Critical care : the official journal of the Critical Care Forum
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Review Comparative Study
Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis?
Two international multicentre randomised controlled trials of drotrecogin alfa (activated) (DrotAA), the Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) and Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trials, have produced inconsistent results. When 28-day mortality data from these trials for patients with severe sepsis and at high risk of death are pooled using a standard random-effects meta-analysis technique, there is no statistically significant survival benefit (for patients with Acute Physiology and Chronic Health Evaluation (APACHE II) scores of 25 or more), or a borderline significant benefit (for patients with multi-organ failure). ⋯ These concerns call into question the effectiveness of DrotAA in any patients with severe sepsis. Consequently, further randomised trials of this agent in prospectively defined high-risk patients are required to clarify its role in the management of severe sepsis.
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Review
Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis.
Endotoxin tolerance is defined as a reduced responsiveness to a lipopolysaccharide (LPS) challenge following a first encounter with endotoxin. Endotoxin tolerance protects against a lethal challenge of LPS and prevents infection and ischemia-reperfusion damage. Endotoxin tolerance is paralleled by a dramatic reduction of tumor necrosis factor (TNF) production and some other cytokines in response to LPS. ⋯ Studies on cellular signaling within leukocytes from septic and SIRS patients reveal numerous alterations reminiscent of those observed in endotoxin tolerant cells. However, altered responsiveness to LPS of leukocytes from sepsis and SIRS patients is not synonymous with a global down-regulation of cellular reactivity. The term 'cellular reprogramming', which has been proposed to qualify the process of endotoxin tolerance, defines well the immune status of circulating leukocytes in septic and SIRS patients.
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The pressure-volume (PV) curve is a physiological tool proposed for diagnostic or monitoring purposes during mechanical ventilation of acute respiratory distress syndrome. The reduction in compliance measured by the PV curve and the different inflection points on the curve are considered interesting markers of the severity of and the levels of opening and closing pressures. ⋯ In some individuals tracing the curve may even have moderate hemodynamic effects. Fortunately, on average, most of these effects are transient or negligible and do not invalidate the PV curve measurement.
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Because no bedside method is currently available to evaluate myocardial contractility independent of loading conditions, a biological marker that could detect myocardial dysfunction in the early stage of severe sepsis would be a helpful tool in the management of septic patients. Clinical and experimental studies have reported that plasma cardiac troponin levels are increased in sepsis and could indicate myocardial dysfunction and poor outcome. The high prevalence of elevated levels of cardiac troponins in sepsis raises the question of what mechanism results in their release into the circulation. ⋯ A possible direct cardiac myocytotoxic effect of endotoxins, cytokines or reactive oxygen radicals induced by the infectious process and produced by activated neutrophils, macrophages and endothelial cells has been postulated. The presence of microvascular failure and regional wall motion abnormalities, which are frequently observed in positive-troponin patients, also suggest ventricular wall strain and cardiac cell necrosis. Altogether, the available studies support the contention that cardiac troponin release is a valuable marker of myocardial injury in patients with septic shock.
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The plasmatic strong ion difference (SID) is the difference between positively and negatively charged strong ions. At pH 7.4, temperature 37 degrees C and partial carbon dioxide tension 40 mmHg, the ideal value of SID is 42 mEq/l. The buffer base is the sum of negatively charged weak acids ([HCO3(-)], [A-], [H2PO4(-)]) and its normal value is 42 mEq/l. ⋯ Of note, volume modifications vary the concentration of charges in the solution. An expansion of extracellular volume leads to acidosis (SID decreases), whereas a contraction of extracellular volume leads to alkalosis (SID increases). A thorough understanding of acid-base equilibrium mandates recognition of the importance of urinary SID.