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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Studies indicate that polymicrobial sepsis in humans and animals is characterized by a biphasic response, which is dominated early by proinflammation, but over time develops into a state of generalized anti-inflammation (depressed Th1 cell response and decreased macrophage (M0) capacity to release proinflammatory cytokines). However, with respect to the macrophage, it remains unknown what mechanism(s) controls this change. In this regard it is well documented that the p38 mitogen activated protein kinase pathway (MAPK) plays a central role in the regulation of Mphi functions. ⋯ Mice were given 100 mg of SB203580/kg body weight or saline vehicle (intraperitoneal) either immediately post-CLP or 12 h post-CLP. Delayed administration of SB203580 significantly improved survival, while also preventing the increased NO and IL-10 release and improving IL-12 release by macrophages. These results suggest that p38 MAPK pathway plays a critical role in the induction of an immune-suppressive macrophage phenotype, and that inhibition of p38 MAPK markedly improves survival following polymicrobial sepsis.
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Previous work suggests that neutrophils (PMNs) and/or prostaglandins might mediate the progressive respiratory failure after severe pulmonary contusion. Since reactive oxygen metabolites are closely associated with both these factors, we examined the actions of a novel antioxidant after swine received a unilateral injury followed by 25% hemorrhage. An infusion (2mL/kg/h intravenously x 6 h) of either polynitroxylated 5% Dextran + Tempol (PND, n = 9), 5% Dextran (D, n = 6), or lactated Ringers (LR, n = 13) was begun 60 min post-injury to mimic 'pre-hospital resuscitation.' After 15 min, standard resuscitation was initiated (3x shed blood as LR in 30 min) plus further LR for 6 h to maintain hemodynamics. ⋯ In the contralateral (uninjured) lung, the effects were similar, but the increases were less for PMNs (8+/-2 versus 10+/-2 or 14+/-4 x 10(5)/mL) and for protein (609 +/-153 versus 1,955+/-671 or 1486+/-357 mg %). Despite these significant BAL changes, there was no obvious improvement in cardiopulmonary dysfunction. Thus oxidants probably have some role in the pathogenic mechanism of progressive secondary injury after thoracic trauma, but further work is needed to determine the therapeutic potential of antioxidants because no clinical improvement was detected.
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Comparative Study
Comparison of the effects of bolus vs. slow infusion of 7.5% NaCl/6% dextran-70 in a model of near-lethal uncontrolled hemorrhage.
Bolus infusion of of 7.5% NaCl/6% dextran-70 (HSD-B) improves outcome from controlled hemorrhage. In contrast, HSD-B during uncontrolled hemorrhage increases bleeding and short-term mortality. The purpose of this study was to compare the effects of bolus vs. slow infusion of HSD in a near-fatal vascular injury hemorrhage model. ⋯ In group I, MAP, AF, cardiac indices, and O2 delivery gradually returned to baseline levels and were significantly greater than group II at 30 min and throughout the remainder of the protocol. In this model of near-lethal uncontrolled hemorrhage, slow infusion of HSD restored cardiodynamics while minimizing hemorrhage volume and mortality. Resuscitation regimens that cause early increases in blood flow and pressure may result in greater hemorrhage and mortality than those regimens that yield comparable flow and pressure increases late in resuscitation.
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Studies have shown that cell mediated immunity is suppressed markedly following thermal injury. Macrophages and the activation of an inflammatory cascade that includes interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNFalpha) and PGE2 have been implicated as causative factors. Burn wound excision and grafting is a common clinical practice that decreases patient morbidity and mortality. ⋯ In contrast, the elevated production of other inflammatory mediators (IL-1beta, IL-6, nitric oxide, PGE2) post-burn was unaffected by burn wound excision and grafting. Moreover, splenic T-lymphocyte proliferation was also suppressed at 7 days post-burn and was not improved by burn wound excision and grafting. These results, therefore, suggest that the beneficial effects of burn wound excision and grafting are likely to be related to the normalization of macrophage TNFalpha production as well as the maintenance of skin barrier function.
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Previous reports have shown beneficial effects of pentoxifylline (PTX) and hypertonic saline (HS) in the treatment of hemorrhagic shock. We compared the effects of these solutions to those of conventional lactated Ringer's (LR) treatment on bacterial translocation (BT), lung injury and total and differential cell count in the bronchoalveolar lavage fluid (BAL) after hemorrhagic shock. Rats (280-330 g) were bled to a MAP of 35 mmHg for 1 h and then randomized into 4 groups: LR (3x shed blood); HS (7,5% NaCl, 4 mL/kg); LR+PTX (25 mg/kg) and SHAM (no shock, no treatment). ⋯ HS and PTX reduced BT and lung injury after hemorrhage. Attenuation of lung injury could be the result of less neutrophil infiltration into the lungs of HS and PTX treated animals. LR resuscitation caused pronounced lung injury and BT.