Transfusion thresholds and other strategies for guiding red blood cell transfusion

The optimal haemoglobin threshold for use of red blood cell (RBC) transfusions in anaemic patients remains an active area of research. Blood is a limited resource, and there are concerns about risks, including transmitted infections. If a liberal transfusion strategy does not improve clinical outcomes, or if it is equivalent, then adopting a more restrictive approach should be recognised as the standard of care.

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 to direct transfusion (most commonly, 9.0 g/dL to 10.0 g/dL). Increasingly, investigators are considering other strategies including physiological triggers (i.e. central venous oxygen saturation), alone or in combination with such thresholds, to determine when a transfusion is indicated, so it is important to assess this growing body of evidence in tandem.

We searched CENTRAL, MEDLINE, Embase, Transfusion Evidence Library, Web of Science Conference Proceedings Citation Index, trial registries and PubMed on 14 October 2024. We checked reference lists of published reviews and papers for additional trials.

We included randomised trials of surgical or medical participants that recruited adults or children. We excluded studies that focused on preterm neonates. Eligible trials assigned intervention groups based on different transfusion strategies or thresholds, usually defined by a haemoglobin concentration below which a RBC transfusion would be administered. 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.

We used standard Cochrane methods. We pooled risk ratios across trials using a random-effects model. We assessed risk of bias using the Cochrane RoB 1 tool, and assessed the certainty of evidence using GRADE. 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.

Adult threshold comparison We included 61 trials (27,639 participants), across a range of clinical contexts: orthopaedic, cardiac or vascular surgery; critical care; neurocritical care; gastrointestinal bleeding; trauma; acute myocardial infarction; haematological malignancies and postpartum haemorrhage. The haemoglobin concentration used to define the restrictive transfusion group in most trials was between 7.0 g/dL and 8.0 g/dL. The main outcomes were exposure to blood transfusion, 30-day mortality, neurologic function, myocardial infarction, congestive heart failure, cerebral vascular accident, infection and thromboembolism. Studies were generally at low risk of bias. Restrictive transfusion strategies reduced the risk of receiving at least one RBC transfusion by 42% when combining all clinical contexts (risk ratio (RR) 0.58, 95% confidence interval (CI) 0.52 to 0.65; high-certainty evidence), with a large amount of heterogeneity between trials (I² = 97%), reflecting diversity in the strength of estimates, not the efficacy of the policy. When combining all clinical contexts, restrictive transfusion strategies did not modify the risk of 30-day mortality compared with liberal transfusion strategies (RR 1.01, 95% CI 0.90 to 1.14; 44 studies, 22,575 participants; high-certainty evidence) or any of the other outcomes assessed including myocardial infarction, stroke, thromboembolism or infection (moderate to high-certainty evidence). There were two exceptions in clinical populations. In gastrointestinal bleeding, 30-day mortality was lower with a restrictive transfusion strategy (RR 0.63, 95% CI 0.42 to 0.95; 4 studies, 1574 participants). In critically ill patients with brain injury, unfavourable neurological outcome at 6 to 12 months was lower with a liberal transfusion strategy (RR 1.14, 95% CI 1.05 to 1.22; 4 studies, 2297 participants) (moderate-certainty evidence). Transfusion-specific reactions are uncommon, but occurred more frequently with the liberal strategy (Peto odds ratio 0.47, 95% CI 0.36 to 0.62; 18 studies, 11,505 participants). Paediatric threshold comparison We included eight trials (2764 participants), across a limited range of clinical contexts (critical care, cardiac surgery, haematological malignancies and severe malarial anaemia). The haemoglobin concentration used to define the restrictive group in critical care and haematological malignancies trials was between 6.5 g/dL and 8.0 g/dL, and between 7.0 g/dL and 9 g/dL in cardiac surgery trials, depending on the cardiac abnormality and stage of repair. Studies were generally at low risk of bias. There was no clear difference in 30-day mortality between restrictive and liberal transfusion strategies, although confidence intervals were wide (RR 1.22, 95% CI 0.72 to 2.08; 7 studies, 2571 participants; low-certainty evidence). There was moderate-certainty evidence of no clear difference between threshold strategies for infection; very low-certainty evidence of little to no difference for thrombosis and very low-certainty evidence of little to no difference for the outcomes multiple organ dysfunction and cerebrovascular accident. Physiological triggers Nine trials in adults (3818 participants) and one trial in children (100 participants) were identified. These tested different interventions and measures of physiological parameters in diverse clinical populations. The risk of bias was variable. Meta-analysis was not appropriate due to heterogeneity.

A restrictive transfusion strategy significantly decreased the proportion of adults and children exposed to RBC transfusion. In most clinical contexts, there was no evidence of harm from a restrictive compared with a liberal transfusion strategy. Neurocritically ill patients, however, have better neurological outcomes at 6 to 12 months with a liberal transfusion strategy. Further work is needed to improve our understanding of outcomes beyond mortality, and to what degree the optimal strategies for transfusion should be modified in some patient populations, including different types of acute bleeding, cancers and subgroups of patients with myocardial infarction and other neurological injuries. New studies need to recognise the clinical context and the limitations of the adoption of a single threshold of haemoglobin, and to consider evaluating the use of physiological parameters to modify transfusion.