losartan-potassium and Multiple-Organ-Failure

Transfusion of red blood cells in the trauma patient can be lifesaving. The question is how much and when? It is important to weigh the risks and benefits of red blood cell transfusions, as well alternatives to transfusion as these products are not benign.. We explore the evidence, and provide the rationale for current and future red blood cell transfusion strategies within a framework of prehospital and hospital care of the trauma patient. We also describe how red blood cell transfusion trends are changing in trauma, discuss alternatives to red blood cell transfusion and present evidence from randomized controlled trials that support a lower transfusion trigger.. Optimal transfusion practice and use of alternatives in trauma is a rapidly expanding and important area of research. Strong clinical evidence derived by future randomized controlled trials in the area of transfusion triggers as well as transfusion alternatives is required to determine their roles in clinical practice.

Topics: Blood Substitutes; Blood Transfusion; Critical Care; Erythrocyte Transfusion; Erythropoietin; Hemostatics; Humans; Leukocyte Reduction Procedures; Multiple Organ Failure; Oxygen Consumption; Randomized Controlled Trials as Topic; Risk Assessment; Wounds and Injuries

Critically ill patients receive an extraordinarily large number of blood transfusions. Between 40% and 50% of all patients admitted to intensive care units receive at least 1 red blood cell (RBC) unit during their stay, and the average is close to 5 RBC units. RBC transfusion is not risk free. There is little evidence that 'routine' transfusion of stored allogeneic RBCs is beneficial to critically ill patients. The efficacy of perioperative recombinant human erythropoietin (rHuEPO) has been demonstrated in a variety of elective surgical settings. Similarly, in critically ill patients with multiple organ failure, rHuEPO therapy will also stimulate erythropoiesis. In a randomized, placebo-controlled trial, therapy with rHuEPO resulted in a significant reduction in RBC transfusions. Despite receiving fewer RBC transfusions, patients in the rHuEPO group had a significantly greater increase in hematocrit. Strategies to increase the production of RBCs are complementary to other approaches to reduce blood loss in the intensive care unit, and they decrease the transfusion threshold in the management of all critically ill patients.

Topics: Anemia; Critical Care; Erythrocyte Transfusion; Erythropoietin; Europe; Humans; Intensive Care Units; Multiple Organ Failure; Phlebotomy; Recombinant Proteins; Treatment Outcome; United States

Traumatic brain injury (TBI) is a major cause of morbidity and mortality. Multiple organ dysfunction syndrome (MODS) occurs frequently after TBI and independently worsens outcome. The present study aimed to identify potential admission characteristics associated with post-TBI MODS.. The authors performed a secondary analysis of a recent randomized clinical trial studying the effects of erythropoietin and blood transfusion threshold on neurological recovery after TBI. Admission clinical, demographic, laboratory, and imaging parameters were used in a multivariable Cox regression analysis to identify independent risk factors for MODS following TBI, defined as maximum total Sequential Organ Failure Assessment (SOFA) score > 7 within 10 days of TBI.. Two hundred patients were initially recruited and 166 were included in the final analysis. Respiratory dysfunction was the most common nonneurological organ system dysfunction, occurring in 62% of the patients. International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) probability of poor outcome at admission was significantly associated with MODS following TBI (odds ratio [OR] 8.88, 95% confidence interval [CI] 1.94-42.68, p < 0.05). However, more commonly used measures of TBI severity, such as the Glasgow Coma Scale, Injury Severity Scale, and Marshall classification, were not associated with post-TBI MODS. In addition, initial plasma concentrations of interleukin (IL)-6, IL-8, and IL-10 were significantly associated with the development of MODS (OR 1.47, 95% CI 1.20-1.80, p < 0.001 for IL-6; OR 1.26, 95% CI 1.01-1.58, p = 0.042 for IL-8; OR 1.77, 95% CI 1.24-2.53, p = 0.002 for IL-10) as well as individual organ dysfunction (SOFA component score ≥ 1). Finally, MODS following TBI was significantly associated with mortality (OR 5.95, 95% CI 2.18-19.14, p = 0.001), and SOFA score was significantly associated with poor outcome at 6 months (Glasgow Outcome Scale score < 4) when analyzed as a continuous variable (OR 1.21, 95% CI 1.06-1.40, p = 0.006).. Admission IMPACT probability of poor outcome and initial plasma concentrations of IL-6, IL-8, and IL-10 were associated with MODS following TBI.

Topics: Adolescent; Adult; Aged; Biomarkers; Brain Injuries, Traumatic; Cytokines; Erythropoietin; Female; Glasgow Outcome Scale; Humans; Male; Middle Aged; Multiple Organ Failure; Probability; Young Adult

To investigate erythropoietin (EPO) production and the erythropoietic potency of recombinant human EPO in the multiple organ dysfunction syndrome.. Randomized, prospective, controlled clinical trial.. Patients received either 600 IU/kg intravenous EPO three times weekly (n = 9) or saline (control, n = 10).. EPO levels, circulating soluble receptors for tumor necrosis factor and interleukin-2, levels of interleukin-6 and intercellular adhesion molecule, and early peripheral blood cell progenitors.. EPO production in the control group remained low. Pharmacologic EPO blood levels were associated with increased reticulocyte counts compared with both controls (p < 0.04) and baseline (p < 0.006). Increased levels of soluble receptors for tumor necrosis factor in the treatment group compared with the controls did not prevent this effect. Interleukin 6 inhibited reticulocyte production.. Despite increased cytokine levels, pharmacologic EPO blood levels were associated with increased reticulocyte counts in patients with multiple organ dysfunction syndrome.

Topics: Cytokines; Erythrocyte Count; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Iron; Male; Middle Aged; Multiple Organ Failure; Prospective Studies; Recombinant Proteins; Reticulocytes

Hemorrhagic shock (HS) still has a high mortality rate and none of the known resuscitative regimens completely reverse its adverse outcomes. This study investigated the effects of different models of resuscitative therapy on the healing of organ damage in a HS model. Male Wistar rats were randomized into six groups: Sham, without HS induction; HS, without resuscitation; HS+Blood, resuscitation with the shed blood; HS+Blood+NS, resuscitation with blood and normal saline; HS+Blood+RL, resuscitation with blood and Ringer's lactate; EPO, erythropoietin was added to the blood and RL. Blood and urine samples were obtained 3 h after resuscitation. Kidney, liver and brain tissue samples were harvested for multiple organ failure evaluation. Survival rate was the highest in the Sham, EPO and HS+Blood+RL groups compared to others. Plasma creatinine concentration, ALT, AST, urinary NAG activity and renal NGAL mRNA expression significantly increased in the HS+Blood+RL group compared to the Sham group. There was a significant increase in tissue oxidative stress markers and pro-inflammatory cytokines in HS+Blood+RL group compared to the Sham rats. EPO had more protective effects on multiple organ failure compared to the HS+Blood+RL group. EPO, as a resuscitative treatment, attenuated HS-induced organ damage. It seems that it has a potential to be attractive for clinical trials.

Topics: Animals; Anti-Inflammatory Agents; Critical Illness; Dose-Response Relationship, Drug; Erythropoietin; Male; Models, Animal; Multiple Organ Failure; Oxidative Stress; Rats; Rats, Wistar; Resuscitation; Severity of Illness Index; Shock, Hemorrhagic; Treatment Outcome; Viscera

Acute respiratory distress syndrome (ARDS) is a devastating disorder. Despite enormous efforts in clinical research, effective treatment options are lacking, and mortality rates remain unacceptably high.. A male patient with severe ARDS showed no clinical improvement with conventional therapies. Hence, an emergent experimental intervention was performed.. We performed intratracheal administration of autologous peripheral blood-derived mononuclear cells (PBMCs) and erythropoietin (EPO).. We found that after 2 days of initial PBMC/EPO application, lung function improved and extracorporeal membrane oxygenation (ECMO) support was reduced. Bronchoscopy and serum inflammatory markers revealed reduced inflammation. Additionally, serum concentration of miR-449a, b, c and miR-34a, a transient upregulation of E-cadherin and associated chromatin marks in PBMCs indicated airway epithelial differentiation. Extracellular vesicles from PBMCs demonstrated anti-inflammatory capacity in a TNF-α-mediated nuclear factor-x03BA;B in vitro assay. Despite improving respiratory function, the patient died of multisystem organ failure on day 38 of ECMO treatment.. This case report provides initial encouraging evidence to use locally instilled PBMC/EPO for treatment of severe refractory ARDS. The observed clinical improvement may partially be due to the anti-inflammatory effects of PBMC/EPO to promote tissue regeneration. Further studies are needed for more in-depth understanding of the underlying mechanisms of in vivo regeneration.

Topics: Cadherins; Cytokines; Down-Regulation; Erythropoietin; Extracorporeal Membrane Oxygenation; Fatal Outcome; Humans; Leukocytes, Mononuclear; Male; MicroRNAs; Multiple Organ Failure; Respiratory Distress Syndrome; Snail Family Transcription Factors; Transcription Factors; Transplantation, Autologous; Up-Regulation; Young Adult

The protective effect of erythropoietin (EPO) on tissues following ischemia and reperfusion injuries remains poorly understood. We aimed to investigate the effect of EPO in preventing endotoxin-induced organ damage. Rat model of multiple organ failure (MOF) was established by tail vein injection of 10 mg/kg lipopolysaccharide (LPS). Recombinant human EPO treatment (5000 U/kg) was administered by tail vein injection at 30 min after LPS challenge. Twenty-four h after EPO treatment, changes in serum enzyme levels, including aspartate aminotransferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN) and creatinine (Cr), were evaluated by biochemical analysis. Serum levels of tumor necrosis factor-α (TNF-α) were determined by using immunoradiometric assay. Histological examination of tissue sections was carried out by hematoxylin and eosin staining, while ultrastructure evaluation of organ tissues was assessed by transmission electron microscopy. Protein expression levels were detected by using Western blotting. EPO treatment showed a modest effect in preventing LPS-induced elevation of AST, ALT, BUN, Cr, and TNF-α levels, and in protecting against LPS-induced tissue degeneration and injured ultrastructure in the lung, liver, and kidney. Moreover, LPS promoted phosphorylation of alanine aminotransferase (AKT) and increased nuclear factor-κB (NF-κB) activation in the lung, liver, and kidney (P<0.05 vs. control). However, EPO treatment significantly decreased the LPS-induced pAKT up-regulation in these tissues (P<0.05 vs. LPS treatment alone). The present study demonstrates that EPO may play a protective role against LPS-induced MOF by reducing the inflammatory response and tissue degeneration, possibly via the phosphatidylinositol 3-kinase/AKT and NF-κB signaling pathways.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Urea Nitrogen; Blotting, Western; Creatinine; Endotoxins; Erythropoietin; Injections, Intravenous; Kidney; Lipopolysaccharides; Liver; Lung; Male; Microscopy, Electron, Transmission; Multiple Organ Failure; NF-kappa B; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Recombinant Proteins; Tumor Necrosis Factor-alpha

Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI.. RATS WERE RANDOMIZED INTO THREE GROUPS: control; CLP; and CLP+CERA (5 µg/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting--to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-κB)--and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1β, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection.. Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-κB was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats.. CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.

Topics: Acute Kidney Injury; Animals; Cecum; Cytokines; Erythropoietin; Gene Expression Regulation; Hemodynamics; Kidney Tubules; Ligation; Macrophages; Male; Multiple Organ Failure; NF-kappa B; Polyethylene Glycols; Punctures; Rats; Rats, Wistar; Receptors, Erythropoietin; Sepsis; Toll-Like Receptor 4

A 26-year-old male bodybuilder was admitted to the surgical department of a Danish community hospital for hematemesis. During the clinical interview, he revealed that he had recently finished a course of anabolic steroids and erythropoietin. The patient also had a previous history of infections and chronic ulcers due to paraffin-oil injections in both upper arms one year before. Over the course of the next few hours, the patient developed signs of multi-organ dysfunction, including pancreatitis, hemorrhagic gastritis, nephropathy with temporary anuria, and respiratory insufficiency, and was transferred to the ICU. After manometric monitoring on the patient's upper arms proved difficult, invasive blood pressure monitoring was used and revealed that the patient was in a state of hypertensive crisis. This case of multi-organ dysfunction was possibly caused by multi-substance-induced hypercalcemia.

Topics: Adult; Anabolic Agents; Critical Care; Denmark; Erythropoietin; Humans; Hypercalcemia; Male; Multiple Organ Failure; Substance-Related Disorders; Weight Lifting

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Darbepoetin alfa; Erythropoietin; Humans; Multiple Organ Failure; Oxidative Stress; Recombinant Proteins; Shock; Time Factors

Topics: Anemia; Blood Transfusion; Erythropoietin; Evidence-Based Medicine; Humans; Multiple Organ Failure; Practice Guidelines as Topic; Recombinant Proteins; Wounds and Injuries

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

Eryptosis, a suicidal death of mature erythrocytes, is characterized by decrease of cell volume, cell membrane blebbing, and breakdown of cell membrane asymmetry with phosphatidylserine exposure at the cell surface. Triggers of eryptosis include increased cytosolic Ca(2+) activity, which could result from activation of Ca(2+)-permeable cation channels. Ca(2+) triggers phosphatidylserine exposure and activates Ca(2+)-sensitive K(+) channels, leading to cellular K(+) loss and cell shrinkage. The cation channels and thus eryptosis are stimulated by Cl(-) removal and inhibited by erythropoietin. The present experiments explored eryptosis in transgenic mice overexpressing erythropoietin (tg6). Erythrocytes were drawn from tg6 mice and their wild-type littermates (WT). Phosphatidylserine exposure was estimated from annexin binding and cell volume from forward scatter in fluorescence-activated cell sorting (FACS) analysis. The percentage of annexin binding was significantly larger and forward scatter significantly smaller in tg6 than in WT erythrocytes. Transgenic erythrocytes were significantly more resistant to osmotic lysis than WT erythrocytes. Cl(-) removal and exposure to the Ca(2+) ionophore ionomycin (1 microM) increased annexin binding and decreased forward scatter, effects larger in tg6 than in WT erythrocytes. The K(+) ionophore valinomycin (10 nM) triggered eryptosis in both tg6 and WT erythrocytes and abrogated differences between genotypes. An increase of extracellular K(+) concentration to 125 mM blunted the difference between tg6 and WT erythrocytes. Fluo-3 fluorescence reflecting cytosolic Ca(2+) activity was larger in tg6 than in WT erythrocytes. In conclusion, circulating erythrocytes from tg6 mice are sensitized to triggers of eryptosis but more resistant to osmotic lysis, properties at least partially due to enhanced Ca(2+) entry and increased K(+) channel activity.

Topics: Animals; Annexins; Buffers; Calcium; Cell Death; Erythrocytes; Erythropoietin; Female; Flow Cytometry; Hematocrit; Life Expectancy; Mice; Mice, Transgenic; Multiple Organ Failure; Osmolar Concentration; Phosphatidylserines; Physical Exertion; Polycythemia; Reticulocytes

The hematopoietic cytokine erythropoietin has cytoprotective effects in endothelial cells in vitro that are mediated through direct activation of the pro-survival Akt tyrosine kinase signaling pathway. We tested the hypothesis that low-dose therapy with the long-acting recombinant human erythropoietin analogue darbepoetin alpha protects vascular endothelium in vivo in a classic remnant kidney rat model characterized by severe endothelial damage, progressive vascular sclerosis, and ischemia-induced tissue fibrosis.. Using a parallel group study design, we randomly assigned animals after 5/6 nephrectomy to treatment with either saline (n=36) or 0.1 microg/kg body wt darbepoetin (n=24) subcutaneously once weekly. We monitored hematocrit, blood pressure, and serum creatinine regularly and obtained renal tissue 6 weeks after nephrectomy for morphological and immunohistochemical analysis. Darbepoetin-treated animals had significantly improved survival compared with saline-treated controls (63% versus 33%; P<0.05), although hematocrit levels were similar in both groups. Darbepoetin treatment ameliorated endothelial damage; attenuated the composite tissue injury score (saline 1.9+/-0.4; darbepoetin 0.4+/-0.2; P<0.001), which included vascular sclerosis, glomerulosclerosis, and tubulointerstitial damage; and preserved renal function. We found persistent activation of the pro-survival Akt signaling pathway in endothelial and epithelial glomerular cells in darbepoetin-treated animals, accompanied by a significant reduction of apoptotic cell death in renal tissue.. Low-dose darbepoetin treatment confers vascular and tissue protection that is associated with persistent stimulation of the pro-survival Akt signaling pathway. The use of recombinant human erythropoietin or analogues may have utility in preventing ischemia-related progressive vascular injury and organ failure.

Topics: Animals; Apoptosis; Darbepoetin alfa; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Endothelium, Vascular; Erythropoietin; Glomerulosclerosis, Focal Segmental; Hematocrit; Hematopoietic Stem Cell Mobilization; Hypertension, Renal; Ischemia; Kidney; Life Tables; Male; Multiple Organ Failure; Nephrectomy; Nephritis, Interstitial; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Random Allocation; Rats; Rats, Sprague-Dawley; Signal Transduction

Topics: Erythropoietin; Female; Hemoglobin SC Disease; Humans; Middle Aged; Multiple Organ Failure