Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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The in vivo study of microvascular oxygen transport requires accurate and challenging measurements of several mass transfer parameters. Although recommended, blood flow and oxygenation are typically not measured in many studies where treatments for ischemia are tested. Therefore, the aim of this communication is to briefly review cardinal aspects of oxygen transport, and the effects of perfluorocarbon (PFC) treatment on blood flow and oxygenation based mostly on studies performed in our laboratory. ⋯ In several cases, enhancement of flow and oxygenation could be demonstrated. Similar results were found in vitro: PFC emulsion mixed with blood (from healthy donors and sickle cell disease patients) enhanced oxygen transport. In summary, PFCs may provide beneficial effects in these models by mechanisms at the microvascular level including facilitated diffusion and bubble reabsorption leading to improved blood flow and oxygenation.
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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. ⋯ 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.
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Multicenter Study
Military Supplement: Assessment of Coagulation Homeostasis in Blunt, Penetrating, and Thermal Trauma: Guidance for a Multi-Center Systems Biology Approach.
Provisioning care for traumatically injured patients makes conducting research very proximal to injury difficult. These studies also inherently have regulatory barriers to overcome. Here we outline a protocol for acute-phase enrollment of traumatically injured patients into a prospective observational clinical trial with precise and comprehensive sample acquisition in support of a systems biology approach to a research study. ⋯ We used an iterative, interdisciplinary process to develop a systematic and robust protocol for comprehensive assessment of coagulation in traumatically injured patients. This MOO can be a template for future studies in the acute setting.
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This article reviews the key biochemical mechanisms that govern O2 transport, NO scavenging, and oxidative degradation of acellular hemoglobin (Hb) and how these ideas have been used to try to develop strategies to engineer safer and more effective hemoglobin-based oxygen carriers (HBOCs). Significant toxicities due to acellular Hb have been observed after the administration of HBOCs or after the lysis of red cells, and include rapid clearance and kidney damage due to dissociation into dimers, haptoglobin binding, and macrophage activation; early O2 release leading to decreased tissue perfusion in capillary beds; interference with endothelial and smooth muscle signaling due to nitric oxide (NO) scavenging; autooxidization of heme iron followed by production of reactive oxygen species; and iron overload symptoms due to hemin loss, globin denaturation, iron accumulation, and further inflammation. Protein engineering can be used to mitigate some of these side effects, but requires an in-depth mechanistic understanding of the biochemical and biophysical features of Hb that regulate quaternary structure, O2 affinity, NO dioxygenation, and resistance to oxidation, hemin loss, and unfolding.
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Multicenter Study
Relative Efficacies of HBOC-201 and Polyheme to Increase Oxygen Transport Compared to Blood and Crystalloids. "2017 Military Supplement".
Because total hemoglobin in circulation ([THb]) is an established predictor of clinical outcomes in anemic individuals, the relative efficacies of resuscitation fluids to increase [THb] can be used to design better hemoglobin-based oxygen carrier (HBOC) clinical trials. ⋯ Greater anemia in subjects randomized to HBOC-201 was consistent with the relative efficacies of HBOC-201 and pRBCs to increase [THb] and may have contributed to more SAEs in the HBOC arm of HEM-0115 and greater long-term mortality in the PolyHeme trial.