Abstract

BACKGROUND Anemia is a significant problem in patients on ICU. Its commonest cause, iron deficiency (ID), is difficult to diagnose in the context of inflammation. Hepcidin is a new marker of ID. We aimed to assess whether hepcidin levels would accurately guide treatment of ID in critically ill anemic patients after a prolonged ICU stay and affect the post-ICU outcomes. METHODS In a controlled, single-blinded, multicenter study, anemic (WHO definition) critically ill patients with an ICU stay ≥ 5 days were randomized when discharge was expected to either intervention by hepcidin treatment protocol or control. In the intervention arm, patients were treated with intravenous iron (1 g of ferric carboxymaltose) when hepcidin was < 20 μg/l and with intravenous iron and erythropoietin for 20 ≤ hepcidin < 41 μg/l. Control patients were treated according to standard care (hepcidin quantification remained blinded). Primary endpoint was the number of days spent in hospital 90 days after ICU discharge (post-ICU LOS). Secondary endpoints were day 15 anemia, day 30 fatigue, day 90 mortality and 1-year survival. RESULTS Of 405 randomized patients, 399 were analyzed (201 in intervention and 198 in control arm). A total of 220 patients (55%) had ID at discharge (i.e., a hepcidin < 41 μg/l). Primary endpoint was not different (medians (IQR) post-ICU LOS 33(13;90) vs. 33(11;90) days for intervention and control, respectively, median difference - 1(- 3;1) days, p = 0.78). D90 mortality was significantly lower in intervention arm (16(8%) vs 33(16.6%) deaths, absolute risk difference - 8.7 (- 15.1 to - 2.3)%, p = 0.008, OR 95% IC, 0.46, 0.22-0.94, p = 0.035), and one-year survival was improved (p = 0.04). CONCLUSION Treatment of ID diagnosed according to hepcidin levels did not reduce the post-ICU LOS, but was associated with a significant reduction in D90 mortality and with improved 1-year survival in critically ill patients about to be discharged after a prolonged stay. TRIAL REGISTRATION www.clinicaltrial.gov NCT02276690 (October 28, 2014; retrospectively registered).

Abstract

OBJECTIVE Anemia is very common in critical care patients, on admission (affecting about two-thirds of patients), but also during and after their stay, due to repeated blood loss, the effects of inflammation on erythropoiesis, a decreased red blood cell life span, and haemodilution. Anemia is associated with severity of illness and length of stay. METHODS A committee composed of 16 experts from four scientific societies, SFAR, SRLF, SFTS and SFVTT, evaluated three fields: (1) anemia prevention, (2) transfusion strategies and (3) non-transfusion treatment of anemia. Population, Intervention, Comparison, and Outcome (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Analysis of the literature and formulation of recommendations were then conducted according to the GRADE(®) methodology. RESULTS The SFAR-SRLF guideline panel provided ten statements concerning the management of anemia in adult critical care patients. Acute haemorrhage and chronic anemia were excluded from the scope of these recommendations. After two rounds of discussion and various amendments, a strong consensus was reached for ten recommendations. Three of these recommendations had a high level of evidence (GRADE 1±) and four had a low level of evidence (GRADE 2±). No GRADE recommendation could be provided for two questions in the absence of strong consensus. CONCLUSIONS The experts reached a substantial consensus for several strong recommendations for optimal patient management. The experts recommended phlebotomy reduction strategies, restrictive red blood cell transfusion and a single-unit transfusion policy, the use of red blood cells regardless of storage time, treatment of anaemic patients with erythropoietin, especially after trauma, in the absence of contraindications and avoidance of iron therapy (except in the context of erythropoietin therapy).

Abstract

OBJECTIVES The primary objectives of this meta-analysis in critically ill adult patients admitted to the intensive care unit (ICU) were to analyse whether erythropoiesis-stimulating agents (ESAs) reduced the number of patients receiving red blood cell (RBC) transfusion and resulted in a change in haemoglobin (Hb) concentration. Our secondary objectives were adverse events and mortality. BACKGROUND Anaemia is common in ICU patients, and currently, the standard therapy is RBC transfusion, which is known to be associated with adverse events. ESA could potentially reduce the need for RBC transfusion. METHODS EMBASE, Cochrane and PubMed were searched up to January 2020. RESULTS A total of 1357 articles were identified, of which 18 articles met the inclusion criteria for the qualitative synthesis. Eight of these studies were used in the meta-analyses. Comparing ESA vs control group, there was a small reduction in the proportion of patients who received one or more RBC transfusions (relative risk [RR] 0.88; confidence interval [CI] 0.78-1.00, moderate certainty). The change in Hb concentration was trivial (mean difference -0.31 g/dL; CI -0.51 to -0.05, high certainty). The number of serious adverse events (RR 1.02; 0.90-1.15, low certainty) and the overall short-term mortality were similar (RR 0.80; CI 0.61-1.05, low certainty) between the groups. CONCLUSION ESA resulted in a small reduction in the proportion of patients transfused and a trivial increase in haemoglobin concentration, both of questionable clinical relevance, without impacting adverse events or mortality. These results do not support the routine use of ESA to treat anaemia in critically ill adults.

Abstract

BACKGROUND AND STUDY AIMS To evaluate the effects of enteral administration of recombinant human erythropoietin (rhEPO) on feeding-related complications in preterm infants. PATIENTS AND METHODS This double-blind, randomized controlled pilot study enrolled 120 preterm infants born ≤ 32 weeks' gestation who were admitted to the neonatal intensive care unit in a tertiary hospital; 60 patients randomly received recombinant human erythropoietin while the other 60 received placebo. Newborns who underwent cardiopulmonary resuscitation, infants with genetic syndromes, infants with inborn errors of metabolism, infants with major congenital or acquired gastrointestinal tract malformations, infants with previous use of parenteral growth factors such as recombinant human erythropoietin and granulocyte-macrophage colony-stimuating factor (GM-CSF) and infants previously treated with intravenous immunoglobulin were excluded. Overall, 48 patients withdrew from the study because of intravenous haematopoietic growth factor intake or death before treatment was completed. A total of 72 preterm infants remained in the study: 36 preterm infants in the erythropoietin (EPO) group, and 36 preterm infants in the placebo group. The day that enteral feeding was successfully started, the time to establishing one-half, two-thirds, and full enteral feedings (reaching at least 150 mL/kg/day), the number of episodes of feeding intolerance, the time to regain birth weight and the incidence of necrotizing enterocolitis (NEC) were recorded. RESULTS Both groups showed no significant difference in the time to achieve one-half, two-thirds, or full enteral feeding, no signs of feeding intolerance, and no cases of NEC were recorded. CONCLUSION Enteral erythropoietin does not appear to affect feeding intolerance or NEC incidence.

Abstract

PURPOSE Severe immune dysregulation is common in patients admitted to the intensive care unit (ICU) and is associated with adverse outcomes. Erythropoietin-stimulating agents (ESAs) have immune-modulating and anti-apoptotic effects. However, their safety and efficacy in critically ill patients remain uncertain. We evaluated whether ESAs, administered to critically unwell adult patients admitted to the ICU, reduced mortality at hospital discharge. METHODS The search strategy was conducted according to a predetermined protocol and included OVID MEDLINE, OVID EMBASE and The Cochrane Central Register of Controlled Trials from inception until 20 May 2019. Publications were eligible for inclusion if they were randomized controlled trials (RCTs) including adult patients admitted to an ICU, that identified and reported a group receiving ESA therapy compared to a group not receiving ESA therapy and reported mortality. There were no language restrictions. RESULTS The systematic review included 21 studies with 5452 participants. In-hospital mortality, reported in 16 studies of which only one was at low risk of bias, was lower in the ESA group (276 of 2187 patients, 12.6%) than the comparator group (339 out of 2204 patients, 15.4%), [relative risk (RR) 0.82, 95% CI 0.71-0.94, P = 0.006, I(2) = 0.0%]. The RR of SAEs and thromboembolic events for the ESA and comparator groups were similar, RR 1.11 (95% CI 0.94-1.31, P = 0.228, I(2) 66%) and 1.22 (95% CI 0.95-1.58, P = 0.086, I(2) 47%), respectively. CONCLUSIONS In heterogenous populations of critically ill adults, evidence from RCTs of mainly low or unclear quality, suggests that ESA therapy may decrease mortality.

Abstract

Erythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta-analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings.

Abstract

BACKGROUD The aim of the study was to evaluate the effect of early parenteral iron supplementation combined erythropoietin for prevention of anemia in preterm infants. METHODS In total, 96 preterm infants were randomly assigned to 3 groups: a control group receiving standard parenteral nutrition (group 1: n = 31), an iron-supplemented group (group 2: IS, n = 33), and an iron-supplemented combined erythropoietin group (group 3: IS+EPO, n = 32). The primary objective was to assess hemoglobin (Hb) levels. The secondary objectives included assessment of red blood cell counts (RBC), mean cell volume (MCV), serum iron, ferritin, percentages of reticulocyte (RET), total iron binding capacity (TIBC) and oxidative stress, which was assessed by measuring plasma levels of malondialdehyde and superoxide dismutase at baseline and at 2 weeks. The blood routine indices including Hb, RBC, MCV, and percentages of RET were measured at corrected age of 1 and 3 months. RESULTS At 2 weeks of life, the percentages of reticulocyte in group 2 and group 3 were significantly higher than those in group 1 (2.1+/-0.4, 2.5+/-0.3, and 1.7+/-0.3, respectively, P < 0.001, P<0.001), whereas TIBC were significantly lower than those in group 1 (36.7+/-4.6, 36.0+/-4.7, and 41.6 +/- 5.2 respectively, P = 0.011, P = 0.006). There were no significant differences in RBC counts, the levels of hemoglobin, ferritin, malondialdehyde, and superoxide dismutase among the 3 groups at 2weeks of life. RBC, Hb, MCV, body weight, body length, and head circumference at a corrected age of 1 month did not differ among 3 groups. At corrected age of 3months, more infants in the control group had abnormal Hb and MCV levels (Hb levels: 114.3 +/- 21.3, 123.7 +/- 31.6, and 125.1 +/- 21.2, P = 0.021, P = 0.034, respectively; MCV: 74.1 +/- 3.5, 78.3 +/- 4.7 and 79.1 +/- 5.2, P = 0.017, P = 0.012, respectively), whereas cases of oral iron, cases of breastfeeding, RBC, body weight, body length, and head circumference were not different among 3 groups. CONCLUSION Early parenteral iron supplementation combined erythropoietin in preterm infants improved the percentages of reticulocyte, decreased total iron binding capacity, and improved the Hb and MCV levels at 3 months of age. Early parenteral iron supplementations with EPO were beneficial for the preterm infants.

Abstract

BACKGROUND Excess of iron and oxidant injury shortly after birth may be associated with neonatal morbidities in preterm infants. AIMS The aim was to determine whether administration of erythropoietin without iron supplementation decreases iron load and morbidity. STUDY DESIGN AND SUBJECTS In a randomized trial, we administered erythropoietin (EPO 250IU/kg daily during the first 6days of life) or placebo to 39 preterm infants (BW 700-1500g, GA≤30.0weeks). OUTCOME MEASURES The iron status, postnatal morbidities and follow-up at the age of two years were investigated. RESULTS In all, 21 EPO- and 18 placebo-treated infants were recruited. A requirement of red blood cell transfusions during first 28days was similar between the study groups. EPO treatment decreased total serum iron concentration (p=0.035). EPO supplementation had no significant effect on serum transferrin receptors or reactive non-protein-bound iron. There were no differences in neonatal morbidity or in survival without major neurological abnormality at two years of age. CONCLUSIONS A 6-day course of EPO decreased the iron load in preterm infants. There was no change in reactive, non-protein bound iron plasma levels and no influence on the outcomes during early childhood. Whether the neurocognitive effects of early EPO treatment can be detectable later in childhood remained to be verified.

Abstract

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 E

Abstract

PURPOSE Both anaemia and allogenic red blood cell transfusion are common and potentially harmful in patients admitted to the intensive care unit. Whilst intravenous iron may decrease anaemia and RBC transfusion requirement, the safety and efficacy of administering iron intravenously to critically ill patients is uncertain. METHODS The multicentre, randomized, placebo-controlled, blinded Intravenous Iron or Placebo for Anaemia in Intensive Care (IRONMAN) study was designed to test the hypothesis that, in anaemic critically ill patients admitted to the intensive care unit, early administration of intravenous iron, compared with placebo, reduces allogeneic red blood cell transfusion during hospital stay and increases the haemoglobin level at the time of hospital discharge. RESULTS Of 140 patients enrolled, 70 were assigned to intravenous iron and 70 to placebo. The iron group received 97 red blood cell units versus 136 red blood cell units in the placebo group, yielding an incidence rate ratio of 0.71 [95 % confidence interval (0.43-1.18), P = 0.19]. Overall, median haemoglobin at hospital discharge was significantly higher in the intravenous iron group than in the placebo group [107 (interquartile ratio IQR 97-115) vs. 100 g/L (IQR 89-111), P = 0.02]. There was no significant difference between the groups in any safety outcome. CONCLUSIONS In patients admitted to the intensive care unit who were anaemic, intravenous iron, compared with placebo, did not result in a significant lowering of red blood cell transfusion requirement during hospital stay. Patients who received intravenous iron had a significantly higher haemoglobin concentration at hospital discharge. The trial was registered at http://www.anzctr.org.au as # ACTRN12612001249842.