losartan-potassium and Wounds-and-Injuries

Low-dose hydrocortisone reduces the dose of vasopressors and hospital length of stay; it may also decrease the rate of hospital-acquired pneumonia and time on ventilator. No major side effect was reported, but glycemia and natremia should be monitored. Progesterone did not enhance outcome of trauma patients. A meta-analysis suggested that oxandrolone was associated with shorter length of stay and reduced weight loss. Erythropoietin did not enhance neurologic outcome of traumatic brain-injured patients; such treatment, however, could reduce the mortality in subgroups of patients. This review focuses mainly on glucocorticoids, which are the most extensively investigated treatments in hormone therapy.

Topics: Erythropoietin; Female; Hormones; Humans; Hydrocortisone; Length of Stay; Male; Oxandrolone; Progesterone; Wounds and Injuries

Erythropoietin (EPO) is a 34kD pleiotropic cytokine that was first identified as being essential for red blood cell (RBC) production. It is now recognized however that EPO is produced by many tissues. It plays a key role in the modulation of the response to injury, inflammation, and tissue hypoxia via the inhibition of apoptosis. Large clinical trials in the critically ill failed to demonstrate a role for EPO as an RBC transfusion sparing agent; however, improved clinical outcomes, attributable to EPO role in tissue protection are observed in critically ill trauma patients. Further research to confirm or refute these observations is required.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Apoptosis; Cell Proliferation; Critical Illness; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Male; Middle Aged; Wounds and Injuries

EPO is an autologous hormone, which is known to regulate erythropoiesis. For 30 years it has been used for the therapy of diverse forms of anaemia, such as renal anaemia, tumour-related anaemias, etc. Meanwhile, a multitude of scientific publications were able to demonstrate its pro-regenerative effects after trauma. These include short-term effects such as the inhibition of the "primary injury response" or apoptosis, and mid- and long-term effects for example the stimulation of stem cell recruitment, growth factor production, angiogenesis and re-epithelialisation. Known adverse reactions are increases of thromboembolic events and blood pressure, as well as a higher mortality in patients with tumour anaemias treated with EPO. Scientific investigations of EPO in the field of plastic surgery included: free and local flaps, nerve regeneration, wound healing enhancement after dermal thermal injuries and in chronic wounds.Acute evidence for the clinical use of EPO in the field of plastic surgery is still not satisfactory, due to the insufficient number of Good Clinical Practice (GCP)-conform clinical trials. Thus, the initiation of more scientifically sound trials is indicated.

Topics: Anemia; Chronic Disease; Clinical Trials as Topic; Erythropoietin; Graft Survival; Humans; Nerve Regeneration; Plastic Surgery Procedures; Regenerative Medicine; Skin; Surgical Flaps; Wound Healing; Wounds and Injuries

Erythropoietin (EPO) is a well-known therapeutic protein employed widely in the treatment of anemia. Over the past decade, abundant evidence has shown that in addition to its systemic role in the regulation of plasma pO(2) by modulating erythrocyte numbers, EPO is also a cytoprotective molecule made locally in response to injury or metabolic stress. Many studies have shown beneficial effects of EPO administration in reducing damage caused by ischemia-reperfusion, trauma, cytotoxicity, infection and inflammation in a variety of organs and tissues. Notably, the receptor mediating the nonerythropoietic effects of EPO differs from the one responsible for hematopoiesis. The tissue-protective receptor exhibits a lower affinity for EPO and is a heteromer consisting of EPO receptor monomers in association with the common receptor that is also employed by granulocyte macrophage colony-stimulating factor, interleukin 3, and interleukin 5. This heteromeric receptor is expressed immediately following injury, whereas EPO production is delayed. Thus, early administration of EPO can dramatically reduce the deleterious components of the local inflammatory cascade. However, a high dose of EPO is required and this also stimulates the bone marrow to produce highly reactive platelets and activates the vascular endothelium into a prothrombotic state. To circumvent these undesirable effects, the EPO molecule has been successfully altered to selectively eliminate erythropoietic and prothrombotic potencies, while preserving tissue-protective activities. Very recently, small peptide mimetics have been developed that recapitulate the tissue-protective activities of EPO. Nonerythropoietic tissue-protective molecules hold high promise in a wide variety of acute and chronic diseases.

Topics: Amino Acid Sequence; Animals; Cytokine Receptor Common beta Subunit; Cytokines; Drug Design; Erythropoietin; Feedback, Physiological; Hematinics; Hematopoiesis; Humans; Inflammation; Inflammation Mediators; Janus Kinase 2; Models, Molecular; Molecular Sequence Data; Protein Conformation; Protein Multimerization; Receptors, Erythropoietin; Recombinant Proteins; Reperfusion Injury; STAT Transcription Factors; Stress, Physiological; Wounds and Injuries

In forensic pathology, while classical morphology remains a core procedure to investigate deaths, a spectrum of ancillary procedures has been developed and incorporated to detail the pathology. Among them, postmortem biochemistry is important to investigate the systemic pathophysiological changes involved in the dying process that cannot be detected by morphology. In addition, recent advances in molecular biology have provided a procedure to investigate genetic bases of diseases that might present with sudden death, which is called 'molecular autopsy'. Meanwhile, the practical application of RNA analyses to postmortem investigation has not been accepted due to rapid decay after death; however, recent experimental and practical studies using real-time reverse transcription-PCR have suggested that the relative quantification of mRNA transcripts can be applied in molecular pathology for postmortem investigation of deaths, which may be called 'advanced molecular autopsy'. In a broad sense, forensic molecular pathology implies applied medical sciences to investigate the genetic basis of diseases, and the pathophysiology of diseases and traumas leading to death at a biological molecular level in the context of forensic pathology. The possible applications include analyses of local pathology, including tissue injury, ischemia/hypoxia and inflammation at the site of insult or specific tissue damage from intoxication, systemic responses to violence or environmental hazards, disorders due to intoxication, and systemic pathophysiology of fatal process involving major life-support organs. A review of previous studies suggests that systematic postmortem quantitative analysis of mRNA transcripts can be established from multi-faceted aspects of molecular biology and incorporated into death investigations in forensic pathology, to support and reinforce morphological evidence.

Topics: Aging; Animals; Asphyxia; Biomarkers; Erythropoietin; Forensic Pathology; Gene Expression; Glucose Transporter Type 1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Ischemia, Brain; Immunohistochemistry; Postmortem Changes; Pulmonary Surfactant-Associated Proteins; Respiratory Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Shock; Specimen Handling; Vascular Endothelial Growth Factor A; Violence; Wounds and Injuries

High energy trauma is often responsible for acute bleeding. Long bone and pelvis fractures are correlated with increased blood loss. Hypovolaemia could become a life threatening complication especially in elderly patients because of the reduced physiological response. Furthermore it could compromise the course of associated morbidities. Haemorrage is also associated in both comminuted fractures and osteoporosis. An increased intraoperative bleeding often occurs when a prolonged surgical time is required to obtain an appropriate ostheosynthesis. The final consequence of a mayor bleeding is hypovolaemic shock. The reduced oxygen tension of the tissue may be responsible for heart attack, arrhythmia, stroke, multi organ deficiency. For these reasons, it is important to immediately recognize and correct all potential bleeding in order to avoid complications.

Topics: Blood Loss, Surgical; Blood Transfusion; Erythropoietin; Hematinics; Humans; Orthopedics; Shock; Wounds and Injuries

Trauma patients often present in a state of haemorrhagic shock. Blood products remain the gold standard of resuscitation, but allogeneic blood transfusions (ABTs) are associated with several risks. The stimulating effect of recombinant-erythropoietin (EPO-A) on erythropoiesis has raised interest in its administration as an alternative. The existing evidence on the early use of EPO-A in the acute phase of trauma patients management consists of only 14 publications. The level of evidence of these studies and the number of treated patients was not found to be adequate to support its generalised use, despite their favourable results. Its safety profile, the preliminary proofs of its efficacy, and the additional cyto-protective properties of EPO-A strongly encourage further controlled studies assessing its use in the acute setting of initial trauma management.

Topics: Accidental Falls; Accidents, Traffic; Emergency Medical Services; Erythropoietin; Hematopoiesis; Humans; Jehovah's Witnesses; Recombinant Proteins; Shock, Hemorrhagic; Stimulation, Chemical; Wounds and Injuries

In its classic hormonal role, erythropoietin (EPO) is produced by the kidney and regulates the number of erythrocytes within the circulation to provide adequate tissue oxygenation. EPO also mediates other effects directed towards optimizing oxygen delivery to tissues, e.g. modulating regional blood flow and reducing blood loss by promoting thrombosis within damaged vessels. Over the past 15 years, many unexpected nonhaematopoietic functions of EPO have been identified. In these more recently appreciated nonhormonal roles, locally-produced EPO signals through a different receptor isoform and is a major molecular component of the injury response, in which it counteracts the effects of pro-inflammatory cytokines. Acutely, EPO prevents programmed cell death and reduces the development of secondary, pro-inflammatory cytokine-induced injury. Within a longer time frame, EPO provides trophic support to enable regeneration and healing. As the region immediately surrounding damage is typically relatively deficient in endogenous EPO, administration of recombinant EPO can provide increased tissue protection. However, effective use of EPO as therapy for tissue injury requires higher doses than for haematopoiesis, potentially triggering serious adverse effects. The identification of a tissue-protective receptor isoform has facilitated the engineering of nonhaematopoietic, tissue-protective EPO derivatives, e.g. carbamyl EPO, that avoid these complications. Recently, regions within the EPO molecule mediating tissue protection have been identified and this has enabled the development of potent tissue-protective peptides, including some mimicking EPO's tertiary structure but unrelated in primary sequence.

Topics: Animals; Apoptosis; Cytokines; Erythropoiesis; Erythropoietin; Humans; Protein Isoforms; Receptors, Erythropoietin; Recombinant Proteins; Wound Healing; Wounds and Injuries

Major transfusion-free orthopaedic surgery can be performed successfully. This requires advanced planning, good routines and close collaborative team efforts. Since most blood saving techniques reduce blood usage by just 1-2 units, a series of integrated preoperative, intraoperative and postoperative blood saving approaches is required. These include preoperative autologous donation, erythropoietic support, acute normovolemic hemodilution, intraoperative autotransfusion, individualized assessment of anemia tolerance, meticulous surgical techniques and the use of pharmacologic agents for limiting blood loss. For various reasons, we do not recommend the transfusion of wound drainage. This article describes the various methods for bloodless medical care.

Topics: Adult; Anemia; Blood Coagulation Tests; Blood Loss, Surgical; Blood Transfusion, Autologous; Child; Clinical Trials as Topic; Contraindications; Cost-Benefit Analysis; Drainage; Erythropoiesis; Erythropoietin; Hematocrit; Hemodilution; Hemoglobinometry; Humans; Intraoperative Care; Jehovah's Witnesses; Meta-Analysis as Topic; Orthopedic Procedures; Preoperative Care; Risk Factors; Time Factors; Wounds and Injuries

Topics: Endothelin A Receptor Antagonists; Erythropoietin; Humans; Hypoxia; Neovascularization, Physiologic; Neuroprotective Agents; Wounds and Injuries

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

Topics: Adult; Animals; Antifibrinolytic Agents; Blood Coagulation; Blood Component Transfusion; Blood Transfusion; Blood Transfusion, Autologous; Child; Controlled Clinical Trials as Topic; Erythrocyte Transfusion; Erythropoietin; Female; Hemodilution; Hemoglobins; Humans; Immunosuppression Therapy; Male; Middle Aged; Plasmapheresis; Platelet Transfusion; Pregnancy; Preoperative Care; Retrospective Studies; Risk Factors; Surgical Procedures, Operative; Transfusion Reaction; Trauma Severity Indices; Wounds and Injuries

Topics: Anemia; Animals; Blood Pressure; Blood Substitutes; Blood Transfusion; Christianity; Erythropoietin; Ethics, Nursing; Female; Humans; Middle Aged; Religion and Medicine; Severity of Illness Index; Shock; United States; Wounds and Injuries

Topics: Blood Component Transfusion; Blood Loss, Surgical; Blood Transfusion, Autologous; Erythropoietin; Hemodilution; Humans; Plasma; Recombinant Proteins; Wounds and Injuries

Achieving a higher hemoglobin (Hb) level might allow the anemic, critically ill, trauma patient to have an improved outcome during rehabilitation therapy.. Patients with major blunt trauma orthopedic injuries were administered epoetin alfa or placebo weekly both in hospital and for up to 12 weeks after discharge or until the Hb level was >12.0 g/dL, whichever occurred first. The 36-question Short Form Health Assessment questionnaire (SF-36) was used to evaluate physical function (PF) outcomes at baseline, at hospital discharge, and at several time points posthospital discharge.. One hundred ninety-two patients were enrolled (epoetin alfa [n = 97], placebo [n = 95]). Hb increased from baseline to hospital discharge in both groups (epoetin alfa: 1.2 g/dL vs placebo: 0.9 g/dL), and transfusion requirements were similar between groups. Both groups showed improvements in SF-36 PF; there were no significant differences in the average of all posthospital discharge scores (epoetin alfa: 27.3 vs placebo 30.9; P = 0.38). Thromboembolic events were similar between groups.. No differences were observed in physical function outcomes or safety in anemic, critically ill, trauma patients treated with epoetin alfa compared with placebo.

Topics: Adult; Anemia; Critical Illness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Injections, Subcutaneous; Injury Severity Score; Male; Prospective Studies; Recombinant Proteins; Reference Values; Risk Assessment; Survival Rate; Treatment Outcome; Wounds and Injuries; Wounds, Nonpenetrating; Young Adult

If controllable, stem cell activation following injury has the therapeutic potential for supporting regeneration in acute or chronic wounds. Human dermally-derived stem cells (FmSCs) were exposed to the cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) in the presence of erythropoietin (EPO). Cells were cultured under ischemic conditions and phenotypically characterized using flow cytometry. Topical EPO application was performed in three independent clinical wound healing attempts. The FmSCs expressed the receptor for EPO. EPO had a strong inhibitory effect on FmSC growth in the absence of IL-6 and TNF-α. With IL-6, the EPO effects were reversed to that of growth stimulation. TNF-α had the strongest stimulatory effect. In contrast, IL-1β had an inhibitory effect. Topically applied EPO considerably enhanced wound healing and improved wound conditions of acute and chronic wounds. Site specificity of stem cell activation is mediated by IL-6 and TNF-α. In trauma, EPO ceases its inhibitory role and reverts to a clinically relevant boosting function. EPO may be an important therapeutic tool for the topical treatment of acute and chronic wounds.

Topics: Acute Disease; Adult; Aged; Biomarkers; Cell Proliferation; Cells, Cultured; Child, Preschool; Chronic Disease; Cytokines; Dermis; Drug Synergism; Erythropoietin; Female; Flow Cytometry; Humans; Male; Middle Aged; Phenotype; Receptors, Erythropoietin; Sequence Analysis, Protein; Stem Cells; Wounds and Injuries

A randomized, double-blind, placebo-controlled, multicenter trial (EPO-2, N = 1,302) in anemic critically ill patients demonstrated a 29-day survival benefit in the trauma subgroup receiving epoetin alfa (mortality 8.9% vs. 4.1%). A second similarly designed trial (EPO-3, N = 1,460) confirmed this survival benefit in the epoetin alfa-treated trauma cohort (mortality 6.7% vs. 3.5%). This analysis presents trauma cohort data from both trials for evaluation of the impact of baseline factors including trauma-specific variables on outcomes.. Patients received 40,000 U epoetin alfa or placebo weekly, for a total of 4 (EPO-2) or 3 (EPO-3) doses, starting on ICU day 3. Kaplan-Meier survival curves for the two groups were compared using the log-rank test. Univariate and multivariate Cox proportional hazard regression methods were used to evaluate relationship between baseline factors and mortality.. Demographic and trauma variables at baseline were comparable. Mortality was consistently reduced by approximately 50% in both studies (EPO-2--day 29 unadjusted HR: 0.46, 95% CI: 0.24-0.89; EPO-3--day 29 unadjusted HR: 0.51, 95% CI: 0.27-0.98.). Adjusting for baseline and trauma variables had minimal effect on hazard ratios for mortality at day 29 (EPO-2--day 29 adjusted HR: 0.50, 95% CI: 0.26-0.97; EPO-3--day 29 adjusted HR: 0.38, 95% CI: 0.19-0.74) and day 140 (EPO-3--adjusted HR: 0.39, 95% CI: 0.21-0.72). In EPO-3, there appeared to be an increase in clinically relevant thrombovascular events in the epoetin alfa treated group (16.4% vs. 12.5%, RR: 1.3, 95% CI: 0.93-1.85) but not in EPO-2 (11.1% vs. 13.3%, RR: 0.84, 95% CI: 0.56-1.28).. Epoetin alfa demonstrated a survival advantage in both of the critically ill trauma patient cohorts of two prospective, randomized clinical trials, which was not affected by baseline factors including trauma-specific variables. A definitive study in trauma subjects is warranted.

Topics: Blood Transfusion; Comorbidity; Critical Illness; Double-Blind Method; Epoetin Alfa; Erythropoietin; Humans; Kaplan-Meier Estimate; Proportional Hazards Models; Recombinant Proteins; Wounds and Injuries

Anemia, which is common in the critically ill, is often treated with red-cell transfusions, which are associated with poor clinical outcomes. We hypothesized that therapy with recombinant human erythropoietin (epoetin alfa) might reduce the need for red-cell transfusions.. In this prospective, randomized, placebo-controlled trial, we enrolled 1460 medical, surgical, or trauma patients between 48 and 96 hours after admission to the intensive care unit. Epoetin alfa (40,000 U) or placebo was administered weekly, for a maximum of 3 weeks; patients were followed for 140 days. The primary end point was the percentage of patients who received a red-cell transfusion. Secondary end points were the number of red-cell units transfused, mortality, and the change in hemoglobin concentration from baseline.. As compared with the use of placebo, epoetin alfa therapy did not result in a decrease in either the number of patients who received a red-cell transfusion (relative risk for the epoetin alfa group vs. the placebo group, 0.95; 95% confidence interval [CI], 0.85 to 1.06) or the mean (+/-SD) number of red-cell units transfused (4.5+/-4.6 units in the epoetin alfa group and 4.3+/-4.8 units in the placebo group, P=0.42). However, the hemoglobin concentration at day 29 increased more in the epoetin alfa group than in the placebo group (1.6+/-2.0 g per deciliter vs. 1.2+/-1.8 g per deciliter, P<0.001). Mortality tended to be lower at day 29 among patients receiving epoetin alfa (adjusted hazard ratio, 0.79; 95% CI, 0.56 to 1.10); this effect was also seen in prespecified analyses in those with a diagnosis of trauma (adjusted hazard ratio, 0.37; 95% CI, 0.19 to 0.72). A similar pattern was seen at day 140 (adjusted hazard ratio, 0.86; 95% CI, 0.65 to 1.13), particularly in those with trauma (adjusted hazard ratio, 0.40; 95% CI, 0.23 to 0.69). As compared with placebo, epoetin alfa was associated with a significant increase in the incidence of thrombotic events (hazard ratio, 1.41; 95% CI, 1.06 to 1.86).. The use of epoetin alfa does not reduce the incidence of red-cell transfusion among critically ill patients, but it may reduce mortality in patients with trauma. Treatment with epoetin alfa is associated with an increase in the incidence of thrombotic events. (ClinicalTrials.gov number, NCT00091910 [ClinicalTrials.gov].).

Topics: Adult; Aged; Critical Illness; Double-Blind Method; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Intensive Care Units; Kaplan-Meier Estimate; Length of Stay; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Recombinant Proteins; Respiration, Artificial; Thrombosis; Trauma Severity Indices; Wounds and Injuries

Patient blood management aims to improve patient outcome and safety by reducing the number of unnecessary red blood cell transfusions and vitalizing patient-specific anemia reserves. While this is increasingly recognized as best clinical practice in elective surgery, the implementation in the setting of trauma is restrained because of typically nonelective (emergency) surgery and, in specific circumstances, allogeneic blood transfusions as life-saving therapy.. Viscoelastic diagnostics allow a precise identification of trauma-induced coagulopathy. A coagulation factor concentrate-based therapy is increasingly recognized as a fast and effective concept to correct coagulopathy and minimize blood loss. Using smaller tubes has a great potential to reduce the severity of phlebotomy-induced anemia. Washed cell salvage may reduce the number of allogeneic blood transfusions. Intravenous iron (with or without erythropoietin) may result in an increase of hemoglobin levels and reduced red blood cell transfusion requirements. Although a restrictive transfusion strategy is recommended in general, a target hemoglobin level of 7-9 g/dl is recommended in acute bleeding patients.. In the setting of trauma, options to avoid unnecessary blood loss and reduce blood transfusion are manifold. These are likely to improve safety and outcome of trauma patients while potentially reducing therapeutic costs.

Topics: Anemia; Blood Coagulation Disorders; Blood Loss, Surgical; Blood Transfusion; Erythropoietin; Hemorrhage; Humans; Monitoring, Physiologic; Operative Blood Salvage; Treatment Outcome; Wounds and Injuries

The cause of persistent injury-associated anemia is multifactorial and includes acute blood loss, an altered erythropoietin (EPO) response, dysregulation of iron homeostasis, and impaired erythropoiesis in the setting of chronic inflammation/stress. Hepcidin plays a key role in iron homeostasis and is regulated by anemia and inflammation. Erythropoietin is a main regulator of erythropoiesis induced by hypoxia. A unique rodent model of combined lung injury (LC)/hemorrhagic shock (HS) (LCHS)/chronic restraint stress (CS) was used to produce persistent injury-associated anemia to further investigate the roles of EPO, hepcidin, iron, ferritin, and the expression of EPO receptors (EPOr).. Male Sprague-Dawley rats were randomly assigned into one of the four groups of rodent models: naive, CS alone, combined LCHS, or LCHS/CS. Plasma was used to evaluate levels of EPO, hepcidin, iron, and ferritin. RNA was isolated from bone marrow and lung tissue to evaluate expression of EPOr. Comparisons between models were performed by t tests followed by one-way analysis of variance.. After 7 days, only LCHS/CS was associated with persistent anemia despite significant elevation of plasma EPO. Combined LCHS and LCHS/CS led to a persistent decrease in EPOr expression in bone marrow on Day 7. The LCHS/CS significantly decreased plasma hepcidin levels by 75% on Day 1 and 84% on Day 7 compared to LCHS alone. Hepcidin plasma levels are inversely proportional to EPO plasma levels (Pearson R = -0.362, p < 0.05).. Tissue injury, hemorrhagic shock, and stress stimulate and maintain high levels of plasma EPO while hepcidin levels are decreased. In addition, bone marrow EPOr and plasma iron availability are significantly reduced following LCHS/CS. The combined deficit of reduced iron availability and reduced bone marrow EPOr expression may play a key role in the ineffective EPO response associated with persistent injury-associated anemia.

Topics: Anemia; Animals; Bone Marrow; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Hepcidins; Lung Injury; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Restraint, Physical; Shock, Hemorrhagic; Stress, Physiological; Wounds and Injuries

Disease processes provoke a balancing act between tissue damage and repair. In the 1980s, the discovery that tumor necrosis factor (TNF)-α is a general mediator of disease-related injury led to the development of novel therapeutics to neutralize its activity. In contrast, identification of potential mediator(s) of tissue repair remained elusive. Studies performed over the last 15 years have documented that the type 1 cytokine erythropoietin (EPO), produced by cells within surrounding regions subjected to injury, acts as a master regulator, controlling both damage and repair. The transducer of these activities is the previously unrecognized innate repair receptor (IRR), which is comprised of the EPO receptor and β common receptor subunits. Notably, although proinflammatory cytokines upregulate the IRR, EPO and proinflammatory cytokines inhibit each other's production, resulting in a relative underproduction of EPO. Although exogenous EPO attenuates disease activity in many preclinical models, its clinical utility is limited by serious hematopoietic and thrombotic adverse effects. To circumvent this problem, novel compounds engineered from the structure of EPO have been developed as selective ligands of the IRR. These compounds possess no hematopoietic activity, yet are fully tissue-protective and reparative. The lead molecule of this development effort (the 11-amino acid peptide ARA290) tips the balance toward healing in diverse preclinical models of disease and is currently under evaluation in advanced clinical trials as a disease-modifying agent in painful neuropathy and diabetes.

Topics: Animals; Cytokines; Erythropoietin; Humans; Receptors, Erythropoietin; Wound Healing; Wounds and Injuries

Topics: Erythropoietin; Hematoma; Hemothorax; Humans; Iron; Jehovah's Witnesses; Male; Pneumothorax; Vitamin B 12; Vitamin B Complex; Wounds and Injuries

Topics: Aged; Erythropoietin; Hematoma; Hemothorax; Humans; Iron; Jehovah's Witnesses; Male; Pneumothorax; Stress Disorders, Post-Traumatic; Time Factors; Trauma Severity Indices; Vitamin B 12; Vitamin B Complex; Wounds and Injuries

Topics: Administration, Topical; Diabetes Complications; Erythropoietin; Humans; Skin; Wound Healing; Wounds and Injuries

The relationship between the dressing and the wound is vital to clinical effectiveness. The more-or-less standard wound-surface coverings have been replaced with initial dressings, referred to as modern dressings, which contain an oily and sticky compound. They provide a moist medium by applying the basic mechanistic principles (liquid absorption and release). Other types of products and techniques modify the behaviour of wound cells by acting directly through irritation, biochemical stimulation or genetic modification of the cells, which accelerates the healing process.

Topics: Bandages; Becaplermin; Chronic Disease; Coated Materials, Biocompatible; Collagen; Debridement; Erythropoietin; Humans; Platelet-Derived Growth Factor; Protease Inhibitors; Proto-Oncogene Proteins c-sis; Skin Transplantation; Skin, Artificial; Wound Healing; Wounds and Injuries

Wound healing in diabetic patients is slower than in healthy individuals. Erythropoietin (EPO) has non-hemopoietic targets in the skin, and systemically administered EPO promotes wound healing in experimental animals. This study investigated the effect of topical EPO treatment on defective wound repair in the skin of diabetic rats. Full-thickness excisional skin wounds were made in 38 rats, of which 30 had diabetes. The wounds were then treated topically with a cream that contained either vehicle, 600 IU ml(-1) EPO (low dose), or 3,000 IU ml(-1) (high dose) EPO. We assessed the rate of wound closure during the 12-day treatment period, and microvascular density (MVD), vascular endothelial growth factor (VEGF), and hydroxyproline (HP) contents, and the extent of apoptosis in wound tissues at the end of the 12-day treatment period. Topical EPO treatment significantly reduced the time to final wound closure. This increased rate of closure of the two EPO-treated wounds in diabetic rats was associated with increased MVD, VEGF, and HP contents, and a reduced extent of apoptosis. In light of our finding that topical EPO treatment promotes skin wound repair in diabetic rats, we propose that topical EPO treatment is a therapeutically beneficial method of treating chronic diabetic wounds.

Topics: Administration, Topical; Animals; Apoptosis; Diabetes Mellitus, Experimental; Erythropoietin; Hydroxyproline; Male; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley; Skin; Vascular Endothelial Growth Factor A; Wound Healing; Wounds and Injuries

Erythropoietin (EPO) is a cytokine with erythropoietic and tissue protective activities. Its action as a tissue protective agent requires, however, high dosage that results in limiting side effects associated with abnormally augmented erythropoiesis. Elimination of the erythropoietic activity of EPO while preserving its tissue protective properties was nevertheless achieved in carbamoylated EPO (CEPO), whose therapeutic activity and apparent safety were documented in experimental models of nervous, heart, kidney and other tissue damage, justifying ongoing clinical trials. Here, we review patent application WO2009094172 by Araim Pharmaceuticals, which describes novel EPO-derived peptides having tissue protective but no erythropoietic activity. The preferred peptide, UEQLERALNSS, which mimics the external 3D structure of the helix B of EPO, was shown to exhibit the same spectrum of tissue protective activity as CEPO in several in vivo models. In addition, it could reduce radiation-induced mortality when administered 24 h after irradiation in mice, suggesting its possible utility in emergency situations after mass irradiation casualties. Owing to their low manufacturing cost, high stability and low immunogenicity, such peptides might well offer a superior alternative to CEPO for therapeutic tissue protection in human pathologies and are likely to provide valuable probes to study the molecular mechanisms of EPO-mediated cytoprotection.

Topics: Animals; Cytoprotection; Disease Models, Animal; Erythropoietin; Humans; Mice; Patents as Topic; Peptides; Protective Agents; Protein Stability; Radiation Injuries; Wounds and Injuries

Topics: Erythropoietin; Humans; Recombinant Proteins; Skin Aging; Stem Cells; Wounds and Injuries

We previously demonstrated that utilization of erythropoietin (r-EPO) did not significantly reduce blood utilization in trauma patients. We undertook this study to analyze blood utilization 1 year after r-EPO removal from our trauma service anaemia practice management guideline.. Electronic records of patients admitted to the trauma service were retrospectively reviewed for units of packed red blood cells (pRBCs) transfused and for units of r-EPO administered 12 months before the initiation of an anaemia practice guideline (PRE), 12 months during the use of an anaemia guideline (GUIDE), and 12 months following removal of r-EPO from the guideline (POST). Hospital acquisition cost was also reviewed for the respective time periods. Nominal data were analyzed using chi-squared or Fisher's exact tests, and interval data were compared using ANOVA followed by Tukey's test where appropriate. Results were considered significant for P<0.05.. Over the 3-year study period, 4881 patients were admitted to the trauma service and included in this study. The hospital length of stay, intensive care unit length of stay, and units of pRBC transfused were similar among all three groups. Group I (PRE) received a total of 228 doses of r-EPO at a cost of $102,600. Group II (GUIDE) received a total of 410 doses at a cost of $184,500. Group III (POST) received 28 doses of r-EPO at a cost of $12,600.. Removal of erythropoietin from our trauma service anaemia practice management guideline did not result in increased blood utilization. However, it yielded a hospital acquisition cost savings of $171,900.

Topics: Acute Disease; Adult; Analysis of Variance; Anemia; Cost Savings; Critical Care; Electronic Health Records; Erythrocyte Transfusion; Erythropoietin; Health Care Costs; Humans; Length of Stay; Middle Aged; Recombinant Proteins; Retrospective Studies; Trauma Centers; Wounds and Injuries

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

Despite numerous studies in critically ill patients, physiological adaptation to acute anaemia and the pattern of erythropoietin (EPO) secretion has not been well described in severely injured patients. The aim of this study was to describe EPO secretion and its relationship with haemoglobin (Hb) levels in severely injured patients.. We performed an observational, prospective clinical study in our intensive care unit (ICU). For all patients with severe trauma (Injury Severity Score>15), EPO measurement was obtained on admission, during the first 3 days and then when Hb level was measured. Maximal EPO level (EPOmax) and minimal Hb level (Hbmin) during the ICU stay was determined for all patients.. One hundred and seventy-one consecutives patients were included (440 EPO measurements). Seventy-nine patients (46.2%) showed an increased value (> or =25 UI/l) EPOmax value. Most EPOmax values were observed early after the trauma [within 4 days for 63 patients (82.8%)]. Plotting EPOmax to Hbmin values show that a threshold Hbmin value of 105 g/l best discriminated patients with and without an elevated EPO secretion. Less than 10% of the patients with Hbmin<105 g/l did not increase their EPO secretion.. In severely traumatized patients a marked response to acute anaemia is observed in most patients. In our study, Hb threshold for a significant EPO secretion following post-traumatic acute anaemia was 105 g/l. The peak level was achieved early in the course of the anaemia.

Topics: Adult; Anemia; Erythropoietin; Female; Hemoglobins; Hospital Mortality; Humans; Injury Severity Score; Length of Stay; Male; Prospective Studies; Reference Values; Time Factors; Wounds and Injuries

Topics: Critical Illness; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hemoglobins; Humans; Recombinant Proteins; Thrombosis; Wounds and Injuries

Topics: Critical Illness; Data Interpretation, Statistical; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hemoglobins; Humans; Recombinant Proteins; Wounds and Injuries

We investigated whether the mobilization of endothelial progenitor cells (EPCs) by exogenous erythropoietin (Epo) promotes the repair of injured endothelium. Recombinant human Epo was injected (1000 IU/kg for the initial 3 days) after wire injury of the femoral artery of mice. Neointimal formation was inhibited by Epo to 48% of the control (P<0.05) in an NO-dependent manner. Epo induced a 1.4-fold increase in reendothelialized area of day 14 denuded vessels, 55% of which was derived from bone marrow (BM) cells. Epo increased the circulating Sca-1(+)/Flk-1(+) EPCs (2.0-fold, P<0.05) with endothelial properties NO dependently. BM replacement by GFP- or beta-galactosidase-overexpressing cells showed that Epo stimulated both differentiation of BM-derived EPCs and proliferation of resident ECs. BM-derived ECs increased 2.2- to 2.7-fold (P<0.05) in the Epo-induced neoendothelium, where the expression of Epo receptor was upregulated. Epo induced Akt/eNOS phosphorylation and NO synthesis on EPCs and exerted an antiapoptotic action on wire-injured arteries. In conclusion, Epo treatment inhibits the neointimal hyperplasia after arterial injury in an NO-dependent manner by acting on the injured vessels and mobilizing EPCs to the neo-endothelium.

Topics: Animals; Apoptosis; Bone Marrow Cells; Bone Marrow Transplantation; Cell Movement; Cells, Cultured; Endothelium, Vascular; Enzyme Activation; Erythropoietin; Femoral Artery; Humans; Hyperplasia; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Recombinant Proteins; Tunica Intima; Wound Healing; Wounds and Injuries

The effects of recombinant human erythropoietin (rHuEPO) in diabetes-related healing defects were investigated by using an incisional skin-wound model produced on the back of female diabetic C57BL/KsJ-m(+/+)Lept(db) mice (db(+)/db(+)) and their normoglycemic littermates (db(+/+)m). Animals were treated with rHuEPO (400 units/kg in 100 microl s.c.) or its vehicle alone (100 microl). Mice were killed on different days (3, 6, and 12 days after skin injury) for measurement of vascular endothelial growth factor (VEGF) mRNA expression and protein synthesis, for monitoring angiogenesis by CD31 expression, and for evaluating histological changes. Furthermore, we evaluated wound-breaking strength at day 12. At day 6, rHuEPO injection in diabetic mice resulted in an increase in VEGF mRNA expression (vehicle = 0.33 +/- 0.1 relative amount of mRNA; rHuEPO = 0.9 +/- 0.09 relative amount of mRNA; P < 0.05) and protein wound content (vehicle = 23 +/- 5 pg/wound; rHuEPO = 92 +/- 12 pg/wound; P < 0.05) and caused a marked increase in CD31 gene expression (vehicle = 0.18 +/- 0.05 relative amount of mRNA; rHuEPO = 0.98 +/- 0.21 relative amount of mRNA; P < 0.05) and protein synthesis. Furthermore, rHuEPO injection improved the impaired wound healing and, at day 12, increased the wound-breaking strength in diabetic mice (vehicle = 12 +/- 2 g/mm; rHuEPO 21 +/- 5 g/mm; P < 0.05). Erythropoietin may have a potential application in diabetes-related wound disorders.

Topics: Animals; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Erythrocyte Count; Erythropoietin; Female; Glycated Hemoglobin; Hemoglobins; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neovascularization, Physiologic; Platelet Endothelial Cell Adhesion Molecule-1; Recombinant Proteins; RNA, Messenger; Skin; Vascular Endothelial Growth Factor A; Wound Healing; Wounds and Injuries

In this study, we investigated the role of the hematopoietic cytokine erythropoietin (EPO) during wound healing, the physiological response to tissue injury. We used an in vivo wound-healing assay (fibrin Z-chambers) consisting of fibrin-filled chambers implanted subcutaneously in rats. The fibrin inside the chambers is replaced by granulation tissue consisting of new blood vessels, macrophages and fibroblasts as part of the wound-healing response. Local, exogenous recombinant EPO administration into the fibrin matrix significantly increased granulation tissue formation in a dose-dependent manner. To investigate the physiological role of endogenous EPO during wound healing, we used soluble EPO receptor or anti-EPO monoclonal antibodies to neutralize EPO and observed dose-dependent inhibition of granulation tissue formation, consistent with an important role for EPO in the wound-healing cascade. The ability of recombinant EPO to promote wound healing was associated with a proangiogenic effect during granulation tissue formation. We also found abundant expression of EPO receptor protein in macrophages, cells that play a pivotal role during wound healing. Modulation of wound healing because of administration of recombinant EPO or inhibition of endogenous EPO-EPO receptor correlated with changes in levels of inducible nitric oxide synthase protein in granulation tissue. These data demonstrate a novel function for EPO by providing in vivo evidence for a physiological role during fibrin-induced wound healing.

Topics: Animals; Antibodies; Erythropoietin; Female; Fibrin; Macrophages; Neovascularization, Physiologic; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; Rats, Inbred F344; Receptors, Erythropoietin; Recombinant Proteins; Skin; Solubility; Wound Healing; Wounds and Injuries

Jehovah's Witnesses can create perplexing treatment problems by their refusal of blood transfusions. This dilemma is especially difficult for the trauma surgeon faced with critically low hemoglobin levels or life-threatening blood loss in an injured Jehovah's Witness.. Retrospective review of the records of 58 Jehovah's Witnesses admitted to a single trauma center between July 1992 and June 1995.. There were 53 blunt and 5 penetrating injuries. Four patients (7 percent) received blood transfusions; one received banked blood and three received autotransfusions. Two patients were sedated and paralyzed to optimize oxygen utilization; one patient received erythropoietin. Eighteen patients had a general anesthetic and underwent an operative procedure; one underwent controlled hypotensive anesthesia with normovolemic hemodilution. The records of 21 patients (36 percent) included documentation of absolute refusal of blood or blood products; the exact status of consent for blood transfusion was not documented in the records of 33 patients (57 percent). One death and six complications occurred, none of which were attributed to acute blood loss or anemia. Treatment options and special techniques for the severely anemic patient refusing blood transfusions are discussed.. Documentation of religious status and beliefs about blood transfusion, as well as knowledge of special treatment options available for anemic Jehovah's Witnesses, is necessary to provide quality care to this unique trauma population.

Topics: Adolescent; Adult; Blood Substitutes; Blood Transfusion; Blood Transfusion, Autologous; Child; Child, Preschool; Christianity; Erythropoietin; Female; Hemodilution; Humans; Infant; Infant, Newborn; Male; Middle Aged; Religion and Medicine; Retrospective Studies; Wounds and Injuries

Topics: Aged; Aged, 80 and over; Anemia; Blood Transfusion; Christianity; Erythropoietin; Humans; Informed Consent; Kidney Failure, Chronic; Male; Religion and Medicine; Wounds and Injuries

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Brain Neoplasms; Child; Child, Preschool; Dogs; Electric Stimulation; Erythropoiesis; Erythropoietin; Ethacrynic Acid; Haplorhini; Humans; Hydronephrosis; Hypertension; Hypothalamus; Infant; Iron Isotopes; Kidney Diseases; Kidney Neoplasms; Lung Neoplasms; Male; Mice; Middle Aged; Polycythemia Vera; Rats; Testicular Neoplasms; Testosterone; Urinary Calculi; Urologic Diseases; Wilms Tumor; Wounds and Injuries