Therapeutic Strategies in Acute Intracerebral Hemorrhage

H. Bart Brouwers 0 1 Joshua N. Goldstein 0 1 0 J. N. Goldstein Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School , Boston, MA 02114, USA 1 H. B. Brouwers Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School , Boston, MA 02114, USA 2 ) J. Philip Kistler Stroke Research Center, Massachusetts General Hospital , 175 Cambridge Street - Suite 300, Boston, MA 02114, USA Intracerebral hemorrhage is a devastating disease, and no specific therapy has been proven to reduce mortality in a randomized controlled trial. However, management in a neuroscience intensive care unit does appear to improve outcomes, suggesting that many available therapies do in fact provide benefit. In the acute phase of intracerebral hemorrhage care, strategies aimed at minimizing ongoing bleeding include reversal of anticoagulation and modest blood pressure reduction. In addition, the monitoring and regulation of glucose levels, temperature, and, in selected cases, intracranial pressure are recommended by many groups. Selected patients may benefit from hematoma evacuation or external ventricular drainage. Ongoing clinical trials are examining aggressive blood pressure management, hemostatic therapy, platelet transfusion, stereotactic hematoma evacuation, and intraventricular thrombolysis. Finally, preventing recurrence of intracerebral hemorrhage is of pivotal importance, and tight blood pressure management is paramount. - Spontaneous intracerebral hemorrhage (ICH) accounts for 10 to 15% of all strokes worldwide or 10 to 30 cases per 100,000 people per year [1]. Patients with ICH show the worst outcome of all stroke subtypes with a 30day mortality rate of 30 to 50% [25]. Moreover, longterm outcomes of ICH are even more devastating, with 75% of patients severely disabled or deceased at 1 year [4]. ICH is more frequently seen in men than women, especially in the Japanese population, and ICH is twice as common in Asians compared to other ethnic groups. The incidence of ICH appears to increase with advanced age [4, 6]. ICH is classified as primary or secondary based on the underlying cause. Primary ICH is the result of spontaneous rupture of small vessels and accounts for 78 to 88% of all ICH cases [7]. Causes include hypertension and cerebral amyloid angiopathy. Secondary ICH (accounting for 12 to 22% of all ICH) is due to a cause other than small vessel rupture (e.g., aneurysm, arteriovenous malformation, hemorrhagic transformation of ischemic stroke, and neoplasms [7]. Following both types of ICH, edema formation will occur, perilesional blood flow will change, and some hematomas will expand with time. All these pathophysiological processes are described in more detail as follows, however, this review primarily focuses on the acute management of primary ICH. Numerous risk factors for ICH have been identified over the past several decades, including genetics, race, lifestyle, and pre-existing medical conditions [7]. Genetic risk factors include the apolipoprotein E 2 and 4 alleles, whereas both raise the risk for ICH in the lobar brain regions, only the 4 allele is associated with deep ICH [8]. A first-degree relative with ICH is also an independent risk factor for ICH [9]. Lifestyle risk factors include smoking, excessive alcohol intake, drug abuse, unhealthy diet, and a lack of regular physical activity [9, 10]. Risk factors in a patients past medical history include prior stroke, hypertension, diabetes mellitus, psychosocial stress, cerebral amyloid angiopathy, coagulopathy, and an underlying vascular lesion [7, 9, 10]. Although many of these factors cannot be modified, some offer therapeutic targets. In particular, the population attributable risk of hypertension for ICH is quite high [9], and treatment of hypertension has been shown to decrease this risk for both cerebral amyloid angiopathy-related and hypertension-related ICH [11]. Initial hematoma volume is the strongest predictor of 30day mortality, with 96% sensitivity and 98% specificity [12]. In addition, it predicts poor functional outcome [13, 14]. The apolipoprotein E 2 allele is associated with larger hematomas, which appears to explain its effect on outcome [15]. The relation between oral anticoagulation use and baseline hematoma volume is unclear; some studies have shown increased baseline volumes [16, 17], whereas others have not [15, 18]. Hematoma location is also an important aspect of the initial hematoma, because location influences 30-day mortality rates: 44% for deep ICH, 46% for lobar ICH, 60% for brainstem ICH, and 34% for cerebellar ICH [3]. In a study of more than 1000 patients, the distribution of hematoma location showed 50% deep, 35% lobar, 10% cerebellar, and 6% brainstem ICH [19]. The presence of intracerebral hemorrhage causes edema formation surrounding the hematoma (termed perihematomal edema) starting within hours of ICH onset and progresses with time [20, 21]. The physiology of edema formation consists of 2 stages. Early edema is due to the accumulation of serum proteins of the clot that contains osmotic activity [22]. Subsequently, the presence of cytotoxic and vasogenic edema leads to bloodbrain barrier disturbances, sodium pump failure, and ultimately the death of neurons [23, 24]. The first hours after ICH onset, the bloodbrain barrier continues to be nonpermeable for larger molecules, but after 8 to 12 hours the permeability increases and therefore fosters further edema formation [20]. In addition, an inflammatory reaction starts early after ICH and peaks a few days post-ICH, leading to secondary brain injury [20]. Perilesional Blood Flow In addition to edema, perilesional or perihematomal blood flow is of clinical interest because of a theoretical concern that lowering the systemic blood pressure may cause perilesional ischemia. Several studies, with heterogeneous results, have investigated this topic. A computed tomographic (CT) perfusion study showed reduced regional cerebral blood flow adjacent to the hematoma, which increased as the distance from the hematoma center increased [25]. In a single-photon emission computed tomography (SPECT) study, edema increased by 36% in the first 72 hours, and during this period the perilesional blood flow normalized [26]. An additional, more recent CT perfusion study also showed a reduced regional cerebral blood flow surrounding the hematoma, accompanied by a reduced oxygen extraction fraction. This decreased oxygen demand might be due to tissue damage caused by an inflammation process initiated by hematoma components [27]. Of note, 2 magnetic resonance image (MRI)-based studies found no evidence of decreased perilesional blood flow [28, 29]. Another predictor of poor outcome is ongoing bleeding after hospital arrival, or hematoma expansion. Seventy three percent of patients express some degree of expansion, and 30 to 40% of patients expand more than 33% from baseline volume [13, 18, 30, 31]. T (...truncated)