Effects Of Transfusion Thresholds Research Articles

Red Blood Cell Transfusion in European Neonatal Intensive Care Units, 2022 to 2023

Red blood cell (RBC) transfusions are frequently administered to preterm infants born before 32 weeks of gestation in the neonatal intensive care unit (NICU). Two randomized clinical trials (Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants [ETTNO] and Transfusion of Prematures [TOP]) found that liberal RBC transfusion thresholds are nonsuperior to restrictive thresholds, but the extent to which these results have been integrated into clinical practice since publication in 2020 is unknown. To describe neonatal RBC transfusion practice in Europe. This international prospective observational cohort study collected data between September 1, 2022, and August 31, 2023, with a 6-week observation period per center, from 64 NICUs in 22 European countries. Participants included 1143 preterm infants born before 32 weeks of gestation. Admission to the NICU. Study outcome measures included RBC transfusion prevalence rates, cumulative incidence, indications, pretransfusion hemoglobin (Hb) levels, volumes, and transfusion rates, Hb increment, and adverse effects of RBC transfusion. A total of 1143 preterm infants were included (641 male [56.1%]; median gestational age at birth, 28 weeks plus 2 days [IQR, 26 weeks plus 2 days to 30 weeks plus 2 days]; median birth weight, 1030 [IQR, 780-1350] g), of whom 396 received 1 or more RBC transfusions, totaling 903 transfusions. Overall RBC transfusion prevalence rate during postnatal days 1 to 28 was 3.4 transfusion days per 100 admission days, with considerable variation across countries, only partly explained by patient mix. By day 28, 36.5% (95% CI, 31.6%-41.5%) of infants had received at least 1 transfusion. Most transfusions were given based on a defined Hb threshold (748 [82.8%]). Hemoglobin levels before transfusions indicated for threshold were below the restrictive thresholds set by ETTNO in 324 of 729 transfusions (44.4%) and TOP in 265 of 729 (36.4%). Conversely, they were between restrictive and liberal thresholds in 352 (48.3%) and 409 (56.1%) transfusions, respectively, and above liberal thresholds in 53 (7.3%) and 55 (7.5%) transfusions, respectively. Most transfusions given based on threshold had volumes of 15 mL/kg (470 of 738 [63.7%]) and were administered over 3 hours (400 of 738 [54.2%]), but there was substantial variation in dose and duration. In this cohort study of very preterm infants, most transfusions indicated for threshold were given for pretransfusion Hb levels above restrictive transfusion thresholds evaluated in recent trials. These results underline the need to optimize practices and for implementation research to support uptake of evidence.

Thresholds for blood transfusion in extremely preterm infants: A review of the latest evidence from two large clinical trials.

There are two recently completed large randomized clinical trials of blood transfusions in the preterm infants most at risk of requiring them. Liberal and restrictive strategies were compared with composite primary outcome measures of death and neurodevelopmental impairment. Infants managed under restrictive guidelines fared no worse in regard to mortality and neurodevelopment in early life. The studies had remarkably similar demographics and used similar transfusion guidelines. In both, there were fewer transfusions in the restrictive arm. Nevertheless, there were large differences between the studies in regard to transfusion exposure with almost 3 times the number of transfusions per participant in the transfusion of prematures (TOP) study. Associated with this, there were differences between the studies in various outcomes. For example, the combined primary outcome of death or neurodevelopmental impairment was more likely to occur in the TOP study and the mortality rate itself was considerably higher. Whilst the reasons for these differences are likely multifactorial, it does raise the question as to whether they could be related to the transfusions themselves? Clearly, every effort should be made to reduce exposure to transfusions and this was more successful in the Effects of Transfusion Thresholds on Neurocognitive Outcomes (ETTNO) study. In this review, we look at factors which may explain these transfusion differences and the differences in outcomes, in particular neurodevelopment at age 2 years. In choosing which guidelines to follow, centers using liberal guidelines should be encouraged to adopt more restrictive ones. However, should centers with more restrictive guidelines change to ones similar to those in the studies? The evidence for this is less compelling, particularly given the wide range of transfusion exposure between studies. Individual centers already using restrictive guidelines should assess the validity of the findings in light of their own transfusion experience. In addition, it should be remembered that the study guidelines were pragmatic and acceptable to a large number of centers. The major focus in these guidelines was on hemoglobin levels which do not necessarily reflect tissue oxygenation. Other factors such as the level of erythropoiesis should also be taken into account before deciding whether to transfuse.

EBNEO Commentary: Red blood cell transfusion thresholds in extremely low birthweight infants.

Franz AR, Engel C, Bassler D, Rüdiger M, Thome UH, Maier RF, Krägeloh-Mann I, Kron M, Essers J, Bührer C, Rellensmann G, Rossi R, Bittrich HJ, Roll C, Höhn T, Ehrhardt H, Avenarius S, Körner HT, Stein A, Buxmann H, Vochem M, Poets CF; ETTNO Investigators. Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial. JAMA. 2020 Aug 11;324(6):560–570. PMID: 32780138. Erin Grace. Neonatal Fellow. Department of Neonatal Medicine, Women's and Children's Hospital, North Adelaide, South Australia. SAHMRI Women and Kids, South Australian Health and Medical Institute, North Adelaide, South Australia. Robinson Research Institute and the Adelaide Medical School, the University of Adelaide, Adelaide, South Australia. Cathie Hilditch. Paediatric Registrar. SAHMRI Women and Kids, South Australian Health and Medical Institute, North Adelaide, South Australia. Robinson Research Institute and the Adelaide Medical School, the University of Adelaide, Adelaide, South Australia. Amy Keir. Consultant Neonatologist. Department of Neonatal Medicine, Women's and Children's Hospital, North Adelaide, South Australia. Healthy Mothers, Babies and Children Theme, South Australian Health and Medical Institute, North Adelaide, South Australia. Robinson Research Institute and the Adelaide Medical School, the University of Adelaide, Adelaide, South Australia. In this European multicentre randomised controlled trial, the Effects of Transfusion Thresholds on Neurocognitive Outcome of Extremely Low birth Weight Infants (ETTNO), 1013 preterm infants with a birthweight less than 1000 grams were included. The study was undertaken across 2011–2014 with longer term follow-up beyond this period.1 At 24 months’ corrected age, rates of the primary outcome of death or neurodevelopmental impairment were similar in the liberal and restrictive threshold groups (44.4% and 42.9%; odds ratio, 1.05). The rates of mortality, cognitive impairment and complications including bronchopulmonary dysplasia and necrotising enterocolitis were similar between groups. To examine the study more closely, randomisation occurred with the first 72 hours of age with the majority of infants randomised at 2.5 days of age. Twenty-five per cent of infants in each group received at least one red blood cell transfusion prior to randomisation. Deferred/delayed cord clamping (DCC) for 30–45 seconds was implemented at each study site with 308/492 (63%) in the liberal group and 319/519 (61%) in the restrictive group receiving DCC. The mean difference in mean haematocrits ranged from 1.5 to 3.4% from the week of randomisation to week 11. Whether this difference is clinically meaningful is worth considering. The authors note that the separation in these haematocrit values, and consequently the potential oxygen-carrying capacity achieved, may be too small to cause a difference in study outcomes.1 The lowest mean haematocrit in the restrictive group was in week 9 at 31.7% (SD 4.6). A comprehensive list of further study limitations is well laid out by the authors. These included potential limited generalisability due to the infants being primarily from a white German population group, the changes in clinical practices that may have occurred since 2011–2014, and the proportion of infants who received a red blood cell transfusion not justified by the study protocol. Risk of bias (ROB) in the study, assessed using the Cochrane ROB tool,2 was deemed low risk overall. The potential for post randomisation confounding exists, with 14% of infants receiving a transfusion not justified by the protocol and 7% did not receive a transfusion when dictated by the protocol. Analysis of the per-protocol population was consistent with the primary analysis findings. Other postrandomisation confounding risks were deemed low as there was minimal loss to follow up with similar numbers between groups. The results of the recently published Transfusion of Prematures (TOP) trial are consistent with this trial. Combining the results will hopefully enable a much anticipated individual patient data meta-analysis.1 Anaemia of prematurity is a term used broadly across the highly variable and complex course of prematurity in relation to red blood cell transfusion practice. It is possible that a difference approach to transfusion in the first days of age requires a transfusion trigger based on optimisation of oxygen kinetics, rather than a threshold per se.4 At this point, however, lower red cell transfusion thresholds compared to more liberal thresholds seem an appropriate clinical approach, especially for those preterm infants 48–72 hours of age or older. https://ebneo.org/transfusion-thresholds-low-birthweight-infants The authors have no conflicts of interest to declare.

Guidelines on transfusion for fetuses, neonates and older children.

Guidelines on transfusion for fetuses, neonates and older children.

The ‘Effects of Transfusion Thresholds on Neurocognitive Outcome of Extremely Low Birth-Weight Infants (ETTNO)’ Study: Background, Aims, and Study Protocol

Background: Infants with extremely low birth weight uniformly develop anemia of prematurity and frequently require red blood cell transfusions (RBCTs). Although RBCT is widely practiced, the indications remain controversial in the absence of conclusive data on the long-term effects of RBCT. Objectives: To summarize the current equipoise and to outline the study protocol of the ‘Effects of Transfusion Thresholds on Neurocognitive Outcome of extremely low birth-weight infants (ETTNO)’ study. Methods: Review of the literature and design of a large pragmatic randomized controlled trial of restrictive versus liberal RBCT guidelines enrolling 920 infants with birth weights of 400–999 g with long-term neurodevelopmental follow-up. Results and Conclusions: The results of ETTNO will provide definite data about the efficacy and safety of restrictive versus liberal RBCT guidelines in very preterm infants.

Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion.

Most clinical practice guidelines recommend restrictive red cell transfusion practices with the goal of minimising exposure to allogeneic blood (from an unrelated donor). The purpose of this review is to compare clinical outcomes in patients randomised to restrictive versus liberal transfusion thresholds (triggers). To examine the evidence on the effect of transfusion thresholds, on the use of allogeneic and/or autologous blood, and the evidence for any effect on clinical outcomes. Trials were identified by: computer searches of OVID Medline (1966 to December 2000), Current Contents (1993 to Week 48 2000), and the Cochrane Controlled Trials Register (2000 Issue 4). References in identified trials and review articles were checked and authors contacted to identify any additional studies. Controlled trials in which patients were randomised to an intervention group or to a control group. Trials were included where the intervention groups were assigned on the basis of a clear transfusion "trigger", described as a haemoglobin (Hb) or haematocrit (Hct) level below which a RBC transfusion was to be administered. Trial quality was assessed using criteria proposed by Schulz et al. (1995). Relative risks of requiring allogeneic blood transfusion, transfused blood volumes and other clinical outcomes were pooled across trials using a random effects model. Ten trials were identified that reported outcomes for a total of 1780 patients. Restrictive transfusion strategies reduced the risk of receiving a red blood cell (RBC) transfusion by a relative 42% (RR=0.58: 95%CI=0.47,0.71). This equates to an average absolute risk reduction (ARR) of 40% (95%CI=24% to 56%). The volume of RBCs transfused was reduced on average by 0.93 units (95%CI=0.36,1.5 units). However, heterogeneity between these trials was statistically significant (p<0.00001) for these outcomes. Mortality, rates of cardiac events, morbidity, and length of hospital stay were unaffected. Trials were of poor methodological quality. The limited published evidence supports the use of restrictive transfusion triggers in patients who are free of serious cardiac disease. However, most of the data on clinical outcomes were generated by a single trial. The effects of conservative transfusion triggers on functional status, morbidity and mortality, particularly in patients with cardiac disease, need to be tested in further large clinical trials. In countries with inadequate screening of donor blood the data may constitute a stronger basis for avoiding transfusion with allogeneic red cells.