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Interventions for chronic kidney disease in people with sickle cell disease
Roy, N. B., Carpenter, A., Dale-Harris, I., Dorée, C., Estcourt, L. J.
The Cochrane database of systematic reviews. 2023;8(8):Cd012380
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Editor's Choice
Abstract
BACKGROUND Sickle cell disease (SCD), one of the commonest severe monogenic disorders, is caused by the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD. Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD. Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, with increased prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease. This is an update of a review first published in 2017. OBJECTIVES To assess the effectiveness of any intervention for preventing or reducing kidney complications or chronic kidney disease in people with sickle cell disease. Possible interventions include red blood cell transfusions, hydroxyurea, and angiotensin-converting enzyme inhibitors (ACEIs), either alone or in combination. SEARCH METHODS We searched for relevant trials in the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, CENTRAL, MEDLINE, Embase, seven other databases, and two other trials registers. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing interventions to prevent or reduce kidney complications or CKD in people with SCD. We applied no restrictions related to outcomes examined, language, or publication status. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias, and assessed the certainty of the evidence (GRADE). MAIN RESULTS We included three RCTs with 385 participants. We rated the certainty of the evidence as low to very low across different outcomes according to GRADE methodology, downgrading for risk of bias concerns, indirectness, and imprecision. Hydroxyurea versus placebo One RCT published in 2011 compared hydroxyurea to placebo in 193 children aged nine to 18 months. We are unsure if hydroxyurea compared to placebo reduces or prevents progression of kidney disease assessed by change in glomerular filtration rate (mean difference (MD) 0.58 mL/min /1.73 m(2), 95% confidence interval (CI) -14.60 to 15.76; 142 participants; very low certainty). Hydroxyurea compared to placebo may improve the ability to concentrate urine (MD 42.23 mOsm/kg, 95% CI 12.14 to 72.32; 178 participants; low certainty), and may make little or no difference to SCD-related serious adverse events, including acute chest syndrome (risk ratio (RR) 0.39, 99% CI 0.13 to 1.16; 193 participants; low certainty), painful crisis (RR 0.68, 99% CI 0.45 to 1.02; 193 participants; low certainty); and hospitalisations (RR 0.83, 99% CI 0.68 to 1.01; 193 participants; low certainty). No deaths occurred in either trial arm and the RCT did not report quality of life. Angiotensin-converting enzyme inhibitors versus placebo One RCT published in 1998 compared an ACEI (captopril) to placebo in 22 adults with normal blood pressure and microalbuminuria. We are unsure if captopril compared to placebo reduces proteinuria (MD -49.00 mg/day, 95% CI -124.10 to 26.10; 22 participants; very low certainty). We are unsure if captopril reduces or prevents kidney disease as measured by creatinine clearance; the trial authors stated that creatinine clearance remained constant over six months in both groups, but provided no comparative data (very low certainty). The RCT did not report serious adverse events, all-cause mortality, or quality of life. Angiotensin-converting enzyme inhibitors versus vitamin C One RCT published in 2020 compared an ACEI (lisinopril) with vitamin C in 170 children aged one to 18 years with normal blood pressure and microalbuminuria. It reported no data we could analyse. We are unsure if lisinopril compared to vitamin C reduces proteinuria in this population: the large drop in microalbuminuria in both arms of the trial after only one month on treatment may have been due to an overestimation of microalbuminuria at baseline rather than a true effect. The RCT did not report serious adverse events, all-cause mortality, or quality of life. AUTHORS' CONCLUSIONS We are unsure if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration in children aged nine to 18 months, but it may improve their ability to concentrate urine and may make little or no difference to the incidence of acute chest syndrome, painful crises, and hospitalisations. We are unsure if ACEI compared to placebo has any effect on preventing or reducing kidney complications in adults with normal blood pressure and microalbuminuria. We are unsure if ACEI compared to vitamin C has any effect on preventing or reducing kidney complications in children with normal blood pressure and microalbuminuria. No RCTs assessed red blood cell transfusions or any combined interventions to prevent or reduce kidney complications. Due to lack of evidence, we cannot comment on the management of children aged over 18 months or adults with any known genotype of SCD. We have identified a lack of adequately designed and powered studies, although we found four ongoing trials since the last version of this review. Only one ongoing trial addresses renal function as a primary outcome in the short term, but such interventions have long-term effects. Trials of hydroxyurea, ACEIs or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction of kidney complications in people with SCD.
PICO Summary
Population
Children and adults with sickle cell disease (3 randomised controlled trials, n= 385).
Intervention
Interventions to prevent or reduce kidney complications or chronic kidney disease, including: hydroxyurea, and angiotensin-converting enzyme inhibitors (ACEIs), either alone or in combination.
Comparison
Placebo.
Outcome
This systematic review is an update of a review first published in 2017. The authors rated the certainty of the evidence as low to very low across different outcomes. The authors are unsure if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration in children aged nine to 18 months, but it may improve their ability to concentrate urine and may make little or no difference to the incidence of acute chest syndrome, painful crises, and hospitalisations. The authors are unsure if ACEI compared to placebo has any effect on preventing or reducing kidney complications in adults with normal blood pressure and microalbuminuria. The authors are unsure if ACEI compared to vitamin C has any effect on preventing or reducing kidney complications in children with normal blood pressure and microalbuminuria.
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The Impact of Restrictive Transfusion Practices on Hemodynamically Stable Critically Ill Children Without Heart Disease: A Secondary Analysis of the Age of Blood in Children in the PICU Trial
Steffen KM, Tucci M, Doctor A, Reeder R, Caro JJ, Muszynski JA, Spinella PC
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2023;24(2):84-92
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Editor's Choice
Abstract
OBJECTIVES Guidelines recommend against RBC transfusion in hemodynamically stable (HDS) children without cardiac disease, if hemoglobin is greater than or equal to 7 g/dL. We sought to assess the clinical and economic impact of compliance with RBC transfusion guidelines. DESIGN A nonprespecified secondary analysis of noncardiac, HDS patients in the randomized trial Age of Blood in Children (NCT01977547) in PICUs. Costs analyzed included ICU stay and physician fees. Stabilized inverse propensity for treatment weighting was used to create a cohort balanced with respect to potential confounding variables. Weighted regression models were fit to evaluate outcomes based on guideline compliance. SETTING Fifty international tertiary care centers. PATIENTS Critically ill children 3 days to 16 years old transfused RBCs at less than or equal to 7 days of ICU admission. Six-hundred eighty-seven subjects who met eligibility criteria were included in the analysis. INTERVENTIONS Initial RBC transfusions administered when hemoglobin was less than 7 g/dL were considered "compliant" or "non-compliant" if hemoglobin was greater than or equal to 7 g/dL. MEASUREMENTS AND MAIN RESULTS Frequency of new or progressive multiple organ system dysfunction (NPMODS), ICU survival, and associated costs. The hypothesis was formulated after data collection but exposure groups were masked until completion of planned analyses. Forty-nine percent of patients (338/687) received a noncompliant initial transfusion. Weighted cohorts were balanced with respect to confounding variables (absolute standardized differences < 0.1). No differences were noted in NPMODS frequency (relative risk, 0.86; 95% CI, 0.61-1.22; p = 0.4). Patients receiving compliant transfusions had more ICU-free days (mean difference, 1.73; 95% CI, 0.57-2.88; p = 0.003). Compliance reduced mean costs in ICU by $38,845 U.S. dollars per patient (95% CI, $65,048-$12,641). CONCLUSIONS Deferring transfusion until hemoglobin is less than 7 g/dL is not associated with increased organ dysfunction in this population but is independently associated with increased likelihood of live ICU discharge and lower ICU costs.
PICO Summary
Population
A subgroup of haemodynamically stable critically ill children without heart disease, enrolled in the Age of Blood in Children (ABC-PICU trial) at 50 international tertiary care centers (n= 687).
Intervention
Initial red blood cells (RBCs) transfusion when haemoglobin was less than 7 g/dL (Compliant, n= 349).
Comparison
Initial RBCs transfusion when haemoglobin was greater than or equal to 7 g/dL (Non-compliant, n= 338).
Outcome
This secondary analysis of the ABC-PICU trial assessed the clinical and economic impact of compliance with RBCs transfusion guidelines. 49% of patients (338/687) received a non-compliant initial transfusion, and 51% (349/687) received a compliant initial transfusion. Weighted cohorts were balanced with respect to confounding variables. No differences were noted in new or progressive multiple organ system dysfunction frequency (relative risk, 0.86, 95% CI: 0.61-1.22). Patients receiving compliant transfusions had more ICU-free days (mean difference, 1.73, 95% CI: 0.57-2.88). Compliance reduced mean costs in ICU by $38,845 U.S. dollars per patient (95% CI: $65,048-$12,641).
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Cerebral and intestinal oxygen saturation of different volumes of red blood cell transfusion in preterm infants
Chen, R., Lai, S. H., Xiu, W. L., Cai, W. H., Chen, Z. Q., Xie, Y. L.
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2023;:103839
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Editor's Choice
Abstract
OBJECTIVES The purpose of this study was to investigate and compare the effects of 20 ml/kg and 15 ml/kg red blood cell transfusion (RBCT) on cerebral and intestinal tissue oxygenation, the number of administered transfusions, and neonatal complications in premature infants with anemia. METHODS This prospective, randomized, partially blinded observational study investigated anemic neonates of gestational age < 32 weeks (Registration ID: ChiCTR 1,900,026,672). The infants were randomly assigned to receive 15 or 20 ml/kg red blood cell transfusion. Cerebral and intestinal tissue oxygen saturation (cer rSO(2) and int rSO(2)) were collected 2 h before transfusion, 2, 4, 6, 12, 24, and 48 h after the beginning of transfusion by Near-infrared spectroscopy (NIRS). We also collected vital signs including heart rate (HR), peripheral oxygen saturation (SpO(2)), and mean arterial blood pressure (MABP) 2 h before infusion, 2 h, and 6 h after the beginning of transfusion. Then we analyzed and compared regional oxygen saturation(rSO(2))(,) fractional tissue oxygen extraction (FTOE), and other outcome readouts (blood transfusion numbers, changes in hematocrit and hemoglobin, hospitalization days, HR, SpO2, MABP, and complications) between the two groups. The intraindividual comparisons of the above readouts before transfusion and those after transfusion were also evaluated within each group. RESULT 73 newborns received 20 ml/kg (large volume group) and 78 newborns received 15 ml/kg transfusion (small volume group). There was no significant difference in cer rSO2, int rSO(2), Cerebral fractional tissue oxygen extraction (cFTOE), and intestinal fractional tissue oxygen extraction (iFTOE) between the two groups. rSO(2,) MABP, and SpO(2) increased; HR, cFTOE, and iFTOE decreased following transfusion in both groups. The transfusion number of the large volume group is significantly less than that of the small volume group (1.9 ± 0.3 vs. 2.6 ± 0.9, p < 0.01) and hospitalization days were also less than those in the low volume group (44.3 ± 8.2 vs. 47.6 ± 9.8, p < 0.05). The increases in hematocrit and hemoglobin were higher in the large volume group than those in small volume (hematocrit increment (%),10.7 ± 4.2 vs. 10.1 ± 5.9, p = 0.015; Hb concentration after blood transfusion (g/L) 132.3 ± 11.1 vs. 127.4 ± 15.4, p = 0.028). CONCLUSION After the transfusion, cer rSO2 and int rSO(2) increased significantly, FTOE decreased and vital signs improved in both the 15 ml/kg and 20 ml/kg groups, and these changes were not significantly different between the two groups. However, the larger group showed a more pronounced increase in hematocrit and hemoglobin, a reduction in the total number of transfusions, and a shorter duration of hospitalization after transfusion in preterm infants without increasing complications.
PICO Summary
Population
Premature infants with anaemia (n= 151).
Intervention
15 ml/kg red blood cell transfusion (small volume group, n= 78).
Comparison
20 ml/kg red blood cell transfusion (large volume group, n= 73).
Outcome
There was no significant difference in cerebral tissue oxygen saturation, intestinal tissue oxygen saturation, cerebral fractional tissue oxygen extraction, and intestinal fractional tissue oxygen extraction between the two groups. Regional oxygen saturation, mean arterial blood pressure, and peripheral oxygen saturation increased; heart rate, cerebral fractional tissue oxygen extraction, and intestinal fractional tissue oxygen extraction decreased following transfusion in both groups. The transfusion number of the large volume group was significantly less than that of the small volume group (1.9 ± 0.3 vs. 2.6 ± 0.9) and hospitalization days were also less than those in the low volume group (44.3 ± 8.2 vs. 47.6 ± 9.8,). The increases in haematocrit and haemoglobin were higher in the large volume group than those in small volume (haematocrit increment (%) 10.7 ± 4.2 vs. 10.1 ± 5.9; haemoglobin concentration after blood transfusion (g/L) 132.3 ± 11.1 vs. 127.4 ± 15.4).
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Effective management of foetal anaemia in Rh(D) alloimmunised pregnant women with intrauterine transfusion: a Systematic Review
Prescott, B., Jackson, D. E.
Hematology, transfusion and cell therapy. 2023
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Abstract
BACKGROUND Foetal anaemia is caused by a severe pregnancy complication, haemolytic disease of the foetus and newborn. Intrauterine transfusions (IUTs) are performed to treat foetal anaemia in alloimmunised pregnant women. If left untreated hydrops can develop thereby reducing the chance of survival. Survival rates have improved but the procedure is not without complications. Procedure-related complications can be associated with early gestational age, hence delaying IUT could improve outcomes. This review aims to determine the effectiveness and safety of IUTs by examining survival and mortality rates, procedure-related complications with associated foetal mortality and the influence of hydrops. STUDY DESIGN AND METHOD A systematic review was conducted by searching keywords in four scientific databases from January 2000 to April 2022. A meta-analysis was performed with the OpenMeta-Analyst software using an arcsine transformed proportion with the binary random-effects model and maximum likelihood method. RESULTS Fifteen studies were identified as eligible and used in the meta-analysis. The forest plots all showed statistically significant outcomes with heterogeneity of data. Results indicated a greater foetal survival rate with IUT to treat anaemic foetuses, a low foetal mortality rate, and low risk of procedure-related complications associated with foetal loss but a higher risk of foetal mortality when hydrops is present. CONCLUSION The findings of this systematic review and meta-analysis provide evidence that IUT is a safe and effective treatment for foetal anaemia in the absence of hydrops when experienced personnel perform the procedure to minimise the risk of procedure-related complications.
PICO Summary
Population
Rh(D) alloimmunised pregnant women (15 studies).
Intervention
Systematic review and meta-analysis to determine the effectiveness and safety of intrauterine transfusions (IUTs).
Comparison
Outcome
The forest plots all showed statistically significant outcomes with heterogeneity of data. Results indicated a greater foetal survival rate with IUT to treat anaemic foetuses, a low foetal mortality rate, and low risk of procedure-related complications associated with foetal loss but a higher risk of foetal mortality when hydrops is present.
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Effect of red blood cell storage time in pediatric cardiac surgery patients: A subgroup analysis of a randomized controlled trial
Martin, S. M., Tucci, M., Spinella, P. C., Ducruet, T., Fergusson, D. A., Freed, D. H., Lacroix, J., Poirier, N., Sivarajan, V. B., Steiner, M. E., et al
JTCVS open. 2023;15:454-467
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Editor's Choice
Abstract
OBJECTIVE This study aimed to determine whether or not transfusion of fresh red blood cells (RBCs) reduced the incidence of new or progressive multiple organ dysfunction syndrome compared with standard-issue RBCs in pediatric patients undergoing cardiac surgery. METHODS Preplanned secondary analysis of the Age of Blood in Children in Pediatric Intensive Care Unit study, an international randomized controlled trial. This study included children enrolled in the Age of Blood in Children in Pediatric Intensive Care Unit trial and admitted to a pediatric intensive care unit after cardiac surgery with cardiopulmonary bypass. Patients were randomized to receive either fresh (stored ≤7 days) or standard-issue RBCs. The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured up to 28 days postrandomization or at pediatric intensive care unit discharge, or death. RESULTS One hundred seventy-eight patients (median age, 0.6 years; interquartile range, 0.3-2.6 years) were included with 89 patients randomized to the fresh RBCs group (median length of storage, 5 days; interquartile range, 4-6 days) and 89 to the standard-issue RBCs group (median length of storage, 18 days; interquartile range, 13-22 days). There were no statistically significant differences in new or progressive multiple organ dysfunction syndrome between fresh (43 out of 89 [48.3%]) and standard-issue RBCs groups (38 out of 88 [43.2%]), with a relative risk of 1.12 (95% CI, 0.81 to 1.54; P = .49) and an unadjusted absolute risk difference of 5.1% (95% CI, -9.5% to 19.8%; P = .49). CONCLUSIONS In neonates and children undergoing cardiac surgery with cardiopulmonary bypass, the use of fresh RBCs did not reduce the incidence of new or progressive multiple organ dysfunction syndrome compared with the standard-issue RBCs. A larger trial is needed to confirm these results.
PICO Summary
Population
Children admitted to a paediatric intensive care unit after cardiac surgery with cardiopulmonary bypass, enrolled in the Age of Blood in Children in Pediatric Intensive Care Unit trial (ABC-PICU), (n= 178).
Intervention
Fresh (stored ≤7 days) red blood cells (RBCs), (n= 89).
Comparison
Standard-issue RBCs (n= 89).
Outcome
The authors performed a preplanned subgroup analysis of the ABC-PICU trial. The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured up to 28 days post-randomization or at paediatric intensive care unit discharge, or death. There were no statistically significant differences in new or progressive multiple organ dysfunction syndrome between fresh (43 out of 89 [48.3%]) and standard-issue RBCs groups (38 out of 88 [43.2%]), with a relative risk of 1.12; 95% CI [0.81, 1.54] and an unadjusted absolute risk difference of 5.1%; 95% CI [-9.5%, 19.8%].
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A randomized controlled trial to explore the safety and efficacy of irradiated buffy-coat granulocytes in pediatric patients with febrile neutropenia
Ramachandran, M., Gupta, A. K., Meena, J. P., Upadhyay, A. D., Coshic, P., Lodha, R., Seth, R.
American journal of blood research. 2023;13(5):152-161
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Editor's Choice
Abstract
BACKGROUND Transfusion of granulocytes obtained by apheresis is beneficial in febrile neutropenia (FN) but expensive and time-consuming. Buffy-coat-derived granulocytes could be an alternative. We studied the efficacy and safety of the administration of irradiated buffy-coat-derived granulocytes along with the standard of care in pediatric high-risk (HR) FN. METHODS Sixty children ≤18 years with malignancy and chemotherapy-induced HR FN were randomized to either the granulocyte transfusion (GT) arm which received irradiated buffy-coat derived granulocyte transfusion along with the standard treatment or the standard treatment (ST) arm. RESULTS Baseline characteristics, day-to-defervescence, antibiotic duration, hospital stay, and mortality were comparable between the groups. A significant difference was seen in days to achieve absolute neutrophil count (ANC) >500/mm(3) in the 2 groups: 4.5 days (3-6.5) in the GT arm v/s 8 days (4-11) in the ST arm (P=0.01). CONCLUSION Buffy-coat-derived granulocyte transfusion was safe and led to early hematological recovery but was not associated with survival benefits. Future studies with earlier initiation in the intended dose could be undertaken to generate more evidence.
PICO Summary
Population
Children with malignancy and chemotherapy-induced high-risk febrile neutropenia (n= 60).
Intervention
Irradiated buffy-coat derived granulocyte transfusion along with the standard treatment (GT arm, n= 30).
Comparison
Standard treatment, including: antimicrobials, blood component support, and G-CSF as per the protocol (ST arm, n= 30).
Outcome
Baseline characteristics, day-to-defervescence, antibiotic duration, hospital stay, and mortality were comparable between the groups. A significant difference was seen in days to achieve absolute neutrophil count >500/mm(3) in the 2 groups: 4.5 days (3, 6.5) in the GT arm versus 8 days (4, 11) in the ST arm.
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An Individualized Red Blood Cell Transfusion Strategy Using Pediatric Perioperative-Transfusion-Trigger Score Reduced Perioperative Blood Exposure for Children: A Randomized Controlled Clinical Trial
Luo Z, Li Y, Li X, Liao R
Therapeutics and clinical risk management. 2023;19:229-237
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Editor's Choice
Abstract
OBJECTIVE The optimal red blood cell transfusion strategy for children remains unclear. We developed an individualized red blood cell transfusion strategy for children and tested the hypothesis that transfusion guided by this strategy could reduce blood exposure, without increasing perioperative complications in children. METHODS In this randomized controlled clinical trial, 99 children undergoing noncardiac surgeries who had blood loss of more than 20% total blood volume were randomly assigned to an individualized-strategy group using Pediatric Perioperative-Transfusion-Trigger Score or a control group. The amount of transfused red blood cell was counted, and patients were followed up for postoperative complications within 30 days. RESULTS Twenty-six children (53.1%) in the individualized-strategy group received transfusion perioperatively, as compared with 37 children (74%) in the control group (p < 0.05). During surgery, children in the individualized-strategy group were exposed to fewer transfusions than in the control group (0.87±1.03 vs 1.33±1.20 Red-Blood-Cell units per patient, p = 0.02). The incidence of severe complications in the individualized-strategy group had a lower trend compared to the control group (8.2% vs 18%, p = 0.160). No significant difference was found in the other outcomes. CONCLUSION This trial proved that red blood cell transfusion guided by the individualized strategy reduced perioperative blood exposure in children, without increasing the incidence of severe complications. This conclusion needs to be reaffirmed by larger-scale, multicenter clinical trials.
PICO Summary
Population
Children undergoing non-cardiac surgery who had blood loss of more than 20% total blood volume (n= 99).
Intervention
Individualized red blood cell (RBC) transfusion strategy using Pediatric Perioperative-Transfusion-Trigger Score (individualized-strategy group, n= 49).
Comparison
RBC transfusion initiated when the patient’s haemoglobin concentration was lower than 8g per deciliter, or lower than 10g per deciliter for newborns (control group, n= 50).
Outcome
Twenty-six children (53.1%) in the individualized-strategy group received transfusion perioperatively, as compared with 37 children (74%) in the control group. During surgery, children in the individualized-strategy group were exposed to fewer transfusions than in the control group (0.87±1.03 vs. 1.33±1.20 red blood cell units per patient). The incidence of severe complications in the individualized-strategy group had a lower trend compared to the control group (8.2% vs. 18%). No significant difference was found in the other outcomes.
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Two-year outcomes following a randomised platelet transfusion trial in preterm infants
Moore CM, D'Amore A, Fustolo-Gunnink S, Hudson C, Newton A, Santamaria BL, Deary A, Hodge R, Hopkins V, Mora A, et al
Archives of disease in childhood. Fetal and neonatal edition. 2023
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Editor's Choice
Abstract
OBJECTIVE Assess mortality and neurodevelopmental outcomes at 2 years of corrected age in children who participated in the PlaNeT-2/MATISSE (Platelets for Neonatal Transfusion - 2/Management of Thrombocytopenia in Special Subgroup) study, which reported that a higher platelet transfusion threshold was associated with significantly increased mortality or major bleeding compared to a lower one. DESIGN Randomised clinical trial, enrolling from June 2011 to August 2017. Follow-up was complete by January 2020. Caregivers were not blinded; however, outcome assessors were blinded to treatment group. SETTING 43 level II/III/IV neonatal intensive care units (NICUs) across UK, Netherlands and Ireland. PATIENTS 660 infants born at less than 34 weeks' gestation with platelet counts less than 50×10(9)/L. INTERVENTIONS Infants were randomised to undergo a platelet transfusion at platelet count thresholds of 50×10(9)/L (higher threshold group) or 25×10(9)/L (lower threshold group). MAIN OUTCOMES MEASURES Our prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age. RESULTS Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR 1.54, 95% CI 1.09 to 2.17, p=0.017). CONCLUSIONS Infants randomised to a higher platelet transfusion threshold of 50×10(9)/L compared with 25×10(9)/L had a higher rate of death or significant neurodevelopmental impairment at a corrected age of 2 years. This further supports evidence of harm caused by high prophylactic platelet transfusion thresholds in preterm infants. TRIAL REGISTRATION NUMBER ISRCTN87736839.
PICO Summary
Population
Preterm infants enrolled in the PlaNeT-2/MATISSE trial, at 43 neonatal intensive care units across UK, Netherlands and Ireland (n= 660).
Intervention
Higher platelet transfusion threshold (n= 296).
Comparison
Lower platelet transfusion threshold (n= 305).
Outcome
The prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age. Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR: 1.54; 95% CI [1.09, 2.17]).
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Effect of washed versus unwashed red blood cells on transfusion-related immune responses in preterm newborns
Crawford TM, Andersen CC, Hodyl NA, Robertson SA, Stark MJ
Clinical & translational immunology. 2022;11(3):e1377
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Editor's Choice
Abstract
OBJECTIVES Transfusion with washed packed red blood cells (PRBCs) may be associated with reduced transfusion-related pro-inflammatory cytokine production. This may be because of alterations in recipient immune responses. METHODS This randomised trial evaluated the effect of transfusion with washed compared with unwashed PRBCs on pro-inflammatory cytokines and endothelial activation in 154 preterm newborns born before 29 weeks' gestation. Changes in plasma cytokines and measures of endothelial activation in recipient blood were analysed after each of the first three transfusions. RESULTS By the third transfusion, infants receiving unwashed blood had an increase in IL-17A (P = 0.04) and TNF (P = 0.007), whereas infants receiving washed blood had reductions in IL-17A (P = 0.013), TNF (P = 0.048), IL-6 (P = 0.001), IL-8 (P = 0.037), IL-12 (P = 0.001) and IFN-γ (P = 0.001). The magnitude of the post-transfusion increase in cytokines did not change between the first and third transfusions in the unwashed group but decreased in the washed group for IL-12 (P = 0.001), IL-17A (P = 0.01) and TNF (P = 0.03), with the difference between the groups reaching significance by the third transfusion (P < 0.001 for each cytokine). CONCLUSION The pro-inflammatory immune response to transfusion in preterm infants can be modified when PRBCs are washed prior to transfusion. Further studies are required to determine whether the use of washed PRBCs for neonatal transfusion translates into reduced morbidity and mortality.
PICO Summary
Population
Pre-term newborns (n= 154).
Intervention
Washed leucodepleted packed red blood cells (PRBCs), (n= 77).
Comparison
Standard unwashed leucodepleted PRBCs (n= 77).
Outcome
Changes in plasma cytokines and measures of endothelial activation in recipient blood were analysed after each of the first three transfusions. By the third transfusion, patients receiving unwashed blood had an increase in IL-17A and TNF, whereas patients receiving washed blood had reductions in IL-17A, TNF, IL-6, IL-8, IL-12 and IFN-γ. The magnitude of the post-transfusion increase in cytokines did not change between the first and third transfusions in the unwashed group but decreased in the washed group for IL-12, IL-17A and TNF, with the difference between the groups reaching significance by the third transfusion for each cytokine.
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Safety and Short-term Outcomes of High-Dose Erythropoietin in Preterm Infants With Intraventricular Hemorrhage: The EpoRepair Randomized Clinical Trial
Wellmann S, Hagmann CF, von Felten S, Held L, Klebermass-Schrehof K, Truttmann AC, Knöpfli C, Fauchère JC, Bührer C, Bucher HU, et al
JAMA network open. 2022;5(12):e2244744
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Abstract
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.
PICO Summary
Population
Preterm infants with intraventricular haemorrhage enrolled in the EpoRepair trial, in 8 Swiss and Austrian tertiary neonatal units (n= 121).
Intervention
Intravenous high-dose erythropoietin (n= 60).
Comparison
Placebo (n= 61).
Outcome
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.