Is Blood Thicker than Water for Acute Brain Injury?
Ethan L Sanford MD, Shawn Jackson MD PhD, Justin L Lockman MD MSEd
Emboldened by the rapid changes that quality improvement and implementation science can achieve, some (including us) have questioned whether rigorous, controlled trials which devour time and money are still worth the effort and expense. Today’s PAAD illustrates the continued value of these costly trials to address simple yet critical questions. In this case, that question is “when should we transfuse blood in patients with acute brain injury?”
Original article
Taccone FS, Rynkowski Bittencourt C, Møller K, Lormans P, Quintana-Díaz M, Caricato A, Cardoso Ferreira MA, Badenes R, Kurtz P, Søndergaard CB, Colpaert K, Petterson L, Quintard H, Cinotti R, Gouvêa Bogossian E, Righy C, Silva S, Roman-Pognuz E, Vandewaeter C, Lemke D, Huet O, Mahmoodpoor A, Blandino Ortiz A, van der Jagt M, Chabanne R, Videtta W, Bouzat P, Vincent JL; TRAIN Study Group. Restrictive vs Liberal Transfusion Strategy in Patients With Acute Brain Injury: The TRAIN Randomized Clinical Trial. JAMA. 2024 Oct 9. doi: 10.1001/jama.2024.20424. Epub ahead of print. PMID: 39382241.
Taccone et al.1 present their results of the TRAIN Study Group: Restrictive vs Liberal Transfusion Strategy in Patients With Acute Brain Injury: The TRAIN Randomized Clinical Trial. The authors performed a randomized, controlled trial (RCT) to test whether higher (9 g/dL) or lower (7 g/dL) hemoglobin targets would impact neurologic recovery after traumatic brain injury, subarachnoid hemorrhage or intracerebral hemorrhage among of 850 randomized adults (>18 years).
In traumatic brain injury, we care greatly about oxygen delivery to the penumbra (the “at risk” areas of brain), but how to improve oxygen delivery is not obvious. Higher hemoglobin levels increase the oxygen content of blood but at the expense of increased viscosity, impaired microvascular flow, and a myriad of immunomodulatory, inflammatory, and endothelial cell signaling changes. Despite years of debate and lack of consensus about a theoretically “optimal” level, lower hemoglobin goals (so called “restrictive transfusion”) have been adopted as studies have not detected differences in important outcomes with higher hemoglobin thresholds. The most recent TAXI guidelines suggest tolerance of hemoglobin values as low as 5 g/dL in asymptomatic children in the ICU.2 Specific to children with acute brain injury, transfusion thresholds of 7-10 g/dL have been proposed, though with acknowledgement of minimal evidence.3,4
While today’s PAAD is based on adult brain injured patients, it is important because the authors found that higher hemoglobin was associated with lower occurrence of unfavorable neurologic outcomes (said another way, higher hemoglobin patients did better) – and this is the largest population studied to date. Neurologic function was measured by the Glasgow Outcome Scale Extended which includes death as a score of 1. However, no difference in 28-day mortality occurred, and breakdown of the scores by intervention demonstrated mortality was not the primary difference between groups.
Importantly, the results contrast with a prior, smaller RCT which showed no difference in neurologic outcome and increased thromboembolic events with hemoglobin threshold of 10 g/dL (co-administered with erythropoietin, confounding these results) in adults with TBI.5 This may, then, be a goldilocks situation wherein a greater oxygen carrying capacity helps but only up to a point – the magic “optimal” hemoglobin. Importantly, today’s PAAD compares only the thresholds of 7 and 9, and cannot answer the question about what hemoglobin is “optimal.” But in this population, it does seem that 9 is better than 7.
We recognize that most physicians have a bias for higher hemoglobin levels and that efforts to change this have been a priority. Today’s PAAD shouldn’t be misrepresented to support the erosion of the many years of effort to limit liberal, unnecessary transfusions. Instead, it should inform our tailoring of blood product management to specific clinical scenarios. Which, if any, pediatric populations might benefit from higher hemoglobin concentrations is an important area for future study. And these thresholds must always be interpreted in the setting of ongoing surgical bleeding; most of the studies in this area, including today’s article, focus on anemia in stable medical patients and not hemorrhage in surgical patients.
How does your institutional culture impact your decisions in transfusion? What do you think of today’s PAAD? Will this study change your practice for children with acute brain injury? What about elective neurosurgery? We hope this discussion can prompt some multicenter collaborative trials in children! Send your thoughts and comments to Myron at myasterster@gmail.com so he can post them in a Friday Reader Response.
References
1. Taccone FS, Rynkowski Bittencourt C, Møller K, et al. Restrictive vs Liberal Transfusion Strategy in Patients With Acute Brain Injury: The TRAIN Randomized Clinical Trial. Jama 2024 (In eng). DOI: 10.1001/jama.2024.20424.
2. Valentine SL, Bembea MM, Muszynski JA, et al. Consensus Recommendations for RBC Transfusion Practice in Critically Ill Children From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. Pediatr Crit Care Med 2018;19(9):884-898. DOI: 10.1097/PCC.0000000000001613.
3. Tasker RC, Turgeon AF, Spinella PC, et al. Recommendations on RBC Transfusion in Critically Ill Children With Acute Brain Injury From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. Pediatr Crit Care Med 2018;19(9S Suppl 1):S133-S136. DOI: 10.1097/PCC.0000000000001589.
4. Kochanek PM, Tasker RC, Bell MJ, et al. Management of Pediatric Severe Traumatic Brain Injury: 2019 Consensus and Guidelines-Based Algorithm for First and Second Tier Therapies. Pediatr Crit Care Med 2019;20(3):269-279. DOI: 10.1097/PCC.0000000000001737.
5. Robertson CS, Hannay HJ, Yamal JM, et al. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 2014;312(1):36-47. DOI: 10.1001/jama.2014.6490.