Abstract

OBJECTIVES To present the consensus statements with supporting literature for plasma and platelet transfusions in critically ill neonates and children with malignancy, acute liver disease and/or following liver transplantation, and sepsis and/or disseminated intravascular coagulation from the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding. DESIGN Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children. SETTING Not applicable. PATIENTS Critically ill neonates and children with malignancy, acute liver disease and/or following liver transplantation, and sepsis and/or disseminated intravascular coagulation. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A panel of 13 experts developed evidence-based and, when evidence was insufficient, expert-based statements for plasma and platelet transfusions in critically ill neonates and children with malignancy, acute liver disease and/or following liver transplantation, and sepsis and/or disseminated intravascular coagulation. These statements were reviewed and ratified by the 29 Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding experts. A systematic review was conducted using MEDLINE, EMBASE, and Cochrane Library databases, from inception to December 2020. Consensus was obtained using the Research and Development/University of California, Los Angeles Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 12 expert consensus statements. CONCLUSIONS In the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding program, the current absence of evidence for use of plasma and/or platelet transfusion in critically ill children with malignancy, acute liver disease and/or following liver transplantation, and sepsis means that only expert consensus statements are possible for these areas of practice.

Abstract

IMPORTANCE The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. OBJECTIVE To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). INTERVENTIONS Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. MAIN OUTCOMES AND MEASURES The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. RESULTS The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). CONCLUSIONS AND RELEVANCE Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02735707.

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Abstract

BACKGROUND AND OBJECTIVES Platelet transfusions are used across multiple patient populations to prevent and correct bleeding. This scoping review aimed to map the currently available systematic reviews (SRs) and evidence-based guidelines in the field of platelet transfusion. MATERIALS AND METHODS A systematic literature search was conducted in seven databases for SRs on effectiveness (including dose and timing, transfusion trigger and ratio to other blood products), production modalities and decision support related to platelet transfusion. The following data were charted: methodological features of the SR, population, concept and context features, outcomes reported, study design and number of studies included. Results were synthesized in interactive evidence maps. RESULTS We identified 110 SRs. The majority focused on clinical effectiveness, including prophylactic or therapeutic transfusions compared to no platelet transfusion (34 SRs), prophylactic compared to therapeutic-only transfusion (8 SRs), dose, timing (11 SRs) and threshold for platelet transfusion (15 SRs) and the ratio of platelet transfusion to other blood products in massive transfusion (14 SRs). Furthermore, we included 34 SRs on decision support, of which 26 evaluated viscoelastic testing. Finally, we identified 22 SRs on platelet production modalities, including derivation (4 SRs), pathogen inactivation (6 SRs), leucodepletion (4 SRs) and ABO/human leucocyte antigen matching (5 SRs). The SRs were mapped according to concept and clinical context. CONCLUSION An interactive evidence map of SRs and evidence-based guidelines in the field of platelet transfusion has been developed and identified multiple reviews. This work serves as a tool for researchers looking for evidence gaps, thereby both supporting research and avoiding unnecessary duplication.

Abstract

OBJECTIVES Critically ill children frequently receive plasma and platelet transfusions. We sought to determine evidence-based recommendations, and when evidence was insufficient, we developed expert-based consensus statements about decision-making for plasma and platelet transfusions in critically ill pediatric patients. DESIGN Systematic review and consensus conference series involving multidisciplinary international experts in hemostasis, and plasma/platelet transfusion in critically ill infants and children (Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding [TAXI-CAB]). SETTING Not applicable. PATIENTS Children admitted to a PICU at risk of bleeding and receipt of plasma and/or platelet transfusions. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A panel of 29 experts in methodology, transfusion, and implementation science from five countries and nine pediatric subspecialties completed a systematic review and participated in a virtual consensus conference series to develop recommendations. The search included MEDLINE, EMBASE, and Cochrane Library databases, from inception to December 2020, using a combination of subject heading terms and text words for concepts of plasma and platelet transfusion in critically ill children. Four graded recommendations and 49 consensus expert statements were developed using modified Research and Development/UCLA and Grading of Recommendations, Assessment, Development, and Evaluation methodology. We focused on eight subpopulations of critical illness (1, severe trauma, intracranial hemorrhage, or traumatic brain injury; 2, cardiopulmonary bypass surgery; 3, extracorporeal membrane oxygenation; 4, oncologic diagnosis or hematopoietic stem cell transplantation; 5, acute liver failure or liver transplantation; 6, noncardiac surgery; 7, invasive procedures outside the operating room; 8, sepsis and/or disseminated intravascular coagulation) as well as laboratory assays and selection/processing of plasma and platelet components. In total, we came to consensus on four recommendations, five good practice statements, and 44 consensus-based statements. These results were further developed into consensus-based clinical decision trees for plasma and platelet transfusion in critically ill pediatric patients. CONCLUSIONS The TAXI-CAB program provides expert-based consensus for pediatric intensivists for the administration of plasma and/or platelet transfusions in critically ill pediatric patients. There is a pressing need for primary research to provide more evidence to guide practitioners.

Abstract

IMPORTANCE Auditing and feedback are frequently used to improve patient care. However, it remains unclear how to optimize feedback effectiveness for the appropriate use of treatments such as blood transfusion, a common but costly procedure that is more often overused than underused. OBJECTIVE To evaluate 2 theoretically informed feedback interventions to improve the appropriate use of blood transfusions. DESIGN, SETTING, AND PARTICIPANTS Two sequential, linked 2 × 2 cluster randomized trials were performed in hospitals in the UK participating in national audits of transfusion for perioperative anemia and management of hematological disorders. Data were collected for a surgical trial from October 1, 2014, to October 31, 2016, with follow-up completed on October 31, 2016. Data were collected for a hematological trial through follow-up from July 1, 2015, to June 30, 2017. Trial data were analyzed from November 1, 2016, to June 1, 2019. INTERVENTIONS Hospitals were randomized to standard content or enhanced content to improve feedback clarity and usability and to standard support or enhanced support for staff to act on feedback. MAIN OUTCOMES AND MEASURES The primary end point was appropriateness of transfusions audited at 12 months. Secondary end points included volume of transfusions (aiming for reductions at patient and cluster levels) and transfusion-related adverse events and reactions. RESULTS One hundred thirty-five of 152 eligible clusters participated in the surgical audit (2714 patients; mean [SD] age, 74.9 [14.0] years; 1809 women [66.7%]), and 134 of 141 participated in the hematological audit (4439 patients; median age, 72.0 [IQR, 64.0-80.0] years; 2641 men [59.5%]). Fifty-seven of 69 clusters (82.6%) in the surgical audit randomized to enhanced content downloaded reports compared with 52 of 66 clusters (78.8%) randomized to standard reports. Fifty-nine of 68 clusters (86.8%) randomized to enhanced support logged onto the toolkit. The proportion of patients with appropriate transfusions was 0.184 for standard content and 0.176 for enhanced content (adjusted odds ratio [OR], 0.91 [97.5% CI, 0.61-1.36]) and 0.181 for standard support and 0.180 for enhanced support (adjusted OR, 1.05 [97.5% CI, 0.68-1.61]). For the hematological audit, 53 of 66 clusters (80.3%) randomized to enhanced content downloaded the reports compared with 53 of 68 clusters (77.9%) randomized to standard content. Forty-nine of 67 clusters sites (73.1%) assigned to enhanced support logged into the toolkit at least once. The proportion of patients with appropriate transfusions was 0.744 for standard content and 0.714 for enhanced content (adjusted OR, 0.81 [97.5% CI, 0.56-1.12]), and 0.739 for standard support and 0.721 for enhanced support (adjusted OR, 0.96 [97.5% CI, 0.67-1.38]). CONCLUSIONS AND RELEVANCE This comparison of cluster randomized trials found that interventions to improve feedback usability and guide local action were no more effective than standard feedback in increasing the appropriate use of blood transfusions. Auditing and feedback delivered at scale is a complex and costly program; therefore, effective responses may depend on developing robust local quality improvement arrangements, which can be evaluated using rigorous experimental designs embedded within national programs. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN15490813.

Abstract

BACKGROUND The optimal haemoglobin threshold for use of red blood cell (RBC) transfusions in anaemic patients remains an active field of research. Blood is a scarce resource, and in some countries, transfusions are less safe than in others because of inadequate testing for viral pathogens. If a liberal transfusion policy does not improve clinical outcomes, or if it is equivalent, then adopting a more restrictive approach could be recognised as the standard of care. OBJECTIVES The aim of this review update was to compare 30-day mortality and other clinical outcomes for participants randomised to restrictive versus liberal red blood cell (RBC) transfusion thresholds (triggers) for all clinical conditions. The restrictive transfusion threshold uses a lower haemoglobin concentration as a threshold for transfusion (most commonly, 7.0 g/dL to 8.0 g/dL), and the liberal transfusion threshold uses a higher haemoglobin concentration as a threshold for transfusion (most commonly, 9.0 g/dL to 10.0 g/dL). SEARCH METHODS We identified trials through updated searches: CENTRAL (2020, Issue 11), MEDLINE (1946 to November 2020), Embase (1974 to November 2020), Transfusion Evidence Library (1950 to November 2020), Web of Science Conference Proceedings Citation Index (1990 to November 2020), and trial registries (November 2020). We checked the reference lists of other published reviews and relevant papers to identify additional trials. We were aware of one trial identified in earlier searching that was in the process of being published (in February 2021), and we were able to include it before this review was finalised. SELECTION CRITERIA We included randomised trials of surgical or medical participants that recruited adults or children, or both. We excluded studies that focused on neonates. Eligible trials assigned intervention groups on the basis of different transfusion schedules or thresholds or 'triggers'. These thresholds would be defined by a haemoglobin (Hb) or haematocrit (Hct) concentration below which an RBC transfusion would be administered; the haemoglobin concentration remains the most commonly applied marker of the need for RBC transfusion in clinical practice. We included trials in which investigators had allocated participants to higher thresholds or more liberal transfusion strategies compared to more restrictive ones, which might include no transfusion. As in previous versions of this review, we did not exclude unregistered trials published after 2010 (as per the policy of the Cochrane Injuries Group, 2015), however, we did conduct analyses to consider the differential impact of results of trials for which prospective registration could not be confirmed. DATA COLLECTION AND ANALYSIS We identified trials for inclusion and extracted data using Cochrane methods. We pooled risk ratios of clinical outcomes across trials using a random-effects model. Two review authors independently extracted data and assessed risk of bias. We conducted predefined analyses by clinical subgroups. We defined participants randomly allocated to the lower transfusion threshold as being in the 'restrictive transfusion' group and those randomly allocated to the higher transfusion threshold as being in the 'liberal transfusion' group. MAIN RESULTS A total of 48 trials, involving data from 21,433 participants (at baseline), across a range of clinical contexts (e.g. orthopaedic, cardiac, or vascular surgery; critical care; acute blood loss (including gastrointestinal bleeding); acute coronary syndrome; cancer; leukaemia; haematological malignancies), met the eligibility criteria. The haemoglobin concentration used to define the restrictive transfusion group in most trials (36) was between 7.0 g/dL and 8.0 g/dL. Most trials included only adults; three trials focused on children. The included studies were generally at low risk of bias for key domains including allocation concealment and incomplete outcome data. Restrictive transfusion strategies reduced the risk of receiving at least one RBC transfusion by 41% across a broad range of clinical contexts (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.53 to 0.66; 42 studies, 20,057 participants; high-quality evidence), with a large amount of heterogeneity between trials (I² = 96%). Overall, restrictive transfusion strategies did not increase or decrease the risk of 30-day mortality compared with liberal transfusion strategies (RR 0.99, 95% CI 0.86 to 1.15; 31 studies, 16,729 participants; I² = 30%; moderate-quality evidence) or any of the other outcomes assessed (i.e. cardiac events (low-quality evidence), myocardial infarction, stroke, thromboembolism (all high-quality evidence)). High-quality evidence shows that the liberal transfusion threshold did not affect the risk of infection (pneumonia, wound infection, or bacteraemia). Transfusion-specific reactions are uncommon and were inconsistently reported within trials. We noted less certainty in the strength of evidence to support the safety of restrictive transfusion thresholds for the following predefined clinical subgroups: myocardial infarction, vascular surgery, haematological malignancies, and chronic bone-marrow disorders. AUTHORS' CONCLUSIONS Transfusion at a restrictive haemoglobin concentration decreased the proportion of people exposed to RBC transfusion by 41% across a broad range of clinical contexts. Across all trials, no evidence suggests that a restrictive transfusion strategy impacted 30-day mortality, mortality at other time points, or morbidity (i.e. cardiac events, myocardial infarction, stroke, pneumonia, thromboembolism, infection) compared with a liberal transfusion strategy. Despite including 17 more randomised trials (and 8846 participants), data remain insufficient to inform the safety of transfusion policies in important and selected clinical contexts, such as myocardial infarction, chronic cardiovascular disease, neurological injury or traumatic brain injury, stroke, thrombocytopenia, and cancer or haematological malignancies, including chronic bone marrow failure. Further work is needed to improve our understanding of outcomes other than mortality. Most trials compared only two separate thresholds for haemoglobin concentration, which may not identify the actual optimal threshold for transfusion in a particular patient. Haemoglobin concentration may not be the most informative marker of the need for transfusion in individual patients with different degrees of physiological adaptation to anaemia. Notwithstanding these issues, overall findings provide good evidence that transfusions with allogeneic RBCs can be avoided in most patients with haemoglobin thresholds between the range of 7.0 g/dL and 8.0 g/dL. Some patient subgroups might benefit from RBCs to maintain higher haemoglobin concentrations; research efforts should focus on these clinical contexts.

Abstract

BACKGROUND Prophylactic platelet transfusions prevent bleeding in hemato-oncology patients, but it is unclear how any benefit varies between patients. Our aim was to assess if patients with different baseline risks for bleeding benefit differently from a prophylactic platelet transfusion strategy. STUDY DESIGN AND METHODS Using the data from the randomized controlled TOPPS trial (Trial of Platelet Prophylaxis), we developed a prediction model for World Health Organization grades 2, 3, and 4 bleeding risk (defined as at least one bleeding episode in a 30 days period) and grouped patients in four risk-quartiles based on this predicted baseline risk. Predictors in the model were baseline platelet count, age, diagnosis, disease modifying treatment, disease status, previous stem cell transplantation, and the randomization arm. RESULTS The model had a c-statistic of 0.58 (95% confidence interval [CI] 0.54-0.64). There was little variation in predicted risks (quartiles 46%, 47%, and 51%), but prophylactic platelet transfusions gave a risk reduction in all risk quartiles. The absolute risk difference (ARD) was 3.4% (CI -12.2 to 18.9) in the lowest risk quartile (quartile 1), 7.4% (95% CI -8.4 to 23.3) in quartile 2, 6.8% (95% CI -9.1 to 22.9) in quartile 3, and 12.8% (CI -3.1 to 28.7) in the highest risk quartile (quartile 4). CONCLUSION In our study, generally accepted bleeding risk predictors had limited predictive power (expressed by the low c-statistic), and, given the wide confidence intervals of predicted ARD, could not aid in identifying subgroups of patients who might benefit more (or less) from prophylactic platelet transfusion.

Abstract

BACKGROUND Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).

Abstract

BACKGROUND Guidelines for platelet (PLT) transfusion are an important source of information for clinicians. Although guidelines intend to increase consistency and quality of care, variation in methodology and recommendations may exist that could impact the value of a guideline. We aimed to determine the quality of existing PLT transfusion guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument and to describe the inconsistencies in recommendations. STUDY DESIGN AND METHODS A systematic search was undertaken for evidence-based guidelines from January 1, 2013, to January 25, 2019. Citations were reviewed in duplicate for inclusion and descriptive data extracted. Four physicians appraised the guideline using the AGREE II instrument and the scaled score for each item evaluated was calculated. The protocol was registered in PROSPERO. RESULTS Of 6744 citations, 6740 records were screened. Seven of 28 full-text studies met the inclusion criteria. The median scaled score (and the interquartile range of the scaled score) for the following items were as follows: scope and purpose, 94% (8%); stakeholder involvement, 63% (18%); rigor of development, 83% (14%); clarity of presentation, 94% (6%); applicability, 58% (20%); and editorial independence, 77% (4%). Overall quality ranged from 4 to 7 (7 is the maximum score). Inconsistent recommendations were on prophylactic PLT transfusion in hypoproliferative thrombocytopenia in the presence of risk factors and dose recommendations. CONCLUSION Inconsistencies between guidelines and variable quality highlight areas for future guideline writers to address. Areas of specific attention include issues of stakeholder involvement and applicability.