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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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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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Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death
Fustolo-Gunnink SF, Fijnvandraat K, van Klaveren D, Stanworth S, Curley AE, Onland W, Steyerberg EW, de Kort E, d'Haens E, Hulzebos C, et al
Blood. 2019
Abstract
The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25x109/L compared to 50x109/L for major bleeding and/or mortality in preterm neonates (7% absolute risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25x109/L threshold. We aimed to assess this heterogeneity of treatment effect in the PlaNet-2 trial, in order to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariable logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into four risk quartiles. Within these quartiles we assessed absolute risk difference between the 50x109/L and 25x109/L threshold group. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval 0.58 - 0.68). The 25x109/L threshold was associated with absolute risk reduction in all risk groups, varying from 4.9% in the lowest to 12.3% in the highest risk group. These results suggest that a 25x109/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. Current Controlled Trials number ISRCTN87736839.
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Effect of age of transfused red blood cells on neurologic outcome following traumatic brain injury (ABLE-tbi Study): a nested study of the Age of Blood Evaluation (ABLE) trial
Ruel-Laliberte J, Lessard Bonaventure P, Fergusson D, Lacroix J, Zarychanski R, Lauzier F, Tinmouth A, Hebert PC, Green R, Griesdale D, et al
Canadian Journal of Anaesthesia. 2019;66(6):696-705
Abstract
BACKGROUND Anemia is common in critically ill patients with traumatic brain injury, and often requires red blood cell transfusion. Studies suggest that prolonged storage causes lesions of the red blood cells, including a decreased ability to carry oxygen. Considering the susceptibility of the brain to hypoxemia, victims of traumatic brain injury may thus be more vulnerable to exposure to older red blood cells. METHODS Our study aimed to ascertain whether the administration of fresh red blood cells (seven days or less) results in a better neurologic outcome compared with standard red blood cells in critically ill patients with traumatic brain injury requiring transfusion. The Age of Blood Evaluation in traumatic brain injury (ABLE-tbi) study was a nested study within the ABLE study (ISRCTN44878718). Our primary outcome was the extended Glasgow Outcome Scale (GOSe) at six months. RESULTS In the ABLE study, 217 subjects suffered a traumatic brain injury: 110 in the fresh group, and 107 in the standard group. In the fresh group, 68 (73.1%) of the patients had an unfavourable neurologic outcome (GOSe <= 4) compared with 60 (64.5%) in the standard group (P = 0.21). Using a sliding dichotomy approach, we observed no overall effect of fresh red blood cells on neurologic outcome (odds ratio [OR], 1.34; 95% confidence interval [CI], 0.72 to 2.50; P = 0.35) but observed differences across prognostic bands with a decreased odds of unfavourable outcome in patients with the best prognosis at baseline (OR, 0.33; 95% CI, 0.11 to 0.96; P = 0.04) but an increased odds in those with intermediate and worst baseline prognosis (OR, 5.88; 95% CI,1.66 to 20.81; P = 0.006; and OR, 1.67; 95% CI, 0.53 to 5.30; P = 0.38, respectively). CONCLUSION Overall, transfusion of fresh red blood cells was not associated with a better neurologic outcome at six months in critically ill patients with traumatic brain injury. Nevertheless, we cannot exclude a differential effect according to the patient baseline prognosis. TRIAL REGISTRATION ABLE study (ISRCTN44878718); registered 22 August, 2008.
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Quality of evidence-based guidelines for transfusion of red blood cells and plasma: a systematic review
Pavenski K, Stanworth S, Fung M, Wood E M, Pink J, Murphy M F, Hume H, Nahirniak S, Webert K E, Tanael S, et al
Transfusion Medicine Reviews. 2018
Abstract
Many transfusion guidelines are available, but little appraisal of their quality has been undertaken. The quality of guidelines may potentially influence adoption. Our aim was to determine the quality of evidence-based transfusion guidelines (EBG) for red cells and plasma, using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument, and assess duplication and consistency of recommendations. MEDLINE and EMBASE were systematically searched for EBG from 2005 to June 3, 2016. Citations were reviewed for inclusion in duplicate. A guideline was included if it had a specified clinical question, described a systematic search strategy, included critical appraisal of the literature and a description of how recommendations were developed. Four to six physicians used AGREE II to appraise each guideline. Median and scaled scores were calculated, with each item scored on a scale of one to seven, seven representing the highest score. Of 6174 citations, 30 guidelines met inclusion criteria. Twenty six guidelines had recommendations for red cells and 18 included recommendations for plasma use. The median score, the scaled score and the interquartile range of the scaled score were: scope and purpose: median score 5, scaled score 60%, IQR (49-74%); stakeholder involvement 4, 43%, (33-49%); rigor of development 4, 41%, (19-59%); clarity of presentation 5, 69%, (52-81%); applicability 1, 16%, (9-23%); editorial independence 3, 43%, (20-58%). Sixteen guidelines were evaluated to have a scaled domain score of 50% or less. Variations in recommendations were found for the use of hemoglobin triggers for red cell transfusion in patients with acute coronary syndromes and for plasma use for patients with bleeding. Our findings document, limited rigor in guideline development and duplication and inconsistencies in recommendations for the same topic. The process of developing guidelines for red cells and plasma transfusion can be enhanced to improve implementation.
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The Age of BLood Evaluation (ABLE) randomised controlled trial: description of the UK-funded arm of the international trial, the UK cost-utility analysis and secondary analyses exploring factors associated with health-related quality of life and health-care costs during the 12-month follow-up
Walsh TS, Stanworth S, Boyd J, Hope D, Hemmatapour S, Burrows H, Campbell H, Pizzo E, Swart N, Morris S
Health Technology Assessment (Winchester, England). 2017;21((62)):1-118.
Abstract
BACKGROUND At present, red blood cells (RBCs) are stored for up to 42 days prior to transfusion. The relative effectiveness and safety of different RBC storage times prior to transfusion is uncertain. OBJECTIVE To assess the clinical effectiveness and cost-effectiveness of transfusing fresher RBCs (stored for ≤ 7 days) compared with current standard-aged RBCs in critically ill patients requiring blood transfusions. DESIGN The international Age of BLood Evaluation (ABLE) trial was a multicentre, randomised, blinded trial undertaken in Canada, the UK, the Netherlands and France. The UK trial was funded to contribute patients to the international trial and undertake a UK-specific health economic evaluation. SETTING Twenty intensive care units (ICUs) in the UK, as part of 64 international centres. PARTICIPANTS Critically ill patients aged ≥ 18 years (≥ 16 years in Scotland) expected to require mechanical ventilation for ≥ 48 hours and requiring a first RBC transfusion during the first 7 days in the ICU. INTERVENTIONS All decisions to transfuse RBCs were made by clinicians. One patient group received exclusively fresh RBCs stored for ≤ 7 days whenever transfusion was required from randomisation until hospital discharge. The other group received standard-issue RBCs throughout their hospital stay. MAIN OUTCOME MEASURES The primary outcome was 90-day mortality. Secondary outcomes included development of organ dysfunction, new thrombosis, infections and transfusion reactions. The primary economic evaluation was a cost-utility analysis. RESULTS The international trial took place between March 2009 and October 2014 (UK recruitment took place between January 2012 and October 2014). In total, 1211 patients were assigned to receive fresh blood and 1219 patients to receive standard-aged blood. RBCs were stored for a mean of 6.1 days [standard deviation (SD) +/- 4.9 days] in the group allocated to receive fresh blood and 22.0 days (SD +/- 8.4 days) in the group allocated to receive standard-aged blood. Patients received a mean of 4.3 RBC units (SD +/- 5.2 RBC units) and 4.3 RBC units (SD +/- 5.5 RBC units) in the groups receiving fresh blood and standard-aged blood, respectively. At 90 days, 37.0% of patients in the group allocated to receive fresh blood and 35.3% of patients in the group allocated to receive standard-aged blood had died {absolute risk difference 1.7% [95% confidence interval (CI) -2.1% to 5.5%]}. There were no between-group differences in any secondary outcomes. The UK cohort comprised 359 patients randomised and followed up for 12 months for the cost-utility analysis. UK patients had similar characteristics and outcomes to the international cohort. Mean total costs per patient were pound32,346 (95% CI pound29,306 to pound35,385) in the group allocated to receive fresh blood and pound33,353 (95% CI pound29,729 to pound36,978) in the group allocated to receive standard-aged blood. Approximately 85% of the total costs were incurred during the index hospital admission. There were no significant cost differences between the two groups [mean incremental costs for those receiving fresh vs. standard-aged blood: - pound231 (95% CI - pound4876 to pound4415)], nor were there significant differences in outcomes (mean difference in quality-adjusted life-years -0.010, 95% CI -0.078 to 0.057). LIMITATIONS Adverse effects from the exclusive use of older RBCs compared with standard or fresh RBCs cannot be excluded. CONCLUSIONS The use of RBCs aged ≤ 7 days confers no clinical or economic benefit in critically ill patients compared with standard-aged RBCs. FUTURE WORK Future studies should address the safety of RBCs near the end of the current permitted storage age. TRIAL REGISTRATION Current Controlled Trials ISRCTN44878718. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 62. See the NIHR Journals Library website for further project information. The
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A systematic review and meta-analysis of risks of red cell transfusion for neonatal morbidities or mortality
Keir AK, Pal S, Trivella M, Lieberman L, Callum J, Shehata N, Stanworth S
Vox Sanguinis. 2015;109((Suppl. 1)):31-32.. Abstract No. 3D-S12-02.
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Adverse effects of RBC transfusions in neonates: a systematic review and meta-analysis
Keir A, Pal S, Trivella M, Lieberman L, Callum J, Sheheta N, Stanworth S
Abstracts of the HAA 2015 Annual Scientific Meeting. 2015;:196-7.. Abstract No. 151.
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A therapeutic-only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation
Crighton GL, Estcourt LJ, Wood EM, Trivella M, Doree C, Stanworth S
Cochrane Database of Systematic Reviews.. 2015;((9)):CD010981.
Abstract
BACKGROUND Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in thrombocytopenic patients with bone marrow failure. Although considerable advances have been made in platelet transfusion therapy in the last 40 years, some areas continue to provoke debate, especially concerning the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding.This is an update of a Cochrane review first published in 2004 and updated in 2012 that addressed four separate questions: therapeutic-only versus prophylactic platelet transfusion policy; prophylactic platelet transfusion threshold; prophylactic platelet transfusion dose; and platelet transfusions compared to alternative treatments. We have now split this review into four smaller reviews looking at these questions individually; this review is the first part of the original review. OBJECTIVES To determine whether a therapeutic-only platelet transfusion policy (platelet transfusions given when patient bleeds) is as effective and safe as a prophylactic platelet transfusion policy (platelet transfusions given to prevent bleeding, usually when the platelet count falls below a given trigger level) in patients with haematological disorders undergoing myelosuppressive chemotherapy or stem cell transplantation. SEARCH METHODS We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (Cochrane Library 2015, Issue 6), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 23 July 2015. SELECTION CRITERIA RCTs involving transfusions of platelet concentrates prepared either from individual units of whole blood or by apheresis, and given to prevent or treat bleeding in patients with malignant haematological disorders receiving myelosuppressive chemotherapy or undergoing HSCT. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS We identified seven RCTs that compared therapeutic platelet transfusions to prophylactic platelet transfusions in haematology patients undergoing myelosuppressive chemotherapy or HSCT. One trial is still ongoing, leaving six trials eligible with a total of 1195 participants. These trials were conducted between 1978 and 2013 and enrolled participants from fairly comparable patient populations. We were able to critically appraise five of these studies, which contained separate data for each arm, and were unable to perform quantitative analysis on one study that did not report the numbers of participants in each treatment arm.Overall the quality of evidence per outcome was low to moderate according to the GRADE approach. None of the included studies were at low risk of bias in every domain, and all the studies identified had some threats to validity. We deemed only one study to be at low risk of bias in all domains other than blinding.Two RCTs (801 participants) reported at least one bleeding episode within 30 days of the start of the study. We were unable to perform a meta-analysis due to considerable statistical heterogeneity between studies. The statistical heterogeneity seen may relate to the different methods used in studies for the assessment and grading of bleeding. The underlying patient diagnostic and treatment categories also appeared to have some effect on bleeding risk. Individually these studies showed a similar effect, that a therapeutic-only platelet transfusion strategy was associated with an increased risk of clinically significant bleeding compared with a prophylactic platelet transfusion policy. Number of days with a clinically significant bleeding event per participant was higher in the therapeutic-only group than in the prophylactic group (one RCT; 600 participants; mean difference 0.50, 95% confidence interval (CI) 0.10 to 0.90; moderate-quality evidence). There was insufficient evidence to determine whether there was any difference in the number of participants with severe or
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A randomized noninferiority crossover trial of corrected count increments and bleeding in thrombocytopenic hematology patients receiving 2- to 5- versus 6- or 7-day-stored platelets
MacLennan S, Harding K, Llewelyn C, Choo L, Bakrania L, Massey E, Stanworth S, Pendry K, Williamson LM
Transfusion. 2015;55((8)):1856-65.
Abstract
BACKGROUND Bacterial screening offers the possibility of extending platelet (PLT) storage to Day 7. We conducted a noninferiority, crossover trial comparing PLTs stored for 6 or 7 days versus 2 to 5 days. STUDY DESIGN AND METHODS Stable hematology patients were allocated to receive blocks of 2- to 5- and 6- or 7-day PLTs in random order. The primary outcome was the proportion of successful transfusions during the first block, defined as a corrected count increment (CCI) of more than 4.5 at 8 to 24 hours posttransfusion. RESULTS Of 122 patients with an evaluable first block, 87 (71%) and 84 (69%) had successful transfusions after 2- to 5- and 6- or 7-day PLTs of mean (SD) ages of 3.8 (1.0) and 6.4 (0.5) days, respectively. Six- or 7-day PLTs were declared noninferior to 2- to 5-day PLTs since the upper confidence interval (CI) limit was less than the predefined noninferiority margin of 10% (95% CI, -14.0% to 9.1%; p=0.766). Logistic regression analysis gave an adjusted odds ratio of 0.86 (95% CI, 0.47-1.58; p=0.625). Mean (SD) 8- to 24-hour CCIs were 9.4 (7.9) and 7.7 (7.1) after transfusion with 2- to 5- or 6- or 7-day PLTs (95% CI, -3.31 to 0.03; p=0.054). The proportions of days with bleeding scores of WHO Grade 2 or higher were 13% (38/297 days) and 11% (32/296 days; 95% CI, -3.2 to 7.2; p=0.454). Median interval to next PLT transfusion (2 days) was unaffected (95% CI, -10.5 to 5.4; p=0.531). CONCLUSION In hematology patients, there was no evidence that 6- or 7-day PLTs were inferior to 2- to 5-day PLTs, as measured by proportion of patients with successful transfusions, bleeding events, or interval to next transfusion.Copyright © 2015 AABB.
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Fresh frozen plasma for cardiovascular surgery
Desborough M, Sandu R, Brunskill SJ, Doree C, Trivella M, Montedori A, Abraha I, Stanworth S
Cochrane Database of Systematic Reviews.. 2015;((7)):CD007614.
Abstract
BACKGROUND Fresh frozen plasma (FFP) is a blood component containing procoagulant factors, which is sometimes used in cardiovascular surgery with the aim of reducing the risk of bleeding. The purpose of this review is to assess the risk of mortality for patients undergoing cardiovascular surgery who receive FFP. OBJECTIVES To evaluate the risk to benefit ratio of FFP transfusion in cardiovascular surgery for the treatment of bleeding patients or for prophylaxis against bleeding. SEARCH METHODS We searched 11 bibliographic databases and four ongoing trials databases including the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, 2015), MEDLINE (OvidSP, 1946 to 21 April 2015), EMBASE (OvidSP, 1974 to 21 April 2015), PubMed (e-publications only: searched 21 April 2015), ClinicalTrials.gov, World Health Organization (WHO) ICTRP and the ISRCTN Register (searched 21 April 2015). We also searched the references of all identified trials and relevant review articles. We did not limit the searches by language or publication status. SELECTION CRITERIA We included randomised controlled trials in patients undergoing major cardiac or vascular surgery who were allocated to a FFP group or a comparator (no plasma or an active comparator, either clinical plasma (any type) or a plasma-derived blood product). We included participants of any age (neonates, children and adults). We excluded studies of plasmapheresis and plasma exchange. DATA COLLECTION AND ANALYSIS Two authors screened all electronically derived citations and abstracts of papers identified by the review search strategy. Two authors assessed risk of bias in the included studies and extracted data independently. We took care to note whether FFP was used therapeutically or prophylactically within each trial. MAIN RESULTS We included 15 trials, with a total of 755 participants for analysis in the review. Fourteen trials compared prophylactic use of FFP against no FFP. One study compared therapeutic use of two types of plasma. The timing of intervention varied, including FFP transfusion at the time of heparin neutralisation and stopping cardiopulmonary bypass (CPB) (seven trials), with CPB priming (four trials), after anaesthesia induction (one trial) and postoperatively (two trials). Twelve trials excluded patients having emergency surgery and nine excluded patients with coagulopathies.Overall the trials were small, with only four reporting an a priori sample size calculation. No trial was powered to determine changes in mortality as a primary outcome. There was either high risk of bias, or unclear risk, in the majority of trials included in this review.There was no difference in the number of deaths between the intervention arms in the six trials (with 287 patients) reporting mortality (very low quality evidence). There was also no difference in blood loss in the first 24 hours for neonatal/paediatric patients (four trials with 138 patients; low quality evidence): mean difference (MD) -1.46 ml/kg (95% confidence interval (CI) -4.7 to 1.78 ml/kg); or adult patients (one trial with 120 patients): MD -12.00 ml (95% CI -101.16 to 77.16 ml).Transfusion with FFP was inferior to control for preventing patients receiving any red cell transfusion: Peto odds ratio (OR) 2.57 (95% CI 1.30 to 5.08; moderate quality evidence). There was a difference in prothrombin time within two hours of FFP transfusion in eight trials (with 210 patients; moderate quality evidence) favouring the FFP arm: MD -0.71 seconds (95% CI -1.28 to -0.13 seconds). There was no difference in the risk of returning to theatre for reoperation (eight trials with 398 patients; moderate quality evidence): Peto OR 0.81 (95% CI 0.26 to 2.57). Only one included study reported adverse events as an outcome and reported no significant adverse events following FFP transfusion. AUTHORS' CONCLUSIONS This review has found no evidence to support the prophylactic administration of FFP to patients without coagulopathy undergoing elective cardiac surgery. There was insufficient evidence about treatment of p