Introduction and Objective: Septic shock is a highly lethal syndrome initiated by severe, overwhelming infection. This condition is the leading cause of death in Intensive Care Units in the U.S. The underlying mechanisms that cause this syndrome remain incompletely understood despite more than a half century of scientific investigation. These studies seek to examine septic shock pathogenesis and to explore the potential of novel therapeutic strategies using both small and large models of the syndrome, patients with sepsis, and normal volunteers challenged with endotoxin. progress: Early studies focused on pathophysiology comparing gram positive and gram negative organisms, the role of endotoxemia, and the efficacy of anti-endotoxin therapies such as lipid A analogs and antibodies. Nitric oxide was examined as an important mediator of septic shock. Non-selective nitric oxide synthase inhibitors were sometimes toxic and never beneficial. Normal volunteers challenged with endotoxin were found to release increased amounts of nitric oxide. Although ibuprofen blocked endotoxin-induced increases in nitric oxide production, blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation. More recent work has found that severity of illness (risk of death) influences the therapeutic efficacy of anti-inflammatory agents in septic shock. Proposed Course of Work: Ongoing comparative survival study of commonly used vasopressors in septic shock including epinephrine, norepinephrine and vasopressin. Protocols under development for lymphocyte adoptive transfer, and intra-aortic balloon pump support in septic shock. Validate and apply information on biomarkers and pathogenic pathways obtained from functional genomic investigations.

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Intramural Research (Z01)
Project #
1Z01CL008060-01
Application #
6825426
Study Section
(CCM)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2003
Total Cost
Indirect Cost
Name
Clinical Center
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Moriyama, Brad; Henning, Stacey A; Neuhauser, Melinda M et al. (2009) Continuous-infusion beta-lactam antibiotics during continuous venovenous hemofiltration for the treatment of resistant gram-negative bacteria. Ann Pharmacother 43:1324-37
Cobb, J; Ognibene, Frederick; Ingbar, David et al. (2009) Forging a critical alliance: Addressing the research needs of the United States critical illness and injury community* Crit Care Med :
Eichacker, Peter Q; Natanson, Charles; Danner, Robert L (2007) Separating practice guidelines from pharmaceutical marketing. Crit Care Med 35:2877-8;author reply 2878-80
Deans, Katherine J; Minneci, Peter C; Suffredini, Anthony F et al. (2007) Randomization in clinical trials of titrated therapies: unintended consequences of using fixed treatment protocols. Crit Care Med 35:1509-16
Minneci, Peter C; Deans, Katherine J; Hansen, Bernie et al. (2007) A canine model of septic shock: balancing animal welfare and scientific relevance. Am J Physiol Heart Circ Physiol 293:H2487-500
Eichacker, Peter Q; Natanson, Charles; Danner, Robert L (2006) Surviving sepsis--practice guidelines, marketing campaigns, and Eli Lilly. N Engl J Med 355:1640-2
Solomon, Steven B; Cui, Xizhong; Gerstenberger, Eric et al. (2006) Effective dosing of lipid A analogue E5564 in rats depends on the timing of treatment and the route of Escherichia coli infection. J Infect Dis 193:634-44
Kalil, Andre C; Danner, Robert L (2006) L-Arginine supplementation in sepsis: beneficial or harmful? Curr Opin Crit Care 12:303-8
Sevransky, Jonathan; Vandivier, R William; Gerstenberger, Eric et al. (2005) Prophylactic high-dose N(omega)-monomethyl-L-arginine prevents the late cardiac dysfunction associated with lethal tumor necrosis factor-alpha challenge in dogs. Shock 23:281-8
Haley, Michael; Parent, Chantal; Cui, Xizhong et al. (2005) Neutrophil inhibition with L-selectin-directed MAb improves or worsens survival dependent on the route but not severity of infection in a rat sepsis model. J Appl Physiol 98:2155-62

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