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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Over the past decade, the biotechnology/pharmaceutical industry has been diligently working on the development of immunomodulatory agents for the treatment of shock and sepsis, and the literature is rife with descriptions of novel and innovative molecules that promise to become the panacea for these conditions. Unfortunately, despite promising preclinical evidence, dozens of these new agents have failed to demonstrate clinical efficacy in controlled, randomized clinical trials, abandoning the bedside physician to the traditional armamentarium of drugs and therapeutics for the treatment of patients with these complex, progressive, and life-threatening conditions. The reasons for this quandary are controversial, complex, and multifactorial. ⋯ As a result, it is not surprising that clinical trials of agents based on clinically flawed models failed to demonstrate clinical efficacy. The lack of clinical insight during preclinical development of these agents has contributed to the current impasse of the development of safe, efficacious, and potentially lifesaving agents for the treatment of shock and sepsis. Thus, the goal of this review article is to review the advantages and disadvantages of commonly used sepsis and shock models in light of lessons learned from these clinical trials.
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Diaspirin cross-linked hemoglobin (DCLHb), a hemoglobin-based blood substitute, has been found to improve systemic hemodynamics, cutaneous oxygen tension, and normalization of blood lactate levels and acid-base equilibrium after hemorrhage in animals. The present study was conducted to determine the dose-dependent effect of a 10% solution of DCLHb (20, 50, and 100% of shed blood volume; SBV) on regional blood circulation in hemorrhaged rats. Hemorrhage was induced in urethane-anesthetized rats by bleeding them at a rate of approximately .5 to 1 mL/min until a mean arterial pressure of 35-40 mmHg was achieved. ⋯ Resuscitation with the RL did not produce any improvement in renal cortical perfusion. However, resuscitation with DCLHb significantly increased renal cortical perfusion (364.7%) due to an increase in both CMBC (123.4%) and their velocity (109.9%). It is concluded that DCLHb in a dose of 50% of SBV produces maximal improvement in regional blood circulation of hemorrhaged rats.
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The development of the adult respiratory distress syndrome (ARDS) in the critically ill patient is associated with a significant morbidity and mortality. The pulmonary dysfunction in ARDS is largely secondary to neutrophil-mediated oxidant injury. The purpose of these studies is to examine the effect of the antioxidant N-acetyl cysteine (NAC) on a rodent model of lung injury. ⋯ Importantly, NAC administration up to 2 h after endotoxin challenge was still able to significantly ameliorate LPS-induced lung injury. Our data suggests that the attenuation of acute lung injury by NAC in our rodent model is related to free radical scavenging and inhibition of the neutrophil oxidative burst, rather than by an effect on inflammatory cell migration. These results suggest novel approaches for therapeutic interventions in acute lung injury.
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Randomized Controlled Trial Multicenter Study Comparative Study Clinical Trial
Modulation of immune response by blood transfusion: evidence for a differential effect of allogeneic and autologous blood in colorectal cancer surgery.
Even though blood transfusion-associated immunomodulatory effects have been reported, the basic immune mechanism is still not understood. Data from studies on the clinical effects of allogeneic blood-induced immunosuppression are contradictory. However, there are indications that autologous blood transfusion is not immunologically neutral but has intrinsic immunomodulatory potential. ⋯ IL-10 was found elevated immediately postoperative in allogeneic (p = .011) and nontransfused patients only (p = .042). The data from this study substantiate recent findings of a different immunomodulatory potential of allogeneic and autologous blood transfusion. They furthermore support the hypothesis that autologous blood transfusion does not contain immunologically neutral effects of allogeneic blood, but itself exerts an immunomodulatory effect.