New horizons (Baltimore, Md.)
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The traditional approach to hemostatic disorders in the injured patient has focused on bleeding rather than a hypercoagulable state. This strategy continues despite growing evidence from studies of coagulation disorders in other patient groups highlighting loss of organ function secondary to inappropriate coagulation rather than hemorrhage. While traditional testing is useful in screening for low levels of coagulation factors or platelet dysfunction, only obvious bleeding or significant fibrinolysis is identified. ⋯ More than 20 years have passed since coagulation abnormalities were reported in patients with severe infection. Despite recognition of this association in sepsis, we are only beginning to understand how coagulation abnormalities develop in injury and to consider strategies to counter them. While hemorrhage may be successfully treated in patients following trauma, thrombosis in the microcirculation often contributes to end-organ damage with irreversible ischemic changes that may lead to death.
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Platelet activating factor (PAF) is a phospholipid mediator released upon stimulation of cells, such as mast cells, basophils, neutrophils, and macrophages, by opsonized agents. This mediator produces a variety of biological effects and acts via specific binding sites present on various cell types. This article briefly reviews the nature of PAF, as well as what is understood about its role in the inflammatory response associated with trauma, shock, and sepsis. ⋯ In this respect, several of the PAF antagonists have been examined experimentally and some have been tested clinically in patients with sepsis and septic shock. Experimental and clinical studies suggest that PAF antagonists appear to be effective in cases of severe Gram-negative septic shock. Nonetheless, this mediator may not be a major component involved in the systemic inflammatory response syndrome.
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The management of severe sepsis includes the use of agonists of alpha- and beta-adrenergic, as well as of dopaminergic, receptors. Data suggest that the severe inflammatory immune response seen in sepsis can be modulated by stimulation and inhibition of these receptors both in vitro and in vivo. ⋯ Since the vasopressor and inotrope support of sepsis is not well standardized, variability in the resulting inflammatory mediator response may have consequences to the efficacy of new immunotherapies. This article provides an overview of the effect of the sympathetic nervous system activity and of receptor manipulation on cytokine response to endotoxin, and adds to the perspective on inhibition of phosphodiesterase in the therapy of septic shock.
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Hypoperfusion of tissue results in cell membrane dysfunction. Normally, the cell membrane serves to preserve the milieu interior through the maintenance of a negative charge or membrane potential. Maintenance of a negative membrane potential across the cell membrane serves as a semipermeable barrier, preserving the balance of intra- and extracellular electrolytes and water.
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The continuing study of multiple organ failure (MOF) has led to the development of inflammatory models of tissue injury in contrast to earlier infectious models. This change of focus is in response to more recent clinical observations suggesting that postinjury MOF frequently occurs in the absence of infection. In the alternative "two-hit" inflammatory model that has been proposed, the initial traumatic insult "primes" the inflammatory response such that a delayed, otherwise innocuous, inflammatory insult triggers an exaggerated response. ⋯ PMN priming and activation are also operable in an in vivo model of gut ischemia/reperfusion, a surrogate of shock and trauma resuscitation, leading to distant organ damage. Finally, in clinical studies of severely injured trauma patients, PMN priming and activation sequences identify patients at risk for developing MOF with its associated high mortality. Further characterization of the mechanisms that regulate PMN priming and activation in the trauma patient is necessary for the development of new therapeutic interventions designed to block deleterious PMN responses which lead to MOF while not compromising beneficial PMN functions of host defense and tissue repair.