Transfusion in Acute Brain Injury: Is Less Still More?

Blood transfusions are commonly given to patients with acute brain injury, but there is ongoing debate over whether a restrictive or liberal transfusion strategy is preferable. 

Results of the TRICC trial published more than two decades ago favored a restrictive strategy, which has largely guided transfusion practice. But results of the TRAIN study, recently published in JAMA, favor a more liberal transfusion strategy. 

“Overall, with the TRAIN results, I think practice will probably shift more toward consideration of a liberal transfusion strategy,” Nina Massad, MD, assistant professor of clinical neurology, Division of Neurocritical Care, University of Miami Miller School of Medicine, Miami, Florida, told Medscape Medical News. Massad was not involved in either study. 

TRICCed Into Restrictive Strategy?

Published in 1999, the landmark Transfusion Requirements in Critical Care (TRICC) trial, suggested that a restrictive strategy of red-cell transfusion is at least as effective as, and possibly superior, to a liberal transfusion strategy in critically ill patients.

The trial enrolled more than 800 critically ill but stable ICU patients with hemoglobin concentrations

Overall, mortality at 30 days was lower with the restrictive strategy (18.7% vs 23.3%), but the difference was not statistically significant (P = .11). Inpatient mortality was also lower in the restrictive group (22.2% vs 28.1%; P = .05) as was ICU mortality (13.9% vs 16.2%; P = .29).

The results led to shift in transfusion practice, with restrictive thresholds being widely adopted to avoid inappropriate use of a scarce resource, Alexis Turgeon, MD and Francois Lauzier, MD, Quebec University Hospital Center — Laval University Research Center, noted in a JAMA editorial. 

Yet, the TRICC trial has been called the most misinterpreted study in medicine. 

Among the concerns raised, the trial enrolled few neurocritically ill patients, did not include a subgroup analysis of those with acute brain injury and did not assess long-term functional outcomes, which are “more relevant to these patients than mortality and more impactful for clinical practice,” Turgeon and Lauzier pointed out. 

From TRICC to TRAIN

Enter the TRAIN trial, which showed that liberal transfusion was associated with better neurological outcomes in patients with acute brain injury. 

The trial was conducted at 72 ICUs across 22 countries and included 850 patients with acute traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH). All participants had a hemoglobin level below 9.0 g/dL within the first 10 days after injury and were expected to stay in the ICU for at least 72 hours. 

They were randomly assigned to liberal transfusion (triggered by hemoglobin

Patients receiving the liberal transfusion strategy had a significantly lower rate of unfavorable neurological outcomes (the primary outcome) at 6 months than those in the restrictive group (62.6% vs 72.6%; adjusted relative risk: 0.86; P = .002). 

The findings were consistent across all subgroups of brain injury and post hoc analyses, reported Fabio Silvio Taccone, MD, PhD, with the Free University of Brussels, Belgium, and colleagues. 

There were also fewer cerebral ischemic events in the liberal group (8.8% vs 13.5%; relative risk, 0.65). There was no effect on ICU or hospital length of stay, organ failure at 28 days or mortality. The liberal group required more transfusions than the restrictive group (median, 2 vs 0 units). 

HEMOTION Consistent With TRAIN 

The main findings of the TRAIN trial are consistent with those of the HEMOTION trial, a large-scale, multicenter international trial of 742 adults with moderate or severe TBI and anemia. 

In contrast to TRAIN, HEMOTION included only patients with TBI, used a higher liberal transfusion threshold (10 g/dL), and assessed brain injury severity in the emergency department following stabilization. 

Fewer patients in the liberal than restrictive group had an unfavorable neurological outcome (68.4% vs 73.5%).

However, a separate study published last spring found that a liberal (vs restrictive) transfusion strategy did not decrease the risk for an unfavorable neurologic outcome at 6 months in critically ill TBI patients.

Nonetheless, the weight of the new evidence shows that liberal transfusion thresholds appear “widely beneficial,” Turgeon and Lauzier note in their editorial. 

They added that blood products are now “safer than ever” and the rationale for advocating a restrictive strategy in the TRICC trial era — to “save precious resources without harming patients” — no longer holds.

“Fortunately, the weight of sparing precious resources has now been lifted from the shoulders of neurocritically ill patients, in whom serious concerns about the safety of a restrictive strategy have been raised by the TRAIN and HEMOTION trials. Based on the best available evidence, it is prudent to advocate a liberal transfusion strategy for these neurocritically ill patients,” Turgeon and Lauzier concluded. 

Practice Changing? 

Massad told Medscape Medical News the TRAIN study results “will likely change practice for many providers. I will probably consider a more liberal transfusion goal, particularly who seem to be at higher risk of tissue hypoxia — for example, vasospasm; concern for delayed cerebral ischemia; low brain tissue oxygenation on brain tissue oxygen monitoring.” 

Massad said it remains to be seen whether a liberal strategy helps prevent cerebral ischemia specifically. Another unanswered question concerns the optimal transfusion threshold in acute ischemic stroke.

She also noted that current guidelines from the Neurocritical Care Society for SAH state there is insufficient evidence to provide a recommendation to transfuse for a threshold higher than hemoglobin > 7.0 g/dL in SAH. 

There have been no guidelines to support a liberal transfusion strategy in ICH either, as there are limited studies on this. 

For TBI, the most recent Brain Trauma Foundation guidelines from 2016 do not address transfusion thresholds, although there have been suggestions from other groups to transfuse red-blood cells in the setting of low oxygen on brain tissue oxygenation monitoring, Massad noted. 

“My feeling is that a liberal strategy is going to start being reconsidered for subsequent guideline updates in acute brain injury. More definitive guideline recommendations are probably going to depend on further studies to corroborate these findings,” Massad said.

“Additional studies are currently ongoing, including one investigating this question specifically in SAH patients (SAHaRA trial), so this will hopefully help clarify the question in the SAH population,” she said. 

The TRAIN study was funded by the ESICM NeXT grant and La Fondation des Geules Cassées. Taccone had no relevant disclosures. Turgeon served as chief investigator, and Lauzier as co-principal investigator, of the HEMOTION trial. Massad had no relevant disclosures.