Safety and Short-term Outcomes of High-Dose Erythropoietin in Preterm Infants With Intraventricular Hemorrhage: The EpoRepair Randomized Clinical Trial
JAMA network open. 2022;5(12):e2244744
IMPORTANCE Intraventricular hemorrhage (IVH) is a major cause of neonatal morbidity and mortality in preterm infants without a specific medical treatment to date. OBJECTIVE To assess the safety and short-term outcomes of high-dose erythropoietin in preterm infants with IVH. DESIGN, SETTING, AND PARTICIPANTS Between April 1, 2014, and August 3, 2018, a randomized double-blind clinical trial enrolled 121 preterm infants (gestational age <32 weeks or birth weight <1500 g) aged 8 or less days with moderate to severe IVH identified by cerebral ultrasonography from 8 Swiss and Austrian tertiary neonatal units. Statistical analyses were performed between October 1, 2019, and September 12, 2022. INTERVENTIONS Infants received intravenous high-dose erythropoietin (2000 units/kg body weight) or placebo at 4 time points between weeks 1 and 4 of life. MAIN OUTCOMES AND MEASURES Secondary outcomes included (1) mortality and morbidity rates and (2) brain magnetic resonance imaging findings at term-equivalent age (TEA). The primary outcome was the composite intelligence quotient at 5 years of age (not available before 2023). RESULTS Sixty infants (48% male [n = 29]) were randomly assigned to receive erythropoietin, and 61 infants (61% male [n = 37]) were randomly assigned to receive placebo. The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1 weeks) in the placebo group. The 2 groups had similar baseline characteristics and morbidities. Up to TEA, 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 [95% CI, 0.74-7.66]; P = .15). Infants receiving erythropoietin had higher mean hematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores. CONCLUSIONS AND RELEVANCE This preliminary report of a randomized clinical trial found no evidence that high-dose erythropoietin in preterm infants with IVH affects brain injury scores on conventional magnetic resonance imaging at TEA. Higher mortality in the erythropoietin group was not significant but should be reassessed based on future results from similar trials. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02076373.
Preterm infants with intraventricular haemorrhage enrolled in the EpoRepair trial, in 8 Swiss and Austrian tertiary neonatal units (n= 121).
Intravenous high-dose erythropoietin (n= 60).
Placebo (n= 61).
The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1 weeks) in the placebo group. Both groups had similar baseline characteristics and morbidities. Up to term-equivalent age (TEA), 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 (95% CI 0.74 to 7.66)). Infants receiving erythropoietin had higher mean haematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores.
Postoperative Transfusion Guidelines in Aneurysmal Cerebral Subarachnoid Hemorrhage: A Systematic Review and Critical Summary of Available Evidence
World Neurosurgery. 2022;158:234-243.e5
OBJECTIVE Surgical management of aneurysmal subarachnoid hemorrhage (SAH) often involves red blood cell (RBC) transfusion, which increases the risk of postoperative complications. RBC transfusion guidelines report on chronically critically ill patients and may not apply to patients with SAH. Our study aims to synthesize the evidence to recommend RBC transfusion thresholds among adult patients with SAH undergoing surgery. METHODS A systematic review was conducted using PubMed, Google Scholar, and Web of Science electronic databases according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to critically assess primary articles discussing RBC transfusion thresholds and describe complications secondary to RBC transfusion in adult patients with SAH in the perioperative period. RESULTS Sixteen articles meeting our search strategy were reviewed. Patients with SAH who received blood transfusion were older, female, had World Federation of Neurosurgical Societies grade IV-V and modified Fisher grade 3-4 scores, and presented with more comorbidities such as hypertension, diabetes, and cardiovascular and pulmonary diseases. In addition, transfusion was associated with multiple postoperative complications, including higher rates of vasospasms, surgical site infections, cardiovascular and respiratory complications, increased postoperative length of stay, and 30-day mortality. Analysis of transfused patients showed that a higher hemoglobin (>10 g/dL) goal after SAH was safe and that patients may benefit from a higher whole hospital stay hemoglobin nadir, as shown by a reduction in risk of cerebral vasospasm and improvement in clinical outcomes (level B class II). CONCLUSIONS Among patients with SAH, the benefits of reducing cerebral ischemia and anemia are shown to outweigh the risks of transfusion-related complications.
Allogeneic umbilical cord blood infusion for adults with ischemic stroke: clinical outcomes from a phase 1 safety study
Stem Cells Translational Medicine. 2018;7((7):):521-529
Stroke is a major cause of death and long-term disability, affecting one in six people worldwide. The only currently available approved pharmacological treatment for ischemic stroke is tissue plasminogen activator; however, relatively few patients are eligible for this therapy. We hypothesized that intravenous (IV) infusion of banked unrelated allogeneic umbilical cord blood (UCB) would improve functional outcomes in patients with ischemic stroke. To investigate this, we conducted a phase 1 open-label trial to assess the safety and feasibility of a single IV infusion of non-human leukocyte antigen (HLA) matched, ABO matched, unrelated allogeneic UCB into adult stroke patients. Ten participants with acute middle cerebral artery ischemic stroke were enrolled. UCB units were matched for blood group antigens and race but not HLA, and infused 3-9 days post-stroke. The adverse event (AE) profile over a 12 month postinfusion period indicated that the treatment was well-tolerated in these stroke patients, with no serious AEs directly related to the study product. Study participants were also assessed using neurological and functional evaluations, including the modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS). At 3 months post-treatment, all participants had improved by at least one grade in mRS (mean 2.8 +/- 0.9) and by at least 4 points in NIHSS (mean 5.9 +/- 1.4), relative to baseline. Together, these data suggest that a single i.v. dose of allogeneic non-HLA matched human UCB cells is safe in adults with ischemic stroke, and support the conduct of a randomized, placebo-controlled phase 2 study. Stem Cells Translational Medicine 2018.
Red blood cell transfusion and mortality effect in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis protocol
Systems Review. 2015;4((1)):41.
BACKGROUND Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease that leads to important morbidity and mortality in a young patient population. Anemia following aSAH is common and may be exacerbated by the treatments instituted by clinicians as part of standard care. The role and optimal thresholds for red blood cell (RBC) transfusion in this patient population remains unknown. METHODS/DESIGN We will conduct a systematic review of the literature using MEDLINE, EMBASE, and EBM Reviews (including Cochrane Central databases) using a comprehensive search strategy for observational and interventional studies of RBC transfusion in aSAH. Our primary objective is to evaluate the association of RBC transfusion with mortality in aSAH patients. Secondary objectives include a) determining associations between RBC transfusion and poor neurologic outcome, b) defining an optimal RBC transfusion threshold in aSAH patients, and c) describing complications associated with RBC transfusion in aSAH patients. We plan a descriptive reporting of all included citations including study characteristics, methodological quality, and reported outcomes. Clinical and statistical heterogeneity observed between studies will be described. If appropriate, meta-analyses of suitable studies and interpretation of their results will be performed. Effect measures will be converted to obtain relative risks and odds ratios (RR and ORs) with 95% confidence intervals and pooled according to study design (randomized trials and observational studies respectively) using a random effects model. DISCUSSION This review will summarize the existing observational and trial evidence regarding RBC transfusion in aSAH patients. The analytical plan has made considerations for different study designs, both observational and interventional in nature, and will summarize the best available evidence to inform the end user and policy and guideline producers and to highlight areas in need of further study. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42014014806.
Anemia and transfusion after subarachnoid hemorrhage
Neurocritical Care. 2011;15((2):):342-53.
Delayed cerebral ischemia after subarachnoid hemorrhage (SAH) may be affected by a number of factors, including cerebral blood flow and oxygen delivery. Anemia affects about half of patients with SAH and is associated with worse outcome. Anemia also may contribute to the development of or exacerbate delayed cerebral ischemia. This review was designed to examine the prevalence and impact of anemia in patients with SAH and to evaluate the effects of transfusion. A literature search was made to identify original research on anemia and transfusion in SAH patients. A total of 27 articles were identified that addressed the effects of red blood cell transfusion (RBCT) on brain physiology, anemia in SAH, and clinical management with RBCT or erythropoietin. Most studies provided retrospectively analyzed data of very low-quality according to the GRADE criteria. While RBCT can have beneficial effects on brain physiology, RBCT may be associated with medical complications, infection, vasospasm, and poor outcome after SAH. The effects may vary with disease severity or the presence of vasospasm, but it remains unclear whether RBCTs are a marker of disease severity or a cause of worse outcome. Erythropoietin data are limited. The literature review further suggests that the results of the Transfusion Requirements in Critical Care Trial and subsequent observational studies on RBCT in general critical care do not apply to SAH patients and that randomized trials to address the role of RBCT in SAH are required.
Stroke with transfusions changing to hydroxyurea (SWiTCH): a phase 3 randomized clinical trial for treatment of children with sickle cell anemia, previous stroke, and iron overload
Blood. 2010;116((21):): Abstract No. 844.
Prospective, randomized trial of higher goal hemoglobin after subarachnoid hemorrhage
Neurocritical Care. 2010;13((3):):313-20.
BACKGROUND AND PURPOSE In patients with subarachnoid hemorrhage (SAH), higher hemoglobin (HGB) has been associated with better outcomes, but packed red blood cell (PRBC) transfusions with worse outcomes. We performed a prospective pilot trial of goal HGB after SAH. METHODS Forty-four patients with SAH and high risk for vasospasm were randomized to goal HGB concentration of at least 10 or 11. 5 g/dl. We obtained blinded clinical outcomes at 14 days (NIH Stroke Scale and modified Rankin Scale, mRS), 28 days (mRS), and 3 months (mRS), and blinded interpretation of brain MRI for cerebral infarction at 14 days. This trial is registered at www. stroketrials. org. RESULTS Forty-four patients were randomized. Patients with goal HGB 11. 5 g/dl received more PRBC units per transfusion [1 (1-2) vs. 1 (1-1), P < 0. 001] and more total PRBC units [3 (2-4) vs. 2 (1-3), P = 0. 045]. Prospectively defined safety endpoints were not different between groups. HGB concentration was different between study groups from day 4 onwards. The number of cerebral infarctions on MRI (6 of 20 vs. 9 of 22), NIH Stroke Scale scores at 14 days [1 (0-9. 75) vs. 2 (0-16)], and rates of independence on the mRS at 14 days (65% vs. 44%) and 28 days (80% vs. 67%) were similar, but favored higher goal HGB (P > 0. 1 for all). CONCLUSIONS Higher goal hemoglobin in patients with SAH seems to be safe and feasible. A phase III trial of goal HGB after SAH is warranted.