Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy

Anemia and decreased health-related quality of life (HRQL) are common in patients receiving combination therapy of interferon alfa (IFN) and ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. In a randomized, prospective study evaluating the effectiveness of epoetin alfa in maintaining RBV dose, alleviating anemia, and improving HRQL in anemic (Hb < or = 12 g/dL) HCV-infected patients receiving combination therapy, patients receiving epoetin alfa had significant improvements in HRQL compared with placebo. In this study, 185 patients were randomized to 40,000 units of epoetin alfa subcutaneously weekly or placebo for an 8-week double-blind phase (DBP), followed by an 8-week open-label phase during which all patients received epoetin alfa. To further assess the impact of epoetin alfa on HRQL, post hoc analyses were conducted in the same patient population to compare the HRQL of these patients at randomization with norms of other populations, and to determine the critical relationship between hemoglobin (Hb) levels and HRQL. Mean HRQL scores of anemic HCV-infected patients receiving combination therapy at randomization were significantly lower than those of both the general population and patients who had other chronic conditions. Patients receiving epoetin alfa who had the greatest Hb increases from randomization to the end of the DBP also had the largest improvements in HRQL. Hb improvement was an independent predictor of HRQL improvement in these patients. In conclusion, epoetin alfa provided clinically significant HRQL improvement in HCV-infected patients receiving IFN/RBV therapy.     

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.Among vascular-enriched receptor tyrosine kinases, Tie2 is unusual in at least two functional aspects. First, Tie2 phosphorylation is tightly controlled by the interplay of several proteins: a paralogous receptor, Tie1; a tyrosine phosphatase, vascular endothelial-protein tyrosine phosphatase (VE-PTP); and two secreted ligands, angiopoietin (Angpt)-1 and Angpt-2, the latter of which can act as an agonist, partial agonist, or antagonist depending upon context (1–6). Second, unlike classic growth factor receptors, Tie2 is heavily expressed and phosphorylated throughout the quiescent adult vasculature (7), suggesting that Tie2 signaling has one or more roles in vascular maintenance.Based largely on Angpt-1 overexpression studies, Tie2 has been implicated in vascular barrier defense (8, 9). However, adult-specific deletion of Angpt-1 does not appear to trigger vascular leakage (10). Moreover, Angpt-1 has repeatedly been ascribed functions that are independent of Tie2 (11–13). Finally, observational studies in humans suffering clinical manifestations of vascular leakage have consistently shown a marked imbalance in Tie2 ligands tilting in favor of Angpt-2 (reviewed in 14). Although decreased Tie2 activity has been inferred from these reports, the role of TIE2 gene expression has not been directly queried experimentally or in clinical settings.This question is important not only for understanding control mechanisms of the circulatory system but also to guide the development of strategies to predict, stratify, and treat patients affected by acute vascular leakage. If tonic Tie2 signaling is indeed necessary for vascular barrier maintenance, then reducing the pool of receptors could constitute a ligand-independent means to attenuate barrier-protective signaling in the endothelium. We therefore hypothesized that the level of Tie2 expression modulates the sensitivity of blood vessels, and thereby the entire organism, to noxious stimuli. Cellular, rodent, and human genetics studies were undertaken to test this concept.     

Outcomes of patients with acute respiratory failure after abdominal surgery treated with noninvasive positive pressure ventilation

OBJECTIVES: Little is known about the physiologic and clinical effects of noninvasive positive pressure ventilation (NPPV) in patients who have acute respiratory failure (ARF) after abdominal surgery. We evaluated our clinical experience with the use of NPPV in the treatment of ARF after abdominal surgery. METHODS: We prospectively evaluated NPPV use during a 2-year period in a medical-surgical ICU of a university hospital. We documented demographic and diagnostic data, gas exchange, and clinical outcomes. We compared patients who were not intubated to those who were intubated after a trial of NPPV. RESULTS: Of 72 patients with ARF after abdominal surgery who were treated with NPPV, 48 patients avoided intubation (67%). Patients in the intubated and nonintubated groups had similar demographic characteristics, and similar American Society of Anesthesiologists physical status and simplified acute physiology score II scores at admission. The intubated group had a significantly lower Pa(O2)/fraction of inspired oxygen (Fi(O2)) ratio (123 +/- 62 mm Hg vs 194 +/- 76 mm Hg, p < 0.01) and more extended bilateral alveolar infiltrates (67% vs 31%, p < 0.01) than the non-intubated group. Within the first NPPV observation period, the Pa(O2)/Fi(O2) increased (+ 36 +/- 29% [+/- SD], p = 0.04) and the respiratory rate decreased (28.2 +/- 3.4 breaths/min vs 23.1 +/- 3.8 breaths/min, p < 0.01) significantly only in the non-intubated group. The non-intubated group had significantly lower length of ICU stay (17.3 +/- 10.9 days vs 34.1 +/- 28.5 days, p < 0.01) and mortality rate (6% vs 29%, p < 0.01). CONCLUSION: NPPV may be an alternative to conventional ventilation in selected patients with ARF after abdominal surgery who require ventilatory support.     

A prospective study of agitation in a medical-surgical ICU: incidence, risk factors, and outcomes

STUDY OBJECTIVES: Although agitation is thought to be common in the ICU, it has been poorly studied. We evaluated the incidence, risks factors, and outcomes of agitation in ICU. DESIGN: Prospective observational study. INTERVENTIONS: None. METHOD: All consecutive ICU admissions over an 8-month period were analyzed. MEASUREMENTS AND RESULTS: Two hundred eleven patients were admitted a total of 216 times during the period of the study. Twenty-nine patients were excluded from the study because their pathology findings did not allow an evaluation of their level of consciousness; 182 patients were actually enrolled. Agitation developed in 95 of 182 patients (52%). Agitation began 4.4 +/- 5.6 days (+/- SD) after admission to the ICU and lasted 3.9 +/- 4.1 days. Patients with agitation had a higher Simplified Acute Physiology Score II on ICU admission than those who did not have agitation (40 +/- 16 vs 33 +/- 13, p < 0.01). By stepwise logistic regression, the independent risks factors for development of agitation included psychoactive drug use at the time of ICU admission (odds ratio, 5.63; 95% confidence interval [CI], 1.32 to 23.70), history of alcohol abuse (odds ratio, 3.32; 95% CI, 1.12 to 10.00), dysnatremia (odds ratio, 4.95; 95% CI, 1.95 to 12.54), fever (odds ratio, 4.52; 95% CI, 1.80 to 11.49), use of sedatives in the ICU (odds ratio, 4.03; 95% CI, 1.62 to 10.40), and sepsis (odds ratio, 2.61; 95% CI, 1.03 to 6.58). Agitation was associated with a prolonged ICU stay (16 +/- 19 days vs 6 +/- 6 days, p = 0.0001), nosocomial infections (34% vs 7%, p < 0.0001), unplanned extubations (17% vs 2%, p = 0.003), and unplanned central venous catheter removal (16% vs 1%, p = 0.001), but not with mortality (12% in the agitation group vs 8% in patients without agitation). CONCLUSIONS: Agitation is a common event in a mixed medical-surgical ICU. It is associated with adverse outcomes including prolonged stay, nosocomial infections, and unplanned extubations. A better knowledge of incidence and risk factors should facilitate identification of patients at risk and decrease the incidence of agitation.