losartan-potassium and Shock--Septic

Many advances have improved the care of critically ill patients, but only a few have been through the use of pharmaceutical agents. Recently, the US Food and Drug Administration (FDA) approved drotrecogin alfa (activated), or recombinant human activated protein C, for the treatment of patients with a high risk of death from severe sepsis. Drotrecogin alfa (activated) has antiinflammatory, antithrombotic and fibrinolytic properties. When given as a continuous intravenous infusion, recombinant human activated protein C decreases absolute mortality of severely septic patients by 6.1%, resulting in a 19.4% relative reduction in mortality. The absolute reduction in mortality increases to 13% if the population treated is restricted to patients with an APACHE II score greater than 24, as suggested by the FDA. The most frequent and serious side effect is bleeding. Severe bleeds increased from 2% in patients given placebo to 3.5% in patients receiving drotrecogin alfa (activated). The risk of bleeding was only increased during the actual infusion time of the drug, and the bleeding risk returned to placebo levels 24 hours after the infusion was discontinued. Patients treated in the intensive care unit frequently develop anemia, usually severe enough to require at least one transfusion of red blood cells. With the recent discovery of the harmful effects of allogeneic red blood cell transfusions and the increasing shortage of available red blood cell products, emphasis has been placed on minimizing transfusions. Patients who receive exogenous recombinant human erythropoietin maintain higher hemoglobin levels, in spite of requiring fewer transfusions during their stay in the intensive care unit. Recombinant human erythropoietin appears to be effective whether it is given as 300 units/kg of body weight subcutaneously every other day or as 40,000 units subcutaneously every week. Differences in hemoglobin values were not apparent until at least one week of therapy, but they continued to diverge after that initial week. Furthermore, the incidence of adverse events was similar to that of patients receiving placebo and there was no difference in mortality, suggesting that avoidance of blood transfusions did not translate into increased survival. Thus, recombinant human erythropoietin appears to be both safe and effective in treating the anemia found in critically ill patients, but it is less clear that such treatment is cost effective, especially in the higher dose regimens

Topics: Critical Care; Critical Illness; Epoetin Alfa; Erythropoietin; Humans; Protein C; Recombinant Proteins; Shock, Septic; Vasopressins

Allogenic blood transfusion may be required for the treatment of anemia due to a hematologic disease, the consequences of chemotherapy or other circumstances, such as haemorrage and/or surgery. Transfusion becomes indispensable to prevent the side effects of anemia, such as hypoxia, palpitations, tachycardia, cardiac ischemia and fatigue. However, frequent transfusions can cause several acute problems such as hemolysis, anaphylactic shock and septic shock but also chronic problems such as iron overload (hemochromatosis), alloimmunisation and metabolic disturbances. Each of these complications can produce serious consequences and could even be sometimes fatal. Therefore we should recognise, prevent and if necessary treat all these hazards. Our article emphasises the potential chronic problems. For hemochromatosis, an iron chelator (deferoxamine) should be administered. In the presence of allo-immunisation the more compatible ABO blood group must be chosen and blood products be eliminated by filtration, when there has been blood reaction. When an allo-graft of hematopoitic tissues is considered an irradiation of blood products is necessary. Research is being carried out to develop substitute products for transfusion (haemoglobine solutions) or molecules acting on the syntheses of haemoglobine (butyrate arginine). The efficacy of erythropoitine, (EPO) is well recognised for stimulation of haemoglobine syntheses in renal failure and oncology.

Topics: Anaphylaxis; Chronic Disease; Erythropoietin; Hemolysis; Humans; Iron Overload; Shock, Septic; Transfusion Reaction

Patients with decompensated cirrhosis have significantly reduced survival without liver transplantation. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase survival in patients with acute-on-chronic liver failure, and erythropoietin promoted hepatic regeneration in animal studies. We performed a double-blind, randomized, placebo-controlled trial to determine whether co-administration of these growth factors improved outcomes for patients with advanced cirrhosis.. In a prospective study, consecutive patients with decompensated cirrhosis seen at the Institute of Liver and Biliary Sciences, New Delhi (from May 2011 through June 2012) were randomly assigned to groups given subcutaneous G-CSF (5 μg/kg/d) for 5 days and then every third day (12 total doses), along with subcutaneous darbopoietin α(40 mcg/wk) for 4 weeks (GDP group, n = 29), or only placebos (control group, n = 26). All patients also received standard medical therapy and were followed for 12 months. Histology was performed on liver biopsies. The primary end point was survival at 12 months.. Baseline characteristics of patients were comparable; alcohol intake was the most common etiology of cirrhosis. A higher proportion of patients in the GDP group than controls survived until 12 months (68.6% vs 26.9%; P = .003). At 12 months, Child-Turcotte Pugh scores were reduced by 48.6% in the GDP group and 39.1% in the control group, from baseline (P = .001); Model for End Stage Liver Disease scores were reduced by 40.4% and 33%, respectively (P = .03). The need for large-volume paracentesis was significantly reduced in GDP group, compared with controls (P < .05). A lower proportion of patients in the GDP group developed septic shock (6.9%) during follow-up compared with controls (38.5%; P = .005). No major adverse events were observed in either group.. In a single-center randomized trial, a significantly larger proportion of patients with decompensated cirrhosis given a combination of G-CSF and darbopoietin α survived for 12 months more than patients given only placebo. The combination therapy also reduced liver severity scores and sepsis to a greater extent than placebo. Clinicaltrials.gov ID: NCT01384565.

Topics: Adult; Biopsy; Darbepoetin alfa; Disease Progression; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; India; Injections, Subcutaneous; Kaplan-Meier Estimate; Liver; Liver Cirrhosis; Liver Regeneration; Male; Middle Aged; Paracentesis; Proportional Hazards Models; Prospective Studies; Risk Factors; Severity of Illness Index; Shock, Septic; Time Factors; Treatment Outcome

Patients with systolic heart failure and anemia have worse symptoms, functional capacity, and outcomes than those without anemia. We evaluated the effects of darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anemia.. In this randomized, double-blind trial, we assigned 2278 patients with systolic heart failure and mild-to-moderate anemia (hemoglobin level, 9.0 to 12.0 g per deciliter) to receive either darbepoetin alfa (to achieve a hemoglobin target of 13 g per deciliter) or placebo. The primary outcome was a composite of death from any cause or hospitalization for worsening heart failure.. The primary outcome occurred in 576 of 1136 patients (50.7%) in the darbepoetin alfa group and 565 of 1142 patients (49.5%) in the placebo group (hazard ratio in the darbepoetin alfa group, 1.01; 95% confidence interval, 0.90 to 1.13; P=0.87). There was no significant between-group difference in any of the secondary outcomes. The neutral effect of darbepoetin alfa was consistent across all prespecified subgroups. Fatal or nonfatal stroke occurred in 42 patients (3.7%) in the darbepoetin alfa group and 31 patients (2.7%) in the placebo group (P=0.23). Thromboembolic adverse events were reported in 153 patients (13.5%) in the darbepoetin alfa group and 114 patients (10.0%) in the placebo group (P=0.01). Cancer-related adverse events were similar in the two study groups.. Treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Our findings do not support the use of darbepoetin alfa in these patients. (Funded by Amgen; RED-HF ClinicalTrials.gov number, NCT00358215.).

Topics: Aged; Anemia; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Female; Heart Failure, Systolic; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Shock, Septic; Stroke; Thromboembolism; Treatment Failure

Erythropoietin is a glycoprotein hormone mainly released by the kidney, which stimulates red blood cell production. However, in sepsis, the mechanisms responsible for the final increase in circulating erythropoietin remain unclear Seventeen critically ill patients with Simplified Acute Physiologic Score average 66 (range 43 to 103) were included in this study. Ten patients survived and seven died within 28 days. Blood samples obtained at different times were assayed for erythropoietin, cytokine levels and lactate measurements. PCO2 gap was assessed to detect the presence of gastric mucosal acidosis. Erythropoietin decreased in the patients who survived while it remained high or increased in non-survivors (37+/-6.5 vs 147+/-6. 7 UI/l respectively, P<0.05). Erythropoietin plasma levels were correlated with IL-6 levels (r=0.84, P<0.05) and TNFalpha levels (r=0.84, P<0.05). We observed a significant positive relationship between erythropoietin plasma levels and lactate concentrations (r= 0.89, P< 0. 05) and with PCO2 gap (r=0.9, P < 0.05). No correlation was found between erythropoietin concentration and the other parameters. High serum erythropoietin levels in non-survivors were observed with septic shock despite an increase in the levels of proinflammatory cytokines. We found a relationship between erythropoietin concentration and biological markers of tissue hypoperfusion i.e. lactate levels or PCO2 gap. This relationship could suggest tissue hypoperfusion as the stimulating factor for erythropoietin production in septic shock.

Topics: Adult; Aged; Erythropoietin; Humans; Interleukin-6; Middle Aged; Prognosis; Severity of Illness Index; Shock, Septic; Survival Analysis; Tumor Necrosis Factor-alpha

To investigate a possible relationship between plasma erythropoietin and interleukin-6 (IL-6) in critically ill children with sepsis or septic shock. To examine the modulatory effects of plasma from these patients on erythropoietin production in vitro, employing a cell culture system that uses the erythropoietin-producing Hep 3B cell line.. A prospective, controlled clinical and laboratory study.. A pediatric intensive care unit and research laboratory facility at a children's hospital.. Children admitted to the pediatric intensive care unit with the diagnosis of sepsis or septic shock (n = 16), and control patients without infection or anemia (n = 16) were admitted to the study.. None.. Blood samples were obtained from 16 children with sepsis or septic shock, and 16 age-matched controls. Plasma erythropoletin and IL-6 concentrations were measured using an enzyme-linked immunoassay. Plasma erythropoietin concentrations were significantly higher in children with sepsis or septic shock (120 +/- 26 mlU/mL) than in controls (10 +/- 2 mlU/mL) (p < .001). Plasma IL-6 concentrations were greater in children diagnosed with sepsis or septic shock (12,405 +/- 6662 pg/mL) than in control patients (7 +/- 1 pg/mL) (p < .001), and higher in septic shock patients (27,469 +/- 13,647 pg/mL) than sepsis patients (688 +/- 258 pg/mL) (p = .03). Hep 3B cells were incubated under hypoxic conditions in media containing plasma from control patients, or patients diagnosed with sepsis or septic shock. Media concentrations of erythropoietin were measured using an enzymelinked immunoassay. Hep 3B cells incubated with plasma from patients diagnosed with sepsis or septic shock produced more erythropoietin (216 +/- 23 mlU/mL) than Hep 3B cells incubated under the same conditions in media containing plasma from control patients (152 +/- 11 mlU/mL) (p = .04). Hypoxic Hep 3B cell erythropoietin production in media incubated with plasma from patients diagnosed with sepsis or septic shock correlated significantly (although weakly) with plasma IL-6 values from these same patients (p = .03, r2 = .28).. Plasma erythropoietin and IL-6 values are increased in critically ill children with sepsis or septic shock in comparison with controls. The data indicate that one or more plasma factors are responsible for stimulation of hypoxia-induced erythropoietin production in the Hep 3B cell line and suggest a possible role for IL-6 in the regulation of erythropoletin production in critically ill children with sepsis or septic shock.

Topics: Adolescent; Cells, Cultured; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Infant; Intensive Care Units; Interleukin-6; Male; Prospective Studies; Sepsis; Shock, Septic

Endotoxin shock can induce the production of several inflammatory mediators such as TNF-alpha, IL-6, and IL-1beta, leading to multiple organ dysfunction and death. Erythropoietin (EPO) has been found to interact with its receptor (EPO-R), expressed in a wide variety of non-hematopoietic tissues, to induce a range of pleiotropic cytoprotective actions. We investigated the effects of low doses of EPO (300U/kg, intravenous administration) on the physiopathology and cytokine levels in endotoxin shock in conscious rats. Endotoxin shock was induced by intravenous injection of Escherichia coli lipopolysaccharide (20mg/kg) in conscious rats. Mean arterial pressure (MAP) and heart rate (HR) were continuously monitored for 48h after LPS administration. Levels of biochemical and cytokine parameters, including glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine (Cre), lactic dehydrogenase (LDH), and creatine phosphokinase (CPK) were measured at 0, 1, 3, 6, 9, 12, 18, 24, and 48h after sepsis. Serum TNF-alpha, IL-6, and IL-1beta level was measured at 1h after sepsis. Endotoxin shock significantly increased blood GOT, GPT, BUN, Cre, LDH, CPK, TNF-alpha, IL-6, IL-1beta levels, and HR, while it decreased MAP. EPO further increased the markers of organ injury (GOT, GPT, BUN, Cre, LDH, and CPK), inflammatory biomarkers (TNF-alpha, IL-6, and IL-1beta) and did not affect MAP and HR after LPS. EPO disserved endotoxin shock-induced liver, kidney, lung, and small intestine damage in conscious rats. In conclusion, pre-treatment with low doses of EPO increased the release of TNF-alpha, IL-6, and IL-1beta, along with aggravating endotoxin shock-induced markers of organ injury in conscious rats.

Topics: Animals; Endotoxins; Erythropoietin; Humans; Interleukin-1beta; Interleukin-6; Intestine, Small; Kidney; Lipopolysaccharides; Liver; Lung; Male; Random Allocation; Rats; Rats, Inbred WKY; Shock, Septic; Tumor Necrosis Factor-alpha

Topics: Animals; Apoptosis; Disease Models, Animal; Erythropoietin; Hypoxia; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nitric Oxide Synthase; Oxidative Stress; Oxygen Consumption; Shock, Septic; Survival Rate

Erythropoietin has recently emerged as a cytoprotective cytokine, which possesses the ability to protect many tissues, including the brain, heart, and kidneys, against ischemia or traumatic injury. We investigated the therapeutic effects of erythropoietin in a murine model of endotoxin shock.. Prospective, randomized study.. University-based research laboratory.. Male BALB/c mice.. Mice intraperitoneally received either lipopolysaccharide (LPS) from Escherichia coli or vehicle. Erythropoietin was administered at a dose of 1000 IU/kg subcutaneously at different time points after LPS administration. We also investigated the effect of erythropoietin on the development of septic shock caused by cecal perforation.. Treatment of mice with erythropoietin, within 2 hours after LPS administration, improved the mortality rate. Treatment of cecal perforated mice with erythropoietin extended survival by 12 hours, but all animals died by 72 hours in both groups. Erythropoietin attenuated apoptosis in the lungs, liver, small intestine, thymus, and spleen, as assessed by terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling staining, active caspase-3 immunostaining and immunoblotting, and measurements of caspase-3/7 activity. Erythropoietin also reduced inducible nitric oxide synthase expression, nitric oxide production, peroxynitrite formation, and tissue hypoxia. In contrast, erythropoietin did not affect the degree of LPS-induced inflammation, as assessed by measurements of blood levels of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, growth-related oncogene/keratinocyte-derived cytokine, and high mobility group box 1, the phosphorylation levels of nuclear factor kappaB, and the number of neutrophils infiltrating the lungs and the liver.. The results of the study demonstrate that administration of a large dose of erythropoietin after induction of experimental endotoxemia improved survival and that the beneficial effects of erythropoietin were associated with inhibition of apoptosis, nitric oxide production, and tissue hypoxia, without alterations in inflammatory responses.

Topics: Animals; Disease Models, Animal; Erythropoietin; Male; Mice; Mice, Inbred BALB C; Shock, Septic

Erythropoietin protects many organs against the tissue injury and dysfunction caused by ischaemia/reperfusion and excessive inflammation. This editorial comment discusses the effects of erythropoietin in preclinical models of septic shock, endotoxemia, hemorrhagic shock, spinal cord trauma and zymosan-induced multiple organ failure.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxemia; Erythropoietin; Mice; Multiple Organ Failure; Shock; Shock, Hemorrhagic; Shock, Septic; Spinal Cord Injuries; Treatment Outcome; Zymosan

During sepsis the endocrine, immune and nervous systems elaborate a multitude of biological responses. Little is known regarding the mechanisms responsible for the final circulating erythropoietin (EPO) and renin levels in septic shock. The aim of the present study was to assess the role of EPO and renin as biological markers in patients with septic shock.. A total of 44 critically ill patients with septic shock were evaluated.. Nonsurvivors had significantly higher serum EPO levels than did survivors on admission (median [minimum-maximum]; 61 [10-602] versus 20 [5-369]). A negative relationship between serum EPO and blood haemoglobin concentrations was observed in the survivor group (r = -0.61; P < 0.001). In contrast, in the nonsurvivors the serum EPO concentration was independent of the blood haemoglobin concentration. Furthermore, we observed significant relationships between EPO concentration and lactate (r = 0.5; P < 0.001), arterial oxygen tension/fractional inspired oxygen ratio (r = -0.41; P < 0.005), arterial pH (r = -0.58; P < 0.001) and renin concentration (r = 0.42; P < 0.005). With regard to renin concentration, significant correlations with lactate (r = 0.52; P < 0.001) and arterial pH (r = -0.33; P < 0.05) were observed.. Our findings show that EPO and renin concentrations increased in patients admitted to the intensive care unit with septic shock. Renin may be a significant mediator of EPO upregulation in patients with septic shock. Further studies regarding the regulation of EPO expression are clearly warranted.

Topics: Aged; Biomarkers; Critical Illness; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Hemoglobins; Humans; Intensive Care Units; Interleukin-6; Lactic Acid; Male; Middle Aged; Renin; Shock, Septic; Survivors

To find out whether polymyxin B-immobilized fiber (PMX-F) treatment affects the clinical parameters and plasma concentrations of erythropoietin (EPO) and interleukin (IL)-6.. A prospective case series study.. Intensive care unit of the Department of Internal Medicine, Misato Junshin Hospital, Saitama, and Koto Hospital, Tokyo, Japan.. 17 consecutive patients (10 men, 7 women; mean age 54.6 years) with clinically defined septic shock and 20 healthy volunteers (12 men, 8 women; mean age 52.2 years).. Of the 17 patients with septic shock, 9 (53 %) survived. The systolic blood pressure increased significantly from 78+/-6 to 106+/-8 mm Hg 2 h after PMX-F treatment in patients with septic shock. Plasma endotoxin levels decreased significantly after treatment, from 40+/-6 to 12+/-4 pg/ml. The pretreatment plasma concentrations of EPO and IL-6 were significantly higher in the 8 nonsurviving patients with septic shock (EPO: 400+/-36 mlU/ml; IL-6: 6260+/-1180 pg/ml) than in the 9 surviving patients (EPO: 120+/-22 mlU/ml; IL-6: 680+/-138 pg/ml) and the 20 control subjects (EPO, 12+/-6 mlU/ml; IL-6, 8+/-2 pg/ml). Plasma concentrations of EPO and IL-6 in patients with septic shock decreased significantly after PMX-F treatment (EPO, nonsurviving: 320+/-28 mlU/ml, p < 0.05; survivors: 26+/-8 mlU/ ml, p < 0.001; IL-6, nonsurviving: 3860+/-840 pg/ml, p < 0.01; survivors: 84+/-20 pg/ml, p < 0.001).. Plasma concentrations of EPO and IL-6 may be prognostic indicators in patients with septic shock: PMX-F treatment may be effective in reducing the plasma concentrations of EPO and IL-6 in patients with septic shock.

Topics: Adult; Aged; Anti-Bacterial Agents; Blood Pressure; Case-Control Studies; Endotoxins; Erythropoietin; Female; Hemoperfusion; Humans; Interleukin-6; Male; Middle Aged; Polymyxin B; Prospective Studies; Shock, Septic

The role of the immune system in the control of the production of erythropoietin is still poorly understood. Herein, the levels of circulating immunoreactive erythropoietin, tumour necrosis factor alpha, interleukin-1 beta and interleukin-6 were determined in 10 septic patients for up to 4 d following the admission to an internal intensive care unit. The data show that the production of erythropoietin was not suppressed despite an increase in the levels of proinflammatory cytokines. Circulating erythropoietin and interleukin-6 greatly increased in the 6 nonsurviving patients. The pattern of the serum erythropoietin level in the nonsurvivors resembled that of acute phase proteins and was independent of the blood haemoglobin concentration. Similar to interleukin 6, abnormally high serum erythropoietin levels appear to be a negative prognostic indicator in patients suffering from septic shock.

Topics: Adult; Aged; Biomarkers; Erythropoietin; Female; Humans; Interleukin-1; Interleukin-6; Male; Middle Aged; Prognosis; Sepsis; Shock, Septic; Tumor Necrosis Factor-alpha