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Septic shock is characterized by a dysregulated host response to infection and is associated with a mortality of 45 to 50%. In this multicenter, randomized, double-blind, placebo-controlled trial in 1241 patients, hydrocortisone plus fludrocortisone reduced 90-day mortality.

Whether hydrocortisone reduces mortality among patients with septic shock is unclear. Patients with septic shock undergoing mechanical ventilation were assigned to receive an infusion of hydrocortisone or placebo. Hydrocortisone did not result in lower 90-day mortality.

A large Scandinavian randomized trial showed no important outcome differences between hemoglobin levels of 7 g per deciliter and 9 g per deciliter as transfusion thresholds in patients with septic shock. Blood transfusions are frequently given to patients with septic shock. 1 – 4 Some of these transfusions are given to patients who are bleeding, but many nonbleeding patients also undergo transfusion. 5 The recommendations of the Surviving Sepsis Campaign regarding blood transfusion in patients with septic shock are complex and include a recommendation for transfusion to maintain a hematocrit of more than 30% in the presence of hypoperfusion in the first 6 hours. 6 After that, the transfusion threshold should be a hemoglobin level of less than 7 g per deciliter, aiming at levels between 7 g and 9 g per deciliter in patients . . .

In septic shock, the first few hours of care are critical for survival. In this study, two protocols for the care of patients with septic shock were compared with usual care with respect to 60-day mortality and other outcomes. There were no significant differences in outcome. There are more than 750,000 cases of severe sepsis and septic shock in the United States each year. 1 Most patients who present with sepsis receive initial care in the emergency department, and the short-term mortality is 20% or more. 2 , 3 In 2001, Rivers et al. reported that among patients with severe sepsis or septic shock in a single urban emergency department, mortality was significantly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT) than among those who were given standard therapy (30.5% vs. 46.5%). 4 On the basis of the premise that usual care . . .

In this multicenter, open-label trial, patients with septic shock were treated to maintain a mean arterial pressure target of either 80 to 85 mm Hg or 65 to 70 mm Hg. There were no significant between-group differences in 28-day mortality or in 90-day mortality. Septic shock is characterized by arterial hypotension despite adequate fluid resuscitation. The guidelines of the Surviving Sepsis Campaign 1 recommended initial resuscitation with vasopressors to reverse hypotension, with a mean arterial pressure target of at least 65 mm Hg (grade 1C, indicating a strong recommendation with a low level of evidence). This recommendation is based on the findings of small studies, which showed no significant differences in lactate levels or regional blood flow when the mean arterial pressure was elevated to more than 65 mm Hg in patients with septic shock. 2 , 3 However, as emphasized by the Surviving Sepsis Campaign guidelines, . . .

The efficacy of drotrecogin alpha (activated) (DrotAA) for sepsis has been controversial. In this trial, there was no significant difference in all-cause mortality at 28 or 90 days between adults with sepsis who were treated with DrotAA and those treated with placebo. Recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), was approved for the treatment of severe sepsis in 2001 on the basis of the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study, 1 a phase 3 international, randomized, controlled trial that was stopped early for efficacy after the enrollment of 1690 patients with severe sepsis. Absolute mortality in the intention-to-treat population was reduced by 6.1 percentage points, a relative risk reduction of 19.4%. Subsequent subgroup analysis suggested that the mortality benefit was limited to patients with increased illness severity (i.e., those with more than one . . .

Purpose Machine learning has shown promise to detect useful subgroups of patients with sepsis from gene expression and protein data. This approach has rarely been deployed in metabolomic datasets. Metabolomic data are of interest as they capture effects from the genome, proteome, and environmental. We aimed to discover metabolic sub-phenotypes of septic shock, examine their temporal stability and association with clinical outcome. Methods Analysis was performed in two double-blind randomized trials in septic shock (LeoPARDS (1402 samples from 470 patients) and VANISH (493 samples from 173 patients)). Patients were included soon after the onset of shock and had serum collected at up to four time points. Metabolic clusters were identified from 474 metabolites using k-means clustering in LeoPARDS and predicted in VANISH with an elastic net classifier. Results Three sub-phenotypes were found. The main determinants of cluster membership were lipid species, especially lysophospholipids. Low lysophospholipid sub-phenotypes were associated with higher circulating cytokine levels. Persistence of low lysophospholipid sub-phenotypes was associated with higher mortality compared to the high lysophospholipid sub-phenotype (LeoPARDS: cluster 2 odds ratio 3.66 (95% CI 1.88–7.20), p  = 0.0001, cluster 3 2.49 (1.29–4.81), p  = 0.006; VANISH: cluster 2 4.13 (1.17–15.61), p  = 0.03), cluster 3 3.22 (1.09–9.92), p  = 0.04, vs cluster 1). We found no heterogeneity of treatment effect for any of the trial interventions by baseline metabolic sub-phenotype. Conclusion Three metabolic subgroups exist in septic shock which evolve over time. Persistence of low lysophospholipid sub-phenotypes is associated with mortality. Monitoring these subgroups could help identify patients at risk of poor outcome and direct novel therapies such as lysophospholipid supplementation. Registration Clinicaltirals.gov Identifiers, VANISH: ISRCTN 20769191, LeoPARDS: ISRCTN12776039.

Abstract Rationale Recent retrospective evidence suggests the efficacy of early norepinephrine administration during resuscitation; however, prospective data to support this assertion are scarce. Objectives To conduct a phase II trial evaluating the hypothesis that early low-dose norepinephrine in adults with sepsis with hypotension increases shock control by 6 hours compared with standard care. Methods This single-center, randomized, double-blind, placebo-controlled clinical trial was conducted at Siriraj Hospital, Bangkok, Thailand. The study enrolled 310 adults diagnosed with sepsis with hypotension. The patients were randomly divided into two groups: early norepinephrine (n = 155) and standard treatment (n = 155). The primary outcome was shock control rate (defined as achievement of mean arterial blood pressure ≥65 mm Hg, with urine flow ≥0.5 ml/kg/h for 2 consecutive hours, or decreased serum lactate ≥10% from baseline) by 6 hours after diagnosis. Measurements and Main Results The patients in both groups were well matched in background characteristics and disease severity. Median time from emergency room arrival to norepinephrine administration was significantly shorter in the early norepinephrine group (93 vs. 192 min; P < 0.001). Shock control rate by 6 hours was significantly higher in the early norepinephrine group (118/155 [76.1%] vs. 75/155 [48.4%]; P < 0.001). The 28-day mortality was not different between groups: 24/155 (15.5%) in the early norepinephrine group versus 34/155 (21.9%) in the standard treatment group (P = 0.15). The early norepinephrine group was associated with lower incidences of cardiogenic pulmonary edema (22/155 [14.4%] vs. 43/155 [27.7%]; P = 0.004) and new-onset arrhythmia (17/155 [11%] vs. 31/155 [20%]; P = 0.03). Conclusions Early norepinephrine was significantly associated with increased shock control by 6 hours. Further studies are needed before this approach is introduced in clinical resuscitation practice. Clinical trial registered with www.clinicaltrials.gov (NCT01945983) (CENSER trial).

For more than a decade, early treatment of sepsis has been driven by algorithms. In this study conducted predominantly in Australia and New Zealand, the use of algorithm-based treatment was not superior to usual care. Severe sepsis has a reported annual incidence in adults of up to 300 cases per 100,000 population. 1 – 3 Despite decreasing mortality from sepsis in recent years, 4 the risk of death remains high. 5 , 6 The fundamental principles for the management of sepsis include early recognition, control of the source of infection, appropriate and timely administration of antimicrobial drugs, and resuscitation with intravenous fluids and vasoactive drugs. Patients presenting to the emergency department account for a large proportion of patients with severe sepsis. 7 Reported in-hospital mortality ranges in this subgroup from 20 to 50%. 3 , 8 – 10 In 2001, a proof-of-concept, randomized trial . . .

Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.).