Effect of Perioperative Intravenous Iron Supplementation for Complex Cardiac Surgery on Transfusion Requirements: A Randomized, Double-blinded Placebo-controlled Trial.

OBJECTIVES: We investigated whether routine perioperative intravenous iron replenishment reduces the requirement for packed erythrocytes (pRBC) transfusion. SUMMARY OF BACKGROUND DATA: Patients undergoing complex cardiac surgery are at high risk of developing postoperative iron deficiency anemia, thus requiring transfusion, which is associated with adverse outcomes. METHODS: Patients were randomized to receive either ferric derisomaltose 20 mg/kg (n = 103) or placebo (n = 101) twice during the perioperative period: 3 days before and after the surgery. The primary endpoint was the proportion of patients who received pRBC transfusion until postoperative day (POD) 10. Hemoglobin, reticulocyte count, serum iron profile, hepcidin, and erythropoietin were serially measured. RESULTS: pRBC was transfused in 60.4% and 57.2% of patients in the control and iron group, respectively (P = 0.651). Hemoglobin concentration at 3 weeks postoperatively was higher in the iron group than in the control group (11.6 ± 1.5 g/dL vs 10.9 ± 1.4 g/dL, P < 0.001). The iron group showed higher reticulocyte count [205 (150-267)×103/µL vs 164 (122-207)×103/µL, P = 0.003] at POD 10. Transferrin saturation and serum ferritin were significantly increased in the iron group than in the control group (P < 0.001). Serum hepcidin was higher in the iron group than in the control group at POD 3 [106.3 (42.9-115.9) ng/mL vs 39.3 (33.3-43.6) ng/mL, P < 0.001]. Erythropoietin concentration increased postoperatively in both groups (P = 0.003), with no between-group difference. CONCLUSIONS: Intravenous iron supplementation during index hospitalization for complex cardiac surgery did not minimize pRBC transfusion despite replenished iron store and augmented erythropoiesis, which may be attributed to enhanced hepcidin expression.

Effectiveness of Preoperative Iron Supplementation in Major Surgical Patients With Iron Deficiency: A Prospective Observational Study.

OBJECTIVE: To evaluate the effectiveness of routine intravenous iron in surgical patients with iron deficiency anemia (IDA). BACKGROUND: Anemia is the most common medical disease in the world and is an independent risk factor for morbidity and mortality. Iron deficiency (ID) is the main cause for anemia and constitutes a potentially preventable condition with great impact on surgical outcome. METHODS: In this prospective single-center observational study, surgical patients were screened for the presence of anemia and ID. Patients were assigned to 1 of 4 study groups: A- (no anemia); A-, ID+, T+ (no anemia, iron-deficient, iron supplementation); A+ (anemia); and A+, ID+, T+ (anemia, iron-deficient, iron supplementation) according to hemoglobin level, iron status, and supplementation with iron. RESULTS: Among 1728 patients, 1028 were assigned to A-; 55 to A-, ID+, T+; 461 to A+; and 184 to A+, ID+, T+. While all iron-supplemented IDA patients required less red blood cell (RBC) transfusion during the postoperative period (A+ 42.5% vs A+, ID+, T+ 31.5%), a reduced intraoperative transfusion rate was observed for ID and IDA patients only if iron was supplemented >7 days before surgery. Hospital stay was significantly reduced by 2.8 days in iron-supplemented patients (P < 0.01 comparing 13.9 ±â€Š0.8 days for A+, ID+, T+ vs. 16.7 ±â€Š0.7 days for A+). CONCLUSION: Preoperative IDA management with intravenous iron is effective in improving hemoglobin level, thereby reducing intraoperative RBC transfusion rate particular if iron is administrated >7 days before surgery. Hospital length of stay was reduced in all preoperatively iron-supplemented IDA patients.

Erythropoietin plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non-cardiac surgery.

BACKGROUND: Approximately 30% of adults undergoing non-cardiac surgery suffer from preoperative anaemia. Preoperative anaemia is a risk factor for mortality and adverse outcomes in different surgical specialties and is frequently the reason for blood transfusion. The most common causes are renal, chronic diseases, and iron deficiency. International guidelines recommend that the cause of anaemia guide preoperative anaemia treatment. Recombinant human erythropoietin (rHuEPO) with iron supplementation has frequently been used to increase preoperative haemoglobin concentrations in patients in order to avoid the need for perioperative allogeneic red blood cell (RBC) transfusion. OBJECTIVES: To evaluate the efficacy of preoperative rHuEPO therapy (subcutaneous or parenteral) with iron (enteral or parenteral) in reducing the need for allogeneic RBC transfusions in preoperatively anaemic adults undergoing non-cardiac surgery. SEARCH METHODS: We searched CENTRAL, Ovid MEDLINE(R), Ovid Embase, ISI Web of Science: SCI-EXPANDED and CPCI-S, and clinical trial registries WHO ICTRP and ClinicalTrials.gov on 29 August 2019. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) that compared preoperative rHuEPO + iron therapy to control treatment (placebo, no treatment, or standard of care with or without iron) for preoperatively anaemic adults undergoing non-cardiac surgery. We used the World Health Organization (WHO) definition of anaemia: haemoglobin concentration (g/dL) less than 13 g/dL for males, and 12 g/dL for non-pregnant females (decision of inclusion based on mean haemoglobin concentration). We defined two subgroups of rHuEPO dosage: 'low' for 150 to 300 international units (IU)/kg body weight, and 'high' for 500 to 600 IU/kg body weight. DATA COLLECTION AND ANALYSIS: Two review authors collected data from the included studies. Our primary outcome was the need for RBC transfusion (no autologous transfusion, fresh frozen plasma or platelets), measured in transfused participants during surgery (intraoperative) and up to five days after surgery. Secondary outcomes of interest were: haemoglobin concentration (directly before surgery), number of RBC units (where one unit contains 250 to 450 mL) transfused per participant (intraoperative and up to five days after surgery), mortality (within 30 days after surgery), length of hospital stay, and adverse events (e.g. renal dysfunction, thromboembolism, hypertension, allergic reaction, headache, fever, constipation). MAIN RESULTS: Most of the included trials were in orthopaedic, gastrointestinal, and gynaecological surgery and included participants with mild and moderate preoperative anaemia (haemoglobin from 10 to 12 g/dL). The duration of preoperative rHuEPO treatment varied across the trials, ranging from once a week to daily or a 5-to-10-day period, and in one trial preoperative rHuEPO was given on the morning of surgery and for five days postoperatively. We included 12 trials (participants = 1880) in the quantitative analysis of the need for RBC transfusion following preoperative treatment with rHuEPO + iron to correct preoperative anaemia in non-cardiac surgery; two studies were multiarmed trials with two different dose regimens. Preoperative rHuEPO + iron given to anaemic adults reduced the need RBC transfusion (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.38 to 0.80; participants = 1880; studies = 12; I2 = 84%; moderate-quality evidence due to inconsistency). This analysis suggests that on average, the combined administration of rHuEPO + iron will mean 231 fewer individuals will need transfusion for every 1000 individuals compared to the control group. Preoperative high-dose rHuEPO + iron given to anaemic adults increased the haemoglobin concentration (mean difference (MD) 1.87 g/dL, 95% CI 1.26 to 2.49; participants = 852; studies = 3; I2 = 89%; low-quality evidence due to inconsistency and risk of bias) but not low-dose rHuEPO + iron (MD 0.11 g/dL, 95% CI -0.46 to 0.69; participants = 334; studies = 4; I2 = 69%; low-quality evidence due to inconsistency and risk of bias). There was probably little or no difference in the number of RBC units when rHuEPO + iron was given preoperatively (MD -0.09, 95% CI -0.23 to 0.05; participants = 1420; studies = 6; I2 = 2%; moderate-quality evidence due to imprecision).  There was probably little or no difference in the risk of mortality within 30 days of surgery (RR 1.19, 95% CI 0.39 to 3.63; participants = 230; studies = 2; I2 = 0%; moderate-quality evidence due to imprecision) or of adverse events including local rash, fever, constipation, or transient hypertension (RR 0.93, 95% CI 0.68 to 1.28; participants = 1722; studies = 10; I2 = 0%; moderate-quality evidence due to imprecision). The administration of rHuEPO + iron before non-cardiac surgery did not clearly reduce the length of hospital stay of preoperative anaemic adults (MD -1.07, 95% CI -4.12 to 1.98; participants = 293; studies = 3; I2 = 87%; low-quality evidence due to inconsistency and imprecision). AUTHORS' CONCLUSIONS: Moderate-quality evidence suggests that preoperative rHuEPO + iron therapy for anaemic adults prior to non-cardiac surgery reduces the need for RBC transfusion and, when given at higher doses, increases the haemoglobin concentration preoperatively. The administration of rHuEPO + iron treatment did not decrease the mean number of units of RBC transfused per patient. There were no important differences in the risk of adverse events or mortality within 30 days, nor in length of hospital stay. Further, well-designed, adequately powered RCTs are required to estimate the impact of this combined treatment more precisely.

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

The contribution of iron deficiency to the risk of peripartum transfusion: a retrospective case control study.

BACKGROUND: Iron deficiency in pregnancy is associated with inferior maternal and fetal outcomes. Postpartum depression, prematurity, intrauterine growth restriction, impaired childhood cognition and transfusion are all sequelae of maternal iron deficiency anemia. Transfusion to women of childbearing age has important consequences including increasing the risk of hemolytic disease of the fetus and newborn with future pregnancies. The relative contribution of iron deficiency to transfusion rates in the peripartum period is unknown. This study aimed to identify the prevalence of iron deficiency and anemia in pregnant women that received peripartum transfusions relative to age-matched non-transfused controls. METHODS: We performed a retrospective case-control study of all women that were transfused in the peripartum period from January, 2014 to July, 2018. Cases were compared to the next age matched control to deliver at our institution. The primary objective was to determine the proportion of patients with iron deficiency in pregnancy or anemia in pregnancy in cases and controls. Charts were reviewed for predisposing risk factors for iron deficiency, laboratory measures of iron deficiency and anemia, iron supplementation history and maternal and fetal outcomes. Factors associated with peripartum transfusion were analyzed using a multivariate logistic regression. RESULTS: 169 of 18, 294 (0.9%) women were transfused in the peripartum period and 64 (44%) of those transfused received 1 unit. Iron deficiency or anemia were present in 103 (71%) transfused women and 74 (51%) control women in pregnancy (OR 2.34, 95% CI: 3.7-18.0). Multivariate analysis identified social work involvement (adjusted OR 4.1, 95% CI: 1.8-10.1), intravenous iron supplementation in pregnancy (adjusted OR 3.8, 95% CI: 1.2-17.4) and delivery by unscheduled cesarean section (adjusted OR 2.8, 95% CI: 1.3-6.2) as significant predictors of peripartum transfusion. CONCLUSIONS: Pregnant women being followed by a social worker, receiving intravenous iron supplementation in pregnancy or who deliver by unscheduled cesarean section are more likely to receive a red blood cell transfusion. Women with iron deficiency or anemia in pregnancy are at increased risk of peripartum blood transfusions and warrant early and rigorous iron supplementation.

Hyperbaric oxygen for refractory hemorrhagic cystitis after stem cell transplantation: case report.

Hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (AHSCT) in both children and adults has been associated with significant morbidity and mortality. Early HC can occur within 48 hours of completing the chemotherapy conditioning regimen, is usually associated with agents such as cyclophosphamide, and generally resolves promptly. Late HC is commonly associated with BK and other viruses and can prove refractory to antiviral and supportive therapy. There are limited reports of hyperbaric oxygen (HBO2) therapy showing benefit for refractory HC cases. We describe our experience with salvage HBO2 for a 15-year-old male with refractory HC beginning one month post AHSCT and associated with BK virus. Despite supportive therapies including hyperhydration, forced diuresis, transfusions, intravenous and intravesical cidofovir, macroscopic hematuria persisted and resulted in post-obstructive acute renal failure, need for a suprapubic catheter, then bilateral percutaneous nephrostomy tubes. HBO2 was started two months after the AHSCT and one month after detection of BK viremia. In the week prior to starting HBO2 therapy the patient required transfusion with 25 units of red blood cells and seven units of platelets. After HBO2 was started his transfusion requirements progressively decreased, and he had return of renal function. He had no adverse effect from the HBO2. HBO2 therapy could thus be useful in controlling refractory HC after AHSCT.

Perioperative safety after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei from appendiceal origin: Experience on 254 patients from a single center.

OBJECTIVE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a standard treatment for pseudomyxoma peritonei (PMP) recommended by Peritoneal Surface Oncology Group International (PSOGI). The study is to analyze the incidence of perioperative serious adverse events (SAEs) of CRS + HIPEC to treat PMP patients, and identify the risk factors, for guiding the prevention of SAEs. METHODS: This is a retrospective study on the PMP database established at our center. The clinicopathological features, treatment details and SAEs information on the PMP patients are systematically established in this database. The incidence, organ system distribution and severity of perioperative SAEs are analyzed. Univariate and multivariate analyses are performed to identify the independent risk factors. RESULTS: Among the 272 CRS + HIPEC procedures for 254 PMP patients, there are 93 (34.2%) SAEs. Six systems are involved in the SAEs, including infections (9.6%), digestive system (8.1%), respiratory system (6.3%), cardiovascular system (5.5%), hematological system (2.9%), and urinary system (1.5%), in terms of frequency. In terms of severity, the majority is grade III SAEs (27.9%), followed by grade IV SAEs (4.8%) and grade V SAEs (1.5%). Univariate analysis reveals 4 risk factors for perioperative SAEs: HIPEC regimens (P = 0.020), PCI (P = 0.025), intraoperative red blood cell transfusion volume (P = 0.004), and intraoperative blood loss volume (P = 0.002). Multivariate and logistic regression model analysis identifies only one independent risk factor for perioperative SAEs: intraoperative blood loss volume (P = 0.001, OR = 0.344, 95%CI: 0.182-0.649). CONCLUSIONS: PMP patients treated by CRS + HIPEC at experienced centers could have acceptable safety. Improving the surgical techniques and developing the integrated hemostasis techniques are essential to reduce intraoperative blood loss and decrease SAEs rate.

Reduced bleeding with DRY CUT® transurethral resection of the prostate (TURP) compared to standard TURP.

Objective: To compare bleeding and transfusion rate between patients who undergo standard transurethral resection of the prostate (TURP) and patients who undergo DRY CUT® TURP.Materials and methods: A retrospective comparison was made of 626 patients who underwent a standard monopolar TURP during 2004-2007 at the Karolinska University Hospital Huddinge with 620 patients who underwent monopolar DRY CUT® TURP during 2011-2014 at the same clinic. Transfusion rate, perioperative bleeding, prostate volume, resection weight, use of anticoagulation therapy, presence of prostate cancer, whether the operation was performed by a specialist doctor in urology or a resident and length of hospital stay were evaluated.Results: The median bleeding was 300 ml (IQR = 100-645 ml) in the group of patients who underwent standard TURP compared to 75 ml (IQR 30-268 ml) in the DRY CUT® TURP group. The bleeding quotient for standard TURP was 2.3-times the perioperative bleeding for DRY CUT® TURP. In a logistic regression model the patients who underwent standard TURP were more likely to undergo blood transfusion compared to DRY CUT® TURP (OR = 3.18, 95% CI = 1.72-5.88). The results were not affected by adjustment for patient age, presence of prostate cancer, anticoagulation therapy or operation performed by a specialist in urology. However, the resection weight did influence the bleeding quotient.Conclusions: The shift from standard TURP to DRY CUT® TURP has decreased the perioperative bleeding and need for blood transfusion at our hospital.

Late erythropoiesis-stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants.

BACKGROUND: Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia. Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES: To assess the effectiveness and safety of late initiation of ESAs, between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm or low birth weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 5 June 2018), Embase (1980 to 5 June 2018), and CINAHL (1982 to 5 June 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) or low birth weight (< 2500 grams) neonates. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin.Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported. AUTHORS' CONCLUSIONS: Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Effects of platelet-rich plasmapheresis during cardiovascular surgery: A meta-analysis of randomized controlled clinical trials.

OBJECTIVE: This study aimed to explore the effects of platelet-rich plasmapheresis (PRP) on the amount of postoperative blood loss and the requirements for allogeneic fresh frozen plasma (FFP) and red blood cell (RBC) transfusions during cardiovascular surgery. METHODS: A literature search of 7 online databases was conducted. Randomized control trials (RCT) comparing intraoperative PRP or appropriate control groups were considered suitable for this current study. RESULTS: Fifteen RCTs enrolling a total of 1002 patients, including 501 patients who received PRP and 501 control patients. Meta-analysis of the data from these trials showed that PRP reduced the total volume of postoperative blood loss (standardized mean difference [SMD], -0.74; 95% confidence interval [CI], -1.18 to -0.31; P < 0.05), reduced postoperative fresh frozen plasma (FFP) transfusion (SMD, -0.38; 95%CI, -0.69 to -0.08; P < 0.05), reduced postoperative RBCs transfusion (SMD, -0.44; 95%CI, -0.77 to -0.10; P < 0.05), and reduced the proportion of patients receiving postoperative allogeneic RBC transfusions (relative risk [RR], 0.44; 95%CI, 0.21-0.91, P < 0.05) during cardiovascular surgery. CONCLUSION: Conducting PRP before cardiopulmonary bypass (CPB) and transfusing autologous platelet-rich plasma (aPRP) after reversal of heparin could reduce postoperative blood loss, the requirements for blood products transfusion during cardiovascular surgery. A higher mean platelet count in aPRP may improve the final outcome. However, there was a high degree of undetermined heterogeneity among the analyzed trials, and larger and more precise RCTs are needed to confirm these conclusions.

Long-Term Outcomes Among Patients Discharged From the Hospital With Moderate Anemia: A Retrospective Cohort Study.

Background: Randomized clinical trial findings support decreased red blood cell (RBC) transfusion and short-term tolerance of in-hospital anemia. However, long-term outcomes related to changes in transfusion practice have not been described. Objective: To describe the prevalence of anemia at and after hospital discharge and associated morbidity and mortality events. Design: Retrospective cohort study. Setting: Integrated health care delivery system with 21 hospitals serving 4 million members. Participants: 445 371 surviving adults who had 801 261 hospitalizations between January 2010 and December 2014. Measurements: Hemoglobin levels and RBC transfusion, rehospitalization, and mortality events within 6 months of hospital discharge. Generalized estimating equations were used to examine trends over time, accounting for correlated observations and patient-level covariates. Results: From 2010 to 2014, the prevalence of moderate anemia (hemoglobin levels between 7 and 10 g/dL) at hospital discharge increased from 20% to 25% (P < 0.001) and RBC transfusion declined by 28% (39.8 to 28.5 RBC units per 1000 patients; P < 0.001). The proportion of patients whose moderate anemia had resolved within 6 months of hospital discharge decreased from 42% to 34% (P < 0.001), and RBC transfusion and rehospitalization within 6 months of hospital discharge decreased from 19% to 17% and 37% to 33%, respectively (P < 0.001 for both). During this period, the adjusted 6-month mortality rate decreased from 16.1% to 15.6% (P = 0.004) in patients with moderate anemia, in parallel with that of all others. Limitation: Possible unmeasured confounding. Conclusion: Anemia after hospitalization increased in parallel with decreased RBC transfusion. This increase was not accompanied by a rise in subsequent RBC use, rehospitalization, or mortality within 6 months of hospital discharge. Longitudinal analyses support the safety of practice recommendations to limit RBC transfusion and tolerate anemia during and after hospitalization. Primary Funding Source: National Heart, Lung, and Blood Institute.

Positive impact of retrograde autologous priming in adult patients undergoing cardiac surgery: a randomized clinical trial.

BACKGROUND: Adult cardiac surgery with extracorporeal circulation is known to be associated with increased risk of blood transfusion leading to adverse outcomes. Procedures like retrograde autologous priming (RAP) may reduce these negative side effects. This randomized prospective study was initiated to assess whether RAP using specifically designed RAP bag (Terumo) has immediate effects on patient outcome. METHODS: One hundred eighteen adults undergoing elective CABG or elective aortic valve replacement were randomly assigned by a computer program into two groups: the RAP group (n = 54) in which the retrograde autologous priming was applied and the non-RAP (n = 64) group in which the same setting was used without the possibility to save priming volume. Patient demographics, preoperative characteristics and postoperative outcomes were analyzed for both groups. RESULTS: The primary endpoint defined as rate of intraoperative blood transfusion was significantly reduced in the RAP-group (p = 0.04). The absolute risk reduction for RAP managed patients was 13.5 percent points. There were no significant differences in operation time and blood loss. No deaths and no myocardial infarctions were observed. The number of patients needed to treat to prevent at least one red blood cell transfusion was around 8 (NNT = 7.42). CONCLUSIONS: Retrograde autologous priming is a safe and less invasive procedure which achieves clear benefits for adult cardiac surgery patients. In the light of increasing red blood cell transfusion risks and costs and the wish of patients to avoid a transfusion implementation of retrograde autologous priming is an interesting option. TRIAL REGISTRATION: German Clinical Trials Register ID: DRKS00013512 , registered 04 December 2017.

Intraoperative cell salvage with autologous transfusion in elective right or repeat hepatectomy: a propensity-score-matched case-control analysis.

BACKGROUND: Liver resection may be associated with substantial blood loss, and cell saver use has been recommended for patients at high risk. We performed a study to compare the allogenic erythrocyte transfusion rate after liver resection between patients who had intraoperative cell salvage with a cell saver device versus patients who did not. Our hypothesis was that cell salvage with autologous transfusion would reduce the allogenic blood transfusion rate. METHODS: Cell salvage was used selectively in patients at high risk for intraoperative blood loss based on preoperatively known predictors: right and repeat hepatectomy. Patients who underwent elective right or repeat hepatectomy between Nov. 9, 2007, and Jan. 27, 2016 were considered for the study. Data were retrieved from a liver resection database and were analyzed retrospectively. Patients with cell saver use (since January 2013) constituted the experimental group, and those without cell salvage (2007-2012), the control group. To reduce selection bias, we matched propensity scores. The primary outcome was the allogenic blood transfusion rate within 90 days postoperatively. Secondary outcomes were the number of transfused erythrocyte units, and rates of overall and infectious complications. RESULTS: Ninety-six patients were included in the study, 41 in the cell saver group and 55 in the control group. Of the 96, 64 (67%) could be matched, 32 in either group. The 2 groups were balanced for demographic and clinical variables. The allogenic blood transfusion rate was 28% (95% confidence interval [CI] 12.5%-43.7%) in the cell saver group versus 72% (95% CI 56.3%-87.5%) in the control group (p < 0.001). The overall and infectious complication rates were not significantly different between the 2 groups. CONCLUSION: Intraoperative cell salvage with autologous transfusion in elective right or repeat hepatectomy reduced the allogenic blood transfusion rate.

CONTEXTE: La résection hépatique peut s'accompagner de pertes sanguines importantes et l'utilisation d'un système de récupération de sang autologue est recommandée chez les patients à risque élevé. Nous avons procédé à une étude pour comparer le taux de transfusion de sang allogénique après la résection hépatique selon que les patients avaient ou non été soumis à une intervention de récupération de sang autologue. Notre hypothèse est que la récupération de sang autologue peropératoire pourrait réduire le taux de transfusion de sang allogénique. MÉTHODES: La récupération de sang autologue a été utilisée sélectivement chez des patients exposés à un risque élevé à l'égard de pertes sanguines peropératoires, en fonction de facteurs prédictifs préopératoires connus : hépatectomie droite et reprise de l'hépatectomie. Les patients ayant subi une intervention chirurgicale non urgente pour hépatectomie droite ou reprise d'hépatectomie entre le 9 novembre 2007 et le 27 janvier 2016 ont été considérés comme admissibles à l'étude. Les données ont été récupérées à partir d'une base de données sur la résection hépatique et analysées de manière rétrospective. Les patients soumis à la récupération de sang autologue (à partir de janvier 2013) ont constitué le groupe expérimental, et les autres (2007-2012) ont constitué le groupe témoin. Pour réduire le risque de biais de sélection, nous avons apparié les scores de propension. Le paramètre principal était le taux de transfusion de sang allogénique dans les 90 jours suivant l'opération. Les paramètres secondaires étaient le nombre d'unités transfusées, le taux de complications infectieuses et le taux global de complications. RÉSULTATS: Quatre-vingt-seize patients ont pris part à l'étude, 41 dans le groupe soumis à la récupération de sang autologue et 55 dans le groupe témoin. Parmi les 96 patients de l'étude, 64 (67 %) ont pu être assortis, 32 dans chaque groupe. Les 2 groupes étaient équilibrés aux plans des variables démographiques et cliniques. Le taux d'allotransfusions a été de 28 % (intervalle de confiance [IC] de 95 % 12,5 %-43,7 %) dans le groupe soumis à la récupération de sang autologue, contre 72 % (IC de 95 % 56,3 %-87,5 %) dans le groupe témoin (p < 0,001). Le taux de complications infectieuses et le taux global de complications n'ont pas été significativement différents entre les 2 groupes. CONCLUSION: La récupération de sang autologue peropératoire dans les cas d'hépatectomie droite ou d'hépatectomie répétée a réduit le taux de transfusion de sang allogénique.

Postpartum obstetric red cell transfusion practice: A retrospective study in a tertiary obstetric centre.

BACKGROUND: Traditional management of anaemia due to postpartum haemorrhage (PPH) has relied upon salvage therapy with red cell transfusion. Recently published guidance recommends a change in approach toward holistic patient blood management. AIMS: To determine whether postpartum red cell transfusion practices are consistent with best practice and to identify opportunities for improvement. MATERIALS AND METHODS: A retrospective audit of postpartum red cell transfusions was conducted at a tertiary level obstetrics unit. Relevant clinical and laboratory data were collected for all cases of postpartum red cell transfusions and PPH. Clinical decision making and appropriateness of transfusions were evaluated. RESULTS: Among the 3235 women who delivered in 2013, 110 (3.4%) received a postpartum red cell transfusion. About 101 of the transfusions were associated with primary PPH. Overall PPH complicated 460 (14.2%) deliveries. Antenatal anaemia was identified as a major correctable risk factor for transfusion in women who experienced PPH (odds ratio 6.55, 95% CI: 3.17-13.6). Volume of blood loss and the aetiology of PPH were additional risk factors for transfusion. Transfusion was associated with lower birth weight and increased maternal length of stay. Transfusion triggers were more likely to be appropriate when transfusion took place in the operating theatre, within 12 h of delivery and when prescribed by anaesthetists. Post-transfusion Hb levels were uniformly above target for all women transfused. CONCLUSIONS: A significant number of red cell transfusions were outside the recommendations of the new guidelines. Maximising red cell mass during pregnancy and improving transfusion practices were identified as opportunities for future improvement.

Early erythropoiesis-stimulating agents in preterm or low birth weight infants.

BACKGROUND: Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES: To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions:To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives:Review authors performed subgroup analyses of low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (≤ 5 mg/kg/d), and high (> 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs:To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance:To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives:To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. MAIN RESULTS: This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment.Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low.Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate.Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low.Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the ESA group (weighted mean difference (WMD) 8.22, 95% CI 6.52 to 9.92; I2 = 97% (high heterogeneity); 3 studies, 981 children). The quality of the evidence was low.The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced. Data show no significant difference in risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI -0.02 to 0.04; I2 = 0% (no heterogeneity) for RR; I2 = 34% (low heterogeneity) for RD; 8 studies, 1283 infants). Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL). AUTHORS' CONCLUSIONS: Early administration of ESAs reduces the use of red blood cell (RBC) transfusions, the volume of RBCs transfused, and donor exposure after study entry. Small reductions are likely to be of limited clinical importance. Donor exposure probably is not avoided, given that all but one study included infants who had received RBC transfusions before trial entry. This update found no significant difference in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age, which has been a topic of concern in earlier versions of this review. Early EPO treatment significantly decreased rates of IVH, PVL, and NEC. Neurodevelopmental outcomes at 18 to 22 months and later varied in published studies. Ongoing research should evaluate current clinical practices that will limit donor exposure. Promising but conflicting results related to the neuro protective effect of early EPO require further study. Very different results from the two largest published trials and high heterogeneity in the analyses indicate that we should wait for the results of two ongoing large trials before drawing firm conclusions. Administration of EPO is not currently recommended because limited benefits have been identified to date. Use of darepoetin requires further study.

Iron-chelating therapy with deferasirox in transfusion-dependent, higher risk myelodysplastic syndromes: a retrospective, multicentre study.

Iron chelation is controversial in higher risk myelodysplastic syndromes (HR-MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion-dependent, intermediate-to-very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox (DFX). Thirty-six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000 mg/day (range 375-2500 mg) for a median of 11 months (range 0·4-75). Eight patients (16%) showed grade 2-3 toxicities (renal or gastrointestinal), 4 of whom (8%) required drug interruption. Median ferritin levels decreased from 1709 µg/l at baseline to 1100 µg/l after 12 months of treatment (P = 0·02). Seventeen patients showed abnormal transaminase levels at baseline, which improved or normalized under DFX treatment in eight cases. One patient showed a remarkable haematological improvement. At a median follow up of 35·3 months, median overall survival was 37·5 months. The results of this first survey of DFX in HR-MDS are comparable, in terms of safety and efficacy, with those observed in lower-risk MDS. Though larger, prospective studies are required to demonstrate real clinical benefits, our data suggest that DFX is feasible and might be considered in a selected cohort of HR-MDS patients.

Clinical factors influencing the decision to order red blood cell transfusions for a sample of US dialysis patients
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AIM: To characterize the clinical context for the decision to order red blood cell (RBC) transfusions in dialysis patients. MATERIALS AND METHODS: Retrospective review of medical records from three integrated health systems serving chronic dialysis patients. Subjects were randomly selected from all patients who received at least one transfusion between January 2009 and December 2013. Data abstracted included transfusion setting, prescribing clinician type, patient demographics and hemoglobin (Hb) concentration prior to transfusion, and cataloguing and prioritizing of clinical factors for their contribution to the decision to transfuse. Data from one system were stratified between transfusions before and after the 2011 dialysis payment reform and anemia drug label changes. RESULTS: Charts for 590 patients were reviewed. The primary reason for transfusion was low Hb (51%), medical conditions (22%), symptoms of anemia (18%), surgery-related (6%), and undetermined (3%). In 93% of cases, multiple factors were cited as contributors to the transfusion decision. Mean Hb prior to transfusion was 7.2 g/dL in patients where low Hb was the primary reason for transfusion (range: 4.0 - 9.9 g/dL). CONCLUSIONS: The decision to transfuse dialysis patients is influenced by multiple patient factors and medical conditions, of which low Hb is the main contributor to this decision about half of the time.
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Iron deficiency anemia in the emergency department: over-utilization of red blood cell transfusion and infrequent use of iron supplementation.

OBJECTIVES: Three are no clinical practice guidelines that specifically address the management of patients with iron deficiency anemia (IDA) in the emergency department (ED). The goal of this study was to describe the characteristics of IDA patients who present to the ED, documentation of IDA by emergency physicians, utilization of iron supplementation, and the appropriateness of red blood cell (RBC) transfusions ordered in the ED. METHODS: A retrospective medical chart review was performed of IDA patients who visited the ED of a large tertiary center over a three-month period. Appropriateness of RBC transfusion was determined using a novel algorithm developed by our institution. RESULTS: Over the study period, there was a 0.3% (49/14,394) prevalence of IDA in the ED. In thirty (30/49; 61%) patients, IDA was documented by an emergency physician. RBC transfusions were administered to 19 patients; 10 transfusions (53%) were appropriate, 3 (16%) were appropriate for indication, but more than the required number of units were ordered, and 6 (32%) were inappropriate. Of the patients discharged, one (1/25; 4%) patient received intravenous iron in the ED and 6 of the 11 patients (55%) that were not already taking oral iron received a prescription at discharge from the ED. CONCLUSIONS: This assessment demonstrated that management of IDA patients presenting to the ED may represent an important knowledge-to-practice gap. It revealed that RBC transfusion may be over-utilized and could be replaced by safer, lower-cost alternatives such as intravenous and oral iron. Guidelines for management of IDA in the ED may be necessary to achieve consistent IDA management and avoid inappropriate use of RBC transfusion.

Single-unit transfusions in the obstetric setting: a qualitative study.

BACKGROUND: The rate of obstetric blood transfusion is increasing, and there is hospital variation in its use. Recent Australian guidelines recommend a restrictive transfusion strategy in maternity patients who are not actively bleeding and advocate single-unit red blood cell (RBC) transfusions followed by clinical reassessment to determine the need for further transfusion. STUDY DESIGN AND METHODS: The aim of this study was to identify factors influencing single RBC unit use when initiating transfusion in a postpartum woman with noncritical bleeding. A qualitative research study using semistructured interviews was conducted. Nine maternity hospitals were chosen to cover a range of clinical settings and obstetric transfusion rates in Australia. Interviews were conducted with the key decision makers in obstetric blood transfusion. Interviews were transcribed and coded, and themes were developed. RESULTS: One hundred twenty-five interviews were conducted, including 61 doctors' interviews among obstetric (n = 42) and hematology (n = 19) staff. Most doctors (54%) interviewed would initiate transfusion with 2 RBC units; and, of those who started with single-unit transfusions, most (63%) had practiced obstetrics for less than 5 years. Clinician and external factors influenced decision making. Important clinician factors included perceived utility or clinical need and education/experience. External factors included influence of colleagues, clinical context, availability of RBC units, and regulation mechanisms. CONCLUSION: The decision to use single-unit RBC transfusion varied between and within hospitals. Efforts to reduce exposure to blood in the obstetric setting via the number of units transfused may need to target perceptions regarding the utility of single units and lack of experience with this approach.

The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat chemotherapy-induced anemia (CIA). However, about half of patients do not benefit. OBJECTIVES: To evaluate the benefits and harms related to the use of iron as a supplement to ESA and iron alone compared with ESA alone in the management of CIA. SEARCH METHODS: We searched for relevant trials from the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 1 January 2016), MEDLINE (1950 to February 2016), and www.clinicaltrials.gov without using any language limits. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing 'iron plus ESA' or 'iron alone' versus 'ESA alone' in people with CIA were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included eight RCTs (12 comparisons) comparing ESA plus iron versus ESA alone enrolling 2087 participants. We did not find any trial comparing iron alone versus ESAs alone in people with CIA. None of the included RCTs reported overall survival. There was a beneficial effect of iron supplementation to ESAs compared with ESAs alone on hematopoietic response (risk ratio (RR) 1.17, 95% confidence interval (CI) 1.09 to 1.26; P < 0.0001; 1712 participants; 11 comparisons; high-quality evidence). Assuming a baseline risk of 35% to 80% for hematopoietic response without iron supplementation, between seven and 16 patients should be treated to achieve hematopoietic response in one patient. In subgroup analyses, RCTs that used intravenous (IV) iron favored ESAs and iron (RR 1.20 (95% CI 1.10 to 1.31); P < 0.00001; 1321 participants; eight comparisons), whereas we found no evidence for a difference in hematopoietic response in RCTs using oral iron (RR 1.04 (95% CI 0.87 to 1.24); P = 0.68; 391 participants; three comparisons). There was no evidence for a difference between the subgroups of IV and oral iron (P = 0.16). There was no evidence for a difference between the subgroups of types of iron (P = 0.31) and types of ESAs (P = 0.16) for hematopoietic response.The iron supplementation to ESAs might be beneficial as fewer participants treated with iron supplementation required red blood cell (RBC) transfusions compared to the number of participants treated with ESAs alone (RR 0.74 (95% CI 0.60 to 0.92); P = 0.007; 1719 participants; 11 comparisons; moderate-quality evidence). Assuming a baseline risk of 7% to 40% for RBC transfusion without iron supplementation, between 10 and 57 patients should be treated to avoid RBC transfusion in one patient.We found no evidence for a difference in the median time to hematopoietic response with addition of iron to ESAs (hazard ratio (HR) 0.93 (95% CI 0.67 to 1.28); P = 0.65; 1042 participants; seven comparisons; low-quality evidence). In subgroup analyses, RCTs in which dextran (HR 0.95 (95% CI 0.36 to 2.52); P = 0.92; 340 participants; three comparisons), sucrose iron (HR 1.15 (95% CI 0.60 to 2.21); P = 0.67; 102 participants; one comparison) and sulfate iron (HR 1.24 (95% CI 0.99 to 1.56); P = 0.06; 55 participants; one comparison) were used showed no evidence for difference between iron supplementation versus ESAs alone compared with RCTs in which gluconate (HR 0.78 (95% CI 0.65 to 0.94); P = 0.01; 464 participants; two comparisons) was used for median time to hematopoietic response (P = 0.02). There was no evidence for a difference between the subgroups of route of iron administration (P = 0.13) and types of ESAs (P = 0.46) for median time to hematopoietic response.Our results indicated that there could be improvement in the hemoglobin (Hb) levels with addition of iron to ESAs (mean difference (MD) 0.48 (95% CI 0.10 to 0.86); P = 0.01; 827 participants; seven comparisons; low-quality evidence). In RCTs in which IV iron was used there was evidence for a difference (MD 0.84 (95% CI 0.21 to 1.46); P = 0.009; 436 participants; four comparisons) compared with oral iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) for mean change in Hb level (P = 0.03). RCTs in which dextran (MD 1.55 (95% CI 0.62 to 2.47); P = 0.001; 102 participants; two comparisons) was used showed evidence for a difference with iron supplementation versus ESAs alone compared with RCTs in which gluconate (MD 0.54 (95% CI -0.15 to 1.22); P = 0.12; 334 participants; two comparisons) and sulfate iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) were used for mean change in Hb level (P = 0.007). RCTs in which epoetin was used showed evidence for a difference with iron supplementation versus ESAs alone (MD 0.77 (95% CI 0.25 to 1.29); P = 0.004; 337 participants; five comparisons) compared with darbepoetin use (MD 0.10 (95% CI -0.13 to 0.33); P = 0.38; 490 participants; two comparisons) for mean change in Hb level (P = 0.02).We found no evidence for a difference in quality of life with addition of iron to ESAs (standardized mean difference 0.01 (95% CI -0.10 to 0.12); P = 0.88; 1124 participants; three RCTs; high-quality evidence).We found no evidence for a difference in risk of grade III-IV thromboembolic events (RR 0.95 (95% CI 0.54 to 1.65); P = 0.85; 783 participants; three RCTs; moderate-quality evidence). The incidence of treatment-related mortality (TRM) was 0% (997 participants; four comparisons; high-quality evidence).Other common adverse events included vomiting, asthenia, and leukopenia, and were similar in both arms.Overall the risk of bias across outcomes was high to low. Since the included RCTs had shorter follow-up duration (up to 20 weeks), the long-term effects of iron supplementation are unknown. Our main reasons for downgrading the quality of evidence were inconsistency across the included studies and imprecision of results. AUTHORS' CONCLUSIONS: Our systematic review shows that addition of iron to ESAs offers superior hematopoietic response, reduces the risk of RBC transfusions, and improves Hb levels, and appears to be well tolerated. None of the included RCTs reported overall survival. We found no evidence for a difference in quality of life with iron supplementation.