Thursday, April 5, 2012

Intracerebral Hemorrhage (ICH)

Author: Dr S Andrew Josephson University of California San Francisco 2012-02-20
A stroke is defined as the sudden onset of a neurologic deficit attributable to a vascular cause. A stroke results from lack of blood flow to an area of the brain. Without adequate blood flow, neurons (nerve cells) in the brain will begin to die. Symptoms of a stroke are variable depending on the area of the brain involved but can include weakness or numbness on one side of the body, new problems with vision, dizziness, or severe headache. A stroke is classified as either (1) ischemic (also termed “cerebrovascular accident” [CVA]), where an occluded blood vessel deprives an area of the brain of blood flow or (2) hemorrhagic (also termed intracerebral hemorrhage [ICH]), where there is bleeding into the brain tissue itself; approximately 15-20% of strokes are hemorrhagic in nature and these are the focus of this review.

Nearly 75,000 patients suffer an ICH each year in the United States. It is a tremendously deadly disease: an estimated 35 to 50% of patients die within one month of their ICH. Rapid recognition and treatment of ICH and its complications is essential in an attempt to reduce disability and death. Because ischemic stroke and ICH can have similar symptoms, brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is necessary to identify those patients with hemorrhage. The similarity in clinical presentation of ischemic stroke and ICH means that all stroke patients are initially triaged and treated similarly in the emergency setting until head imaging can make this important distinction.

Etiology of ICH

            Once an ICH has been identified, much of the early diagnostic approach focuses on determining the etiology of the hemorrhage. Trauma to the head may lead to ICH that is small or massive in volume. By far the most common cause of non-traumatic ICH is uncontrolled hypertension (about 60-70% of spontaneous ICH). Hypertensive-related ICH can occur in any location in the brain but has a particular predilection for the putamen in the basal ganglia, the thalamus, the cerebellum, and the pons in the brainstem (Figure 1). Hypertensive-related ICH should be thought of as a diagnosis of exclusion, once other etiologies have been ruled-out. In order to exclude other causes of ICH, a variety of additional imaging tests may be employed, including MRI with contrast, CT or MR Angiography, and conventional catheter-based angiography.

 Figure 1: Non-contrast CT scans of the brain demonstrating typical locations of hypertensive-related ICH: (A) thalamus, (B) putamen (in the basal ganglia), (C) pons (in the brainstem), and (D) cerebellum
         Underlying congenital malformations of the blood vessels (“vascular malformations”) are another important etiology of ICH, especially in younger patients without a history of hypertension. Arteriovenous malformations (AVMs) are abnormal tangles of blood vessels that can be asymptomatic prior to rupture and are usually diagnosed via angiography (Figure 2). Cavernous malformations are a distinct type of vascular malformation that can lead to ICH and are typically identified via MRI (Figure 3). Although ruptured aneurysms may lead to ICH, the more common presentation is that of a subarachnoid hemorrhage (SAH) where blood pools in the spaces surrounding the brain rather than in the brain parenchyma itself [ref SAH knol]. 
    Figure 2: Cerebral catheter-based angiogram of a 38-year-old woman, who presented with a lobar ICH, demonstrating an abnormal tangle of vessels that was removed surgically and found to be an arteriovenous malformation (AVM).
Figure 3: T2-weighted brain MRI demonstrating a cavernous malformation (arrow) with surrounding edema. The patient had presented 4 months prior with an ICH in the same location, but initial MRI failed to demonstrate this lesion as it was obscured by blood at the time.
        Other underlying masses in the brain, such as brain tumors or infectious abscesses, may present with ICH (Figure 4). Initial MRI or CT may not be able to identify these lesions, as blood may obscure their visualization; often repeat scanning, months later, when blood has spontaneously absorbed, will allow for identification of these masses.

Figure 4: Non-contrast CT scan of the brain demonstrating a left-sided lobar ICH. MRI and brain biopsy revealed the etiology to be from an underlying metastatic tumor in the setting of newly-diagnosed renal cell carcinoma.
            Abuse of sympathomimetic drugs such as cocaine and amphetamines can lead to ICH, making toxicology screening an important part of initial ICH evaluation. These compounds lead to ICH both due to their effects on systemic blood pressure, leading to severe transient hypertension, and due to their weakening effects on the walls of cerebral blood vessels with repeated use.
            Other less common causes of ICH include amyloid angiopathy, a disease of the elderly where blood vessel walls are weakened due to deposition of an abnormal protein; coagulopathy, an increased bleeding tendency from disorders such as liver disease, malignancy, or medications used to thin the blood; ischemic stroke with secondary hemorrhage; and inflammatory disorders involving the blood vessels of the brain (“vasculitis”).

Emergency Evaluation of ICH

            Patients with suspected stroke presenting to the emergency department (ED) are quickly imaged with CT or MRI after initial stabilization in order to distinguish ischemic stroke from ICH1. Although MRI is likely as sensitive for identifying ICH, it is much more time consuming and requires more patient cooperation, therefore most hospitals use CT scanning as the initial imaging modality for patients with suspected ICH.
            The evaluation of patients with ICH focuses on identifying ICH risk factors in an attempt to discern the etiology of the hemorrhage. The physical examination looks for signs that may indicate head trauma such as lacerations or fractures. Blood pressure elevation after ICH is common and may provide a clue that hypertension or drug abuse is responsible. Laboratory investigations should focus on excluding systemic coagulopathy with measures of clotting parameters and platelet count. A urinary toxicology screen is important in all patients with ICH in order to rule-out drug-related ICH from cocaine or amphetamine abuse. A careful medication history including over-the-counter and herbal substances is important as some of these compounds have either sympathomimetic properties (such as ephedrine) or interfere with normal coagulation, increasing the risk of ICH.
            The results of initial imaging may provide clues as to the etiology of ICH. Hemorrhages in the deep nuclei of the brain including the putamen and thalamus, along with the pons and cerebellum, are more likely to be hypertensive in etiology while lobar hemorrhages near the surface of the brain may have an alternative etiology such as underlying vascular malformation or amyloid angiopathy. Despite these tendencies, there remains substantial overlap in location of ICH from various causes making it difficult to determine etiology based on ICH location alone. Imaging studies early in ICH can also identify hydrocephalus or other signs of increased intracranial pressure (ICP) that may necessitate emergent therapy (see below).
            A number of authors have attempted to devise models that can predict outcome in ICH in order to allow for more effective communication with families. The ICH score is one widely-used, simple, validated method that can be calculated using information readily available to emergency medical personnel shortly after ICH presentation (Table 1)2. The ICH score has been shown to correlate well with 30-day mortality; those with higher scores are more likely to die in the first month following ICH.

TABLE 1: The ICH score for predicting 30-day mortality
Component                                                      Points

Glasgow Coma Scale score (GCS)
3-4                                                                          2
5-12                                                                        1
13-15                                                                      0
ICH Volume (cc) on CT
≥ 30                                                                       1
< 30                                                                       0
Intraventricular Hemorrhage (IVH)
Yes                                                                         1
No                                                                           0
Infratentorial Origin of ICH
Yes                                                                         1
No                                                                           0
Age (years)
> 80                                                                         1
< 80                                                                         0
Total ICH Score                                                       0-6
GCS = GCS score on initial presentation (or postresuscitation);
IVH = presence of any intraventricular hemorrhage on initial CT

Medical Management of ICH 

            There are currently no U.S. Food and Drug Administration (FDA)-approved treatments for ICH. Patients with ICH should be managed initially in an intensive care unit (ICU) allowing for close, frequent monitoring of the neurologic and medical condition of the patient. Since hypertension is a common cause of ICH, management of high blood pressure remains the central treatment early after a hemorrhage. Most experts agree that lowering the blood pressure of patients with ICH decreases the chances of continued bleeding and expansion of hemorrhage. Intravenous, short-acting blood pressure-lowering agents are usually initially used in the ICU, followed by a transition to oral long-acting blood pressure medications prior to discharge from the hospital. If blood pressure is reduced too aggressively, there is at least the theoretical risk of secondary ischemia due to decreased blood flow to areas of injured brain. Current trials are ongoing to determine the most appropriate blood pressure goals after ICH3; for now, published recommendations endorse a modest reduction of blood pressure in the acute setting1.
            Patients who are found to have coagulopathy should have rapid reversal of these blood clotting abnormalities in order to prevent continued hemorrhage expansion. Patients with low platelet counts should receive a platelet transfusion. Those with coagulopathy secondary to treatment with warfarin should be reversed using vitamin K or fresh frozen plasma in order to replete clotting factors that have been inhibited by this medication. It has been recognized recently that coagulation abnormalities in the setting of warfarin can be reversed much more rapidly, and with smaller volumes of fluid, using compounds containing high levels of purified or recombinant clotting factors such as prothrombin complex concentrate4. Future trials will be needed to weight the benefit of this more rapid strategy against the high cost of these medicines.
            Studies of ICH patients without coagulopathy who undergo serial imaging using CT scanning have demonstrated that nearly one-third experience growth of their hematoma in the first hours following an ICH. Hematoma growth is associated with poor outcome5. This has led to trials of activated factor VII (rFVIIa), another compound containing important clotting factors that rapidly stops bleeding throughout the body, in non-coagulopathic patients with ICH. An initial study of this approach showed great promise, with decreased rates of hematoma growth and decreased mortality among patients treated with rFVIIa6; unfortunately, the large follow-up trial designed to confirm these results demonstrated no benefit of the treatment11. Nonetheless, this strategy of administering therapies in order to prevent hematoma growth in patients with ICH, perhaps in carefully selected patients, merits future investigation.
            High glucose levels (hyperglycemia) and high core body temperature in patients with ICH have each been associated with worse outcomes and should be treated aggressively. Control of hyperglycemia in the ICU usually involves administration of insulin as an intravenous continuous infusion or subcutaneous injection along with frequent measurement of serum glucose levels. Fever control can be accomplished with medications such as acetaminophen or through use of external or internal cooling devices.
            Seizures occur in 4-8% of patients with ICH and are more common with lobar (superficial) ICH location. Once seizures occur in a patient with ICH they should be treated aggressively with anti-epileptic medications. Patients with seizures and ICH should be discharged from the hospital with anti-epileptic drugs for at least 3-6 months in order to prevent further seizures. A more controversial issue is whether all ICH patients should be treated with anti-epileptic medications in order to prevent the initial occurrence of seizures. There is little evidence to support this strategy, and enthusiasm for prevention of seizures should be tempered by the side effects of these medications and the relatively low frequency of seizures following most ICHs. Currently, the decision to administer prophylactic anti-seizure medications varies widely by institution and individual physician.
            Patients with ICH are also at risk for multiple medical complications during their hospitalization. The immobility that accompanies ICH puts patients at risk for deep venous thrombosis and pulmonary embolus; prevention can be accomplished with either pneumatic compression devices on the legs or subcutaneous heparinoid compounds (the latter may be begun 3-4 days after ICH with clear documentation that bleeding has stopped). Adequate nutritional support, via a feeding tube if the patient cannot swallow, has been shown to improve outcome in all types of stroke and should be begun within the first 24-48 hours. Physical, occupational, and speech therapy should be instituted early and aggressively during the course of the hospitalization in order to begin the process of rehabilitation and recovery.

Surgical Management of ICH

            Surgical removal of blood clot in the brain would seem to be an intuitive approach to treatment of ICH, but this strategy may injure normal surrounding brain tissue and exposes patients who are already quite ill to a major neurosurgical procedure. A single multicenter randomized trial, the International Surgical Trial in Intracerebral Hemorrhage (STITCH), attempted to clarify the role of surgery in ICH7. The results of this study did not show any benefit for surgical evacuation of clot in ICH compared with medical management alone. Subgroup analysis suggested that there may be a trend toward benefit from surgery only in the fairly rare case of lobar ICH located within 1 cm of the surface of the brain. Therefore in most cases of ICH, there is no role for surgery, and the hematoma will slowly absorb spontaneously over time. More less invasive surgical approaches are currently being examined in large trials. 
            An important exception to the lack of proven benefit from surgery in ICH involves hemorrhages in the cerebellum. Cerebellar hematomas cause particular difficultly as swelling can lead to rapid deterioration and death due to obstruction of the fourth ventricle and pressure on the brainstem, which contains structures vital to maintaining alertness and the ability to move and breathe. Patients with cerebellar ICH were not included in the STITCH trial, and it is generally recommended that all patients with cerebellar ICH greater than 3 cm in diameter who experience neurologic deterioration should undergo removal of the clot as soon as possible.

Management of Elevated ICP and Hydrocephalus

When blood leaks into the brain during an ICH, one of the most devastating consequences is elevation of intracranial pressure (ICP), and prompt ICP treatment likely leads to improved outcomes. Patients with increased ICP may present with somnolence, headache, vomiting, or a progressively worsening neurologic exam. Because increased ICP may occur anytime in the hours to days following ICH, patients must be monitored carefully, with frequent assessments of neurologic status in an ICU setting.
One important etiology of increased ICP in ICH patients is hydrocephalus, where the fluid-filled ventricles in the brain expand and put pressure on the rest of the brain parenchyma due to an inability to properly drain. Anytime that blood is deposited in the normal clear fluid of the ventricles, hydrocephalus can result. Hydrocephalus can be recognized with CT or MRI imaging of the head (Figure 5). Treatment of hydrocephalus usually involves placing a drain (“ventriculostomy”) through the skull in order to allow cerebrospinal fluid (CSF) to drain externally in a controlled manner. Some patients will only require drainage for a short period of time; however, some ICH patients remain unable to drain CSF and require placement of a permanent internal shunt that drains CSF into various body cavities such as the abdomen (termed a ventriculoperitoneal shunt [VPS]). 
Figure 5: Non-contrast CT scan of the brain demonstrating a right-thalamic ICH with extension of blood into the ventricles and resulting hydrocephalus. A ventriculostomy was placed shortly after this scan to allow for adequate ventricular drainage.

The other common cause of increased ICP aside from hydrocephalus involves swelling (edema) that occurs in the brain tissue surrounding the hemorrhage. Edema usually peaks during the first 3-5 days after an ICH, but lack of effective edema management during these first few days may lead to permanent disability, or even death. Treatment of increased ICP in patients with ICH begins with simple but effective measures, including raising the head of the bed and avoiding fluids that contain a high concentration of water such as D5W and half-normal saline. Adequate sedation and pain control can prevent increases in ICP that occur with patient discomfort.
If ICP remains elevated despite these simple measures, a more aggressive approach is indicated. Although no good trials exist to support this approach, an ICP monitor is usually placed in order to allow physicians to continually measure the ICP and its response to therapy. Most ventriculostomy devices used to treat hydrocephalus also permit accurate intermittent measurement of ICP in addition to drainage.
Hyperventilation is an effective method of rapidly reducing ICP in patients who are mechanically ventilated, but its use is limited by its very transient effect. It also causes a simultaneous lowering of cerebral blood flow, potentially leading to cerebral ischemia. As a result, hyperventilation should be used only on a very temporary basis in patients with elevated ICP8.
Osmotic therapy, using mannitol or hypertonic saline, remains the mainstay of most aggressive ICP management protocols. Mannitol causes the kidneys, and hence the body, to lose water since mannitol is a large molecule that is not absorbed in the distal renal tubule; the net effect is to rapidly reduce swelling from edema. Each dose of mannitol is only effective for a few hours, so dosing needs to be repeated frequently. Mannitol cannot be used in patients with kidney failure, and hypertonic saline solutions are a more appropriate choice in these patients.
In patients whose ICP still remains refractory to treatment despite the measures described above, a variety of third-line approaches are used, including neuromuscular blockade, barbiturate coma, and induced hypothermia. Rigorous evidence-based comparisons of these third-line techniques do not exist and therefore institutional and individual physician preference guides choice of strategy.
Intravenous corticosteroids were previously used in an attempt to reduce cerebral edema in patients with ICH. Although corticosteroids are likely effective in reducing edema in some settings, such as with brain tumors, randomized trials have established no role for these agents in ICH, and their use may even be associated with worse outcome9.
In some patients with ICH and high ICP refractory to medical therapy, surgical hemicraniectomy may be indicated. This approach removes a large portion of the skull so that the brain can swell outward, thereby relieving pressure. While hemicraniectomy has been proven to be effective in young patients with large ischemic strokes, its role in ICH remains unclear and further studies are needed.

Prevention of Secondary ICH

            Preventing recurrent ICH is an important element of ICH management following the acute period. Since hypertension is the single biggest risk factor for ICH, controlling blood pressure to normal levels on discharge from the hospital is imperative. Reduction of ICH risk with appropriate blood pressure control has been demonstrated in multiple, large hypertension trials10. Smoking, heavy alcohol use, and abuse of illicit drugs such as cocaine and methamphetamines should be avoided as they each contribute to an increased risk of ICH. Underlying lesions such as vascular malformations and brain tumors that lead to ICH are usually treated with surgery, radiation, or endovascular techniques after hemorrhage; removal of these lesions, when possible, prevents recurrent ICH.
1.         Morgenstern LB, Hemphill JC 3rd, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for heath care professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41:2108-2129.
2.         Hemphill JC, 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001;32(4):891-897.
3.         Delcourt C, Huang Y, Wang J, et al. The second (main) phase of an open, randomised, multicentre study to investigate the effectiveness of an intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT2). Int J Stroke. 2010;5(2): 110-6.
4.         Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust. 2004;181(9):492-497.
5.         Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66(8):1175-1181.
6.         Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352(8):777-785.
7.         Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005;365(9457):387-397.
8.         Stocchetti N, Maas AI, Chieregato A, van der Plas AA. Hyperventilation in head injury: a review. Chest. 2005;127(5):1812-1827.
9.         Poungvarin N, Bhoopat W, Viriyavejakul A, et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med. 1987;316(20):1229-1233.
10.       Perry HM, Jr., Davis BR, Price TR, et al. Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP). Jama. 2000;284(4):465-471.
11.      Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358(20):2127-37.

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