The combination of acute renal failure and sepsis is associated with an ominous 70 percent mortality. This article discusses the substantial progress in understanding the mechanisms of sepsis-associated acute renal failure.

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Acute renal failure and sepsis.

A better understanding of the inflammatory, procoagulant, and immunosuppressive aspects of sepsis has contributed to rational therapeutic plans. This review considers optimal management of sepsis from the point of early, goal-directed therapy, lung-protective ventilation, antibiotics, and additional therapies, such as activated protein C, as well as the use of corticosteroids, vasopressin, and intensive insulin.

Management of sepsis.

Background:The Institute of Medicine calls for the use of clinical guidelines and practice parameters to promote “best practices” and to improve patient outcomes.Objective:2007 update of the 2002 American College of Critical Care Medicine Clinical Guidelines for Hemodynamic Support of Neonates and C

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Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine*

Background The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown. Methods In a multicenter, open-label trial, we randomly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). The primary end point was mortality at day 28. Results At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P = 0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P = 0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P = 0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality. Conclusions Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.)

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High versus Low Blood-Pressure Target in Patients with Septic Shock

Nitric oxide (NO) is a relative newcomer to pharmacology, as the paper which initiated the field was published only 25 years ago. Nevertheless its impact is such that to date more than 31,000 papers have been published with NO in the title and more than 65,000 refer to it in some way. The identification of NO with endothelium-derived relaxing factor and the discovery of its synthesis from L-arginine led to the realisation that the L-arginine: NO pathway is widespread and plays a variety of physiological roles. These include the maintenance of vascular tone, neurotransmitter function in both the central and peripheral nervous systems, and mediation of cellular defence. In addition, NO interacts with mitochondrial systems to regulate cell respiration and to augment the generation of reactive oxygen species, thus triggering mechanisms of cell survival or death. This review will focus on the role of NO in the cardiovascular system where, in addition to maintaining a vasodilator tone, it inhibits platelet aggregation and adhesion and modulates smooth muscle cell proliferation. NO has been implicated in a number of cardiovascular diseases and virtually every risk factor for these appears to be associated with a reduction in endothelial generation of NO. Reduced basal NO synthesis or action leads to vasoconstriction, elevated blood pressure and thrombus formation. By contrast, overproduction of NO leads to vasodilatation, hypotension, vascular leakage, and disruption of cell metabolism. Appropriate pharmacological or molecular biological manipulation of the generation of NO will doubtless prove beneficial in such conditions.

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The discovery of nitric oxide and its role in vascular biology

Objective: To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was survival at day 28. Design: Multiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study. Setting: A total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia. Patients: A total of 797 patients with septic shock diagnosed for <24 hrs. Interventions: Patients with septic shock were allocated to receive 546C88 or placebo (5% dextrose) for up to 7 days (stage 1) or 14 days (stage 2) in addition to conventional therapy. Study drug was initiated at 0.05 mL·kg 1 ·hr 1 (2.5 mg·kg 1 ·hr 1 546C88) and titrated up to a maximum rate of 0.4 mL·kg 1 ·hr 1 to maintain mean arterial pressure between 70 and 90 mm Hg while attempting to withdraw concurrent vasopressors. Measurements and Main Results: Hemodynamic variables, organ function data, microbiological data, concomitant therapy, and adverse event data were recorded at baseline, throughout treatment, and at follow-up. The primary end point was day-28 survival. The trial was stopped early after review by the independent data safety monitoring board. Day-28 mortality was 59% (259/439) in the 546C88 group and 49% (174/358) in the placebo group (p < .001). The overall incidence of adverse events was similar in both groups, although a higher proportion of the events was considered possibly attributable to study drug in the 546C88 group. Most of the events accounting for the disparity between the groups were associated with the cardiovascular system (e.g., decreased cardiac output, pulmonary hypertension, systemic arterial hypertension, heart failure). The causes of death in the study were consistent with those expected in patients with septic shock, although there was a higher proportion of cardiovascular deaths and a lower incidence of deaths caused by multiple organ failure in the 546C88 group. Conclusions: In this study, the nonselective nitric oxide synthase inhibitor 546C88 increased mortality in patients with septic shock. (Crit Care Med 2004; 32:21‐30)

Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock*

Objective: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. Design: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. Setting: One hundred forty-six intensive care units from nine countries. Patients: Approximately 2,522 patients were planned to be enrolled less than or equal to 12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. Measurements and Main Results: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p = .80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. Conclusions: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

Connecting the debates in social theory with examples from recent advertising that draw on meanings and images of children, this chapter shows how some recent representations of childhood that engage explicitly with new information technologies are forms of economically invested socialization, precisely through their subscription to changing discourses of emotions.

Ángel Juan Gordo López

Papers

Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock*

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

Emotional capital and information technologies in the changing rhetorics around children and childhoods.

Sleep apnea, hypothyroidism and pulmonary edema.

Benzodiazepine withdrawal syndrome after a benzodiazepine antagonist.