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Critical Care (London, England) 1999Early approaches to the development of oxygen carriers involved the use of stroma-free hemoglobin solutions. These solutions did not require blood typing or... (Review)
Review
Early approaches to the development of oxygen carriers involved the use of stroma-free hemoglobin solutions. These solutions did not require blood typing or crossmatching and could be stored for long periods. In addition, a variety of methods have been developed in chemically modifying and stabilizing the hemoglobin molecule. Several hemoglobin therapeutics are now in clinical trials as temporary alternatives to blood or as therapeutic agents for ischemia. The various hemoglobin products under development are derived from three principal sources: human, bovine and genetically engineered hemoglobin. Diaspirin cross-linked hemoglobin (DCLHb), administered at doses ranging from approximately 20-1000 ml, has been investigated in a number of clinical trials in patients undergoing orthopedic, abdominal aortic repair, major abdominal surgery, cardiac surgery and in critically ill patients with septic shock. In several studies, DCLHb was effective in avoiding the transfusion. However, Baxter Healthcare Corporation (Chicago, Illinois, USA) stopped the development of DCLHb after two unsuccessful trials in trauma patients. Bovine polymerized hemoglobin has also been extensively studied. Several phase II and phase III trials have been performed with this product in hemorrhagic surgery, cardiac surgery and vascular surgery, but data have not yet been published. Hemoglobin therapeutics could provide an important new option as an alternative to blood transfusion. Furthermore, they may be able to provide an immediate on-site replacement for traumatic blood loss, prevent global ischemia and organ failure, treat focal ischemia, and provide effective hemodynamic support for septic shock-induced hypotension.
Topics: Animals; Aspirin; Blood Substitutes; Cattle; Critical Care; Hemoglobins; Humans; Surgical Procedures, Operative
PubMed: 11094489
DOI: 10.1186/cc365 -
Clinics (Sao Paulo, Brazil) 2009The complications associated with acquiring and storing whole blood for transfusions have launched substantial efforts to develop a blood substitute. The history of... (Review)
Review
The complications associated with acquiring and storing whole blood for transfusions have launched substantial efforts to develop a blood substitute. The history of these efforts involves a complicated mixture of science, ethics, and business. This review focuses on clinical trials of the three hemoglobin-based oxygen carriers (HBOC) that have progressed to Phase II or III clinical trials: He-mAssist (Baxter; Deerfield, IL, US), PolyHeme (Northfield; Evanston, IL, US), and Hemopure (Biopure; Cambridge, MA, US). Published animal studies and clinical trials carried out in a perioperative setting have demonstrated that these products successfully transport and deliver oxygen, but all may induce hypertension and lead to unexpectedly low cardiac outputs. Overall, these studies suggest that HBOCs resulted in only modest blood saving during and after surgery, no improvement in mortality and an increased incidence of adverse reactions. To date, the results from these perioperative studies have not led to regulatory approval. All three companies instead chose to focus their efforts on large trials of trauma patients in the pre-hospital setting.Baxter abandoned the development of HemAssist after a trial in the U.S. was prematurely halted when the first 100 patients showed significantly increased mortality rates as compared to patients treated with blood products. Northfield's PolyHeme trial demonstrated a non-significant trend towards increased mortality and a very modest reduction in the subsequent need for blood. The testing of Biopure's Hemopure for trauma patients has been halted for several years because of FDA concerns over trial design and study justification. Ethical concerns have also been raised regarding the design and implementation of all HBOC clinical trials.Thus, the available evidence suggests that HemAssist, Polyheme, and Hemopure are associated with a significant level of cardiovascular dysfunction. The next generation of HBOCs remains under development.
Topics: Blood Substitutes; Clinical Trials as Topic; Hemoglobins; Humans
PubMed: 19690667
DOI: 10.1590/S1807-59322009000800016 -
The Cochrane Database of Systematic... Jul 2012Colloids are widely used in the replacement of fluid volume. However, doubts remain as to which colloid is best. Different colloids vary in their molecular weight and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Colloids are widely used in the replacement of fluid volume. However, doubts remain as to which colloid is best. Different colloids vary in their molecular weight and therefore in the length of time they remain in the circulatory system. Because of this, and their other characteristics, they may differ in their safety and efficacy.
OBJECTIVES
To compare the effects of different colloid solutions in patients thought to need volume replacement.
SEARCH METHODS
We searched the Cochrane Injuries Specialised Register (searched 1 December 2011), the Cochrane Central Register of Controlled Trials 2011, issue 4 (The Cochrane Library); MEDLINE (Ovid) (1948 to November Week 3 2011); EMBASE (Ovid) (1974 to 2011 Week 47); ISI Web of Science: Science Citation Index Expanded (1970 to 1 December 2011); ISI Web of Science: Conference Proceedings Citation Index-Science (1990 to 1 December 2011); CINAHL (EBSCO) (1982 to 1 December 2011); National Research Register (2007, Issue 1) and PubMed (searched 1 December 2011). Bibliographies of trials retrieved were searched, and for the initial version of the review drug companies manufacturing colloids were contacted for information (1999).
SELECTION CRITERIA
Randomised controlled trials comparing colloid solutions in critically ill and surgical patients thought to need volume replacement.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted the data and assessed the quality of the trials. The outcomes sought were death, amount of whole blood transfused, and incidence of adverse reactions.
MAIN RESULTS
Eighty-six trials, with a total of 5,484 participants, met the inclusion criteria. Quality of allocation concealment was judged to be adequate in 33 trials and poor or uncertain in the rest.Deaths were reported in 57 trials. For albumin or plasma protein fraction (PPF) versus hydroxyethyl starch (HES) 31 trials (n = 1719) reported mortality. The pooled relative risk (RR) was 1.06 (95% confidence interval (CI) 0.86 to 1.31). When the trials by Boldt were removed from the analysis the pooled RR was 0.90 (95% CI 0.68 to 1.20). For albumin or PPF versus gelatin, nine trials (n = 824) reported mortality. The RR was 0.89 (95% CI 0.65 to 1.21). Removing the study by Boldt from the analysis did not change the RR or CIs. For albumin or PPF versus dextran four trials (n = 360) reported mortality. The RR was 3.75 (95% CI 0.42 to 33.09). For gelatin versus HES 22 trials (n = 1612) reported mortality and the RR was 1.02 (95% CI 0.84 to 1.26). When the trials by Boldt were removed from the analysis the pooled RR was 1.03 (95% CI 0.84 to 1.27). RR was not estimable in the gelatin versus dextran and HES versus dextran groups.Forty-one trials recorded the amount of blood transfused; however, quantitative analysis was not possible due to skewness and variable reporting. Twenty-four trials recorded adverse reactions, with two studies reporting possible adverse reactions to gel and one to HES.
AUTHORS' CONCLUSIONS
From this review, there is no evidence that one colloid solution is more effective or safe than any other, although the CIs were wide and do not exclude clinically significant differences between colloids. Larger trials of fluid therapy are needed if clinically significant differences in mortality are to be detected or excluded.
Topics: Blood Proteins; Colloids; Dextrans; Fluid Therapy; Humans; Hydroxyethyl Starch Derivatives; Plasma Substitutes; Randomized Controlled Trials as Topic; Rehydration Solutions; Resuscitation; Serum Albumin; Serum Albumin, Human; Serum Globulins
PubMed: 22786474
DOI: 10.1002/14651858.CD001319.pub5 -
British Journal of Clinical Pharmacology Jun 2019A population kinetic model was developed for the body fluid shifts occurring when 20% albumin is given by intravenous infusion. The aim was to study whether its efficacy...
AIMS
A population kinetic model was developed for the body fluid shifts occurring when 20% albumin is given by intravenous infusion. The aim was to study whether its efficacy to expand the plasma volume is impaired after major surgery.
METHODS
An intravenous infusion of 3 mL/kg 20% albumin over 30 minutes was given to 15 volunteers and to 15 patients on the 1 day after major open abdominal surgery. Blood samples and urine were collected during 5 hours. Mixed-effect modelling software was used to develop a fluid volume kinetic model, using blood haemoglobin and urine excretion the estimate body fluid shifts, to which individual-specific covariates were added in sequence.
RESULTS
The rise in plasma albumin expanded the plasma volume in excess of the infused volume by relocating noncirculating fluid (rate constant k ), but it also increased losses of fluid from the kinetic system (k ). The balance between k and k maintained the rise in plasma albumin and plasma volume at a virtual steady-state for almost 2 hours. The rate constant for urinary excretion (k ) was slightly reduced by the preceding surgery, by a marked rise in plasma albumin, and by a high preinfusion urinary concentration of creatinine. The arterial pressure, body weight, and plasma concentrations of C-reactive protein and shedding products of the endothelial glycocalyx layer (syndecan-1, heparan sulfate, and hyaluronic acid) did not serve as statistically significant covariates.
CONCLUSIONS
There were no clinically relevant differences in the kinetics of 20% albumin between postoperative patients and volunteers.
Topics: Abdomen; Adult; Albumins; Female; Fluid Shifts; Fluid Therapy; Humans; Infusions, Intravenous; Male; Models, Biological; Plasma Substitutes; Postoperative Care; Sweden; Treatment Outcome; Young Adult
PubMed: 30756411
DOI: 10.1111/bcp.13897 -
Shock (Augusta, Ga.) Oct 2019In blood, the primary role of red blood cells (RBCs) is to transport oxygen via highly regulated mechanisms involving hemoglobin (Hb). Hb is a tetrameric porphyrin... (Review)
Review
In blood, the primary role of red blood cells (RBCs) is to transport oxygen via highly regulated mechanisms involving hemoglobin (Hb). Hb is a tetrameric porphyrin protein comprising of two α- and two β-polypeptide chains, each containing an iron-containing heme group capable of binding one oxygen molecule. In military as well as civilian traumatic exsanguinating hemorrhage, rapid loss of RBCs can lead to suboptimal tissue oxygenation and subsequent morbidity and mortality. In such cases, transfusion of whole blood or RBCs can significantly improve survival. However, blood products including RBCs present issues of limited availability and portability, need for type matching, pathogenic contamination risks, and short shelf-life, causing substantial logistical barriers to their prehospital use in austere battlefield and remote civilian conditions. While robust research is being directed to resolve these issues, parallel research efforts have emerged toward bioengineering of semisynthetic and synthetic surrogates of RBCs, using various cross-linked, polymeric, and encapsulated forms of Hb. These Hb-based oxygen carriers (HBOCs) can potentially provide therapeutic oxygenation when blood or RBCs are not available. Several of these HBOCs have undergone rigorous preclinical and clinical evaluation, but have not yet received clinical approval in the USA for human use. While these designs are being optimized for clinical translations, several new HBOC designs and molecules have been reported in recent years, with unique properties. The current article will provide a comprehensive review of such HBOC designs, including current state-of-the-art and novel molecules in development, along with a critical discussion of successes and challenges in this field.
Topics: Animals; Blood Substitutes; Erythrocytes; Hemoglobins; Humans; Oxygen
PubMed: 31513123
DOI: 10.1097/SHK.0000000000001009 -
Critical Care (London, England) 1999Perfluorocarbon emulsions are being clinically evaluated as artificial oxygen carriers to reduce allogeneic blood transfusions or to improve tissue oxygenation.... (Review)
Review
Perfluorocarbon emulsions are being clinically evaluated as artificial oxygen carriers to reduce allogeneic blood transfusions or to improve tissue oxygenation. Perfluorocarbon emulsions are efficacious in animal experiments, and in humans they are well tolerated and at least as successful to reverse physiologic transfusion triggers than autologous blood. Perfluorocarbon emulsions may be used in the future in the concept of augmented acute normovolaemic haemodilution. In this concept relatively low preoperative haemoglobin levels are targeted during preoperative normovolaemic haemodilution and a perfluorocarbon emulsion is given to augment oxygen delivery during surgery when low endogenous haemoglobin levels are expected. The autologous blood is subsequently retransfused in the postoperative period when the patient's oxygenation is provided primarily by the endogenous haemoglobin. Additional uses of perfluorocarbon emulsions will include treatments of diseases with compromised tissue oxygenation such as cerebral or myocardial ischaemia, air embolism and emergency or trauma surgery as long as no allogeneic blood is available.
Topics: Biological Transport; Blood Substitutes; Consumer Product Safety; Fluorocarbons; Hemodilution; Humans; Oxygen; Surgical Procedures, Operative
PubMed: 11094488
DOI: 10.1186/cc364 -
Platelets Dec 2024Microfluidic technology has emerged as a powerful tool in studying arterial thrombosis, allowing researchers to construct artificial blood vessels and replicate the... (Review)
Review
Microfluidic technology has emerged as a powerful tool in studying arterial thrombosis, allowing researchers to construct artificial blood vessels and replicate the hemodynamics of blood flow. This technology has led to significant advancements in understanding thrombosis and platelet adhesion and aggregation. Microfluidic models have various types and functions, and by studying the fabrication methods and working principles of microfluidic chips, applicable methods can be selected according to specific needs. The rapid development of microfluidic integrated system and modular microfluidic system makes arterial thrombosis research more diversified and automated, but its standardization still needs to be solved urgently. One key advantage of microfluidic technology is the ability to precisely control fluid flow in microchannels and to analyze platelet behavior under different shear forces and flow rates. This allows researchers to study the physiological and pathological processes of blood flow, shedding light on the underlying mechanisms of arterial thrombosis. In conclusion, microfluidic technology has revolutionized the study of arterial thrombosis by enabling the construction of artificial blood vessels and accurately reproducing hemodynamics. In the future, microfluidics will place greater emphasis on versatility and automation, holding great promise for advancing antithrombotic therapeutic and prophylactic measures.
Topics: Humans; Microfluidics; Blood Substitutes; Blood Platelets; Thrombosis; Platelet Adhesiveness
PubMed: 38390892
DOI: 10.1080/09537104.2024.2316743 -
Antioxidants & Redox Signaling Jun 2013There has been a striking advancement in our understanding of red cell substitutes over the past decade. Although regulatory oversight has influenced many aspects of... (Review)
Review
SIGNIFICANCE
There has been a striking advancement in our understanding of red cell substitutes over the past decade. Although regulatory oversight has influenced many aspects of product development in this period, those who have approached the demonstration of efficacy of red cell substitutes have failed to understand their implication at the level of the microcirculation, where blood interacts closely with tissue.
RECENT ADVANCES
The understanding of the adverse effects of acellular hemoglobin (Hb)-based oxygen carriers (HBOCs) has fortunately expanded from Hb-induced renal toxicity to a more complete list of biochemical mechanism. In addition, various unexpected adverse reactions were seen in early clinical studies. The effects of the presence of acellular Hb in plasma are relatively unique because of the convergence of mechanical and biochemical natures.
CRITICAL ISSUES
Controlling the variables using genetic engineering and chemical modification to change specific characteristics of the Hb molecule may allow for solving the complex multivariate problems of acellular Hb vasoactivity. HBOCs may never be rendered free of negative effects; however, quantifying the nature and extent of microvascular complications establishes a platform for designing new ameliorative therapies.
FUTURE DIRECTIONS
It is time to leave behind the study of vasoactivity and toxicity based on bench-top measurements of biochemical changes and those based solely on systemic parameters in vivo, and move to a more holistic analysis of the mechanisms creating the problems, complemented with meaningful studies of efficacy.
Topics: Animals; Blood Substitutes; Blood Vessels; Hemoglobins; Hemorrhage; Humans; Oxidation-Reduction; Transfusion Reaction
PubMed: 22938394
DOI: 10.1089/ars.2012.4922 -
Wiley Interdisciplinary Reviews.... 2010Unlike donor red blood cells (RBCs), blood substitutes can be treated to remove infective agents and can be used on the spot or in the ambulance in emergency without the... (Review)
Review
Unlike donor red blood cells (RBCs), blood substitutes can be treated to remove infective agents and can be used on the spot or in the ambulance in emergency without the time-consuming typing and cross-matching. Donor RBC requires storage at 4 degrees and is only good for 42 days, but blood substitutes can be stored for much longer time. For example, a bovine polyhemoglobin (PolyHb) can be stored at room temperature for more than 1 year. It has been shown as far back as 1957 that artificial RBC can be prepared with ultrathin polymer membranes of nanodimension thickness. To increase the circulation time, the first-generation engineered hemoglobin (Hb) is formed by using glutaraldehyde to crosslink Hb into soluble nanodimension PolyHb that has been tested clinically in patients. Further extension includes conjugated Hb, intramolecularly crosslinked Hb and recombinant Hb. For certain clinical uses, in addition to engineered Hb, we also need antioxidants to remove oxygen radicals to prevent injury from ischemia reperfusion. Thus, we use nanobiotechnology to prepare second-generation engineered Hb by assembling Hb together with superoxide dismutase (SOD) and catalase (CAT) to form a nanodimension soluble complex of polyhemoglobin (PolyHb)-CAT-SOD. A third generation system is to prepare nanodimension complete artificial RBCs that can circulate for sufficient length of time after infusion. One approach uses lipid vesicles to encapsulate hemoglobin (Hb). Another approach is to use biodegradable polymer-like polylactic acid or a copolymer of polyethylene glycol-polylactide (PEG-PLA) to form the membrane of nanodimension complete artificial RBC (www.artcell.mcgill.ca).
Topics: Animals; Blood Substitutes; Hemoglobins; Humans; Nanocapsules; Nanotechnology
PubMed: 20564467
DOI: 10.1002/wnan.95 -
Journal of Infusion Nursing : the... 2015Oxygen delivery capacity during profoundly anemic conditions depends on blood's oxygen-carrying capacity and cardiac output. Oxygen-carrying blood substitutes and blood... (Review)
Review
Oxygen delivery capacity during profoundly anemic conditions depends on blood's oxygen-carrying capacity and cardiac output. Oxygen-carrying blood substitutes and blood transfusion augment oxygen-carrying capacity, but both have given rise to safety concerns, and their efficacy remains unresolved. Anemia decreases oxygen-carrying capacity and blood viscosity. Present studies show that correcting the decrease of blood viscosity by increasing plasma viscosity with newly developed plasma expanders significantly improves tissue perfusion. These new plasma expanders promote tissue perfusion, increasing oxygen delivery capacity without increasing blood oxygen-carrying capacity, thus treating the effects of anemia while avoiding the transfusion of blood.
Topics: Anemia; Erythrocyte Transfusion; Hemorrhage; Humans; Oxygen; Plasma Substitutes
PubMed: 25871869
DOI: 10.1097/NAN.0000000000000103