Hematoma Expansion in Intracerebral Hemorrhage: An Update on Prediction and Treatment

With no treatment you don't want your doctor telling you you have this.

Hematoma Expansion in Intracerebral Hemorrhage: An Update on Prediction and Treatment

Zhifang Li^†, Mingfeng You^†, Chunnan Long, Rentang Bi, Haoqiang Xu, Quanwei He^* and Bo Hu^*

• Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Intracerebral hemorrhage (ICH) is the most lethal type of stroke, but there is no specific treatment. After years of effort, neurologists have found that hematoma expansion (HE) is a vital predictor of poor prognosis in ICH patients, with a not uncommon incidence ranging widely from 13 to 38%. Herein, the progress of studies on HE after ICH in recent years is updated, and the topics of definition, prevalence, risk factors, prediction score models, mechanisms, treatment, and prospects of HE are covered in this review. The risk factors and prediction score models, including clinical, imaging, and laboratory characteristics, are elaborated in detail, but limited by sensitivity, specificity, and inconvenience to clinical practice. The management of HE is also discussed from bench work to bed practice. However, the upmost problem at present is that there is no treatment for HE proven to definitely improve clinical outcomes. Further studies are needed to identify more accurate predictors and effective treatment to reduce HE.

Introduction

Intracerebral hemorrhage (ICH) accounts for about 10–20% of all types of stroke (1, 2) and almost 40% of patients who suffer from ICH will die within the first month, while only 12–39% of survivors achieve long-term functional independence (2), which makes it a severe public health problem. Unfortunately, after decades of effort there is no specific treatment yet for ICH, but recently HE has been found to be a modifiable and independent predictor of clinical neurological deterioration in intracerebral hemorrhagic patients. HE prevention has been accepted as one of the most promising therapeutic strategies in ICH treatment (3). Although numerous efforts have been made to select ICH patients at high risk of developing HE, no uniform prediction score model can be concluded from current studies, which therefore impedes the early detection and subsequent active intervention by clinicians. Moreover, once HE occurs in ICH patients, the treatment is extremely limited and the functional prognosis of those patients is unsatisfactory. Thus, it remains a priority to prospectively detect high-risk HE patients as well as administer more active prevention treatment.

This review refers to the definition, prevalence, risk factors/predictors, prediction score models, mechanisms, and treatment progress of HE. In detail, the predictors of HE are summarized to update the view on the prediction, and suggestions are also provided to establish an accurate and easy-to-use prediction score model. Furthermore, we discuss current HE treatment strategies from the viewpoint of clinicians and also point out future directions for the discovery of more effective therapies.

Definition

HE is defined based on visually discernible hematoma volume changes between the baseline and follow-up CT, and the evaluation of hematoma volume growth is diverse across HE related studies. As one of the earliest researchers of HE, Fujii et al. defined it as absolute hematoma volume growth of more than 20 ml or relative hematoma volume growth of more than 50% (4). Later, Brott et al. used relative hematoma volume growth of more than 33% which can be discovered by CT to define HE (5). Using ROC curve analysis, Kazui et al. applied cut point of hematoma volume increase of 12.5 ml or 40% (6). Some recently published large clinical trials also used relative hematoma growth of more than 33% (7), or combined hematoma growth of 6 mL absolute increase and 33% relative increase (8, 9) to define it. Based on CT angiography contrast extravasation, a 6 mL absolute increase of hematoma volume was proposed in the studies of Thompson et al. and Delgado et al. (10, 11). Of all the different definitions, Dowlatshahi et al. found that absolute growth definitions were more preferable to predict the outcome of ICH (12). Considering that intraventricular hemorrhage (IVH) is a predictor of poor prognosis in ICH, the presence of IVH may also be an indicator of HE. Specifically, Vignan et al. found that addition of IVH into the HE definition improves the prediction of 90 days outcome in ICH patients (13).

A uniform definition of HE considering convenience of measurement and effectiveness in predicting outcome is needed for further study.

Prevalence

Hemostasis was once thought to be over within min after ICH occurrence, but recently HE has been found to be a common phenomenon of ICH with advanced radiology (5). The reported incidence of HE within 6 h from ICH symptom onset ranges widely from 13 to 38% (5, 6, 12), which may be largely explained by different definitions of HE and different time interval between hematoma measurement in the different studies. In the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2), the incidence of HE was 33.1% in the control group (14), while it was 25.3% in Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH2) (15). Notably, the incidence of HE is highest at the hyperacute stage (within 6 h after symptom onset) and HE usually occurs at the internal capsule, thalamus, and brainstem. Thus, it is necessary to maintain hematoma surveillance, especially at the hyperacute stage of ICH.

Risk Factors/Predictors

ICH patients with high risk factors of developing HE are predisposed to experience clinical deterioration and closer neurological monitoring is required, while the absence of the predictors may identify ICH patients with low risk of developing HE. Thus, HE predictors have a vital role to play in selecting high-risk ICH patients and subsequently facilitating the individualized treatment. Based on clinical, imaging, and laboratory characteristics, a series of risk factors/predictors of HE have been identified.

Clinical Predictors

Systolic blood pressure (SBP) is positively related to the initial hematoma volume in ICH patients (16) and the risk of HE is much higher in patients with post-admission SBP over 160 mmHg (P = 0.0074) (17, 18), which may be partly explained by the continuous rupturing and hemorrhaging of small vessels, thus making early blood pressure a potential treatment target. Although baseline blood pressure variability (BPV) is not associated with HE (19), post-admission BPV independently predicts HE as well as poor functional outcomes (20). High mean arterial pressure (MAP) is positively related to HE as well (19).

Medication with antiplatelet or anticoagulant drugs also increases the risk of HE. In high-income countries, more than a quarter of patients with ICH are on prior antiplatelet therapy (APT) (21). An observational study by Toyoda et al. showed that APT was an independent predictor of HE (22), while in the Cerebral Hemorrhage and NXY-059 treatment trial, antiplatelet drug use at ICH onset was not associated with HE (23). On account of their methodological difference, recently this controversy has been laid to rest by a meta-analysis which supports prior APT as a predictor of HE (24). For those with prior medication with anticoagulants, prior oral anticoagulation (OAC) use is not only an independent predictor of larger initial hematoma volume (25) but also increases the risk of HE 6.2 times (26). In contrast to OAC, the incidence of ICH in Non-Vitamin K oral anticoagulants (NOACs) patients is dramatically decreased (27). NOACs-ICH has a lower risk of developing HE and is associated with smaller baseline hematoma volume (28) and better functional outcomes (29–31).

Higher baseline NIHSS or GCS scores (32–34), elevated body temperature (35), baseline weight (36), and history of cerebral infarction (37) or alcohol abuse (38) may increase the risk of HE, as found by some observational studies, and further randomized trials are needed to determine their relevance. In a recent retrospective cohort study of ICH patients with liver fibrosis, fibrosis-4 score and Aspartate Aminotransferase-Platelet Ratio Index were associated with HE (39).

Gender (40) and age (41) are also associated with HE, as men and older subjects (age ≥85 years) are more likely to present HE than women and younger subjects (40, 41).

It is interesting to note that ICH occurring during the daytime tends to be more likely to present HE than when occurring at night (OR, 3.53) (42). In addition, HE is mostly found in early initial CT scan (≤3 h of onset) (5, 6, 43), so time interval from ICH onset to initial CT scan should be considered (Abovementioned clinical predictors are summarized in Table 1).