323
5R24HL064395-03 (2002): $960256
5R24HL064395-02 (2001): $963528
1R24HL064395-01 (2000): $1112548
Sponsored Links Excellgen http://Excellgen.com
FUNCTIONAL ASPECTS OF OXYGEN DELIVERY
Marcos Intaglietta, Chairman Of Board Of Trustees
University Of California San Diego 9500 Gilman Dr, Dept 0934 La Jolla, Ca 920930934
Grant 5R01HL062318-04 from National Heart, Lung, And Blood Institute IRG: ECS
Abstract: Our hypothesis is that arterioles are the principal suppliers of oxygen to skeletal muscle at rest and connective tissue, and that a substantial fraction of the oxygen delivered to the tissue by the arterioles is used by the arteriolar vessel wall. High oxygen consumption by the arteriolar wall/endothelium/smooth muscle causes the presence of large oxygen gradients next to the blood tissue interface. These gradients determine the high rate of oxygen exit from arterioles by diffusion a phenomenon measured by other investigators using oxygen microelectrodes and the change in microvessel blood oxygen saturation and by us using the phosphorescence quenching technique. The rate of oxygen consumption by the arteriolar microvascular wall may account for as much as 30% of total oxygen use by some tissues, a phenomenon also found in whole organ studies by others. Our hypothesis is that arteriolar wall oxygen consumption is increased by vasoconstriction, low shear stress at the blood-endothelium interface, and decreased NO availability which lowers tissue oxygenation. Conversely the opposite effects lower oxygen consumption by the arteriolar wall and increase tissue oxygen. An additional mechanism is that NO curbs or minimizes oxygen consumption of the vessel wall and acts as a brake to oxygen consumption. It is proposed that blood viscosity is a determinant of p02 distribution in the microcirculation because 1) Viscosity is a factor in determining peripheral vascular resistance, blood flow and perfusion; 2) The rate of oxygen exit from the microvessels is the balance between flow velocity and outward diffusion; and, 3) Blood viscosity determines the release of endothelial derived prostaglandin and NO via wall shear stress mediated mechanisms. These mechanisms directly affect functional capillary density, which is a determinant of tissue survival even though capillaries provide minimal oxygen to the tissue. The methods comprise in vivo measurements of microvascular transport properties including micro-p02 and micro-NO measurements in blood and tissue, blood flow velocity, functional capillary density and arteriolar reactivity. Our investigations use the method of mass balance to predict the vessel wall oxygen consumption needed to explain the rate of oxygen exit from the arterioles, and the high resolution phosphorescence quenching oxygen measurement technique to experimentally verify the theoretical predictions. Our research aims at advancing our understanding of tissue oxygenation and provides a new conceptual framework with which to analyze the ischemic process.
Keywords: arteriole, blood circulation, hemodynamics, microcirculation, oxygen consumption, oxygen tension, vascular endothelium, vascular smooth muscle, blood viscosity, diffusion, nitric oxide, oxygen transport, prostaglandin, vascular endothelium permeability, vasomotion, hamster
Project start date: 2001-06-22
Project end date: 2007-04-30
5R01HL062318-04 (2004): $368504
5R01HL062318-03 (2003): $357948
5R01HL062318-02 (2002): $354542
1R01HL062318-01A2 (2001): $372528
Transfusion Trigger Extension By Plasma Expanders
Marcos Intaglietta, Chairman Of Board Of Trustees
University Of California San Diego 9500 Gilman Dr, Dept 0934 La Jolla, Ca 920930934
Grant 2R01HL062354-05A2 from National Heart, Lung, And Blood Institute IRG: HM
Abstract: Our aim is to determine the application of new PEs that specifically maintain microvascular and heart function, allowing the lowering of the transfusion trigger, which would minimize or delay the use of blood transfusions. Conventional plasma expanders (PEs) lower blood viscosity and their use beyond the transfusion trigger causes 1) Arteriolar vasoconstriction and decreased blood flow; 2) Reduced number of capillaries with red blood cell transit (i.e., functional capillary density, FCD); and, 3) Lowered blood pressure. These effects occur also in the microcirculation of the heart, causing heart function, and cardiac output to decrease. In normal conditions, shear stress on the endothelium generated by blood flow produces sufficient nitric oxide (NO) resulting in normal vascular tone and blood flow, restricting mitochondrial tissue oxygen consumption. Conversely, lowered blood viscosity and decreased heart function obtained with the presently used PEs do not generate the vessel wall shear stress necessary to produce sufficient NO for cardiovascular regulation when used beyond the transfusion trigger. We identified alginate, a high viscosity PE and polyethylene glycol conjugated albumin, a moderate viscosity PE, as fluids that restore FCD, heart function and mean arterial blood pressure in extreme hemodilution. We propose that these effects arise from improvement of heart function by maintaining microvascular perfusion of the myocardium and limiting damage to endothelial function and vessel wall integrity by interaction with the glycocalyx. Our research will test the hypothesis that there is a direct relationship between microvascular recovery and improvement of heart function in extreme hemodilution and shock resuscitation. Studies will use microvascular analysis by direct in vivo measurement of micro-pO2, micro-NO, capillary pressure, microvascular flow, FCD, tissue pH, reactive oxygen species (ROS) formation and cellular necrosis and apoptosis. These studies will be correlated with electrocardiographic measurements aimed at documenting myocardial ischemia. Heart function will also be assessed by measuring contractility (dP/dt) and cardiac output. Blood flow distribution to major organs will be measured using fluorescent tracers. Parallel studies will be made in isolated microvessels to determine the effects of the proposed materials on microvessel reactivity by interaction with the glycocalyx. Glycocalyx studies will also be made in the hamster window chamber model. Blood will be substituted with PEs in the hamster window chamber model which can be studied without complications of anesthesia and for long periods. An extreme hemodilution and a hemorrhagic shock model followed by continuous bleeding will be used to simulate realistic clinical conditions. Strategies for optimal follow up of plasma resuscitation and exchange with blood transfusion will be investigated.
Keywords: alginate, blood /plasma substitute, blood transfusion, blood viscosity, blood volume, hemodynamics, polyethylene glycol, vascular resistance, blood circulation, cardiovascular function, electrocardiography, glycoprotein, heart function, hemorrhagic shock, microcirculation, nitric oxide, oxygen consumption, polysaccharide, respiratory oxygenation, vasoconstriction, blood flow measurement, hamster, laboratory rat
Project start date: 2000-09-01
Project end date: 2010-07-31
2R01HL062354-05A2 (2006): $372625
BIOENGINEERING DESIGN OF ARTIFICIAL BLOOD
Marcos Intaglietta
University Of California San Diego, 9500 Gilman Dr, Dept 0934, La Jolla, Ca 92093-0934
Grant 5R01HL064395-09 from National Heart, Lung, And Blood Institute
Abstract: In the first period, work in this BRP demonstrated that MP4 (PEG-modified hemoglobin) overcomes the most significant hurdle to the development of modified hemoglobin-based blood substitutes, namely vasoconstriction. MP4 promotes tissue oxygenation through a combination of O2 transport and maintenance of functional capillary density in spite of its counterintuitive properties, including increased O2 affinity, viscosity and oncotic pressure. MP4 is superior to blood in its ability to resuscitate animals from severe, uncontrolled hemorrhage, and it has been shown to be safe in human clinical trials. In this present application we will test the hypothesis that MP4 is an effective carrier of the heme ligands O2, carbon monoxide (CO)and nitric oxide (NO), and will carry out the related physiological studies in order to understand its effectiveness as a blood substitute and identify new clinical applications for its use. We will test the hypothesis that PEG-Hb formulations are vasodilators which interact with the circulation in ways not related to NO scavenging by Hb. We propose that MP4´s properties are in part due to an increased nitrite reductase activity and NO transport. We will develop a procedure for using MP4 to deliver CO and exploit that CO-MP4 is exceptionally stable, even at elevated temperatures, making it valuable in field use for trauma. Project 1 has a GMP facility that provides MP4 of consistent quality and properties. It will develop and produce new PEG-Hb compounds with goals to optimize concentration without increasing colloid osmotic pressure and augment O2 delivery capacity so as to increase the applicability of MP4 to a wider range of clinical uses. Properties will be screened via biochemical analysis, mathematical modeling, and systemic experiments in rats including the effect on myocardial infarction. Project 2 will examine PEG-Hbs´ effects on the glycocalyx integrity, how PEG-Hbs´ presence influences reactive O2 species (ROS), and will investigate the combined effect of PEG-Hb and enhanced plasma viscosity. MP4 will be used as a delivery vehicle for CO to provide cellular protection during ischemia & hemorrhage. Microcirculation studies will use the awake hamster window chamber model, with direct measurements of O2 and NO levels, flow and diameter in blood vessels and functional capillary density. This research combines physiological analysis of transfusion, fundamentals of engineering transport processes and mechanotransduction with the expertise of two laboratories with more than 12 years of collaboration. Effective blood substitutes will significantly increase the safety and efficacy of blood transfusions in civilian and military settings, streamline and simplify transfusion medicine. Applications for a new type of blood substitute will be developed, one that provides a fundamentally different treatment of ischemia, based on enhancement of microvascular flow, cardiac and renal functions, repair of the endothelium and delivery of heme ligands (O2, NO and CO)
Keywords: 2, 3, 5- triphenyl-2H-tetrazolium, chloride; 2-iminothiolane; Acids; Affinity; Amines; Animal Model; Animal Models and Related Studies; Animals; Apoptosis; Apoptosis Pathway; Armed Forces Personnel; Artificial Erythrocytes; Assay; Autoregulation; Binding; Binding (Molecular Function); Bioassay; Biochemical; Biologic Assays; Biological Assay; Biomedical Engineering; Bleeding; Blood; Blood Circulation; Blood Plasma; Blood Substitutes; Blood Transfusion; Blood Vessels; Blood Volume; Blood capillaries; Blood erythrocyte; Blood normocyte; Blood, Artificial; Bloodstream; Bp50; CD40; CDW40; Caliber; Capillaries; Capillary; Capillary, Unspecified; Carbon Monoxide; Cardiac; Cardiac Output; Cardiac infarction; Cell Coat; Cell Death; Cell Death, Programmed; Characteristics; Chloride; Chloride Ion; Chlorides; Chromatography, High Performance Liquid; Chromatography, High Pressure Liquid; Chromatography, High Speed Liquid; Chronotropism, Cardiac; Chronotropisms, Cardiac; Circulation; Cl- element; Clinical; Clinical Trials; Clinical Trials, Phase II; Clinical Trials, Phase III; Clinical Trials, Unspecified; Collaborations; Colloids; Common Rat Strains; Conscious; Consciousness; Coronary Occlusions; Cricetinae; Data; Development; Diameter; Diffusion; Digestion; Dose; Drug Formulations; Drugs, Nonproprietary; Effectiveness; Endogenous Nitrate Vasodilator; Endothelium; Endothelium-Derived Relaxing Factor; Endotoxins; Engineering; Engineerings; Equation; Erythrocyte Substitutes; Erythrocytes; Erythrocytic; Europe; Ferrate(2-), (7, 12-diethenyl-3, 8, 13, 17-tetramethyl-21H, 23H-porphine-2, 18-dipropanoato(4-)-N21, N22, N23, N24)-, dihydrogen, (SP-4-2)-; Ferroprotoporphyrin; Formulation; Formulations, Drug; Freezing; Gases; Generic Drugs; Glycocalyx; Goals; HPLC; Hamsters; Heart; Heart Rate; Heme; Heme b; Hemodilution; Hemoglobin; Hemorrhage; High Pressure Liquid Chromatography; Homeostasis; Hour; Human; Human, General; Hydration; Hydration status; Infarction; Investigators; Ischemia; Ischemic Heart; Ischemic Heart Disease; Ischemic myocardium; L-Lysine; Laboratories; Length; Ligand Binding; Ligands; Lysine; MGC9013; Macrogols; Maintenance; Maintenances; Maleimides; Mammals, Hamsters; Mammals, Rats; Man (Taxonomy); Man, Modern; Marrow erythrocyte; Math Models; Measurement; Measures; Medicine; Membrane Proteins; Membrane-Associated Proteins; Mercaptans; Mercapto Compounds; Metabolic; Methods; Microcirculation; Military; Military Personnel; Modeling; Molecular Configuration; Molecular Conformation; Molecular Dynamics Simulation; Molecular Interaction; Molecular Models; Molecular Stereochemistry; Molecular Transport; Molecular Weight; Monitor; Mononitrogen Monoxide; Myocardial Infarct; Myocardial Infarction; Myocardial Ischemia; Names; Necrosis; Necrotic; Nitric Oxide; Nitric Oxide, Endothelium-Derived; Nitrite Reductase; Nitrogen Monoxide; Nitrogen Protoxide; Nitrogen oxide; Nucleic Acid Biochemistry, Molecular Modeling; O element; O2 element; Occlusions, Coronary; Osmolalities; Osmotic Pressure; Oxygen; PEG; PEG-Hb; PEG-hemoglobin; Phase; Phase 2 Clinical Trials; Phase 3 Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Physiologic; Physiological; Physiological Homeostasis; Plasma; Polyethylene Glycols; Polyethylene Oxide; Polyethyleneoxide; Polymers; Polyoxyethylenes; Preparation; Pressure; Pressure- physical agent; Procedures; Production; Property; Property, LOINC Axis 2; Protein/Amino Acid Biochemistry, Molecular Modeling; Proteins; Protoheme; Protoheme IX; R Factors; R Plasmids; R01 Mechanism; R01 Program; RPG; Radial; Rat; Rattus; Reaction; Red Blood Cells; Red Cell; Red Cell Substitutes; Red blood corpuscule; Red cell of marrow; Renal function; Reperfusion Therapy; Research; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Research Proposals; Researchers; Resistance Factors; Resuscitation; Reticuloendothelial System, Blood; Reticuloendothelial System, Erythrocytes; Reticuloendothelial System, Serum, Plasma; Role; Safety; Science of Medicine; Serum, Plasma; Site; Solutions; Staging; Structure; Sulfhydryl Compounds; Surface; Surface Proteins; Sweden; System; System, LOINC Axis 4; TNFRSF5; TNFRSF5 gene; TRNSF; Temperature; Test Result; Testing; Thermodynamic; Thermodynamics; Thiols; Time; Toxic effect; Toxicities; Transfusion; Transport Process; Trauma; Tumor Necrosis Factor Receptor Superfamily Member 5 Gene; Vascular constriction (function); Vasoconstriction; Vasodilating Agent; Vasodilator Agents; Vasodilator Drugs; Vasodilators; Viscosity; Weight; Work; alkyl group; awake; base; bioengineering; bioengineering/biomedical engineering; blood corpuscles; blood loss; capillary; cardiac infarct; cardiac occlusion; chemical synthesis; clinical applicability; clinical application; clinical investigation; conformation; conformational state; coronary attack; coronary infarct; coronary infarction; cross-link; crosslink; density; design; designing; endothelial cell derived relaxing factor; experiment; experimental research; experimental study; ferroheme; gene product; generic; heart attack; heart infarct; heart infarct sizing; heart infarction; heart infarction sizing; heart ischemia; heart occlusion; heart output; hemodynamics; improved; in vivo; infarct; kidney function; light scattering; mathematical model; mathematical modeling; methyl 4-mercaptobutyrimidate; model organism; molecular dynamics; molecular modeling; molecular size; myocardial infarct sizing; myocardial infarction sizing; myocardial ischemia/hypoxia; myocardium ischemia; necrocytosis; novel; oxygen transport; p50; phase 2 study; phase 2 trial; phase 3 study; phase 3 trial; phase II trial; phase III trial; polyethylene glycol-hemoglobin conjugate; pressure; protocol, phase II; protocol, phase III; repair; repaired; reperfusion; research study; simulation; social role; study, phase II; study, phase III; sulfhydryl group; tissue oxygen saturation; tissue oxygenation; triphenyltetrazolium; vascular
Project start date: 2000-05-05
Project end date: 2012-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: PAR-06-459
5R01HL064395-09 (2010): $708566
5R01HL064395-08 (2009): $713079
5R01HL064395-07 (2008): $722909
2R01HL064395-06A2 (2007): $748104
TRANSFUSION TRIGGER EXTENSION BY PLASMA EXPANDERS
Marcos Intaglietta, Chairman Of Board Of Trustees
Bioengineeringuniversity Of California San Diego
9500 Gilman Dr, Dept 0934
la Jolla, Ca 920930934
Grant 1R01HL062354-01A2 from National Heart, Lung, And Blood Institute IRG: ECS
Abstract: Adapted ) Colloidal or crystalloid solutions are used to restore blood volume up to the transfusion trigger of 7g Hb/dL. Their use beyond this threshold reduces oxygen carrying capacity, which limits tissue oxygen delivery and survival. This proposal examines the hypothesis that the lack of clinical benefit for plasma expanders (PEs) beyond the transfusion trigger is due to a microvascular malfunction, not due to a reduced oxygen carrying capacity. In particular, alteration of blood properties, including viscosity and oncotic pressure, beyond the transfusion trigger causes 1) arteriolar vasoconstriction and decreased blood flow; 2) reduced functional capillary density (FCD); and, 3) lowered tissue oxygenation. A proposed mechanism underlying these changes is that below the transfusion trigger blood and plasma viscosity are reduced beyond the compensatory capacity of the cardiovascular system, which causes capillary pressure to decrease, capillaries to become obstructed, and a lowering of FCD. Furthermore, the viscosity of blood with conventional PEs is too low to generate endothelial NO through arteriolar wall shear stress, resulting in reduced vascular tone and increased mitochondrial O2 consumption. The proposed studies will use dextran and starch solutions with different viscosities as PEs in hamster studies using the skin fold microcirculatory model. The aim will be to partially restore the viscosity of the circulating blood to near normal values in extreme hemodilution (hemodilution beyond the transfusion trigger.) and examine the stated hypothesis by direct in vivo measurement of micro-p02 and micro-NO in blood and tissue, capillary pressure, blood flow velocity, functional capillary density and arteriolar reactivity. In particular the correlation between FCD, a key determinant of tissue survival, and NO regulation will be explored
Keywords: blood substitute, blood transfusion, blood viscosity, blood volume, hemodynamics, vascular resistance microcirculation, nitric oxide, oxygen consumption, respiratory oxygenation, vasoconstriction hamster, laboratory rat
Project start date: 2000-09-01
Project end date: 2004-08-31
1R01HL062354-01A2 (2000): $414133
Sponsored Links Excellgen http://Excellgen.com
Cellular And Microvascular Tissue Response To Implants
Marcos Intaglietta, Chairman Of Board Of Trustees
La Jolla Bioengineering Institute La Jolla, Ca 920374616
Grant 1R01EB000823-010003 from National Institute Of Biomedical Imaging And Bioengineering IRG: ZRG1
Keywords: biomaterial evaluation, biomaterial interface interaction, implant, inflammation, metal oxide, superoxide, titanium, angiogenesis, arteriole, capillary, ceramic, information system, leukocyte activation /transformation, fluorescence microscopy, hamster, immunocytochemistry, intravital microscopy, laboratory rat, medical implant science
Project start date: 2002-08-15
Project end date: 2007-07-31
MICROHEMODYNAMICS OF BLOOD SUBSTITUTION
Marcos Intaglietta, Chairman Of Board Of Trustees
University Of California San Diego 9500 Gilman Dr, Dept 0934 La Jolla, Ca 920930934
Grant 5P01HL048018-050002 from National Heart, Lung, And Blood Institute
Keywords: blood substitute, hemodynamics, hemoglobin, microcirculation, oxygen transport, respiratory oxygenation, technology /technique, blood viscosity, cardiac output, erythrocyte, hemorrhagic shock, mathematical model, phosphorescence, solution, hamster
Project start date: 1997-09-01
Project end date: 1998-08-31
CORE--SINGLE CELL OXYGEN SATURATION MEASUREMENT
Marcos Intaglietta, Chairman Of Board Of Trustees
University Of Arizona Po Box 3308 Tucson, Az 857223308
Grant 5P01HL017421-209003 from National Heart, Lung, And Blood Institute
Keywords: biomedical facility, blood flow measurement, image processing, microcirculation, oxygen consumption, method development, oscillography, phosphorescence