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Transfusion Evidence Alert and Round-Up

On this page you can view articles from previous editions of the Transfusion Evidence Alert and Round-Up; use the button on the left to sign up to receive future editions direct to your inbox. The Transfusion Evidence Alert is a monthly overview of 10 selected evidence-based publications in the field of transfusion medicine, including relevant COVID-19 articles. The articles are selected by experts in the field from the Systematic Review Initiative, funded by the four UK blood services. The Transfusion Evidence Round-Up is a quarterly overview of the top 10 high quality studies about an internationally relevant subject in the field of transfusion medicine. The articles are selected by members from the International Society of Blood Transfusion and drawn from the Transfusion Evidence Library and where relevant Stem Cell Evidence.

October 2022


  1. Testing equivalence of two doses of intravenous iron to treat iron deficiency in pregnancy: A randomised controlled trial
    BJOG: an international journal of obstetrics and gynaecology. 2022

    Abstract

    OBJECTIVE To test equivalence of two doses of intravenous iron (ferric carboxymaltose) in pregnancy. DESIGN Parallel, two-arm equivalence randomised controlled trial with an equivalence margin of 5%. SETTING Single centre in Australia. POPULATION 278 pregnant women with iron deficiency. METHODS Participants received either 500 mg (n=152) or 1000mg (n=126) of intravenous ferric carboxymaltose in the second or third trimester. MAIN OUTCOME MEASURES The proportion of participants requiring additional intravenous iron (500mg) to achieve and maintain ferritin >30ug/L (diagnostic threshold for iron deficiency) at 4 weeks post-infusion, and at 6 weeks, and 3-, 6- and 12-months postpartum. Secondary endpoints included repeat infusion rate, iron status, birth, and safety outcomes. RESULTS The two doses were not equivalent within a 5% margin at any timepoint. At 4 weeks post infusion, 26/73 (36%) participants required a repeat infusion in the 500 mg group compared with 5/67 (8%) in the 1000 mg group (difference in proportions, 0.283 95% confidence interval (0.177, 0.389)). Overall, participants in the 500 mg arm received twice the repeat infusion rate (0.81 (SD= 0.824 vs 0.40 (SD= 0.69), rate ratio 2.05, 95% CI (1.45, 2.91)). CONCLUSIONS Administration of 1000 mg ferric carboxymaltose in pregnancy maintains iron stores and reduces the need for repeat infusions. A 500 mg dose requires ongoing monitoring to ensure adequate iron stores are reached and sustained.
    PICO Summary

    Population

    Pregnant women with iron deficiency (n= 278).

    Intervention

    500 mg of intravenous ferric carboxymaltose (n= 152).

    Comparison

    1,000 mg of intravenous ferric carboxymaltose (n= 126).

    Outcome

    The two doses were not equivalent within a 5% margin at any timepoint. At 4 weeks post-infusion, 26/73 (36%) participants required a repeat infusion in the 500 mg group compared with 5/67 (8%) in the 1,000 mg group (difference in proportions, 0.283 95% confidence interval (0.177, 0.389)). Overall, participants in the 500 mg arm received twice the repeat infusion rate (0.81 (SD= 0.824 vs. 0.40 (SD= 0.69), rate ratio 2.05, 95% CI (1.45, 2.91)).
  2. Thromboelastography-Guided Therapy Enhances Patient Blood Management in Cirrhotic Patients: A Meta-analysis Based on Randomized Controlled Trials
    Seminars in thrombosis and hemostasis. 2022

    Abstract

    Patients with cirrhosis often have abnormal hemostasis, with increased risk of hemorrhage and thrombosis. Thromboelastography provides a rapid assessment of the coagulation status and can guide product transfusions in adult patients with cirrhosis. This study aimed to determine whether the use of thromboelastography in adult patients with cirrhosis decreases blood product use and impacts adverse events or mortality compared with standard practice. A registered (PROSPERO CRD42020192458) systematic review and meta-analysis was conducted for randomized controlled trials (RCTs) comparing thromboelastography-guided hemostatic management versus standard practice (control). Co-primary outcomes were the number of transfused platelet units and fresh frozen plasma (FFP) units. Secondary outcomes were mortality, adverse events, utilization of individual blood products, blood loss or excessive bleeding events, hospital/intensive care unit stay, and liver transplant/intervention outcomes. The search identified 260 articles, with five RCTs included in the meta-analysis. Platelet use was five times lower with thromboelastography versus the control, with a relative risk of 0.17 (95% confidence interval [CI]: [0.03-0.90]; p = 0.04), but FFP use did not differ significantly. Thromboelastography was associated with less blood product (p < 0.001), FFP + platelets (p < 0.001), and cryoprecipitate (p < 0.001) use. No differences were reported in bleeding rates or longer term mortality between groups, with the thromboelastography group having lower mortality at 7 days versus the control (relative risk [95% CI] = 0.52 [0.30-0.91]; p = 0.02). Thromboelastography-guided therapy in patients with cirrhosis enhances patient blood management by reducing use of blood products without increasing complications.
    PICO Summary

    Population

    Patients with cirrhosis (5 studies, n= 302).

    Intervention

    Thromboelastography-guided haemostatic management.

    Comparison

    Standard coagulation testing (standard practice).

    Outcome

    Platelet use was five times lower with thromboelastography vs. standard practice, with a relative risk of 0.17 (95% confidence interval [CI]: [0.03-0.90]), but fresh frozen plasma (FFP) use did not differ significantly. Thromboelastography was associated with less blood product, FFP + platelets, and cryoprecipitate use. No differences were reported in bleeding rates or longer-term mortality between groups, with the thromboelastography group having lower mortality at 7 days vs. standard practice (relative risk [95% CI] = 0.52 [0.30-0.91]).
  3. A randomized trial of blood donor iron repletion on red cell quality for transfusion and donor cognition and wellbeing
    Blood. 2022

    Abstract

    Although altruistic regular blood donors are vital for the blood supply, many become iron deficient from donation-induced iron loss. The effects of blood donation-induced iron deficiency on red cell transfusion quality or donor cognition are unknown. In this double-blind, randomized trial, adult iron-deficient blood donors (n=79; ferritin <15 mg/L, and zinc protoporphyrin >60 mMol/mol heme) who met donation qualifications were enrolled. A first standard blood donation was followed by the gold-standard measure for red cell storage quality: a 51-chromium post-transfusion red cell recovery study. Donors were then randomized to intravenous iron repletion (one-gram low molecular weight iron dextran) or placebo. A second donation approximately five months later was followed by another recovery study. Primary outcome was the within-subject change in post-transfusion recovery. The primary outcome measure of an ancillary study reported here was the National Institutes of Health (NIH) Toolbox-derived uncorrected standard Cognition Fluid Composite Score. Overall, 983 donors were screened; 110 were iron-deficient and, of these, 39 were randomized to iron repletion and 40 to placebo. Red cell storage quality was unchanged by iron repletion: mean change in post-transfusion recovery was 1.6% (95% CI -0.5 - 3.8) and -0.4% (-2.0 - 1.2) with and without iron, respectively. Iron repletion did not affect any cognition or wellbeing measures. These data provide evidence that current criteria for blood donation preserve red cell transfusion quality for the recipient and protect adult donors from measurable effects of blood donation-induced iron deficiency on cognition. This trial was registered at www.clinicaltrials.gov as NCT02889133 and NCT02990559.
    PICO Summary

    Population

    Adult iron-deficient blood donors enrolled in the Donor Iron Deficiency Study (DIDS), (n= 79).

    Intervention

    Intravenous iron repletion (n= 39).

    Comparison

    Placebo (n= 40).

    Outcome

    A first standard blood donation was followed by the gold-standard measure for red cell storage quality: a 51-chromium post-transfusion red cell recovery study. Donors were then randomized. A second donation approximately five months later was followed by another recovery study. Primary outcome was the within-subject change in post-transfusion recovery. The primary outcome measure was the National Institutes of Health (NIH) Toolbox-derived uncorrected standard Cognition Fluid Composite Score. Overall, 983 donors were screened; 110 were iron-deficient and, of these, 39 were randomized to iron repletion and 40 to placebo. Red cell storage quality was unchanged by iron repletion: mean change in post-transfusion recovery was 1.6% (95% CI -0.5 - 3.8) and -0.4% (-2.0 - 1.2) with and without iron, respectively. Iron repletion did not affect any cognition or wellbeing measures.
  4. A double-blind randomized placebo-controlled trial of albumin in patients with hepatic encephalopathy: HEAL study
    Journal of hepatology. 2022

    Abstract

    BACKGROUND AND AIMS Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QOL), can persist. Treatment options are limited. AIM: Determine the impact of albumin versus saline on MHE and QOL in patients with prior HE already on standard of care using double-blind, placebo-controlled randomized clinical trial. METHODS Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on HE-treatment were included. Patients on regular IV albumin infusions were excluded. Subjects were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5g/kg or saline over 5 weeks (end-of-drug,EOD) and then 1-week post-infusion (end-of-study,EOS). MHE was defined using either Psychometric hepatic encephalopathy score (PHES), Stroop or Critical clicker frequency. MHE and QOL using Sickness Impact profile (SIP total, physical, psychosocial domain, higher=worse) and serum (inflammation, endothelial dysfunction, and ischemia-modified albumin IMA) were compared between baseline, EOD and EOS. RESULTS 48(24/group) subjects were randomized and were balanced at baseline, including HE-medication use. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and IMA decreased only in the albumin group at EOD and EOS vs baseline. PHES and Stroop MHE reversal and improvement was greater in albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical domain improved in the albumin but not placebo group versus baseline at EOD and EOS along with significant reduction in IL-1β, and endothelial dysfunction markers. CONCLUSION In a double-blind, placebo controlled RCT of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial quality of life likely through amelioration of endothelial dysfunction. LAY SUMMARY Patients who have liver cirrhosis often develop confusion that can result in difficulty thinking and processing information, which can negatively impact their quality of life. We performed a clinical trial of weekly injections of albumin (a protein normally made by the liver, and which is low in cirrhosis) and placebo in patients with cirrhosis and persistent brain problems and found that those who received albumin did better on their brain function and quality of life compared to those who received placebo. Albumin injections were also associated with reduction in inflammation and other blood factors that could potentially be a mechanism of this benefit.
    PICO Summary

    Population

    Patients with hepatic encephalopathy enrolled in the HEAL study (n= 48).

    Intervention

    Albumin (n= 24).

    Comparison

    Saline (n= 24).

    Outcome

    Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at end-of-drug and end-of-study vs. baseline. Psychometric hepatic encephalopathy score and Stroop minimal hepatic encephalopathy reversal and improvement was greater in albumin group at end-of-drug and persisted at end-of-study. Sickness impact profile total and psychosocial, but not physical domain improved in the albumin but not placebo group vs. baseline at end-of-drug and end-of-study along with significant reduction in IL-1β, and endothelial dysfunction markers.
  5. HLA Class II regulation of immune response in sickle cell disease patients: Susceptibility to red blood cell alloimmunization (systematic review and meta-analysis)
    Vox sanguinis. 2022

    Abstract

    BACKGROUND AND OBJECTIVES Sickle cell disease (SCD) patients are commonly treated with red blood cell (RBC) transfusion. Pretransfusion tests commonly involve limited serological antibody testing. RBC alloimmunization to RBC antigens is a frequently encountered complication seen in chronically transfused patients. Genetic factors such as the human leukocyte antigen (HLA) are known to influence and regulate immune responses. HLAs are highly polymorphic and play an essential role in regulating immune responses, including RBC alloimmunization. The aim of this study was to conduct a systematic review and meta-analysis to evaluate the association between HLA Class II allelic polymorphisms with the possible risk of developing RBC alloantibodies. MATERIALS AND METHODS Four databases were systematically searched for relevant studies between the years 2000 and 2021 following the PRISMA guidelines. Four articles met the eligibility and quality criterion, and three alleles, HLA-DRB1*04, HLA-DRB1*15 and HLA-DQB1*03, that were found to be potentially associated with an increased risk in alloantibody formation were included. RESULTS The primary outcome measure was alloimmunization by RBC antigen exposure in multiply transfused SCD patients. The total estimate of alloimmunization of the SCD patients was 2.33 (95% CI, 1.58-3.44), demonstrating susceptibility to RBC alloantibody formation. Heterogeneity between the studies was insignificant, suggesting the differences associated with random sampling errors. The results showed that SCD patients carry an increased risk of producing RBC alloantibodies. CONCLUSION A strategy to prevent RBC alloimmunization is genotyping for genetically susceptible SCD patients receiving multiple transfusions. Early identification of genetic variants that can potentially increase the risk of RBC alloimmunization could aid in the screening process and selection of phenotypically matched RBC units.
    PICO Summary

    Population

    Sickle cell disease (SCD) patients (4 studies).

    Intervention

    Systematic review and meta-analysis evaluating the association between human leukocyte antigen (HLA) Class II allelic polymorphisms with the possible risk of developing red blood cell (RBC) alloantibodies.

    Comparison

    Outcome

    Three alleles: HLA-DRB1*04, HLA-DRB1*15 and HLA-DQB1*03, found to be potentially associated with an increased risk in alloantibody formation were included in the systematic review. The primary outcome measure was alloimmunization by RBC antigen exposure in SCD patients receiving multiple transfusions. The total estimate of alloimmunization of the SCD patients was 2.33 (95% CI, 1.58-3.44), demonstrating susceptibility to RBC alloantibody formation. Heterogeneity between the studies was insignificant, suggesting the differences associated with random sampling errors. The results showed that SCD patients carry an increased risk of producing RBC alloantibodies.
  6. Thrombelastography (TEG(®) 6s) early amplitudes predict maximum amplitude in severely injured trauma patients
    Scandinavian journal of clinical and laboratory investigation. 2022;:1-5

    Abstract

    Severely injured trauma patients are often coagulopathic and early hemostatic resuscitation is essential. Previous studies have revealed linear relationships between thrombelastography (TEG(®)) five- and ten-min amplitudes (A5 and A10), and maximum amplitude (MA), using TEG(®) 5000 technology. We aimed to investigate the performance of A5 and A10 in predicting low MA in severely injured trauma patients and identify optimal cut-off values for hemostatic intervention based on early amplitudes, using the cartridge-based TEG(®) 6s technology. Adult trauma patients with hemorrhagic shock were included in the iTACTIC randomized controlled trial at six European Level I trauma centers between 2016 and 2018. After admission, patients were randomized to hemostatic therapy guided by conventional coagulation tests (CCT) or viscoelastic hemostatic assays (VHA). Patients with available admission-TEG(®) 6s data were included in the analysis, regardless of treatment allocation. Low MA was defined as <55 mm for Kaolin TEG(®) and RapidTEG(®), and <17 mm for TEG(®) functional fibrinogen (FF). One hundred eighty-seven patients were included. Median time to MA was 20 (Kaolin TEG(®)), 21 (RapidTEG(®)) and 12 (TEG(®) FF) min. For Kaolin TEG(®), the optimal Youden index (YI) was at A5 < 36 mm (100/93% sensitivity/specificity) and A10 < 47 mm (100/96% sensitivity/specificity). RapidTEG(®) optimal YI was at A5 < 34 mm (98/92% sensitivity/specificity) and A10 < 45 mm (96/95% sensitivity/specificity). TEG(®) FF optimal YI was at A5 < 12 mm (97/93% sensitivity/specificity) and A10 < 15 mm (97/99% sensitivity/specificity). In summary, we found that TEG(®) 6s early amplitudes were sensitive and specific predictors of MA in severely injured trauma patients. Intervening on early amplitudes can save valuable time in hemostatic resuscitation.
    PICO Summary

    Population

    Adult trauma patients with haemorrhagic shock enrolled in the iTACTIC study at six European trauma centers (n= 187).

    Intervention

    Haemostatic therapy guided by conventional coagulation tests (CCT).

    Comparison

    Viscoelastic haemostatic assays (VHA).

    Outcome

    The study aimed to investigate the performance of A5 and A10 in predicting low maximum amplitude (MA), and to identify optimal cut-off values for haemostatic intervention based on early amplitudes, using the cartridge-based TEG® 6s technology. Patients with available admission-TEG® 6s data were included in the analysis, regardless of treatment allocation. Low MA was defined as <55 mm for Kaolin TEG® and RapidTEG®, and <17 mm for TEG® functional fibrinogen (FF). Median time to MA was 20 (Kaolin TEG®), 21 (RapidTEG®) and 12 (TEG® FF) min. For Kaolin TEG®, the optimal Youden index (YI) was at A5 < 36 mm (100/93% sensitivity/specificity) and A10 < 47 mm (100/96% sensitivity/specificity). RapidTEG® optimal YI was at A5 < 34 mm (98/92% sensitivity/specificity) and A10 < 45 mm (96/95% sensitivity/specificity). TEG® FF optimal YI was at A5 < 12 mm (97/93% sensitivity/specificity) and A10 < 15 mm (97/99% sensitivity/specificity).
  7. Health-related quality of life after restrictive versus liberal RBC transfusion for cardiac surgery: Sub-study from a randomized clinical trial
    Transfusion. 2022

    Abstract

    BACKGROUND Transfusion Requirements in Cardiac Surgery III (TRICS III), a multi-center randomized controlled trial, demonstrated clinical non-inferiority for restrictive versus liberal RBC transfusion for patients undergoing cardiac surgery. However, it is uncertain if transfusion strategy affects long-term health-related quality of life (HRQOL). STUDY DESIGN AND METHODS In this planned sub-study of Australian patients in TRICS III, we sought to determine the non-inferiority of restrictive versus liberal transfusion strategy on long-term HRQOL and to describe clinical outcomes 24 months postoperatively. The restrictive strategy involved transfusing RBCs when hemoglobin was <7.5 g/dl; the transfusion triggers in the liberal group were: <9.5 g/L intraoperatively, <9.5 g/L in intensive care, or <8.5 g/dl on the ward. HRQOL assessments were performed using the 36-item short form survey version 2 (SF-36v2). Primary outcome was non-inferiority of summary measures of SF-36v2 at 12 months, (non-inferiority margin: -0.25 effect size; restrictive minus liberal scores). Secondary outcomes included non-inferiority of HRQOL at 18 and 24 months. RESULTS Six hundred seventeen Australian patients received allocated randomization; HRQOL data were available for 208/311 in restrictive and 217/306 in liberal group. After multiple imputation, non-inferiority of restrictive transfusion at 12 months was not demonstrated for HRQOL, and the estimates were directionally in favor of liberal transfusion. Non-inferiority also could not be concluded at 18 and 24 months. Sensitivity analyses supported these results. There were no differences in quality-adjusted life years or composite clinical outcomes up to 24 months after surgery. DISCUSSION The non-inferiority of a restrictive compared to a liberal transfusion strategy was not established for long-term HRQOL in this dataset.
    PICO Summary

    Population

    Patients undergoing cardiac surgery enrolled in the multi-center randomised controlled trial: Transfusion Requirements in Cardiac Surgery III (TRICS III), (n= 617).

    Intervention

    Restrictive transfusion strategy (n= 311).

    Comparison

    Liberal transfusion strategy (n= 306).

    Outcome

    Health-related quality of life (HRQOL) data were available for 208/311 patients in the restrictive and 217/306 patients in the liberal group. After multiple imputation, non-inferiority of restrictive transfusion at 12 months was not demonstrated for HRQOL, and the estimates were directionally in favor of liberal transfusion. Non-inferiority also could not be concluded at 18 and 24 months. Sensitivity analyses supported these results. There were no differences in quality-adjusted life years or composite clinical outcomes up to 24 months after surgery.
  8. Hydroxyurea (hydroxycarbamide) for sickle cell disease
    The Cochrane database of systematic reviews. 2022;9(9):Cd002202

    Abstract

    BACKGROUND Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising foetal haemoglobin (HbF). This is an update of a previously published Cochrane Review. OBJECTIVES The aims of this review are to determine through a review of randomised or quasi-randomised studies whether the use of hydroxyurea in people with SCD alters the pattern of acute events, including pain; prevents, delays or reverses organ dysfunction; alters mortality and quality of life; or is associated with adverse effects. In addition, we hoped to assess whether the response to hydroxyurea in SCD varies with the type of SCD, age of the individual, duration and dose of treatment, and healthcare setting. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. The date of the most recent search was 17 February 2022. SELECTION CRITERIA Randomised and quasi-randomised controlled trials (RCTs and quasi-RCTs), of one month or longer, comparing hydroxyurea with placebo or standard therapy in people with SCD. DATA COLLECTION AND ANALYSIS Authors independently assessed studies for inclusion, carried out data extraction, assessed the risk of bias and assessed the quality of the evidence using GRADE. MAIN RESULTS We included nine RCTs recruiting 1104 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months. We judged the quality of the evidence for the first two comparisons below as moderate to low as the studies contributing to these comparisons were mostly large and well-designed (and at low risk of bias); however, the evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events, and the results are applicable only to individuals with HbSS and HbSβºthal genotypes. We judged the quality of the evidence for the third and fourth comparisons to be very low due to the limited number of participants, the lack of statistical power (both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes. Hydroxyurea versus placebo Five studies (784 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; four recruited individuals with only severe disease and one recruited individuals with all disease severities. Hydroxyurea probably improves pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use) and life-threatening illness, but we found no difference in death rates (10 deaths occurred during the studies, but the rates did not differ by treatment group) (all moderate-quality evidence). Hydroxyurea may improve measures of HbF (low-quality evidence) and probably decreases neutrophil counts (moderate-quality evidence). There were no consistent differences in terms of quality of life and adverse events (including serious or life-threatening events) (low-quality evidence). There were fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. Hydroxyurea and phlebotomy versus transfusion and chelation Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) contributed to this comparison. There were no consistent differences in terms of pain alteration, death or adverse events (low-quality evidence) or life-threatening illness (moderate-quality evidence). Hydroxyurea with phlebotomy probably increased HbF and decreased neutrophil counts (moderate-quality evidence), but there were more occurrences of acute chest syndrome and infections. Quality of life was not reported. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early. Hydroxyurea versus observation One study (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation. Pain alteration and quality of life were not reported. There were no differences in life-threatening illness, death (no deaths reported in either group) or adverse events (very low-quality evidence). We are uncertain if hydroxyurea improves HbF or decreases neutrophil counts (very low-quality evidence). Treatment regimens with and without hydroxyurea One study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea. Pain alteration, life-threatening illness and quality of life were not reported. There were no differences in death rates (no deaths reported in either group), adverse events or neutrophil levels (very low-quality evidence). We are uncertain if hydroxyurea improves HbF (very low-quality evidence). AUTHORS' CONCLUSIONS There is evidence to suggest that hydroxyurea may be effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial Doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly with regard to preventing chronic complications of SCD, or recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with the HbSC genotype. Future studies should be designed to address such uncertainties.
    PICO Summary

    Population

    Adults and children with sickle cell disease (9 studies, n= 1,104).

    Intervention

    Hydroxyurea.

    Comparison

    Standard therapy. Placebo.

    Outcome

    Hydroxyurea vs. placebo: Hydroxyurea probably improved pain alteration and life-threatening illness, but there was no difference in death rates. Hydroxyurea may improve measures of raising foetal haemoglobin (HbF) and probably decreased neutrophil counts. There were no consistent differences in terms of quality of life and adverse events. There were fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. Hydroxyurea and phlebotomy vs. transfusion and chelation: There were no consistent differences in terms of pain alteration, death or adverse events or life-threatening illness. Hydroxyurea with phlebotomy probably increased HbF and decreased neutrophil counts, but there were more occurrences of acute chest syndrome and infections. Hydroxyurea vs. observation: There were no differences in life-threatening illness, death or adverse events. The authors were uncertain if hydroxyurea improved HbF or decreased neutrophil counts. Treatment regimens with and without hydroxyurea: There were no differences in death rates, adverse events or neutrophil levels. The authors were uncertain if hydroxyurea improved HbF.
  9. Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial
    Intensive care medicine. 2022;:1-14

    Abstract

    PURPOSE Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs . METHODS We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) . RESULTS Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (- 1, 21) vs 10 (- 1, to 21) in subphenotype-2; 1.5 (- 1, 21) vs 12 (- 1, to 21) in suphenotype-3, and 0 (- 1, 21) vs 0 (- 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008). CONCLUSIONS We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.
    PICO Summary

    Population

    Critically ill COVID-19 patients enrolled in the REMAP-CAP trial (n= 1,239).

    Intervention

    High-titer convalescent plasma.

    Comparison

    Usual care.

    Outcome

    Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N= 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N= 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N= 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR)). Organ support free days at 21 days (OSFD-21) in convalescent plasma vs. usual care was 0 (- 1, 21) vs. 10 (- 1, to 21) in subphenotype-2; 1.5 (- 1, 21) vs. 12 (- 1, to 21) in suphenotype-3, and 0 (- 1, 21) vs. 0 (- 1, to 21) in subphenotype-1.
  10. Predictors of transfusion in trauma and their utility in the prehospital environment: a scoping review
    Prehospital emergency care. 2022;:1-25

    Abstract

    Background: Hemorrhage is a leading cause of preventable mortality from trauma, necessitating resuscitation through blood product transfusions. Early and accurate identification of patients requiring transfusions in the prehospital setting may reduce delays in time to transfusion upon arrival to hospital, reducing mortality. The purpose of this study is to characterize existing literature on predictors of transfusion and analyze their utility in the prehospital context.Objectives: The objectives of this study are to characterize the existing quantity and quality of literature regarding predictor scores for transfusion in injured patients, and to analyse the utility of predictor scores for massive transfusions in the prehospital setting and identify prehospital predictor scores for future research.Methods: A search strategy was developed in consultation with information specialists. A literature search of OVID MEDLINE from 1946 to present was conducted for primary studies evaluating the predictive ability of scoring systems or single variables in predicting transfusion in all trauma settings.Results: Of the 5824 studies were identified, 5784 studies underwent title and abstract screening, 94 studies underwent full text review, and 72 studies were included in the final review. We identified 16 single variables and 52 scoring systems for predicting transfusion. Amongst single predictor variables, fluids administered and systolic blood pressure had the highest reported sensitivity (100%) and specificity (89%) for massive transfusion protocol (MTP) activation respectively. Amongst scoring systems for transfusion, the Shock Index and Modified Shock Index had the highest reported sensitivity (96%), while the Pre-arrival Model had the highest reported specificity (95%) for MTP activation. Overall, 20 scores were identified as being applicable to the prehospital setting, 25 scores were identified as being potentially applicable, and seven scores were identified as being not applicable.Conclusions: We identified an extensive list of predictive single variables, validated scoring systems, and derived models for massive transfusion, presented their properties, and identified those with potential utility in the prehospital setting. By further validating applicable scoring tools in the prehospital setting, we may begin to administer more timely transfusions in the trauma population.
    PICO Summary

    Population

    Trauma patients (72 studies).

    Intervention

    Scoping review to characterize the existing literature regarding predictor scores for transfusion in injured patients, to analyse the utility of predictor scores for massive transfusions in the prehospital setting, and to identify pre-hospital predictor scores for future research.

    Comparison

    Outcome

    Sixteen single variables and fifty-two scoring systems were identified for predicting transfusion. Amongst single predictor variables, fluids administered and systolic blood pressure had the highest reported sensitivity (100%) and specificity (89%) for massive transfusion protocol (MTP) activation respectively. Amongst scoring systems for transfusion, the Shock Index and Modified Shock Index had the highest reported sensitivity (96%), while the Pre-arrival Model had the highest reported specificity (95%) for MTP activation. Overall, 20 scores were identified as being applicable to the pre-hospital setting, 25 scores were identified as being potentially applicable, and seven scores were identified as being not applicable.