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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Hypertonic saline (HTS) resuscitation inhibits acute lung injury in animal models of shock, but some argue this may simply represent more efficient fluid resuscitation. Inflammatory mediators within mesenteric lymph have been identified as a link between splanchnic hypoperfusion and acute respiratory distress syndrome (ARDS). We hypothesize that HTS resuscitation abrogates post-shock lymph-mediated neutrophil (PMN) priming and PMN-mediated human endothelial cell cytotoxicity. ⋯ Hypertonic resuscitation (HTS) abrogates PHSML pniming of the PMN and PMN-mediated HMVEC cytotoxicity. Furthermore, incubation of PMNs in clinically relevant HTS (180 mM NaCl) prevents PHSML PMN priming and PMN:HMVEC interactions. These studies suggest inhibition of PMN signal transduction is a mechanism whereby HTS resuscitation abrogates acute lung injury.
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Comparative Study
Effects of dopamine on systemic and regional blood flow and metabolism in septic and cardiac surgery patients.
Dopamine is used in the clinical setting to support cardiac output and blood pressure and to improve diuresis. Experimental studies suggest that dopamine may reduce splanchnic perfusion and redistribute blood flow locally. To assess the effects of dopamine on splanchnic perfusion, we used dopamine to increase cardiac output by 25% in nine septic patients and 11 patients after cardiac surgery. ⋯ Dobutamine in these patients [6.4 (4.2-9.5) microg x kg(-1) x min(-1)] increased splanchnic blood flow from 1.20 (0.44) L x min(-1) x m(-2) to 1.43 (0.57) L x min(-1) x m(-2) (P = 0.008), while splanchnic oxygen consumption did not change 72 (25) mL x min(-1) x m(-2) vs. 76 (22) mL x min(-1) x m(-2) (not significant)]. The reduction of splanchnic oxygen consumption by dopamine in sepsis suggests an impairment of hepatosplanchnic metabolism despite an increase in regional perfusion. The safety and indications of dopamine use in sepsis should be re-evaluated.
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We have shown previously that bum trauma activates the stress responsive proteins, p38 mitogen-activated protein kinase (MAPK), c-jun NH2-terminal kinase (JNK), and NF-kappaB, and we have shown further that p38 MAPK is an important mediator of cardiomyocyte TNF-alpha secretion and cardiac dysfunction in burn trauma. Since burn trauma causes a rise in circulating catecholamine levels, we hypothesized that this increased sympathetic activity may function as an upstream activator of the p38 MARK pathway in burn trauma. This study determined whether the alpha1-adrenergic receptor ligand phenylephrine could mimic burn trauma activation of p38 MAPK, JNK, and NF-kappaB nuclear translocation; and the effect of the alpha1-adrenergic receptor antagonist prazosin on either phenylephrine or burn-mediated activation of the stress response pathway was examined. ⋯ Burn trauma activated cardiac p38 MAPK/JNK and NF-kappaB, increased TNF-alpha secretion by cardiomyocytes, and impaired cardiac function. Prazosin treatment in burns interrupted the burn-mediated signaling cascade, decreasing TNF-alpha secretion by cardiomyocytes and preventing post-burn cardiac contractile dysfunction. Thus, burn trauma-related sympathetic activity likely activates the stress-responsive cascade, which regulates myocardial TNF-alpha transcription/translation and culminates in cardiac contraction and relaxation defects.
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Recent studies have demonstrated gender differences in the immune response following hemorrhagic shock with an enhanced immune function and lower mortality following subsequent sepsis in females. Early interleukin-10 (IL-10) treatment has been shown to have beneficial effects on the depressed immune function in males, but not in females following shock. However, it remains unclear if the observed gender-related effect of IL-10 treatment results in an advantage following subsequent polymicrobial sepsis. ⋯ Early IL-10 treatment restored depressed proinflammatory immune response in males (TNF-alpha and PGE2), which was associated with an enhanced survival (P < 0.05) following subsequent sepsis as compared with placebo-treated mice (8/20 and 1/20, respectively). In contrast, the immune response and survival in females receiving IL-10 was not significantly changed, although females treated with IL-10 had a trend towards higher mortality (7/15 and 2/15, respectively; P = 0.08). Thus, early IL-10 anti-inflammatory treatment following hemorrhage has potential beneficial effects only in males associated with enhanced survival following subsequent sepsis.