The present study examines the corrections between outcome and endothelial cell activation markers following spontaneous ICH and produces the following major findings. First, sICAM-1 and sVCAM-1 concentrations markedly increased in patients with spontaneous ICH at presentation (205.0 and 709.7 ng/mL, respectively), whereas sL-selectin markedly decreased (759.4 ng/mL) (Table
1). Second, plasma concentrations of sICAM-1 and sVCAM-1 elevated significantly after ICH onset, peaked on day 10 (sICAM-1) and day 4 (sVCAM-1), and then slightly decreased thereafter (Figure
1a,b). Furthermore, plasma sL-selectin levels decreased significantly after onset of ICH, reached its lowest level on day 4, and then increased thereafter (Figure
1d). Third, when the therapeutic outcomes of the 60 spontaneous ICH cases as determined by mMRS score were compared, sICAM and sE-selectin concentration levels increased significantly from days 1 to 14 in patients with poor outcome (Figure
2a,e). Fourth, GCS score on admission, hyperlipidemia as the underlying disease, and sICAM-1 (
P = 0.039, 0.042, and 0.022, respectively) were independently associated with outcome of acute spontaneous ICH.
Adhesion molecules
Several studies have shown that adhesion molecules play a patho-physiologic role in cerebrovascular diseases [
11,
16,
17,
20]. One study has demonstrated that sICAM-1 and sVCAM-1 levels in CSF and sera of patients with acute subarachnoid hemorrhage are elevated compared with those of healthy controls [
16]. Two studies by Kraus and colleagues [
17,
20] have found that highly elevated levels of sICAM-1 and sVCAM-1 in ventricular CSF, but not in serum, are associated with lethal outcome after ICH. Only sICAM-1 and sVCAM-1 levels in CSF, not in serum, are significantly correlated with basal ganglia hemorrhage volume and edema volume. However, there is no significant correlation with outcome at day 8 or at 6 months later [
20].
In the former study by Kraus and colleagues [
17], patients were categorized into one of two groups (patients who survived and patients who died). In the former study by Kraus and colleagues [
17],there were no normal subjects for comparison that may mask the true difference in adhesion molecules in different disease severities. Furthermore, the two studies have relatively small groups of patients (n = 10 and 11, respectively). The present study shows increased concentration levels of sICAM-1 and sVCAM-1 in patients with acute spontaneous ICH. This activation persists for at least 14 days after ICH onset and suggests that the activation of adhesion molecules, especially sICAM-1 and sVCAM-1, plays a patho-physiologic role in the acute phases after spontaneous ICH.
The inflammatory response in ICH is characterized by the activation of local immune cells such as microglial cells. This local inflammatory reaction is partly responsible for damages to the brain after injury. Mounting evidence also suggests that systemic immune cells, specifically blood-derived leukocytes, are the primary sources of this damage [
4]. In focal ischemic stroke models, systemic immune cell recruitment is mediated in part by the increase in adhesion molecule expression along the endothelial cell walls [
8]. As a result, these systemic immune cells propagate local immune response by releasing pro-inflammatory cytokines at the site of injury, increasing cerebral edema, and worsening neuro-behavioral function [
5,
9,
10].
Previous studies on ICH indicate that brain edema increases progressively in the first 24 hours and remains elevated for several days because of an inflammatory response characterized by the infiltration of neutrophils and macrophages as well as the activation of microglia [
6]. The cause of secondary brain injury and edema formation is uncertain. The results of the present study show that an inflammatory response occurs after ICH and that adhesion molecules, especially sICAM-1 and sE-selectin, may play an important role in the inflammatory response, contributing to secondary brain injury and worsened neuro-behavioral function.
Delayed cerebral infarction
Five (8.3%) of 60 patients in the present study had delayed cerebral infarction during hospitalization, and this incidence is similar to that of a previous report [
21]. However, these adhesion molecules are not correlated with the occurrence of delayed cerebral infarction, and patients who had delayed cerebral infarction do not account for the outcome in this study. Several mechanisms are implicated in the development of cerebral infarctions following spontaneous ICH. One is the massive release of blood and blood breakdown products into the CSF and subsequent inflammatory changes in the smooth muscle of the large cerebral arteries as well as released vasoactive substances involving inflammatory host reactions [
22‐
24]. As the disease progresses, inflammatory changes result in endothelial dysfunction with consequences that include loss of cerebrovascular autoregulation and increased permeability of the BBB. Decreased cerebral blood flow becomes apparent and leads to cerebral ischemia [
25,
26]. The possible reasons that delayed cerebral infarction does not significantly correlate with adhesion molecules in the present study are that the conditions of the ICH patient population are mild at admission: median GCS score of 14.5 (IQR of 10.3 to 15.0) and median ICH volume of 10.0 mL (IQR of 5.7 to 25.8 mL). Therefore, the inflammatory condition in the patient population may be less severe and does not cause worse outcome.
Of the 60 patients enrolled in this study, 42 (70%) were mild, eight (13.3%) were moderate, and 10 (16.7%) were severe in their initial GCS score. The hematoma volume was relatively small: the median volume of intracerebral hematoma was 10.0 mL (IQR of 5.7 to 25.8 mL) at presentation. The small hematoma volume will cause less volume effect, and this may explain why the intracerebral hematoma volume is not an independent factor associated with the outcome.
In this study, underlying disease with hyperlipidemia is independently associated with outcome of acute spontaneous ICH. At the moment of acute spontaneous ICH, the patients were all being treated for hyperlipidemia with statin drugs. Previous studies reveal that pre-treatment with intense low-density lipoprotein cholesterol-reducing drugs improves the clinical outcome in patients with ischemic and hemorrhagic stroke [
27‐
29]. Previous reports demonstrate an induction of apoptosis, inflammation, and excitotoxic cascades after ICH [
30]. There is also increasing evidence that statins have anti-inflammatory and anti-thrombotic effects, aside from their cholesterol-lowering effect [
31,
32].
In the patient population here, neuro-surgical intervention is significantly associated with poor outcome. It is reasonable to postulate that surgical intervention can affect the serum levels of various adhesion molecules. All of the neuro-surgical treatments were done within 4 days after ICH. However, only the level of sICAM-1 had a statistically significant difference on day 4 (P = 0.025) between patients with neuro-surgical intervention and those without it. Furthermore, when included in the multiple logistic regression analysis, neuro-surgical intervention is not an independent factor associated with outcome of acute spontaneous ICH. Thus, neuro-surgical intervention may affect the serum levels of various adhesion molecules but does not confound the major findings of the study.
This study has several limitations. First, patients who were deeply comatose or those with imminent death were excluded. There is uncertainty in assessing the expression of these adhesion molecules in critically ill and high-risk patients. Second, sICAM-1, sVCAM-1, sP-selectin, sL-selectin, and sE-selectin are only part of the endothelium-leukocyte-platelet adherent molecules expressed after cerebrovascular diseases. Therefore, increased levels of these markers may not necessarily be reflected in the actual patho-physiologic function. Third, serial changes of adhesion molecules may be influenced by the expression of platelet adhesion molecules (CD62P, CD63, and CD40L), platelet-leukocyte interaction, and several drugs (for example, statins and calcium channel blockers), which are commonly used in patients with ICH. Lastly, the case numbers are small and the follow-up period is short. Large-scale studies with longer follow-up periods to evaluate the association between clinical outcome and the expression of adhesion molecules are warranted.