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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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
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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Randomized Controlled Trial Multicenter Study
Incidence, Patient Characteristics, Mode of Drug Delivery, and Outcomes of Septic Shock Patients Treated with Vasopressors in the Arise Trial.
To describe the utilization of vasopressors (VP) in patients enrolled in the Australasian Resuscitation In Sepsis Evaluation (ARISE) trial, and to explore the association between time to VP and 90-day mortality. ⋯ 50% of the ARISE cohort commenced VP within 4.4 h of ED presentation, and many did so prior to central venous access. Earlier initiation of VP was associated with greater crude and adjusted 90-day mortality.
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Multicenter Study Clinical Trial
Cirrhotic Patients Admitted to the ICU with Septic Shock: Factors Predicting Short and Long-Term Outcome.
Cirrhotic patients with septic shock have a poor prognosis in ICU compared to general population of critically ill patients. Little is known about long-term outcome in these patients. We performed a retrospective analysis of a prospective cohort of cirrhotic patients with septic shock. ⋯ The results emphasize the poor prognosis of cirrhotic patients with septic shock admitted to the ICU. The need for organ supports appears to be a better predictor of short-term outcome than the underlying hepatic disease. Renal replacement therapy is associated with both short and long-term outcomes.
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Several adverse events have been associated with the infusion of hemoglobin-based oxygen carriers (HBOCs), including transient hypertension, gastrointestinal, pancreatic/liver enzyme elevation, and cardiac/renal injury in humans. Although several mechanisms have been suggested, the basis of HBOC toxicity is still poorly understood. Scavenging of vascular endothelial nitric oxide (NO) and heme-mediated oxidative side reactions are thought to be the major causes of toxicity. ⋯ HBOCs display a diversity of physicochemical properties, including molecular size/cross-linking characteristics leading to differences in oxygen affinity, allosteric, redox properties, and even oxidative inactivation by protein/heme clearing mechanisms. These diverse characteristics can therefore be manipulated independently, leaving open the possibility of engineering a safe and effective HBOC. To date, several antioxidative strategies have been proposed to counteract the redox side reactions of current generation HBOCs.