Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established. In this multicenter, open-label trial, we randomly assigned 1818 patients with severe sepsis, in 100 intensive care units (ICUs), to receive either 20% albumin and crystalloid solution or crystalloid solution alone. In the albumin group, the target serum albumin concentration was 30 g per liter or more until discharge from the ICU or 28 days after randomization. The primary outcome was death from any cause at 28 days. Secondary outcomes were death from any cause at 90 days, the number of patients with organ dysfunction and the degree of dysfunction, and length of stay in the ICU and the hospital. During the first 7 days, patients in the albumin group, as compared with those in the crystalloid group, had a higher mean arterial pressure (P=0.03) and lower net fluid balance (P<0.001). The total daily amount of administered fluid did not differ significantly between the two groups (P=0.10). At 28 days, 285 of 895 patients (31.8%) in the albumin group and 288 of 900 (32.0%) in the crystalloid group had died (relative risk in the albumin group, 1.00; 95% confidence interval [CI], 0.87 to 1.14; P=0.94). At 90 days, 365 of 888 patients (41.1%) in the albumin group and 389 of 893 (43.6%) in the crystalloid group had died (relative risk, 0.94; 95% CI, 0.85 to 1.05; P=0.29). No significant differences in other secondary outcomes were observed between the two groups. In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days. (Funded by the Italian Medicines Agency; ALBIOS ClinicalTrials.gov number, NCT00707122.)

Background— Circulating cardiac troponin T, a marker of cardiomyocyte injury, predicts adverse outcome in patients with heart failure (HF) but is detectable in only a small fraction of those with chronic stable HF. We assessed the prognostic value of circulating cardiac troponin T in patients with stable chronic HF with a traditional (cTnT) and a new precommercial highly sensitive assay (hsTnT). Methods and Results— Plasma troponin T was measured in 4053 patients with chronic HF enrolled in the Valsartan Heart Failure Trial (Val-HeFT). Troponin T was detectable in 10.4% of the population with the cTnT assay (detection limit ≤0.01 ng/mL) compared with 92.0% with the new hsTnT assay (≤0.001 ng/mL). Patients with cTnT elevation or with hsTnT above the median (0.012 ng/mL) had more severe HF and worse outcome. In Cox proportional hazards models adjusting for clinical risk factors, cTnT was associated with death (780 events; hazard ratio=2.08; 95% confidence interval, 1.72 to 2.52; P <0.0001) and first hospitalization for HF (655 events; hazard ratio=1.55; 95% confidence interval, 1.25 to 1.93; P <0.0001). HsTnT was associated with the risk of death in unadjusted analysis for deciles of concentrations and in multivariable models (hazard ratio=1.05; 95% confidence interval, 1.04 to 1.07 for increments of 0.01 ng/mL; P <0.0001). Addition of hsTnT to well-calibrated models adjusted for clinical risk factors, with or without brain natriuretic peptide, significantly improved prognostic discrimination (C-index, P <0.0001 for both outcomes). Conclusions— In this large population of patients with HF, detectable cTnT predicts adverse outcomes in chronic HF. By the highly sensitive assay, troponin T retains a prognostic value at previously undetectable concentrations.

The cytokine erythropoietin (Epo) is tissue-protective in preclinical models of ischemic, traumatic, toxic, and inflammatory injuries. We have recently characterized Epo derivatives that do not bind to the Epo receptor (EpoR) yet are tissue-protective. For example, carbamylated Epo (CEpo) does not stimulate erythropoiesis, yet it prevents tissue injury in a wide variety ofin vivoandin vitromodels. These observations suggest that another receptor is responsible for the tissue-protective actions of Epo. Notably, prior investigation suggests that EpoR physically interacts with the common β receptor (βcR), the signal-transducing subunit shared by the granulocyte-macrophage colony stimulating factor, and the IL-3 and IL-5 receptors. However, because βcR knockout mice exhibit normal erythrocyte maturation, βcR is not required for erythropoiesis. We hypothesized that βcR in combination with the EpoR expressed by nonhematopoietic cells constitutes a tissue-protective receptor. In support of this hypothesis, membrane proteins prepared from rat brain, heart, liver, or kidney were greatly enriched in EpoR after passage over either Epo or CEpo columns but covalently bound in a complex with βcR. Further, antibodies against EpoR coimmunoprecipitated βcR from membranes prepared from neuronal-like P-19 cells that respond to Epo-induced tissue protection. Immunocytochemical studies of spinal cord neurons and cardiomyocytes protected by Epo demonstrated cellular colocalization of Epo βcR and EpoR. Finally, as predicted by the hypothesis, neither Epo nor CEpo was active in cardiomyocyte or spinal cord injury models performed in the βcR knockout mouse. These data support the concept that EpoR and βcR comprise a tissue-protective heteroreceptor.

Acute respiratory distress syndrome (ARDS) is a clinical condition that entails high mortality¹ and may be associated with severe hypoxemia. Prone positioning is currently suggested for patients with ARDS, for whom high fraction of inspired oxygen (FIO₂) or high plateau pressure makes mechanical ventilation potentially injurious.² Moreover, prone positioning has been advocated as a rescue maneuver for severe hypoxemia, owing to its positive effects on oxygenation,^3-5 which have been repeatedly documented since its first description in 1976.⁶ However, no randomized clinical trial has yet demonstrated a significant reduction in mortality rate associated with prone positioning.^7-9 In a previous randomized trial⁷ we had observed, in a hypothesis-generating post hoc analysis,¹⁰ that in the subgroup of patients with the most severe hypoxemia and with ARDS, survival was better in the prone than in the supine position. In that study, prone positioning was limited to 6 hours per day for up to 10 days, and no modification of mechanical ventilation settings was allowed when patients were turned from the supine to the prone position.

The renin-angiotensin system plays a role in the etiology of hypertension and the pathophysiology of cardiac and renal diseases in humans. Ang II is the central product of this system and is involved in regulating immune responses, inflammation, cell growth, and proliferation by acting through Ang II type 1 receptors (AT₁ and AT₂). Here, we show that targeted disruption of the Agtr1a gene that encodes AT_1A results in marked prolongation of life span in mice. Agtr1a^–/– mice developed less cardiac and vascular injury, and multiple organs from these mice displayed less oxidative damage than wild-type mice. The longevity phenotype was associated with an increased number of mitochondria and upregulation of the prosurvival genes nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in the kidney. In cultured tubular epithelial cells, Ang II downregulated Sirt3 mRNA, and this effect was inhibited by an AT₁ antagonist. These results demonstrate that disruption of AT₁ promotes longevity in mice, possibly through the attenuation of oxidative stress and overexpression of prosurvival genes, and suggests that the Ang II/AT₁ pathway may be targeted to influence life span in mammals.