Clinical manifestations

Presentation and course

In hypertensive intracerebral hemorrhage, focal neurologic deficits depend on the location, size, and effects (mass effect and edema) of the hemorrhage. The classic signs of intracerebral hemorrhage are summarized in Table 1 (19).

As the hematoma grows, symptoms and neurologic deficits reach a maximum intensity over a period of 10 to 30 minutes in most cases, or as long as 3 hours (19). A large hematoma produces a characteristic syndrome consisting of progressive focal neurologic signs accompanied by vomiting, headache, and decreased alertness. Conversely, small hematomas can mimic ischemic lacunar syndromes. Early improvement and a fluctuating course are not consistent with hemorrhage. Most intracerebral hemorrhages occur during activity hours.

Alertness is impaired in approximately 60% of cases due to involvement of the reticular activating system. Coma is common in patients with hemorrhages into the thalamus or pons. When stupor and coma develop in patients with putaminal or lobar hemorrhage, the prognosis is poor.

Headache, present in at least 60% of patients (112), results from pressure on the pain-sensitive meninges or surface arteries. Vomiting, caused by pressure on the floor of the fourth ventricle, occurs in half of the patients (19).

Table 1. Signs of Intracerebral Hemorrhage at Various Sites

Prognosis and complications

The overall mortality of primary intracerebral hemorrhage is approximately 25% to 50% (156; 19). Fatal outcome correlates with the size of the hematoma and correlates with Glasgow Coma Scale score and hematoma volume on admission (90).

Coma at presentation correlates with 64% mortality (161). Mortality within the first week is 32 times higher in patients with a Glasgow Coma Scale score lower than 8 and 14.5 times higher in those with signs of brainstem compression (188). Among these are absent corneal and occulocephalic responses and lack of localization of the painful stimulus (164).

Mortality within 30 days of onset is associated with intracerebral hemorrhage volume greater than 32 ml supratentorially or 21 ml infratentorially (151). The prognosis of lesions smaller than 1.5 cm is generally excellent, except in elderly patients or when there may be a significant amount of intraventricular bleeding (81).

Radiological predictors of death are acute hydrocephalus and intraventricular hemorrhage (164). Intraventricular hemorrhage is associated with 66% death and disability as compared to 49% in intracerebral hemorrhage alone (74). Horizontal displacement (midline shift) of the pineal body of 3 to 4 mm from the midline is associated with drowsiness, 6 to 8.5 mm with stupor, and 8 to 13 mm with coma (144).

Mortality increases dramatically with thalamic and cerebellar hemorrhages larger than 3 cm in diameter and pontine hemorrhages larger than 1 cm in diameter. For cerebellar hematomas, mortality was 17% in responsive patients and 75% in unresponsive patients (129).

Early neurologic deterioration was caused by hematoma expansion in approximately half of the patients. This is defined radiologically by increase in size by 12.5 cm³ or greater than 1.4 times. Expansion occurs in up to 36% of patients within 24 hours but is very rare afterwards (79). Hematoma expansion was more frequent in patients with ionized calcium lower than 1.12 mmol/L (194).

Age and systolic blood pressure at admission are also associated with death (69). Other risk factors for poor outcome are hyperglycemia, body temperature higher than 37.5°C, elevated neutrophil count, serum fibrinogen levels of greater than 523 mg/dL on admission, and hypodensities on CT head (93; 168; 08).

Approximately 60% of patients with stroke present with elevated blood pressure (134). High blood pressure within the first 24 hours after onset is associated with increased risk of perihematomal edema (174), severe morbidity, and mortality (30). Edema formation starts within 3 hours (165); it increases gradually and peaks at 10 to 20 days (71). There is a positive association between perihematomal edema and hyperthermia, likely mediated by the inflammatory response (70).

The intracerebral hemorrhage score is used to determine mortality at 30 days. The elements of this score are Glasgow Coma Scale score, the hemorrhage volume, presence of intraventricular blood, infratentorial origin of blood, and age (58). The functional outcome of intracerebral hemorrhage may be predicted with the FUNC score (145).

Recurrence rate of intracerebral hemorrhage is approximately 2.4% per year, with a 3.8-fold increase for lobar hemorrhage (64). In another study, all but one hemorrhages occurred at a different site (25). Up to 20% of recurrent intracerebral hemorrhages had a different cause, suggesting the need to investigate thoroughly every instance of recurrence (192; 185).

The risk factors for intracerebral hemorrhage recurrence include poor functional status after the first hemorrhage, prior history of ischemia, lobar location, older age, ongoing anticoagulation, multiple microbleeds on MRI, surgical treatment, and renal insufficiency. SSRIs or NSAIDs were not associated with increased risk of recurrence, and antihypertensive medication reduces this risk (82; 59; 158).

Recurrent hemorrhage was also associated with variant genotype combinations of ACE and αADDUCIN (109) and presence of apolipoprotein E ε2 and ε4 alleles (108). The HAS-BLED score was developed to assess the risk of recurrent intracerebral hemorrhage (22).

Seizures occur in approximately 25% of patients with primary intracerebral hemorrhage, especially in lobar hemorrhage (54%), when blood extends into the cerebral cortex. In one half of these, the seizure begins within 24 hours of the onset of the hemorrhage. Seizures are relatively rare with basal ganglia hemorrhage (19%) and do not occur in patients with thalamic, pontine, or cerebellar hematomas (38).

Seizures usually begin focally and occur more often with cortical lesions, nonhypertensive intracerebral hemorrhage, younger age, and severe neurologic deficits (119).

Continuous EEG discovered seizures in up to 31% of patients with intracerebral hemorrhage despite anticonvulsant therapy (176; 27).

Hyperthermia, seen in approximately 39% of patients, is associated with increased mortality. In 71% of cases the cause is not infectious. The factors associated with hyperthermia are the volume of intracerebral hemorrhage, intraventricular hemorrhage, external ventricular drainage or surgical evacuation, and positive blood cultures (48). Noninfectious fever may occur with pontine hemorrhages and may be difficult to treat (154).

Hypothermia occurs more often in intracerebral hemorrhage than in traumatic brain injury, acute ischemic stroke, or subarachnoid hemorrhage. Mortality is increased compared with fever (140).

Biological basis

Etiology and pathogenesis

Chronic hypertension is the major cause of nontraumatic or spontaneous intracerebral hemorrhage. Thirty-nine single nucleotide polymorphisms (SNP) were found to be related to blood pressure. Although no single SNP was associated with ICH or pre-ICH hypertension, the blood pressure-based unweighted genetic risk score was associated with the risk of ICH and ICH in the deep regions, but not with lobar ICH (36).

The diagnosis of hypertensive intracerebral hemorrhage is based on (1) history of hypertension; (2) bleeding into a site typical for penetrating artery territories, such as putamen, thalamus, pons, and cerebellum; and (3) no other cause of hemorrhage. Elevated blood pressure on admission may reflect altered hemodynamics due to the increased intracranial pressure or acute release of catecholamines. Chronic hypertension may be distinguished from this stress response by findings of cardiomegaly on chest x-ray, left ventricular hypertrophy by electrocardiogram or echocardiogram, renal dysfunction, or hypertensive retinopathy on funduscopic examination.

In a large population study, the relative risk of hypertension for intracerebral hemorrhage was 3.9 (13). For the presence of hypertension by history, left ventricular hypertrophy, and cardiomegaly, the relative risk was 5.4. For black persons with a history of hypertension, the relative risk was 8.2; for hypertension, left ventricular hypertrophy, and cardiomegaly, the relative risk was 13.3.

Pathology. A pathogenetic classification of intracerebral hemorrhage was proposed—SMASH-U: structural vascular lesions (S), medication (M), amyloid angiopathy (A), systemic disease (S), hypertension (H), or undetermined (U). Structural lesions, like cavernomas and arteriovenous malformations, caused 5% of the hemorrhages. Approximately 14% of cases were caused by anticoagulation and 5% by systemic disease. Amyloid angiopathy and hypertensive angiopathy were the most common causes at 20% and 35% respectively. Etiology remained undetermined in 21% of cases (106).

Hypertension is postulated to cause intracerebral hemorrhage by two mechanisms: (1) rupture of arteries previously damaged by chronic hypertension and (2) acute or subacute increases in blood pressure or blood flow in regions of previously normal small arteries, arterioles, and capillaries, such as in the context of emotional stress, exposure to cold weather, severe dental pain, sympathomimetic drug abuse, and trigeminal stimulation (18; 89).

Rupture of small arteriolar microaneurysms (saccular or fusiform) was thought to cause intracerebral hemorrhage (23). Charcot-Bouchard aneurysm was not found to be a significant cause of intracerebral hemorrhage but rather a marker for severe cerebrovascular disease (99).

Postmortem angiography revealed more often miliary aneurysms in patients with hypertension than in those without. These aneurysms were found in small vessels (100 to 300 µm in diameter) of the basal ganglia, internal capsule, thalamus, and, less commonly, centrum semiovale and cortical gray matter (148; 28).

Histological studies show that hypertensive intracerebral hemorrhage results from a rupture of lipohyalinotic arteries. Both aneurysmal and nonaneurysmal hemorrhages were described (42). A later study found ruptured miliary aneurysms in a minority of histological specimens. The predominant finding was degenerative changes of the media at or near a bifurcation of the vessels, the most likely site for rupture (167).

Most hypertensive hemorrhages occur in the deep structures: putamen (40% to 50% of cases), subcortical white matter–lobar (20%), thalamus (15%), cerebellum (8%), pons (8%), and caudate nucleus (8%) (19). These areas are supplied by small perforating arteries, including the lateral and medial lenticulostriate branches of the middle cerebral artery, Heubner's branch of the anterior cerebral artery, the thalamo-perforating branch of the posterior communicating artery, the thalamogeniculate branch of the posterior cerebral artery, the median and paramedian branches of the basilar artery, or the superior cerebellar artery. Most hypertensive intracerebral hemorrhages originate from the rupture of arterioles with diameters between 50 and 200 µm (42).

Hematoma expansion is seen in approximately 22% of patients and may lead to poor prognosis. Expansion is associated with a short interval between onset and the CT head, irregular shape of hematoma, and increasing plasma level of matrix metalloproteinase-9 (191).

Arterial rupture leads to accumulation of blood, which compresses and injures the brain parenchyma locally and dissects for some distance. If the hematoma is large, midline shift and compression of brainstem vital centers may lead to coma and death. Within 1 hour from onset, accumulation of serum proteins resulting from blood clot retraction leads to formation of the perihematoma edema (181).

After 2 to 4 days, inflammatory cells arrive at the margins of the hemorrhage. Hemosiderin-laden macrophages and extracellular deposits of hematoidin are present after 3 weeks. The level of CD163, a scavenger receptor for hemoglobin, was significantly lower in patients with larger perihematoma edema and may be a useful prognostic biomarker (146).

Astrocytic proliferation occurs in the neighboring parenchyma. Apoptosis plays a major role in cell death after intracerebral hemorrhage and is associated with activation of nuclear factor-kB (NF-kB), ICAM-1 IL-1B (184). In the chronic stage, the hematoma shrinks to a cavity lined by hemosiderin-laden macrophages.

Extension of the hemorrhage into the subarachnoid space has been associated with fever and worse outcome (53).

Epidemiology

Intracerebral hemorrhage accounts for approximately 10% of strokes (103; 112). The annual incidence is estimated to be between 10 and 22.9 per 100,000 (52; 12) with a male predominance (60%) (87).

Hypertension is the leading cause of intracerebral hemorrhage. The significantly higher incidence in the black population as compared to the white population (32 vs. 12 per 100,000) may reflect the higher prevalence of hypertension (52). Additionally, if hypertension is not treated, the risk of intracerebral hemorrhage in all anatomic locations is greater in blacks and Hispanics relative to whites (182). Over the past several decades, the proportion of patients with intracerebral hemorrhage who were hypertensive declined from 84% to 50% (45). This may reflect both improvement in hypertension treatment and diagnostic imaging of alternative causes of intracerebral hemorrhage.

In young adults (16 to 49 years of age), the incidence is lower, 4.9 out of 100,000. The most common risk factors are hypertension (29.8%) and smoking (22.3%). Structural lesions are more common in young compared to elderly patients (25% vs. 4.9%). In patients younger than 40 years of age, intracerebral hemorrhage tends to be less severe and has a better prognosis (147). In 22.5% of cases, no etiology was found after MRI and angiography were performed (86).

Although no seasonal variation has been identified, the risk of intracerebral hemorrhage increases significantly between 8:00 am and 4:00 pm (125). In a small study, drop in atmospheric pressure 2 days before ictus was associated with deep but not lobar intracerebral hemorrhage, suggesting a link to hypertensive etiology (67).

Prevention

It was estimated that by eliminating hypertension from the population, the incidence of intracerebral hemorrhage would decrease by 49% (13). Uncontrolled blood pressure at 3 months following the initial hemorrhagic stroke was associated with higher recurrent stroke risk and mortality. Those presenting with poorly controlled blood pressure and Black, Hispanic, and Asian survivors of intracerebral hemorrhage were at the highest risk for uncontrolled hypertension at 3-month follow-up (07). A decrease of diastolic blood pressure by 10 mmHg may reduce the risk of stroke by up to 56% (98). The treatment of isolated systolic hypertension is equally important (160).

After the acute intracerebral hemorrhage period, a reasonable goal is a target normal blood pressure of less than 130/80 mmHg (59).

Differential diagnosis

Confusing conditions

As the clinical features of ischemic and hemorrhagic stroke often overlap, CT is used to quickly and reliably differentiate between types of stroke. Determining the cause of intracerebral hemorrhage is based on demographic and risk factors and the location and appearance of the lesion on CT and MRI.

Amyloid angiopathy. Amyloid angiopathy occurs in the elderly and results in microinfarcts, subarachnoid hemorrhage, intracerebral hemorrhage, and dementia. Multiple hemorrhages occur over time at several sites within the cerebral hemispheres, especially in the posterior portion of the hemisphere in the parietal and occipital lobes. Bleeding in the basal ganglia, thalamus, pons, and cerebellum is rare. Beta-amyloid may be detected by temporal artery biopsy (171).

Drug-related intracerebral hemorrhage. Sympathomimetic drugs and stimulants associated with intracerebral hemorrhage include amphetamines, cocaine, phencyclidine, phenylpropanolamine, ephedrine, and methylphenidate (124; 17). The diagnosis depends on drug use during the previous 1 to 2 days and a positive drug screen. Patients usually complain of headache, drowsiness, and confusion, and they may appear psychotic. The location of the drug-induced intracerebral hemorrhage closely mimics hypertensive intracerebral hemorrhage except that more of the drug-related hematomas are lobar.

Anticoagulant and antiplatelet-related intracerebral hemorrhage. Intracerebral hemorrhage due to anticoagulation occurs at a rate of nearly 1% per year; 70% are intracerebral hematomas, of which 60% are fatal. Risk factors include older age, hypertension, prior ischemic stroke, and intensity of anticoagulation. Heparin, especially if given as a bolus (57), warfarin use if INR is greater than 3.0 (43), and aspirin are associated with intracerebral hemorrhage (15). In a population-based study, prior use of either warfarin or aspirin are independent risk factors for death after intracerebral hemorrhage (153).

Thrombolytic therapy–related intracerebral hemorrhage. Thrombolysis-related hemorrhage occurs in 0.36% of patients with acute myocardial infarction and in 6.4% of patients with ischemic stroke (121). The location can be deep, lobar, or in the region of an infarction. In a pooled analysis, 7 of 10 patients who died of thrombolysis-related hemorrhage and underwent autopsy had cerebral amyloid angiopathy (105).

Hematological disorders. A few examples are hemophilia, thrombocytopenia, and leukemia.

Vascular malformation and aneurysm. Any young patient with lobar or subependymal intracerebral hemorrhage who is not hypertensive should be evaluated for a vascular malformation with a contrast-enhanced CT or MRI. Delayed scans may detect lesions missed in the acute stage due to compression by the adjacent hematoma.

Brain tumor. Among primary brain tumors, glioblastoma multiforme is the most frequent cause of intracerebral hemorrhage (96). Although choriocarcinoma and malignant melanoma have a high frequency of intracerebral hemorrhage (50% and 29%, respectively), the most common cause of intracerebral hemorrhage is bronchogenic carcinoma (152). Tumor diagnosis is suggested by a contrast-enhanced lesion surrounded by vasogenic edema on CT or MRI.

Hemorrhagic infarction. Hemorrhagic transformation of a cerebral infarction usually results from a cerebral embolus. Its detection increases for several weeks after stroke onset. The neurologic deficits are usually maximal at onset, but mild transformation may be asymptomatic. The CT scan shows a spotted and mottled appearance of high attenuation inside the infarction.

Unusual causes of intracerebral hemorrhage. The following conditions all have in common an acute rise in blood pressure or blood flow: exposure to cold weather, dental pain or manipulation, manipulation of the trigeminal nerve, carotid endarterectomy, and correction of congenital heart defects and cardiac transplantation in the young (19). The location of the hematomas in these conditions is identical to that of intracerebral hemorrhage in chronically hypertensive patients.

Associated or underlying disorders

Left ventricular hypertrophy. Left ventricular hypertrophy is associated with chronic hypertension and intracerebral hemorrhage (130).

Hypothyroidism. Hypothyroidism leads to endothelial disorders and atherosclerosis and was found more often in patients with intracranial hemorrhage (68).

Diagnostic workup

Any patient with intracerebral hemorrhage should have coagulation parameters (prothrombin time and international normalized ratio) tested in addition to a hemogram and a blood chemistry panel.

CT may detect hematomas a few millimeters in diameter. The characteristic appearance of high density represents an absorption value in the range of 40 to 90 Hounsfield units (159). This high-density lesion is due mainly to the hemoglobin protein (globin) contained in the extravasated blood (120). CT not only allows a precise localization of the hemorrhage and its effects, like midline shift, surrounding edema, and ventricular extension (196) but also provides rapid diagnosis of small or clinically atypical hemorrhages that in past years were misdiagnosed as an infarction.

Contrast-enhanced CT may help in the diagnosis of an arteriovenous malformation or a neoplasm. "Ring enhancement" occurs between 1 to 6 weeks from the onset of intracerebral hemorrhage and may last up to 2 to 6 months. It is due to hypervascularity at the periphery of the evolving hematoma (196) or disruption of the blood-brain barrier (34). The acute hematoma is commonly surrounded by vasogenic edema, which is thought to be plasma derived (16). After 7 to 10 days, the high-attenuation values of the hematoma start to decrease, always from the periphery towards the center. The entire hematoma becomes isodense in 2 to 3 weeks if small or in 2 months if large (120). The reduction in size and attenuation values in intracerebral hemorrhage have been estimated at rates of 0.65 mm and 1.4 Hounsfield units per day, respectively (34). The final stage in the CT evolution is the complete absorption of the necrotic and hemorrhagic tissue, leaving a residual cavity after 2 to 4 months. At times, this cavity can be indistinguishable from that of an old cerebral infarct.

Contrast extravasation on early CT angiography (“spot sign”) may predict hematoma expansion (50; 178). The Spot Sign Score (SSSc) that includes the number of spot signs, their maximum axial dimension, and attenuation was validated prospectively for prediction of significant expansion of hematoma, severe disability, and mortality (142). The “blush sign,” another predictor for hematoma expansion, seems to be a better predictor than the spot sign (173).

MRI not only distinguishes hemorrhage from infarction but also provides insight into the evolution of hemorrhage by detecting the chemical changes of hemoglobin. Five stages of an evolving hematoma have been described: (1) hyperacute (first 24 hours), (2) acute (1 to 3 days), (3) early subacute (longer than 3 days), (4) late subacute (longer than 7 days), and (5) chronic (longer than 2 weeks). Four zones have also been described: (1) inner core, (2) outer core, (3) rim, and (4) reactive brain (09). However, no MRI-autopsy correlation has been reported. The different stages of hemorrhage, the changes of hemoglobin, and the intensity on MRI are as follows (Table 2) (09).

Table 2. Stages of Hemorrhage

Using diffusion-, T2-, and T2* -weighted images, MRI has been shown to detect intracerebral hemorrhage within 6 hours of onset. The hemorrhage is typically target-like appearance (39). The hyperacute hemorrhage is composed of three distinct areas: (1) center: isotense to hyperintense signal on T2* - and T2-weighted images; (2) peripheral: hypointense (deoxyhemoglobin) mostly on T2* -weighted images; (3) rim: hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging, representing vasogenic edema encasing the hematoma (95).

Gradient-echo T2-weighted MRI detects chronic microbleeds in more than half of the patients (54%) with primary intracerebral hemorrhage. Microbleeds are seen as round, hypointense foci smaller than 5 mm due to the perivascular hemosiderin. They result either from hypertensive vasculopathy or from cerebral amyloid angiopathy (177). The microbleeds located in basal ganglia, thalamus, and the infratentorial region are more likely to be associated with primary intracerebral hemorrhage (143).

Enlarged perivascular spaces (EPVS) seen on brain MRI are a promising marker of small vessel disease and are common in patients with intracerebral hemorrhage. Based on their anatomical distribution, the mechanism of formation may be inferred. Severe centrum semiovale EPVS may indicate cerebral amyloid angiopathy, whereas basal ganglia EPVS suggests hypertensive arteriopathy (24).

Cerebral arteriography is used in selected cases for further confirmation or plan of treatment of arteriovenous malformation, aneurysm, tumor, and vasculitis. Patients younger than 45 years without hypertension or hemorrhage in the putaminal, thalamic, or posterior fossa may benefit from cerebral angiography (195). In patients without a clear cause and negative angiogram, a repeat angiogram after the resolution of the hematoma may help uncover small vascular malformations (66). Extension of intracerebral hemorrhage into the ventricular system is not usually associated with vascular malformations and the yield of catheter angiography is low (77).

Although CT angiography is as accurate as digital subtraction angiography for the diagnosis of vascular lesions, it cannot characterize the angioarchitecture (187). A simple, practical score to detect secondary intracerebral hemorrhage (SICH) based on noncontrast CT characteristics, age, and presence of hypertension or coagulopathy may help the choice of further cerebrovascular imaging (31). CT angiographies must be carefully reviewed even in elderly patients with a hemorrhage in a location typical for hypertensive arteriopathy. For example, an aneurysm of the lateral posterior choroidal artery was found on the CT angiogram of a 60-year-old man (44).

In 2% to 3% of all the hemorrhagic strokes there are multiple foci of bleeding. It has been hypothesized that sustained hypertension during a cerebral hemorrhage could trigger another bleeding by the acute vascular changes in the penetrating arteries. These hemorrhages must be differentiated from hematologic disorders, vasculitis, anticoagulant therapy, illicit drug use, cerebral amyloid angiopathy, or hemorrhage due to multiple infarctions with hemorrhagic transformation (104).

Management

The most important measures to control hypertensive intracerebral hemorrhage include the following:

The American Heart Association/American Stroke Association has provided a comprehensive review for the management of spontaneous intracerebral hemorrhage in adults (59).

Maintenance of airway patency and adequate oxygenation. Airway patency and maintenance oxygen saturation above 95% are the first concerns. Endotracheal intubation is needed in case of impaired consciousness, hypoxia (PO2 < 60 mmHg, PCO2 > 50 mmHg), or aspiration of secretions (128). Prolonged coma or pulmonary complications beyond 2 weeks may require elective tracheostomy.

Blood pressure. Increased blood pressure is common in acute intracerebral hemorrhage (134). In a study, hypertension was associated with hematoma expansion (126), but this relationship was not confirmed and raises the question of whether hematoma growth may be contributing to high blood pressure (75). Other studies found an association between hematoma growth and systolic blood pressure higher than 200 mmHg (79) and systolic blood pressure load, defined as the proportion of readings higher than 180 mmHg (141). Aggressive blood pressure control does not seem to injure the tissue surrounding the hematoma. Here, the metabolism is reduced (80) and the cerebrovascular reactivity is preserved (132). Another study using diffusion- and perfusion-weighted MRI showed no evidence for a perihemorrhagic ischemic penumbra (157).

So far, intensive systolic blood pressure control failed to improve clinical outcome or mortality (72; 03; 73; 135). A meta-analysis of four studies including 3315 patients found that although intensive blood pressure reduction was safe, it did not reduce the unfavorable outcome (170).

The lack of improved outcome despite increasingly aggressive management of blood pressure was illustrated by the case report of global cerebral ischemia in a patient in whom the blood pressure was promptly reduced to normal level (47). Moreover, the ATACH-2 trial showed that patients whose systolic blood pressure was lowered below 140 mmHg within 2 hours and maintained for at least 2 hours had higher rates of neurologic deterioration and cardiac-related adverse events (136). Another study of 286 patients found decreased systolic blood pressure below 120 mmHg to be associated with ischemic lesions, whereas no patients with minimal systolic blood pressure above 130 mmHg had such lesions (14).

Although the optimum blood pressure target and how fast it is achieved are unknown, the current guidelines recommend treatment based on the level of mean arterial pressure and intracranial pressure, with a goal of cerebral perfusion pressure greater than 60 mmHg. Acute lowering of systolic blood pressure to 140 mmHg for those patients presenting with a systolic blood pressure of 150 to 220 mmHg seems to be safe. In a small study, atenolol was found to decrease mortality, SISRS, and pneumonia, compared to amlodipine (78). Insufficient data exist regarding treatment of severe, sustained systolic blood pressure higher than 220 mmHg.

Increased intracranial pressure. Intracranial pressure above 20 mmHg for more than 5 minutes is considered elevated. This may be caused by the mass effect of hematoma and secondary hydrocephalus. The compartmentalized structure of the brain favors an increase in intracranial pressure only around the hematoma (21).

The treatment of intracranial hypertension was inspired from traumatic brain injury. It is reasonable to monitor intracranial pressure in patients with a Glasgow Coma Scale score lower than 8 due to the hematoma, clinical evidence for transtentorial herniation, significant intraventricular hemorrhage, or hydrocephalus. A catheter inserted into the lateral ventricle helps control the intracranial pressure by draining cerebrospinal fluid. The cerebral perfusion pressure goal is 50 to 70 mmHg, depending on the status of cerebral autoregulation (59).

However, in the only multicenter-controlled trial in traumatic brain injury patients, conducted in Ecuador and Bolivia, invasive monitoring of increased intracranial pressure failed to improve outcome compared to using clinical status and CT imaging (49). A systematic review and meta-analysis of 14 studies including 24,792 patients found no reduction in mortality by invasive monitoring. However, the studies published after 2012 showed a benefit of invasive monitoring (193).

Noninvasive monitoring of intracranial pressure based on transcranial Doppler or optic nerve sheath diameter are promising developments (100; 20). General measures for intracranial pressure management include elevation of the head of the bed to 30°, mild sedation, and avoidance of endotracheal tube ties that might impair the cerebral venous return (186). Stool softeners may also help.

Infusion of hypertonic solutions aims to reduce edema, but neither mannitol nor hypertonic saline of 3% reduced mortality (06; 180). A meta-analysis did not find a significant difference between these agents (139). One limitation of hypertonic solutions is the rebound phenomenon, by which the volume of edema increases disproportionately compared to the hematoma (137).

Controlled hyperventilation with hypocarbia (pCO₂ 25 to 33 mmHg) causes cerebral vasoconstriction (91). Cerebral blood flow reduction is almost immediate, though peak intracranial pressure reduction may take up to 30 minutes after pCO₂ change. If elevation of intracranial pressure is refractory, induced barbiturate coma is an option.

Ventriculostomy for CSF drainage can reduce the intracranial pressure and improve the outcome in patients with hydrocephalus. However, this invasive procedure may be complicated by hemorrhage and infections (33). If intracranial pressure is refractory to all medical management, decompressive craniectomy has been used; however, even if performed early (less than 48 hours), it does not improve mortality compared to medical treatment (122).

Cerebral microdialysis for determination of the lactate/pyruvate ratio as a marker of brain tissue hypoxia (84) and invasive brain oxygen monitoring (60) are still in the experimental stages. A small prospective randomized study showed that brain oxygen monitoring seems to be superior to intracranial pressure monitoring alone (94).

Intraventricular hemorrhage. Intraventricular hemorrhage occurs in 45% of patients with spontaneous intracerebral hemorrhage (54). A retrospective review demonstrated that external ventricular drain reduced mortality and improved short-term outcomes in these patients (62). The CLEAR-IVH trial showed that in patients with small intracerebral hemorrhage and large intraventricular hemorrhage, administration of low-dose tPA in the ventricular system in order to accelerate blood clot removal is safe; however, the impact on functional recovery is unknown (114). The CLEAR III trial showed that although ventricular irrigation with alteplase was safe, it did not improve functional outcomes at the mRS=3 cutoff compared to saline (56).

Continuous electrocardiogram monitoring and serial cardiac enzymes should be obtained.

Seizures. Depressed levels of consciousness out of proportion to the size or location of the hemorrhage should prompt continuous EEG monitoring. Clinical or electrographic seizures should be treated, but the use of anticonvulsants prophylactically in patients without documented seizures is not recommended (107).

Recombinant activated factor rFVIIa. rFVIIa failed to show significant difference in clinical outcome, despite its ability to prevent hematoma enlargement (11; 37).

Medical complications. Fluid and electrolyte balance should be monitored, particularly for those treated with hyperosmolar agents and diuretics. Inappropriate antidiuretic hormone secretion can occur in patients with intracerebral hemorrhage. In general, patients should receive nothing by mouth for the first 24 to 48 hours, and normocaloric parenteral nutrition or enteral nutrition (via Dobbhoff tube) should be instituted within 48 hours.

Dysphagia was diagnosed in 68% of patients with intracerebral hemorrhage (166). All patients with intracerebral hemorrhage should be undergo formal dysphagia screening to prevent aspiration pneumonia (65). Percutaneous endoscopic gastrostomy was needed in 25% of intracerebral hemorrhage cases (83).

Myocardial infarction. Approximately 0.3% of patients with intracerebral hemorrhage develop acute myocardial infarction during the first 3 days of treatment and have increased mortality (14.5% vs. 2%) (46). Elevated troponin was associated with increased in-hospital mortality in a study (155) but not at 30 days if not associated with ECG changes in another study (102).

Neurogenic pulmonary edema develops in 35% of patients with intracerebral hemorrhage and is associated with 37% mortality at 1 year (76). Acute respiratory distress syndrome occurs in 27% of patients with intracerebral hemorrhage; it is common in patients ventilated with a high tidal volume and is associated with in-patient mortality (35). Low tidal volume ventilation with attention to avoid increased intracranial pressure or hypoxia is reasonable (101).

Renal failure occurred in 8% of patients with intracerebral hemorrhage and is not increased by CT angiography (127). Renal dysfunction is also associated with cerebral microbleeds in patients with intracerebral hemorrhage (88). Acute renal failure is associated with higher rates of in-hospital mortality and moderate to severe disability at discharge (150)

Glucose level should be monitored, and both hypoglycemia and hyperglycemia avoided.

Pulmonary embolism may occur in bedridden individuals with hemiplegia. Deep vein thrombosis can be prevented by heparin (5000 IU subcutaneous injections every 12 hours) or low molecular weight heparin in patients with lack of mobility after 1 to 4 days from onset. Pneumatic devices also decrease the risk of pulmonary embolism (59).

A do-not-resuscitate order instituted early is an independent predictor for poor outcome as it implies a lower intensity of care (61). Avoidance of do-not-resuscitate orders within the first 5 days, along with management according to the guidelines, reduces mortality more than expected based on the intracerebral hemorrhage score (117).

Statin use after intracerebral hemorrhage could be associated with early neurologic improvement and may reduce mortality at 6 months (168). Moreover, discontinuation of statins may be related to an increased mortality (169).

Fever occurs frequently and is associated with increased mortality. Infections or inflammatory causes should be investigated and treated. A Cochrane analysis failed to prove benefit of targeted temperature management (32).

Surgical treatment. Preoperative state of alertness and hematoma volume are the main determinants of outcome. A GCS less than 8 and a hematoma volume greater than 60 ml had a mortality rate of 91% (10). Intraventricular extension of hemorrhage is associated with worse outcome (162).

A large clinical trial, International Surgical Trial for Intracerebral Hemorrhage (STICH), failed to show benefit of early surgery, within 24 hours of randomization, versus initial conservative treatment. Patients with lobar clots larger than 30 mL and within 1 cm of the surface appeared to benefit from surgery (162). The STICH II trial that enrolled conscious patients with superficial lesions between 10 and 100 mL did not show a benefit of early surgery (163).

A meta-analysis of 10 trials with 2059 patients concluded that surgery for supratentorial hematomas was associated with reduction in death and disability, but the result is not very robust (133).

Optimal timing of surgery for supratentorial hemorrhage is unknown. A randomized feasibility study of surgery within 24 hours of onset did not show improved morbidity at 3 months (197). Surgery performed within 12 hours of randomization was not more effective than conservative management. However, the patients with poor prognosis were more likely to benefit from early surgery (163). A meta-analysis of eight surgical trials (2816 cases) shows that surgery improves outcome if the patients were randomized within 8 hours of ictus; the Glasgow Coma Scale was 9 to 12, and the hematoma volume was 20 to 50 ml (51). Subgroup analysis of the patients with supratentorial hematoma showed a small benefit from surgery earlier than 21 hours (163). Ultra-early (within 4 hours from onset) surgery was associated with increased risk of rebleeding and mortality (116).

For cerebellar hematoma larger than 3 cm associated with clinical signs (ipsilateral, horizontal gaze palsy, facial palsy, facial hypoesthesia), surgical decompression is recommended as soon as possible (59). Initial loss of consciousness strongly predicts poor survival (41). Patients with obliterated cisterns had a poor outcome irrespective of treatment and ventricular drainage alone is not indicated (172). Criteria for management were proposed based on the admission GCS and the diameter of the hematoma on CT scan: (1) if GCS is 14 to 15 and hematoma diameter is smaller than 40 mm, patients are treated conservatively; (2) if GCS is lower than 13 and hematoma diameter is larger than 40 mm, decompressive surgery is the treatment of choice; (3) if brainstem reflexes are lost with flaccid tetraplegia or poor general condition, intensive therapy is not indicated (85). Others suggested a threshold GCS of 9 and hematoma diameter of 30 mm and location of hematoma for decision making (97).

There is a lack of information on the intervention in patients with Glasgow Coma Scale less than 8. In a small retrospective series of spontaneous intracerebral hemorrhage, all comatose patients who lost upper brainstem reflexes and had extensor posturing died despite emergency craniotomy (138). For patients with GCS less than 8, surgical intervention was associated with increased risk or poor outcome and is probably harmful (162). Decompressive hemicraniectomy without clot evacuation in dominant-sided hemorrhage with intracranial pressure crisis was also attempted in five patients with a GCS that was 5 to 9. At 6 months, one patient died, two were dependent (mRS 4 and 5), and two were independent (mRS 2 and 3) (63).

Minimally invasive surgery aims to reduce the morbidity associated with conventional craniectomy. In a randomized trial, minimally invasive surgery of the basal ganglia hemorrhage did not reduce mortality but improved the functional outcome at 3 months in the surviving patients (183). A systematic review and meta-analysis of five randomized controlled trials and nine prospective controlled studies involving 2466 patients showed that patients with supratentorial intracerebral hemorrhage benefit more from minimally invasive surgery than from craniectomy (189).

Addition of thrombolysis with rtPA to the minimally invasive surgery for intracerebral hemorrhage evacuation (MISTIE) trial reduced the clot size and perihematomal edema compared to patients who received placebo, but it did not improve clinical outcome (115; 118; 110; 111).

An alternative to tPA thrombolysis, still in the experimental stage, is transcranial MR-guided focused ultrasound (113).

Endoscopic surgery showed promise in small studies (04; 26; 123). Real-time ultrasound guided endoscopic surgery may minimize brain injury during basal ganglia hematoma evacuation (149). For cerebellar hematomas, endoscopic and stereotactic or navigation-guided burr hole aspiration have been attempted (190; 92). Frameless, image-driven robotic stereotactic assistance (ROSA) of catheter insertion is a new development (02). A pilot study of CT-guided endoscopic surgery (Intraoperative Computed Tomography–guided Endoscopic Surgery for Brain Hemorrhage, ICES) showed similar results to the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation, MSTIE, but was not powered to detect benefit (175).

A meta-analysis of 28 studies comparing mild hypothermia and minimally invasive surgery to minimally invasive surgery alone showed improved neurologic outcome and decreased mortality (55).

The impact on the clinical outcome of these emerging interventions is not yet known, and more studies are needed before they can be recommended.

Not all hospitals have neurosurgical services. Considering the uncertainty regarding efficacy of the surgical intervention, the decision to transfer a patient with intracerebral hemorrhage to a neurosurgical center is often made. In a study of 1175 cases, the transferred patients had a lower risk of death relative to those remaining at the referral center, despite whether they had surgery (01). Where remote consultation is considered, decision making should rely not only on head CT imaging but also on the video assessment of the patient (179).

Early decision to not resuscitate accounted for much of the observed difference. Data from a nationwide inpatient sample show that in the United States, the in-hospital mortality of patients who underwent surgical treatment was 27.2%, and the complication rate was 41%. Male gender, preoperative comorbidities, complications, and low surgery volume were associated with increased in-hospital mortality (131).

Special considerations

Pregnancy

In the United States it has been found that 6.1 pregnancy-related intracerebral hemorrhage per 100,000 deliveries and 7.1 pregnancy-related intracerebral hemorrhage occur per 100,000 at-risk person-years (compared to 5.0 per 100,000 person-years for nonpregnant women) in the age range of 15 to 44 years. The risk of intracerebral hemorrhage associated with pregnancy is greatest in the postpartum period, advanced maternal age (greater than or equal to 35 years), African American race, hypertension, coagulopathy, and tobacco abuse. The rate of eclampsia or preeclampsia is 30.5% in the patients with pregnancy-related intracerebral hemorrhage (05).