New horizons (Baltimore, Md.)
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In the past, most investigators failed to consider time relationships in their studies of circulatory problems. Because of this, data obtained in middle- or late-stage shock during organ failure are often presented as being characteristic of specific shock syndromes. Even "early" studies are not physiologically early, but instead have often come to mean early after ICU admission or early after life-threatening hypotensive events. ⋯ Data of survivors revealed increased cardiac function (CI and oxygen delivery) shortly after surgery, trauma, and sepsis; this response is needed to meet the increased metabolic demands defined by the increased oxygen consumption. Nonsurvivors have limited responses to the added metabolic demands of external stressors. Therapy should augment naturally occurring compensations, but it must be given promptly within appropriate time limits.
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Calcium functions as a critical intracellular second messenger and regulates many cellular processes such as muscle contractility, glycogen and protein turnover, hormone secretion, and vascular smooth muscle tone which are markedly abnormal during sepsis/endotoxemia. There also is increasing recognition of the role of calcium in the production of a variety of cytokines such as tumor necrosis factor alpha and interleukin-1 beta, which are important mediators of sepsis. Our hypothesis is that disturbances in cellular calcium regulation are responsible for or contribute to many of the metabolic manifestations of sepsis/endotoxemia and may be the driving force behind the development of multiorgan failure. ⋯ An important message is that there are fundamental differences in the pathophysiology of the endotoxin model versus the cecal ligation and perforation (CLP) model of sepsis. Although calcium antagonists improve survival in the endotoxin model, they increase mortality in the CLP model of sepsis. Possible reasons for the differences in the effect of the drugs in the two different models and insight into the mechanisms of cell injury in endotoxin versus sepsis are presented.
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The evolution of renal replacement therapy has permitted the treatment of critically ill patients with acute renal failure. In intensive care settings, continuous renal replacement therapies have been shown to be better tolerated and clinically useful. Continuous hemofiltration is now performed with blood pumps and double-lumen venous catheters, thus avoiding the complications found in previous arteriovenous treatments. ⋯ Continuous therapies are today moving toward newer indications and applications. The ability to remove proinflammatory substances by filtration and/or adsorption has opened a series of potential indications. The concept that renal support and protection take place during hemofiltration suggests that very early use of this technique is desirable, even before the onset of oliguria or azotemia.
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Despite the often multifactorial nature of renal insults in critically ill patients, inadequate renal blood flow (RBF) is common and frequently causes a reduction in the glomerular filtration rate (GFR). Renal autoregulation acts to maintain both the RBF and GFR constant across a broad range of renal perfusion pressure (RPP) levels; however, the lower limit of this range (approximately 80 mm Hg for RBF, and 10-15 mm Hg higher for GFR) is often above the RPP achieved in critically ill patients. Furthermore, renal autoregulation is often lost, resulting in a linear pressure-flow relationship in the "at-risk" kidney. ⋯ Preliminary data, using nitric oxide (NO.) synthase inhibitors to augment blood pressure, showed a detrimental effect on renal perfusion, perhaps due to the central role of NO. in the normal vasoregulation of the kidney. Dopaminergic agonists have been commonly used as renal vasodilators; however, their actions are complex and include a proximal tubular diuretic effect, renal vasodilation, and systemic hemodynamic effects. Their specific action to increase RBF and GFR has not been demonstrated in clinically relevant studies and no prospective randomized study has shown a reduction in the incidence of renal impairment or acute renal failure.
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Continuous hemofiltration was first described as a new form of renal replacement for critically ill patients in the late 1970s. Since then, it has undergone remarkable technical and conceptual modifications and has become a widely used form of dialytic therapy in the ICU. More recent insights into the pathogenesis of sepsis and the role of soluble molecules in the mediation of organ injury during septic shock have led to a resurgence of the concept of blood purification during life-threatening infection. ⋯ Experimental studies have shown that continuous hemofiltration has beneficial hemodynamic effects in septic animals and that such effects may correlate with the intensity of ultrafiltration. Cardiac function also appears to improve and myocardial depressant factors are removed from the circulation. Continuous hemofiltration offers some promise as an adjunctive form of treatment in severe sepsis.