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Minimizing transfusion requirements for children undergoing craniosynostosis repair: the CHoR protocol.
Vega, RA, Lyon, C, Kierce, JF, Tye, GW, Ritter, AM, Rhodes, JL
Journal of neurosurgery. Pediatrics. 2014;(2):190-5
Abstract
OBJECT Children with craniosynostosis may require cranial vault remodeling to prevent or relieve elevated intracranial pressure and to correct the underlying craniofacial abnormalities. The procedure is typically associated with significant blood loss and high transfusion rates. The risks associated with transfusions are well documented and include transmission of infectious agents, bacterial contamination, acute hemolytic reactions, transfusion-related lung injury, and transfusion-related immune modulation. This study presents the Children's Hospital of Richmond (CHoR) protocol, which was developed to reduce the rate of blood transfusion in infants undergoing primary craniosynostosis repair. METHODS A retrospective chart review of pediatric patients treated between January 2003 and Febuary 2012 was performed. The CHoR protocol was instituted in November 2008, with the following 3 components; 1) the use of preoperative erythropoietin and iron therapy, 2) the use of an intraoperative blood recycling device, and 3) acceptance of a lower level of hemoglobin as a trigger for transfusion (< 7 g/dl). Patients who underwent surgery prior to the protocol implementation served as controls. RESULTS A total of 60 children were included in the study, 32 of whom were treated with the CHoR protocol. The control (C) and protocol (P) groups were comparable with respect to patient age (7 vs 8.4 months, p = 0.145). Recombinant erythropoietin effectively raised the mean preoperative hemoglobin level in the P group (12 vs 9.7 g/dl, p < 0.001). Although adoption of more aggressive surgical vault remodeling in 2008 resulted in a higher estimated blood loss (212 vs 114.5 ml, p = 0.004) and length of surgery (4 vs 2.8 hours, p < 0.001), transfusion was performed in significantly fewer cases in the P group (56% vs 96%, p < 0.001). The mean length of stay in the hospital was shorter for the P group (2.6 vs 3.4 days, p < 0.001). CONCLUSIONS A protocol that includes preoperative administration of recombinant erythropoietin, intraoperative autologous blood recycling, and accepting a lower transfusion trigger significantly decreased transfusion utilization (p < 0.001). A decreased length of stay (p < 0.001) was seen, although the authors did not investigate whether composite transfusion complication reductions led to better outcomes.
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Effect of iron loading on peripheral blood lymphocyte subsets and on circulating cytokine levels in iron-depleted hemodialysis patients receiving erythropoietin.
Tsouchnikas, I, Tsilipakou, M, Daniilidis, M, Kyriazis, G, Pasadakis, P, Parapanissiou, E, Vargemezis, V, Tsakiris, D
Nephron. Clinical practice. 2007;(3):c97-102
Abstract
BACKGROUND/AIMS: High doses of iron are recommended intravenously in iron-depleted hemodialysis (HD) patients receiving recombinant erythropoietin (EPO). Iron deficiency and mainly iron overload impair cellular and humoral immune response mechanisms. Imbalances in T cell subsets are common findings in disorders of iron metabolism. The aim of this study was to evaluate the effect of iron load on peripheral blood lymphocytes subsets and on circulating cytokine levels in HD iron depleted patients, treated with EPO. METHODS We studied 19 stable adult HD patients, 12 males, with a mean age 59 +/- 11 years and mean HD duration 24 +/- 14 months. All patients were iron deficient and were treated with unchanged EPO dose for the last 4 months before entering the study. The administered dose of iron was infused intravenously (1,000 mg iron sucrose) in 10 doses, during 10 consecutive HD sessions. Patients were screened before the commencement of the HD session on two occasions, once prior to the first dose of iron and 2 days after the 10th dose. Hematocrit (Ht), hemoglobin (Hb), iron, serum ferritin, transferrin saturation, interleukin (IL)-2, IL-4, IL-10, interferon-gamma and tumor necrosis factor-alpha were measured. Major lymphocyte subsets (CD3+, CD19+, CD4+, CD8+, CD16+/56+, CD3+CD16+CD56+) and the ratio CD4+/CD8+ were also determined by two-color immunofluorescent analysis using flow cytometry. RESULTS Hb, transferrin saturation and ferritin increased significantly at the end of the study 11.2 +/- 0.9 to 11.6 +/- 0.8 g/dl, p < 0.005, 17.5 +/- 6.9 to 23.0 +/- 10.8 %, p < 0.05, and 70 +/- 43 to 349 +/- 194 microg/l, p < 0.005, respectively. IL-2 also increased significantly 27.8 +/- 15.2 to 38.9 +/- 12.8 pg/ml, p < 0.05. After iron load there was no significant change to the major lymphocyte subsets examined but a significant increase of the percentage and number of T lymphocytes with positive natural killer receptors (NKR+ T) cells was observed, 5.1 +/- 3.7% to 6.3 +/- 3.46%, p < 0.05, and 76.4 +/- 40 to 101.5 +/- 48 cells/microl, p < 0.005, respectively. CONCLUSION Iron load in iron-deficient EPO-treated HD patients did not produce any changes in major lymphocyte subsets in peripheral blood, but it resulted in a significant increase of NKR+ T cells, a subpopulation important for local immune responses. Iron load for a relatively short period improved anemia of HD patients and influenced the levels of the circulating IL-2, which may regulate factors affecting the survival of patients.
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Cancer-related anemia: pathogenesis, prevalence and treatment.
BirgegÄrd, G, Aapro, MS, Bokemeyer, C, Dicato, M, Drings, P, Hornedo, J, Krzakowski, M, Ludwig, H, Pecorelli, S, Schmoll, H, et al
Oncology. 2005;:3-11
Abstract
Cancer-related anemia is a cytokine-mediated disorder resulting from complex interactions between tumor cells and the immune system. Overexpression of certain inflammatory cytokines results in shortened survival of red blood cells, suppression of erythroid progenitor cells, impaired iron utilization, and inadequate erythropoietin production. Numerous other factors may also contribute to the development of anemia in cancer patients. The European Cancer Anaemia Survey (ECAS) has provided the most current, comprehensive, prospectively collected data on the incidence and prevalence of anemia among cancer patients, as well as important perspectives on anemia treatment and relationship of hemoglobin and performance status. ECAS enrolled over 15,000 treated and untreated patients with various malignancies from cancer centers in 24 European countries and followed them for up to 6 months. The initial analysis of the ECAS data revealed that 39% of the total cancer patient population was anemic (hemoglobin <12.0 g/dl) at enrollment, although the rate varied according to tumor type, disease status, and cancer treatment status. Of the patients who were not anemic at enrollment and started cancer treatment during the survey, those undergoing chemotherapy--either alone or in combination with radiotherapy--had the highest incidence of anemia (63 and 42%, respectively). Low hemoglobin levels correlated with poor performance status and only 40% of patients who were anemic at some time during the survey received treatment for their anemia. These findings are noteworthy, since a growing body of clinical evidence indicates that the treatment of anemia can significantly improve patients' quality of life and may also improve the clinical outcome.
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Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin.
Weiss, G, Meusburger, E, Radacher, G, Garimorth, K, Neyer, U, Mayer, G
Kidney international. 2003;(2):572-8
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Abstract
BACKGROUND Anemia in patients with end-stage renal disease (ESRD) is treated with recombinant human erythropoietin (rhEPO) often in combination with iron. However, iron catalyzes the formation of toxic radicals, which might promote vascular damage, is a nutrient for microorganisms, and negatively affects immune pathways, thus increasing the risk for severe infections. METHODS We investigated 28 patients on chronic hemodialysis who were randomized to receive either rhEPO alone (N = 15) or rhEPO in combination with intravenous iron (N = 13) for a period of 12 weeks. We analyzed iron therapy associated changes in cytokine patterns and endogenous radical formation. RESULTS Tumor necrosis factor-alpha (TNF-alpha) levels were increased in ESRD patients at study entry and then decreased significantly over time in subjects receiving additional iron, while they increased with rhEPO alone. In contrast, we found serum concentrations of the anti-inflammatory cytokine interleukin (IL)-4 to increase with iron therapy. A significant negative correlation between iron availability, as determined by transferrin saturation, and TNF-alpha levels (P = 0.008) and a positive one between transferring saturation and IL-4 (P = 0.02) pointed to the potential role of iron to induce immunologic changes. Interestingly, iron therapy resulted in a slight decrease in the amounts of endogenous peroxides, which may be referred to reduced TNF-alpha concentrations since peroxide concentrations were positively correlated to TNF-alpha levels (P = 0.046) and negatively to transferrin saturation (P = 0.02). CONCLUSION Iron supplementation in ESRD patients down-regulates proinflammatory immune effector pathways and stimulates the expression of the anti-inflammatory cytokine IL-4. Such a condition is detrimental for host response toward invading pathogens. However, tissue damage by radicals such as endogenous peroxides may be reduced in this condition due to impaired TNF-alpha formation.
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[Erythropoietin administration in diabetic patients].
Zukowska-Szczechowska, E, Tomaszewski, M, Sedkowska, A, Grzeszczak, W
Przeglad lekarski. 2003;(8):532-5
Abstract
This paper presents the role of erythropoietin application in diabetic patients with accompanying renal failure. The main cause of anemia in diabetics are: nephropathy, structural lesions of erythrocyte membrane and blood loss connected with diagnostic and therapeutic actions. There are publications which demonstrate that in patients with diabetes type 1 or 2 with accompanying nephropathy, anemia appears more frequently than in the group of patients with chronic renal failure caused by other factors. It is supposed, that the impaired erythropoietin synthesis in diabetics can be caused by autonomic neuropathy. Erythropoietin administration in case of diabetic nephropathy has a beneficial influence on fat metabolism, immune response and reduction of insuline resistance. Erythropoietin because of reduction of vascular endothelial growth factor synthesis blocks the development of diabetic retinopathy and macroangiopathy. Erythropoietin reduces the risk of the left-ventricular hypertrophy caused by anemia. Very important is that the erythropoietin resistance is lower in diabetics. Scientists who are adverse to erythropoietin administration in patients with diabetic nephropathy maintain, that it can lead to vascular complications and the deterioration of glycemia control.
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Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines.
Macdougall, IC, Cooper, AC
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2002;:39-43
Abstract
Up to 10% of patients with renal disease receiving recombinant human erythropoietin (rHuEPO) therapy show poor responsiveness to the drug. Even in patients who do respond to rHuEPO, there is a marked variability in drug sensitivity. Several factors have been recognized as causing resistance to rHuEPO, notably iron deficiency, infection/inflammation, and under dialysis. However, when these factors are excluded, the wide variation in responsiveness to rHuEPO persists. The mechanism of this effect needs to be fully elucidated. One hypothesis is that patients with uraemia showing resistance to rHuEPO may have enhanced levels of immune activation, causing increased release of pro-inflammatory cytokines in the bone marrow. Uraemia is known to be a chronic inflammatory state, with some patients showing considerably increased laboratory markers of inflammation and immune activation. Chronic inflammation can modify the process of erythropoiesis, probably mediated via pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). The concept that rHuEPO resistance is due to enhanced levels of immune activity has been investigated by studying T-cell phenotypes using flow cytometry, as well as cytokine release from T cells and monocytes in 'good' and 'poor' responders to rHuEPO. Poor responders had significantly reduced CD28 expression on both CD4+ and CD8+ cells, enhanced IL-10 generation from peripheral blood mononuclear cells (PBMCs), higher plasma IL-12 levels, and increased TNF-alpha and IFN-gamma release from PBMCs. Anti-cytokine antibodies may be useful for studying inflammatory cytokine secretion from T cells in patients with renal failure. Strategies utilizing anti-cytokine therapy may prove to be a useful adjuvant in optimizing the response to rHuEPO therapy.
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The inflammatory response and epoetin sensitivity.
Macdougall, IC, Cooper, A
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2002;:48-52
Abstract
Patients receiving epoetin therapy show wide variability in their responsiveness to the drug. Many factors may be responsible for this, particularly iron deficiency, acute infection and under-dialysis. Even after excluding factors known to cause resistance to epoetin, the marked variability in sensitivity to epoetin remains. The exact mechanism of this effect is unclear. It is, however, recognized that uraemia is a chronic inflammatory state, with some patients showing quite significantly increased laboratory markers of inflammation and immune activation. It is also known that chronic inflammation can modify the process of erythropoiesis, and this is probably mediated via pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). It is hypothesized, therefore, that some patients showing resistance to epoetin may have enhanced levels of immune activation, causing increased release of pro-inflammatory cytokines in the bone marrow. This has been investigated by studying T-cell phenotypes by flow cytometry, along with cytokine release from T cells and monocytes in 'good' and 'poor' responders to epoetin. Poor responders were found to have significantly reduced CD28 expression on both CD4(+) and CD8(+) cells, enhanced IL-10 generation from peripheral blood mononuclear cells (PBMCs), higher plasma IL-12 levels and enhanced TNF-alpha release from PBMCs. The patients in this study, who were followed-up for the subsequent 24 months, had a considerably lower survival if they were poor responders (54% vs 88% for good responders; P<0.05). Further work in this area is required to confirm or contest the hypothesis that epoetin resistance is due to enhanced levels of immune activation.