Liberal Blood Transfusions Deliver Brain Function Benefit for the Critically Ill

A liberal blood transfusion strategy was associated with better neurological outcomes in patients with acute brain injury, a multicenter phase III randomized trial showed.

In the TRAIN trial of critically ill people with traumatic brain injury, aneurysmal subarachnoid hemorrhage, or intracerebral hemorrhage, unfavorable neurological function at 180 days was less likely when transfusion was triggered by hemoglobin <9 g/dL versus <7 g/dL (62.6% vs 72.6%; adjusted relative risk [RR] 0.86, 95% CI 0.79-0.94), reported researchers led by Fabio Taccone, MD, PhD, of Hôpital Erasme, Université Libre de Bruxelles in Belgium.

The neurological benefit with liberal transfusion was consistent across prespecified subgroups, they noted in JAMA. A bad neurological outcome was defined by Glasgow Outcome Scale Extended (GOS-E) scores of 1 (death) to 5 (lower moderate disability). The scale ranges up to 8, which indicates “full recovery with no current problems relating to the injury.”

The findings were simultaneously presented at the European Society of Intensive Care Medicine’s LIVES 2024 annual congress in Barcelona.

Of note, the liberal strategy had no effect on intensive care unit (ICU) and hospital lengths of stay, organ failure at 28 days, or mortality.

The best threshold for blood transfusions remains controversial in critically ill patients. While a liberal transfusion strategy might improve oxygen delivery and reduce brain tissue hypoxia, it has the potential downsides of increasing complications and mortality.

Unlike most studies favoring the safety and effectiveness of a resource-saving restrictive approach to blood transfusions, TRAIN was able to show some benefit with the liberal strategy.

“The absence of a difference in mortality suggests that while a liberal transfusion approach may not influence survival, it could contribute to better neurological recovery among survivors,” Taccone and colleagues suggested. “This benefit appears to be associated with a lower occurrence of cerebral infarction in the liberal transfusion group.”

In the study, cerebral ischemic events were less frequent in the liberal transfusion group (8.8% vs 13.5%; RR 0.65, 95% CI 0.44-0.97).

“Despite proliferation of dedicated neurocritical care units and improvements in patient management over past decades, very few interventions clearly improve patient-oriented, clinically significant long-term functional outcomes,” wrote Alexis Turgeon, MD, MSc, and François Lauzier, MD, MSc, both of Centre Hospitalier Universitaire de Québec-Université Laval Research Center in Québec City, in an accompanying editorial. “Any interventions that could improve functional status in these patients may have a substantial impact.”

“One barrier to the use of liberal transfusion thresholds in neurocritically ill patients is the concern about potential complications associated with transfusions,” they noted. “Blood products are now safer than ever.”

Although the duo’s recent HEMOTION trial could not prove that a liberal blood transfusion strategy significantly improves neurologic outcomes at 6 months in critically ill patients with traumatic brain injury, the conflicting result may come down to study design differences, such as TRAIN’s stricter hemoglobin transfusion threshold for controls (9 vs 10 g/dL), expanded definition of unfavorable neurological outcomes (GOS-E 1-5 vs 1-4), and a more heterogeneous cohort.

“Based on the best available evidence, it is prudent to advocate a liberal transfusion strategy for these neurocritically ill patients,” Turgeon and Lauzier argued.

“In TRAIN and HEMOTION, the adverse event rates, including thromboembolic events, were comparable between groups, with no clinically significant impact on patient-relevant outcomes,” they added. “Although potential adverse effects of blood products should not be minimized, they must be weighed against significant improvement of clinically relevant and patient-relevant outcomes.”

The TRAIN trial was conducted from September 2017 through December 2022 in 72 ICUs in 22 countries and included 850 patients with traumatic brain injury, aneurysmal subarachnoid hemorrhage, or intracerebral hemorrhage who had hemoglobin values below 9 g/dL within the first 10 days after injury.

They were randomized to liberal or restrictive blood transfusions over a maximum of 28 days, and 820 completed the trial (mean age 51 years, 45.9% women).

Baseline characteristics were comparable between groups, according to Taccone and colleagues. Around 60% of the cohort had a traumatic brain injury, with a minority presenting with brain bleeds. Study participants were randomized a median 3 days after ICU admission.

Of the study participants, 89.9% in the liberal strategy group required transfusion during their ICU stay compared with 48.5% in the restrictive strategy group (P<0.001). The liberal strategy group received a median 2 units of blood compared with 0 units for controls.

Chief among the limitations of TRAIN was its open-label design that could have resulted in some bias. Additionally, the trial lacked standardized evaluations of cerebral infarctions and may have therefore underestimated their occurrence.

“Given the heterogeneous neurocritically ill population in TRAIN and the fact that most patients had traumatic brain injuries, some uncertainty may remain regarding the effectiveness of the liberal strategy in the less well-represented subpopulations with subarachnoid hemorrhage and intracerebral hemorrhage despite the apparent lack of differential effect in these subgroups,” wrote Turgeon and Lauzier.

In that regard, the recently completed SAHaRA trial is expected to provide more information about transfusion decisions in adults with anemia and acute subarachnoid hemorrhage.

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