Intracerebral hemorrhage (ICH) is the deadliest type of stroke and one of the leading causes of death in the United States. Treatment efforts focus on rapid delivery of care to establish effective hemostasis and to prevent secondary brain injury to optimize patients’ long-term outcomes. However, there are critical gaps in knowledge for appropriate therapeutic targets that treat these processes to improve patient outcomes.
Physicians from NewYork-Presbyterian and Columbia performed a multicenter study to shed light on this conundrum by clarifying the role that hemoglobin and anemia have on ICH outcomes. They found that hemoglobin can decline rapidly in the days after ICH, and that greater hemoglobin decrements and it’s resulting anemia is related to secondary brain injury visible on MRI as ischemic lesions. These results may lead to the identification of anemia being a potential therapeutic target to improve ICH outcomes.
Below, David J. Roh, MD, a neurologist at NewYork-Presbyterian and Columbia and senior author of the study, explains this research and its implications for the care of patients with ICH.
Most patients with intracerebral hemorrhage experience a significant drop in hemoglobin over time. We have been investigating why these hemoglobin decrements happen, how they impact outcomes, and whether these can be prevented/treated to improve outcomes.
— Dr. David Roh
Research Background and Methods
We and others have identified consistent relationships of low baseline levels of hemoglobin and anemia with poor ICH outcomes. It is known that hemoglobin is critical for oxygen delivery and low levels of hemoglobin has been shown to impair cerebral oxygen delivery, leading to ischemia in other settings. It has been unclear, however, if low hemoglobin levels contribute to secondary ischemic injury in people who have suffered from an ICH, thus contributing to these poor outcomes.
Our prior work has consistently identified a pervasive role of anemia in impairing ICH recovery. Patients who have lower baseline hemoglobin concentrations/anemia evident on their arrival to the hospital have worse ICH characteristics and worse long-term outcomes. However, like other hospitalized or critically ill patients, we have begun to appreciate that ICH patients not anemic at baseline often become anemic rapidly within days after admission. And furthermore, these rapid hemoglobin decrements and anemia development, which occurs frequently, relates to impairment of ICH recovery.
Subsequently, we have begun to realize the potential importance of these dynamic changes that occur during the hospitalization that may provide unique interventional targets during the hospital stay. Thus, our work has recently focused on the novel assessment of serial laboratory/hemoglobin changes over time after ICH and how these changes impact ICH outcomes
We followed two cohorts in our study:
- The ICH Outcomes Project (ICHOP) cohort of 190 spontaneous ICH patients, primarily treated medically, in which we measured changes in hemoglobin levels from admission to brain MRI acquisition
- An external secondary Stereotactic Intracerebral Hemorrhage Underwater Blood Aspiration (SCUBA) cohort of 172 spontaneous ICH patients who all underwent endoscopic neurosurgical hematoma evacuation.
The presence of ischemic lesions on diffusion-weighted MR imaging and six-month clinical outcomes were the primary outcomes.
Key Findings
Among the ICHOP patients, the mean baseline hemoglobin level was 13.4 g/dL. The greatest hemoglobin decrements occurred in the initial 2 days after ICH, with the mean level on hospital day two being 11.7 g/dL. The median time to MRI was two days, and 32% of patients had MRI ischemic lesions. Greater hemoglobin decrements were associated with MRI ischemic lesions and poor 6-month outcomes.
Similar findings were observed among the SCUBA patients. The mean hemoglobin level at admission was 13.9 g/dL and dropped by 2.3 g/dL by hospital day 4. Greater hemoglobin concentration decrements were again associated with MRI ischemic lesions and poor 6-month outcomes.
Our study shows that anemia development during the hospitalization impacts the recovery from a brain bleed by increasing the prevalence of patients encountering ischemic secondary brain injury lesions as well as poor long-term outcomes.
— Dr. David Roh
Clinical Implications
This investigation provides timely insight into the role that anemia has on the injury burden that can occur downstream from a brain bleed. Using MRI neuroimaging modalities, we can detect ischemic secondary brain injury burden not seen on conventional CT neuroimaging but are still impactful as they are known to impair long-term recovery. The drivers for these ischemic secondary brain injury lesions are unclear. They have previously been thought to be driven by impairments of cerebral perfusion (i.e., rapid blood pressure correction) after ICH. However, our study provides perspectives that greater hemoglobin decrements and subsequent anemia development after ICH admission plays a role in these ischemic lesions which in turn impairs long term functional recovery.
It was notable that the hemoglobin decrements seen in our study, while rapid and significant (~2g/dL drop), were not severe enough to trigger a red blood cell (RBC) transfusion using guideline recommended restrictive transfusion approaches (<7g/dL). While RBC transfusions are the mainstay therapies for severe anemia below these thresholds, it is possible that ICH patients may benefit from more liberal RBC transfusion approaches at higher hemoglobin thresholds. The recently published, multicenter randomized TRAIN Trial showed that liberal RBC transfusion approaches (<9g/dL) improved outcomes in acute brain injured patients, and this may have been driven by reduced ischemic events. A smaller subgroup of ICH patients within this trial appeared to demonstrate a similar therapeutic benefit of RBC transfusions, thus providing causal context to the findings from our study.
While it is tempting to implement liberal RBC transfusions as a therapy in ICH given the context of these findings, we believe further studies are needed. RBC transfusions are a limited resource and are not without their own risks. There are underrecognized variabilities in blood transfusion efficacy based on transfusion, donor, and recipient characteristics that need to be considered. In other words, blood product transfusions are not akin to pharmacotherapies with different blood unit bags having different effects/risks for their recipients. It is worth noting that while the TRAIN trial showed benefits of liberal transfusions across acute brain injured patients, these findings have not been replicated in 2 additional large multicenter studies of subarachnoid hemorrhage and traumatic brain injury patients. It is uncertain whether these treatment effect variabilities between these studies were due to study design variations, or the inherent variability of blood products seen across medical centers/countries that needs to be clarified prior to implementing its practice in ICH patients.
Furthermore, one needs to consider that anemia has varying underlying etiologies that may necessitate different types of treatment approaches that could be transfusion-sparing. Thus, our ongoing and future work are aimed at determining etiologic drivers of anemia in ICH patients across and even after their hospitalization to assess whether factors such as iron deficiency, inflammation, nutritional factors, or iatrogenic factors (i.e., phlebotomy) drive anemia and impact ICH outcomes. These human observational studies are being paired with the translational work in our laboratory leveraging our developed animal models of anemia, blood transfusion, and ICH to study transfusion and transfusion-sparing therapeutic approaches in the pre-clinical setting that can be brought back to the bedside.
Additional work will be ongoing to clarify future therapeutic approaches that can be developed from these findings. Yet, there are several practical clinical points that should be considered from our study. Acute blood pressure correction is a critical, protocolized component of acute ICH care (to establish hemostasis). Because this process drops a patient’s elevated blood pressure (at times >200 mmHg) to goals of 130-150 mmHg, this invariably decreases cerebral perfusion pressure. Thus, cerebral oxygen delivery becomes dependent on the oxygen carrying capacity of the blood (i.e., hemoglobin) . Therefore, closer attention needs to be paid to blood pressure and hemoglobin dynamics and their treatment goals over the hospitalization (beyond the acute hemostasis phase) to optimize cerebral oxygen delivery to prevent ischemic secondary brain injury.
NewYork-Presbyterian has a broad network of Joint Commission-certified stroke centers, including Comprehensive Stroke Centers at Columbia and Weill Cornell Medicine featuring all of the experts needed to provide patients with advanced care, including, but not limited to, cross-collaborations between specialists from neurology, neurosurgery, laboratory medicine, and hematology. This interdisciplinary approach is essential to providing high-quality care to patients and conducting meaningful research to help improve our understanding and treatment of ICH.
