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Iron and erythropoietin to heal and recover after intensive care (ITHRIVE): A pilot randomised clinical trial
Litton, E., French, C., Herschtal, A., Stanworth, S., Pellicano, S., Palermo, A. M., Bates, S., Van Der Laan, S., Eroglu, E., Griffith, D., et al
Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine. 2023;25(4):201-206
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Abstract
OBJECTIVE To determine the feasibility of a pivotal randomised clinical trial of intravenous (IV) iron and erythropoietin in adult survivors of critical illness with anaemia requiring treatment in the intensive care unit. DESIGN An investigator-initiated, parallel group, placebo-controlled, randomised feasibility trial. SETTING A tertiary intensive care unit (ICU) in Perth, Western Australia. PARTICIPANTS Adults with anaemia (haemoglobin <100 g/L), requiring ICU-level care for more than 48 h, and likely to be ready for ICU discharge within 24 h. INTERVENTIONS A single dose of IV ferric carboxymaltose and Epoetin alfa (active group) or an equal volume of 0.9% saline (placebo group). MAIN OUTCOME MEASURES Study feasibility was considered met if the pilot achieved a recruitment rate of ≥2 participants per site per month, ≥90% of participants received their allocated study treatment, and≥ 90% of participants were followed up for the proposed pivotal trial primary outcome - days alive and at home to day 90 (DAH(90)). RESULTS The 40-participant planned sample size included twenty in each group and was enrolled between 1/9/2021 and 2/3/2022. Participants spent a median of 3.4 days (interquartile range 2.8-5.1) in the ICU prior to enrolment and had a mean baseline haemoglobin of 83.7 g/L (standard deviation 6.7). The recruitment rate was 6.7 participants per month [95% confidence interval (CI) 4.8-9.0], DAH(90) follow-up was 100% (95% CI 91.2%-100%), and 39 (97.5%, 95% CI 86.8%-99.9%) participants received the allocated study intervention. No serious adverse events were reported. CONCLUSION The iron and erythropoietin to heal and recover after intensive care (ITHRIVE) pilot demonstrated feasibility based on predefined participant recruitment, study drug administration, and follow-up thresholds.
PICO Summary
Population
Adult survivors of critical illness with anaemia requiring treatment in the intensive care unit, enrolled in the ITHRIVE randomised feasibility trial (n= 40).
Intervention
A single dose of intravenous ferric carboxymaltose and Epoetin alfa (active group, n= 20).
Comparison
An equal volume of 0.9% saline (placebo group, n= 20).
Outcome
Study feasibility was considered met if the pilot achieved a recruitment rate of ≥2 participants per site per month, ≥90% of participants received their allocated study treatment, and≥ 90% of participants were followed up for the proposed pivotal trial primary outcome - days alive and at home to day 90 DAH(90). The trial enrolled its planned sample size of 40 participants. The recruitment rate was 6.7 participants per month (95% confidence interval (CI) [4.8, 9.0]), DAH(90) follow-up was 100% (95% CI [91.2%, 100%]), and 39 ((97.5%); 95% CI [86.8%, 99.9%]) participants received the allocated study intervention. No serious adverse events were reported.
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Role of single-dose intravenous iron therapy for the treatment of anaemia after orthopaedic trauma: protocol for a pilot randomised controlled trial
Peterson, D. F., McKibben, N. S., Hutchison, C. E., Lancaster, K., Yang, C. J., Dekeyser, G. J., Friess, D. M., Schreiber, M. A., Willett, N. J., Shatzel, J. J., et al
BMJ open. 2023;13(3):e069070
Abstract
INTRODUCTION Orthopaedic trauma and fracture care commonly cause perioperative anaemia and associated functional iron deficiency due to a systemic inflammatory state. Modern, strict transfusion thresholds leave many patients anaemic; managing this perioperative anaemia is an opportunity to impact outcomes in orthopaedic trauma surgery. The primary outcome of this pilot study is feasibility for a large randomised controlled trial (RCT) to evaluate intravenous iron therapy (IVIT) to improve patient well-being following orthopaedic injury. Measurements will include rate of participant enrolment, screening failure, follow-up, missing data, adverse events and protocol deviation. METHODS AND ANALYSIS This single-centre, pilot, double-blind RCT investigates the use of IVIT for acute blood loss anaemia in traumatically injured orthopaedic patients. Patients are randomised to receive either a single dose infusion of low-molecular weight iron dextran (1000 mg) or placebo (normal saline) postoperatively during their hospital stay for trauma management. Eligible subjects include adult patients admitted for lower extremity or pelvis operative fracture care with a haemoglobin of 7-11 g/dL within 7 days postoperatively during inpatient care. Exclusion criteria include history of intolerance to intravenous iron supplementation, active haemorrhage requiring ongoing blood product resuscitation, multiple planned procedures, pre-existing haematologic disorders or chronic inflammatory states, iron overload on screening or vulnerable populations. We follow patients for 3 months to measure the effect of iron supplementation on clinical outcomes (resolution of anaemia and functional iron deficiency), patient-reported outcomes (fatigue, physical function, depression and quality of life) and translational measures of immune cell function. ETHICS AND DISSEMINATION This study has ethics approval (Oregon Health & Science University Institutional Review Board, STUDY00022441). We will disseminate the findings through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER NCT05292001; ClinicalTrials.gov.
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Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns
Garcia MR, Comstock BA, Patel RM, Tolia VN, Josephson CD, Georgieff MK, Rao R, Monsell SE, Juul SE, Ahmad KA
Pediatric research. 2022
Abstract
BACKGROUND The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD). METHODS A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization. RESULTS Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD. CONCLUSIONS We find no support for an increased risk of BPD with iron supplementation. TRIAL REGISTRATION NUMBER NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.
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Enteral Iron Supplementation in Extremely Preterm Infants and its Positive Correlation with Neurodevelopment; Post Hoc Analysis of the PENUT Randomized Controlled Trial
German KR, Vu PT, Comstock BA, Ohls RK, Heagerty PJ, Mayock DE, Georgieff M, Rao R, Juul SE
The Journal of pediatrics. 2021
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Editor's Choice
Abstract
OBJECTIVES To test whether an increased iron dose is associated with improved neurodevelopment as assessed by the Bayley Scales of Infant Development (BSID-III) among infants enrolled in the Preterm Erythropoietin (Epo) Neuroprotection Trial (PENUT). STUDY DESIGN This is a post hoc analysis of a randomized trial which enrolled infants born at 24 to 28 completed weeks of gestation. All PENUT infants who were assessed with BSID-III at 2 years were included in this study. The associations between enteral iron dose at 60 and 90 days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders. RESULTS 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged 0-14.7 mg/kg/day (IQR 2.1-5.8 mg/kg/day) at day 60, with a mean of 3.6 mg/kg/day in placebo-treated infants and 4.8 mg/kg/day in Epo-treated infants. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose (P = .03). Higher iron doses were associated with higher motor and language scores, but did not reach statistical significance. Results at 90 days were not significant. The effect size in the Epo-treated infants compared with placebo was consistently higher. CONCLUSION A positive association was seen between iron dose at 60 days and cognitive outcomes. Our results suggest that increased iron supplementation in preterm infants, at the doses administered in the PENUT Trial, may have positive neurodevelopmental effects, particularly in infants treated with Epo.
PICO Summary
Population
Infants enrolled in the Preterm Erythropoietin Neuroprotection Trial (PENUT), (n= 692).
Intervention
Erythropoietin (Epo), (n= 337).
Comparison
Placebo (n= 355).
Outcome
Enteral iron supplementation ranged 0-14.7 mg/kg/day (IQR 2.1-5.8 mg/kg/day) at day 60, with a mean of 3.6 mg/kg/day in placebo-treated infants and 4.8 mg/kg/day in Epo-treated infants. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose. Higher iron doses were associated with higher motor and language scores, but did not reach statistical significance. Results at 90 days were not significant. The effect size in the Epo-treated infants compared with placebo was consistently higher.
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Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial
Vu PT, Ohls RK, Mayock DE, German KR, Comstock BA, Heagerty PJ, Juul SE
Pediatric research. 2021;:1-8
Abstract
BACKGROUND Outcomes of extremely low gestational age neonates (ELGANs) may be adversely impacted by packed red blood cell (pRBC) transfusions. We investigated the impact of transfusions on neurodevelopmental outcome in the Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial population. METHODS This is a post hoc analysis of 936 infants 24-0/6 to 27-6/7 weeks' gestation enrolled in the PENUT Trial. Epo 1000 U/kg or placebo was given every 48 h × 6 doses, followed by 400 U/kg or sham injections 3 times a week through 32 weeks postmenstrual age. Six hundred and twenty-eight (315 placebo, 313 Epo) survived and were assessed at 2 years of age. We evaluated associations between BSID-III scores and the number and volume of pRBC transfusions. RESULTS Each transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI of [-1.34, -0.57]), a decrease in mean motor score of 1.51 (-1.91, -1.12), and a decrease in mean language score of 1.10 (-1.54, -0.66). Significant negative associations between BSID-III score and transfusion volume and donor exposure were observed in the placebo group but not in the Epo group. CONCLUSIONS Transfusions in ELGANs were associated with worse outcomes. We speculate that strategies to minimize the need for transfusions may improve outcomes. IMPACT Transfusion number, volume, and donor exposure in the neonatal period are associated with worse neurodevelopmental (ND) outcome at 2 years of age, as assessed by the Bayley Infant Scales of Development, Third Edition (BSID-III). The impact of neonatal packed red blood cell transfusions on the neurodevelopmental outcome of preterm infants is unknown. We speculate that strategies to minimize the need for transfusions may improve neurodevelopmental outcomes.
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Intravenous iron to treat anaemia following critical care: a multicentre feasibility randomised trial
Shah A, Chester-Jones M, Dutton SJ, Marian IR, Barber VS, Griffith DM, Singleton J, Wray K, James T, Drakesmith H, et al
British journal of anaesthesia. 2021
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Abstract
BACKGROUND Anaemia is common and associated with poor outcomes in survivors of critical illness. However, the optimal treatment strategy is unclear. METHODS We conducted a multicentre, feasibility RCT to compare either a single dose of ferric carboxymaltose 1000 mg i.v. or usual care in patients being discharged from the ICU with moderate or severe anaemia (haemoglobin ≤100 g L(-1)). We collected data on feasibility (recruitment, randomisation, follow-up), biological efficacy, and clinical outcomes. RESULTS Ninety-eight participants were randomly allocated (49 in each arm). The overall recruitment rate was 34% with 6.5 participants recruited on average per month. Forty-seven of 49 (96%) participants received the intervention. Patient-reported outcome measures were available for 79/93 (85%) survivors at 90 days. Intravenous iron resulted in a higher mean (standard deviation [sd]) haemoglobin at 28 days (119.8 [13.3] vs 106.7 [14.9] g L(-1)) and 90 days (130.5 [15.1] vs 122.7 [17.3] g L(-1)), adjusted mean difference (10.98 g L(-1); 95% confidence interval [CI], 4.96-17.01; P<0.001) over 90 days after randomisation. Infection rates were similar in both groups. Hospital readmissions at 90 days post-ICU discharge were lower in the i.v. iron group (7/40 vs 15/39; risk ratio=0.46; 95% CI, 0.21-0.99; P=0.037). The median (inter-quartile range) post-ICU hospital stay was shorter in the i.v. iron group but did not reach statistical significance (5.0 [3.0-13.0] vs 9.0 [5.0-16.0] days, P=0.15). CONCLUSION A large, multicentre RCT of i.v. iron to treat anaemia in survivors of critical illness appears feasible and is necessary to determine the effects on patient-centred outcomes. CLINICAL TRIAL REGISTRATION ISRCTN13721808 (www.isrctn.com).
PICO Summary
Population
Patients being discharged from the intensive care unit (ICU) with moderate or severe anaemia (n= 98).
Intervention
Single dose of ferric carboxymaltose (n= 49).
Comparison
Usual care (n= 49).
Outcome
Patient-reported outcome measures were available for 85% survivors at 90 days. Intravenous iron resulted in a higher mean (standard deviation [sd]) haemoglobin at 28 days (119.8 [13.3] vs. 106.7 [14.9] g L(-1)) and 90 days (130.5 [15.1] vs. 122.7 [17.3] g L(-1)), adjusted mean difference (10.98 g L(-1)) over 90 days after randomisation. Infection rates were similar in both groups. Hospital readmissions at 90 days post-ICU discharge were lower in the intravenous iron group (7/40 vs. 15/39). The median (inter-quartile range) post-ICU hospital stay was shorter in the intravenous iron group but did not reach statistical significance (5.0 [3.0-13.0] vs. 9.0 [5.0-16.0]) days.
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Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial
Wood TR, Parikh P, Comstock BA, Law JB, Bammler TK, Kuban KC, Mayock DE, Heagerty PJ, Juul S
EBioMedicine. 2021;72:103605
Abstract
BACKGROUND In the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (<28 weeks' gestation) infants. METHODS Plasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III). FINDINGS Elevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years. INTERPRETATION Elevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice. FUNDING PENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).
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Impact of treating iron deficiency, diagnosed according to hepcidin quantification, on outcomes after a prolonged ICU stay compared to standard care: a multicenter, randomized, single-blinded trial
Lasocki S, Asfar P, Jaber S, Ferrandiere M, Kerforne T, Asehnoune K, Montravers P, Seguin P, Peoc'h K, Gergaud S, et al
Critical care (London, England). 2021;25(1):62
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Editor's Choice
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).
PICO Summary
Population
Critically ill patients with a prolonged ICU stay (n= 399).
Intervention
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, (n= 201).
Comparison
Standard care (n= 198).
Outcome
A total of 220 patients (55%) had iron deficiency at discharge (i.e., a hepcidin < 41 μg/l). The number of days spent in hospital 90 days after ICU discharge was not different (medians: 33 vs. 33) days for intervention and control, respectively. Day 90 mortality was significantly lower in intervention arm (16 (8%) vs. 33 (16.6%) deaths, and one-year survival was improved.
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Erythropoietin Improves Poor Outcomes in Preterm Infants with Intraventricular Hemorrhage
Song J, Wang Y, Xu F, Sun H, Zhang X, Xia L, Zhang S, Li K, Peng X, Li B, et al
CNS drugs. 2021
Abstract
BACKGROUND Intraventricular hemorrhage (IVH) is a common complication in preterm infants that has poor outcomes, especially in severe cases, and there are currently no widely accepted effective treatments. Erythropoietin has been shown to be neuroprotective in neonatal brain injury. OBJECTIVE The objective of this study was to evaluate the protective effect of repeated low-dose recombinant human erythropoietin (rhEPO) in preterm infants with IVH. METHODS This was a single-blinded prospective randomized controlled trial. Preterm infants ≤ 32 weeks gestational age who were diagnosed with IVH within 72 h after birth were randomized to receive rhEPO 500 IU/kg or placebo (equivalent volume of saline) every other day for 2 weeks. The primary outcome was death or neurological disability assessed at 18 months of corrected age. RESULTS A total of 316 eligible infants were included in the study, with 157 in the rhEPO group and 159 in the placebo group. Although no significant differences in mortality (p = 0.176) or incidence of neurological disability (p = 0.055) separately at 18 months of corrected age were seen between the rhEPO and placebo groups, significantly fewer infants had poor outcomes (death and neurological disability) in the rhEPO group: 14.9 vs. 26.4%; odds ratio (OR) 0.398; 95% confidence interval (CI) 0.199-0.796; p = 0.009. In addition, the incidence of Mental Development Index scores of < 70 was lower in the rhEPO group than in the placebo group: 7.2 vs. 15.3%; OR 0.326; 95% CI 0.122-0.875; p = 0.026. CONCLUSIONS Treatment with repeated low-dose rhEPO improved outcomes in preterm infants with IVH. TRIAL REGISTRATION The study was retrospectively registered on ClinicalTrials.gov on 16 April 2019 (NCT03914690).
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Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates: Post Hoc Analysis of a Randomized Clinical Trial
Juul SE, Vu PT, Comstock BA, Wadhawan R, Mayock DE, Courtney SE, Robinson T, Ahmad KA, Bendel-Stenzel E, Baserga M, et al
JAMA pediatrics. 2020
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Editor's Choice
Abstract
IMPORTANCE Extremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have not demonstrated a decrease in donor exposure. OBJECTIVES To determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions. DESIGN, SETTING, AND PARTICIPANTS The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n = 477) or placebo (n = 464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019. INTERVENTIONS In this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks. MAIN OUTCOMES AND MEASURES Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein. RESULTS A total of 936 patients (488 male [52.1%]) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean [SD], 3.5 [4.0] vs 5.2 [4.4]), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean [SD], 47.6 [60.4] vs 76.3 [68.2] mL), with a mean difference of -25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean [SD], 1.6 [1.7] vs 2.4 [2.0]), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean [SD] hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% [5.5%] vs 30.4% [4.6%] (P < .001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P < .001). CONCLUSIONS AND RELEVANCE These findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01378273.
PICO Summary
Population
Extremely preterm infants enrolled in the Preterm Erythropoietin Neuroprotection Trial (PENUT), (n= 941).
Intervention
Erythropoietin, 1000 U/kg followed by 400 U/kg (n = 477).
Comparison
Placebo followed by sham injections (n = 464).
Outcome
Compared to placebo, erythropoietin treatment decreased the number of transfusions (unadjusted mean 3.5 vs 5.), the cumulative transfused volume (mean 47.6 vs 76.3 mL), with a mean difference of -25.7 and donor exposure (mean 1.6 vs 2.4). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants (36.9% vs 30.4%). Of 936 infants, 160 remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group.