Intravenous Administration Of Erythropoietin Research Articles

Effects of the route of erythropoietin administration on hemoglobin variability and cardiovascular events in hemodialysis patients.

IntroductionDespite of the routine use of erythropoietin in hemodialysis patients to correct anemia, its administration route’s effects on hemoglobin variability and cardiovascular events remain elusive. Herein, we determined different erythropoietin administration routes’ effects on hemoglobin variability in hemodialysis patients and the associated factors of hemoglobin variability and cardiovascular events.MethodsThis is a post hoc analysis of a prospective, controlled, randomized, unblinded study with 78 Korean hemodialysis patients receiving intravenous (n = 40) or subcutaneous (n = 38) erythropoietin therapy. We evaluated hemoglobin variability by calculating the frequency of hemoglobin measurements outside the target range during all visits. The high-frequency group was defined by those with hemoglobin variability over the median value (25%) while the low-frequency group was defined by those with hemoglobin variability of <25%.ResultsIn this analysis, 37 patients (51.1%) were male, and the mean age was 50.6 ± 12.5 years. The frequency of the value being outside the target hemoglobin range was higher in the subcutaneous group compared to the intravenous group (p = 0.03). The low-frequency group required significantly lower erythropoietin doses compared to the high-frequency group. In the adjusted Cox analysis, the parameter high group was a significant independent risk factor for cardiovascular events (p = 0.03).ConclusionThe risk out of the target hemoglobin range increased with subcutaneous administration compared with intravenous erythropoietin administration in hemodialysis patients. An increased frequency of the value being outside the target hemoglobin range was also associated with an increased risk of cardiovascular events.

Effect of Single Recombinant Human Erythropoietin Injection on Transfusion Requirements in Preoperatively Anemic Patients Undergoing Valvular Heart Surgery

BACKGROUND The authors investigated the effect of a single preoperative bolus of erythropoietin on perioperative transfusion requirement and erythropoiesis in patients with preoperative anemia undergoing valvular heart surgery. METHODS In this prospective, single-site, single-blinded, randomized, and parallel-arm controlled trial, 74 patients with preoperative anemia were randomly allocated to either the erythropoietin or the control group. The erythropoietin group received 500 IU/kg erythropoietin and 200 mg iron sucrose intravenously 1 day before the surgery. The control group received an equivalent volume of normal saline. The primary endpoint was transfusion requirement assessed during the surgery and for 4 days postoperatively. Reticulocyte count and iron profiles were measured serially and compared preoperatively and on postoperative days 1, 2, 4, and 7. RESULTS Transfusion occurred in 32 patients (86%) of the control group versus 22 patients (59%) of the erythropoietin group (P = 0.009). The mean number of units of packed erythrocytes transfused per patient during the surgery and for 4 postoperative days (mean ± SD) was also significantly decreased in the erythropoietin group compared with the control group (3.3 ± 2.2 vs.. 1.0 ± 1.1 units/patient, P = 0.001). The reticulocyte count was significantly greater in the erythropoietin group at postoperative days 4 (P = 0.001) and 7 (P = 0.001). CONCLUSIONS A single intravenous administration of erythropoietin and an iron supplement 1 day before surgery significantly reduced the perioperative transfusion requirement in anemic patients undergoing valvular heart surgery, implicating its potential role as a blood conservation strategy.

Pretreatment with erythropoietin protects the myocardium from infarction by a PI3-kinase-mediated mechanism

Purpose: The aim of this study was to examine the hypothesis that pretreatment with erythropoietin (EPO) enhances myocardial tolerance against infarction by activation of PI3K/Akt pathway. Methods: Myocardial infarction was induced by 30-min coronary occlusion and 2-hr reperfusion in rabbit hearts in situ with or without intravenous administration of EPO (5000 units/kg) at 5 min before ischemia. Infarct size and area at risk (AR) were determined by tetrazolium staining and fluorescent particles, respectively. In the second series of experiments, rabbit hearts were isolated and perfused with Krebs-buffer in Langendorff mode. Tissue samples were taken before and after 15-min infusion of EPO (1 unit/ml) for immunoblotting of total and phosphor-Akt. Using separate groups of hearts, infarction was induced by 30-min ischemia/2-hr reperfusion with or without infusion of EPO (1 unit/ml) and/or LY-294002 (5 micromol/L), a selective PI3K inhibitor. Results: In hearts in situ, EPO significantly reduced infarct size from 57.9 ± 0.1% of AR to 40.6 ± 4.6% without effects on systemic hemodynamic parameters. In buffer-perfused hearts, infusion of EPO increased level of phosphorylated Akt by 43% and reduced infarct size from 41.8 ± 0.8% of AR to 15.6 ± 4.2%. This protection was completely inhibited by LY-294002 administered before EPO infusion. Conclusion: EPO enhances anti-infarct tolerance of the myocardium by a PI3-kinase-mediated mechanism.

Inhibition of erythrocyte cation channels by erythropoietin.

Recombinant human erythropoietin therapy is used to counteract anemia that is the result of renal insufficiency. It stimulates the formation of peripheral blood erythrocytes by inhibiting apoptosis of erythrocyte precursor cells. Mature erythrocytes have similarly been shown to undergo apoptosis. Hyperosmotic shock and Cl(-) removal activate a Ca(2+)-permeable, ethylisopropylamiloride-inhibitable cation channel. The subsequent increase of cytosolic Ca(2+) activates a scramblase that breaks down cell membrane phosphatidylserine asymmetry, leading to annexin binding. Studied was whether channel activity and erythrocyte cell death are regulated by erythropoietin. Scatchard plot analysis disclosed low-abundance, high-affinity binding of (125)I-erythropoietin to erythrocytes. Whole cell patch clamp experiments revealed significant inhibition of the ethylisopropylamiloride-sensitive current by 1 U/ml erythropoietin. Cl(-) removal triggered annexin binding, an effect abrogated by erythropoietin (1 U/ml) but not by GM-CSF (10 ng/ml). Osmotic shock (700 mOsm) stimulated annexin binding within 24 h in the majority of the erythrocytes, an effect blunted by erythropoietin (1 U/ml) but not by GM-CSF (10 ng/ml). In the nominal absence of Ca(2+), the effect of osmotic shock was blunted and the effect of erythropoietin abolished. In hemodialysis patients, intravenous administration of erythropoietin (50 IU/kg) within 4 h decreased the number of annexin binding circulating erythrocytes. Erythropoietin binds to erythrocytes and inhibits volume-sensitive erythrocyte cation channels and thus the breakdown of phosphatidylserine asymmetry after activation of this channel. The effect could prolong the erythrocyte lifespan and may contribute to the enhancement of the erythrocyte number during erythropoietin therapy in dialysis patients.

Increased blood hemoglobin attenuates splanchnic vasodilation in portal- hypertensive rats by nitric oxide inactivation

BACKGROUND & AIMS: Nitric oxide, which is quenched by hemoglobin, has been implicated in the pathogenesis of portal hypertension. The aim of this study was to investigate the effects of increasing blood hemoglobin concentration by erythropoietin treatment on the gastrointestinal vasodilation associated with portal hypertension. METHODS: Portal-hypertensive and sham-operated rats treated with erythropoietin were studied 2 weeks after surgery. Hemodynamic and rheological parameters were measured in baseline conditions and after N(G)-nitro-L-arginine methyl ester (L-NAME) or sodium nitroprusside treatment. RESULTS: In portal-hypertensive rats, erythropoietin attenuated the increase in gastric mucosal and superior mesenteric artery blood flows and the decrease in arterial blood pressure and splanchnic vascular resistances. Those parameters were not affected by erythropoietin in sham-operated rats. A direct vascular effect of erythropoietin was ruled out by the lack of changes in blood pressure or mesenteric blood flow after intravenous erythropoietin administration and by a similar in vitro relaxation to acetylcholine in mesenteric artery rings. In portal-hypertensive rats, erythropoietin blunted the blood pressure response to sodium nitroprusside and attenuated the gastric and mesenteric blood flow response to L-NAME. CONCLUSIONS: Gastrointestinal vasodilation associated with portal hypertension can be attenuated by increasing blood hemoglobin concentration. Inactivation of overproduced NO by hemoglobin may account for this effect. (Gastroenterology 1996 Apr;110(4):1156-65)

Pharmacokinetics of intravenous recombinant human erythropoietin in patients with chronic renal failure

In order to improve our understanding of the dose-concentration and concentration-effect relationships, the pharmacokinetics of recombinant erythropoietin were studied after the initial dose (n = 6) and after repeated doses (n = 9) administered intravenously in patients with chronic renal failure. Several venous blood samples were collected before (to obtain the baseline concentration) and after an intravenous dose of erythropoietin. A radioimmunoassay was used to determine the erythropoietin concentration in the samples. The apparent volume of distribution at steady state was 4.2 +/- 0.91 (initial dose) and 3.7 +/- 0.61 (repeated dosing), which is close to the assumed plasma volume in these patients. The half-life was 5.3 +/- 1.3 h and 5.8 +/- 1.2 h in the two groups, respectively, and is therefore too short for any accumulation to be expected when dosing three times per week. Consequently, no difference in baseline values could be detected between the groups. The clearance of erythropoietin in the groups was estimated to be 11.4 +/- 7.0 ml min-1 and 7.8 +/- 3.8 ml min-1, respectively. Erythropoietin kinetics did not differ after repeated dosing compared to the single initial dose. Intravenous administration of erythropoietin will result in high peak concentrations followed by a rapid decline to basal values.