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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Liver dysfunction affects a variety of metabolic pathways in the critically ill, but mechanisms remain poorly understood. We prospectively assessed markers of hepatic injury and function in sepsis and I/R injury in vivo and molecular mechanisms in human liver tissue ex vivo. Markers of hepatocellular injury, synthesis, and excretion, including plasma disappearance rate of indocyanine green (ICG), were measured in 48 patients with severe sepsis. ⋯ In conclusion, standard liver tests lack the required sensitivity to assess hepatic injury and function in the critically ill. Dye excretion better reflects excretory and/or microvascular dysfunction but still underestimates impaired canalicular transport. The observed differential susceptibility of the polar surfaces of human hepatocytes has potential implications for monitoring liver function and drug-induced liver injury.
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To investigate changes in protein expression by proteomic analysis in the sera of patients with sepsis and to identify new biomarkers of sepsis. A total of 45 consecutive patients with severe sepsis or septic shock (sepsis group), 22 healthy volunteers, and 23 patients undergoing off-pump coronary artery bypass grafting (control group). Serum samples from eight patients of each group underwent proteomic analysis involving removal of 12 major proteins and subsequent reversed-phase high-performance liquid chromatography fractionation and one-dimensional electrophoresis. ⋯ A positive correlation between sYKL-40 and blood IL-6 level on ICU admission was noted in the sepsis group (r = 0.465, P < 0.01). YKL-40 identified by proteomic analysis is considered as a biomarker of sepsis. However, further investigation is needed to clarify its roles and clinical usefulness as a biomarker.
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The vasoconstrictive and proinflammatory peptide endothelin 1 (ET-1) is highly involved in the pathogenesis of sepsis and associated lung injury. Systemic administration of ET-receptor antagonists has been beneficial in experimental pulmonary hypertension. We wanted to study the effects of inhaled tezosentan, a dual endothelin-receptor antagonist on endotoxin-induced pulmonary hypertension, deterioration of gas exchange, and edema formation. ⋯ Despite similar effects on pulmonary hypertension systemic treatment resulted in significantly higher plasma levels of ET-1 (twofold) and tezosentan (10- to 100-fold). Inhalation of the dual ET-receptor antagonist tezosentan was feasible and efficiently counteracted endotoxin-induced pulmonary hypertension. These effects were obtained with only minor systemic uptake of tezosentan and without affecting circulating levels of plasma ET-1 as compared with intravenous administration.
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Delayed granulocyte apoptosis is implicated in persistent inflammation. Although it is known that males develop sepsis more easily than females, the mechanism for this is not fully understood. Serum IL-18 levels correspond to severity of systemic inflammation. ⋯ Nevertheless, levels of IL-18 in the blood of WT mice were significantly higher in males than in females after intraperitoneal LPS, and the survival rate was significantly higher in KO mice compared with WT mice only in males. This indicates that endogenous IL-18 production decreases survival only in males. Thus, excessive myeloid/granulocyte immunity independent of IL-18 and other IL-18-dependent life-threatening factors in males should be taken into account as therapeutic targets during systemic inflammatory states.
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Hypotensive resuscitation prolongs survival of patients with severe bleeding until they can undergo hemorrhage control. However, its value is limited by continuing ischemic injury. Purified poloxamer 188 (P188), a copolymer with rheological and cytoprotective activities, was known to reduce mortality of hemorrhagic shock when used as an adjunct to full resuscitation with fresh whole blood and crystalloid. ⋯ Additional studies demonstrated that P188 increased survival from 0% to 75% in 50% volume-controlled hemorrhage (P < 0.001). Finally, P188 did not increase bleeding in uncontrolled hemorrhage produced by 75% tail amputation. Because P188 prolongs survival, decreases fluid requirements, and reduces tissue damage, it deserves further consideration as an adjunct to hypotensive resuscitation.