Current intracerebral haemorrhage management

Journal of Clinical Neuroscience (2003) 10(2), 158–167 0967 - 5868/03/$ - see front matter ª 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0967-5868(02)00324-7

Review

Current intracerebral haemorrhage management Kenneth Butcher

MD PHD FRCP(C),

John Laidlaw

MBBS FRACS

Department of Neurosciences (Neurology and Neurosurgery), Royal Melbourne Hospital, Melbourne, Australia

Summary Primary intracerebral haemorrhage (ICH) refers to spontaneous bleeding from intraparenchymal vessels. It accounts for 10–20% of all strokes, with higher incidence rates amongst African and Asian populations. The major risk factors are hypertension and age. In addition to focal neurological findings, patients may present with symptoms of elevated intracranial pressure. The diagnosis of ICH can only be made through neuro-imaging. A CT scan is presently standard, although MRI is increasingly important in the evaluation of acute cerebrovascular disease. A significant proportion of intracerebral haematomas expand in the first hours post-ictus and this is often associated with clinical worsening. There is evidence that the peri-haematomal region is compromised in ICH. This tissue is oedematous, although the precise pathogenesis is controversial. An association between elevated arterial pressure and haematoma expansion has been reported. Although current guidelines recommend conservative management of arterial pressure in ICH, an acute blood pressure lowering trial is overdue. ICH is associated with a high early mortality rate, although a significant number of survivors make a functional recovery. Current medical management is primarily aimed at prevention of complications including pneumonia and peripheral venous thromboembolism. Elevated intracranial pressure may be treated medically or surgically. Although the latter definitively lowers elevated intracranial pressure, the optimal patient selection criteria are not clear. Aggressive treatment of hypertension is essential in the primary and secondary prevention of ICH. ª 2003 Elsevier Science Ltd. All rights reserved. Keywords: risk factors, diagnosis, pathology, prognosis, prevention

INTRODUCTION

Serum cholesterol

Intracerebral haemorrhage (ICH) refers to spontaneous, nontraumatic bleeding from intraparenchymal blood vessels. Bleeding may also extend into the ventricles or subarachnoid space. Primary ICH is the most common form and results from the paroxysmal rupture of blood vessels that are pathologically altered by the effects of long-standing hypertension or cerebral amyloid angiopathy (CAA). Secondary ICH is that associated with vascular malformations, neoplasia and coagulopathies.

An association between low total serum cholesterol levels and ICH was initially observed in Japanese patients.14–17 Other studies have shown low cholesterol to be associated with increased rate of ICH only in combination with other risk factors including age and hypertension.23–25 The precise aetiological role of serum cholesterol in the pathogenesis of ICH is incompletely understood. Importantly, treatment of hypercholesterolemia does not appear to confer an increased risk of haemorrhage.26

EPIDEMIOLOGY AND RISK FACTORS

Alcohol and tobacco

ICH accounts for 10–20% of all strokes worldwide.1–7 Incidence estimates in the post-CT era have been estimated to be between 13.5 and 32 per 100,000 (Table 1). Incidence rates increase exponentially, approximately doubling with each decade of life after the age of 35.8 ICH is more common in Asian, African and Hispanic American populations.9–17 Higher incidence rates are thought to be secondary to a higher prevalence of uncontrolled hypertension in these populations.9;10;18

Excessive alcohol consumption is associated with an increased rate of ICH.18;27 Moderate alcohol use does not raise the risk, although there does appear to be a dose-related increase in the odds ratio of ICH.20 This is likely related to the effects of chronic alcohol intake on blood pressure. Unlike subarachnoid haemorrhage and ischaemic stroke, smoking does not appear to be associated with an increased risk of ICH.20 Iatrogenic ICH

Hypertension Hypertension is the single most important modifiable risk factor for ICH. Approximately 75% of ICH patients have pre-existing hypertension.19 Retrospective studies have shown that high blood pressure confers a two- to sixfold increase in the risk of ICH.1;8;20;21 Patients with recognized hypertension who discontinue their anti-hypertensives have a twofold increase in risk of ICH relative to those who remain compliant with medication.22

Received 25 June 2002 Accepted 26 August 2002 Correspondence to: Kenneth Butcher, Department of Neurology, 4th Floor, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E-mail: [email protected]

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Warfarin is associated with an increased risk of ICH.20;28 Warfarin is prescribed for the prevention of cardio-embolic events, in particular ischaemic stroke. Specific indications are most often atrial fibrillation and prosthetic cardiac valves. The overall risk of intracranial haemorrhage in patients treated with warfarin is 1%/ year.28 Approximately 70% of these bleeds are ICH, and the remainder are mainly sub-dural haematomas. The rate of warfarinrelated ICH is increased further with age, intensity of anticoagulation and previous cerebral ischaemic events.29;30 Older patients with previous ischaemic events are also at higher risk of a thromboembolic event. It should be noted that while warfarin is associated with an increased risk of ICH, the benefits in atrial fibrillation are unequivocal and a 66% relative risk reduction in ischaemic stroke clearly outweighs the risks of symptomatic haemorrhage.31;32 Aspirin and other non-steroidal inflammatory drugs have long been thought to confer a slightly increased risk of ICH. The

Current intracerebral haemorrhage management

Table 1

Selected population based epidemiological studies of intracerebral haemorrhage with CT/autopsy confirmation data

Study site and dates

Standardised annual incidence rate (per 100,000)

Proportion of total stroke

Mortality rate (at 30 days)

Oxfordshire, England 1981–19862 Cincinnati, USA 198812 Rochester, USA 1985–19894

20a 15 13.5

10% N/A 10.6%b

Melbourne, Australia 1996–19975 Innherred, Norway 1994–19966 Dijon, France 1985–19897

16 32 13.9 (#) 12.3 ($)

14.5% 10.5% 8.5% (#) 9.1% ($)

a b

159

50% 44% 32% (#) 55% ($) 45% 37.8% 52%

Proportion of cases with imaging/autopsy confirmation 78% 100% 89% 91% 100% 89%

Incidence rate not age adjusted. 1980–1989; imaging in 81% of cases 1980–1984.

Anti-platelet Trialists Collaboration Trial reported a slight excess of intracranial hemorrhages with aspirin use, but this was not statistically significant.33 A more recent carefully conducted case control study failed to demonstrate an increased risk of ICH in patients taking either low dose ASA or other non-steroidal antiinflammatory drugs.34 Higher doses of ASA ( P 1225 mg per week) were associated with a slight excess of ICH. Thus, at the more common prophylactic doses (75–100 mg per day) prescribed in contemporary practice, ASA does not appear to increase the risk of ICH. The use of thrombolytic agents in the treatment of thromboembolic events can be complicated by ICH. Thrombolysis in myocardial infarction is associated with intracranial hemorrhage rates of 0.3–0.7%, varying with the agent and dose used.35;36 Approximately 80% of the intracranial bleeds are intraparenchymal.37 Patient age, prior cerebrovascular disease and elevated blood pressure are all associated with increased risk of ICH following thrombolysis. A meta-analysis of trials assessing treatment of ischaemic stroke with tissue plasminogen activator (tPA) < 3 h from symptom onset indicates a 6.5% risk of ICH.38 Comparable rates of ICH have been reported in clinical practice registries.39 Despite the increased risk of ICH, tPA is effective within 3 h of ischaemic stroke onset and it is currently underutilized.

Cerebral amyloid angiopathy CAA results from the deposition of the insoluble beta amyloid protein in the tunica media and adventia of leptomeningeal and cortical arteries, arterioles and capillaries.43 Beta amyloid replaces the smooth muscle of the tunica media, making the artery less compliant. The presence of amyloid in blood vessels increases exponentially with age and is found in up to 58% of patients over the age of 90.43 CAA-related ICH in some cases may be related to an interaction with other risk factors, notably hypertension.44;45 CAA-related haemorrhages are cortical or sub-cortically based, often large and have a propensity for extension into the subarachnoid space and ventricles.45 Recurrence of lobar ICH is also indicative of amyloid angiopathy.46 Acute haematoma evolution Upon rupture of a pathologically altered artery, blood extravasates into the surrounding parenchyma. The blood appears to dissect tissue planes, compressing adjacent structures. Serial imaging has shown that 20–38% of ICH haematomas enlarge within 36 h of onset.47;48 Haematomas larger than 25 cm3 are more likely to grow in the first 6 h after symptom onset. In addition, elevated systolic blood pressure and serum glucose levels are independently associated with enlargement of the haematoma.49

PATHOPHYSIOLOGY In a consecutive series of 109 cases of ICH, the most common sites of bleeding were the basal ganglia (42%), lobar (40%), cerebellum (8%), brainstem (6%) and thalamus (4%).40 This series included cases of secondary ICH, most of which were lobar in location. Many clinicians classify lobar haemorrhages in elderly patients, without secondary aetiologies, as CAA related. It should be noted however that correlative studies have shown that the diagnosis of CAA can only reliably be made by histopathology.41 In addition, hypertension may play a greater role in lobar ICH than has previously been recognised.19 Hypertensive ICH Pathological studies have shown that hypertensive ICH is related to lipohyalinosis, a fatty infiltration of the tunica media of small to medium size perforating arteries which results in decreased elasticity.42 Lipohyalinosis develops as a result of long-standing hypertension. At necropsy, Fisher described arterial ruptures filled with a platelet-fibrin mass which appeared to be haemostatic.42 Miliary or microaneurysms, originally described by Charcot/ Bouchard, are also often present in hypertensive vasculopathy, although none have ever been identified as the source of bleeding in ICH. ª 2003 Elsevier Science Ltd. All rights reserved.

Secondary injury There is growing evidence that more than a simple mass effect compromises the region surrounding the haematoma. A region of low attenuation surrounding the haematoma is visible on most sub-acute CT scans in ICH. This corresponds to a rim of hyperintensity on T2 weighted MRI and represents oedema. It is not clear, however, whether this is cytotoxic or vasogenic in origin. Cytotoxic oedema forms secondary to ischaemia, which has been proposed to result from compression of the intraparenchymal microcirculation or possibly vasoconstriction of vessels secondary to metabolites released by the haematoma.50 Alternatively, cerebral autoregulation may be impaired secondary to elevated intracranial pressure. Other investigators believe that this is oedema is vasogenic in origin, originating from the damaged blood vessel itself. A number of SPECT, PET and MRI studies have provided conflicting evidence regarding the origin of peri-haematomal edema.51–58 This is an area of ongoing research, with important implications for treatment. CLINICAL PRESENTATION AND DIAGNOSIS Patients most often present with focal neurological features commensurate with the location of the haemorrhage. Neurological Journal of Clinical Neuroscience (2003) 10(2), 158–167

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symptoms may be maximal within minutes of onset or progress more slowly.40 In addition, symptoms of ICH often include headache, nausea, vomiting or an altered level of consciousness. The diagnosis of ICH cannot be made by history and physical examination. The presentation of ICH is extremely variable and is indistinguishable from ischaemic stroke on clinical grounds alone, making neuro-imaging absolutely necessary. Other useful investigations at the time of presentation include a complete blood count, serum electrolytes, renal function tests and a coagulation profile, which may be abnormal in secondary ICH. An ECG and chest X-ray may also provide evidence of aetiological factors, and serve as a baseline should medical complications arise. Neuro-imaging Urgent CT scan is recommended at present for patients presenting with paroxysmal neurological symptoms, due to its sensitivity for intracranial blood. The hyperdense appearance of acute blood is easily visualised on CT (Fig. 1). MRI can provide more information than CT in cases of secondary ICH as well as ischaemic stroke.59 Although MRI is sensitive for intraparenchymal blood, CT remains the initial procedure of choice pending ongoing investigations.60–63 Cerebral angiography is indicated if an underlying structural lesion is suspected. Initial CT scan findings suggestive of this include sub-arachnoid extension of blood, proximity of the he-

matoma nidus to the circle of Willis or Sylvian fissure, lobar location or abnormal calcification.64 A prospective study of 206 consecutive ICH patients showed that the diagnostic yield of angiography was highest in patients <45 years of age.65 Thus, it has been recommended that younger patients with no history of hypertension be investigated beyond CT scan in order to rule out causes of secondary ICH.66 This may include cerebral angiography and/or MRI depending on the characteristics of the CT scan and the clinical history. Haematoma volume estimation An estimate of haematoma volume can be made using CT or MRI scan data. This information is extremely useful in predicting the patientÕs clinical course and directing management. A number of methods have been proposed to allow the rapid estimation of haematoma volume in the clinical setting. The authors prefer what has come to be known as the ðABCÞ=2 method, first described by Kwak.67 The method has been validated with planimetric measurements.68;69 The formula is based on the assumption that the haematoma of an ICH is elliptical in shape. The slice containing the maximal haematoma diameter, usually near the nidus of the ICH, is selected. The maximum linear length ðAÞ is measured in cm. The perpendicular width ðBÞ is measured as the maximum extent of the haematoma in a perpendicular plane to ðAÞ. The depth ðCÞ of the ICH is calculated as the number of slices in

Fig. 1 Acute CT and T2 weighted MRI images of hypertensive intracerebral haemorrhage at 2.5 (CT) and 5.5 (MRI) hours after symptom onset. The nidus of the haematoma can be seen as a hyperdense region in the putamen. T2 weighted MRI scan demonstrates mixed signal intensity. The hypointense regions within the haematoma represent deoxyhemoglobin. CT and MRI demonstrate sulcal and Sylvian effacement due to mass effect. Following the development of somnolence, the patient was taken to theatre. The haematoma was evacuated and haemostasis was achieved using microsurgical techniques. Post-operative CT (day 2) and MRI (day 4) reveal that the mass effect has been alleviated. A small amount of residual blood remains. The sub-acute T2 weighted MRI demonstrates marked signal hypointensity due to the presence of intracellular methemoglobin. The high signal adjacent to the haematoma represents edema. The patient was discharged to rehabilitation 1 week later and made a functional recovery.

Journal of Clinical Neuroscience (2003) 10(2), 158–167

ª 2003 Elsevier Science Ltd. All rights reserved.

Current intracerebral haemorrhage management

which the haemorrhage is visible multiplied by the slice thickness, which is generally 0.5–1.0 cm on most modern CT scanners. The haematoma volume is then calculated as the product of ðAÞ  ðBÞ  ðCÞ divided by 2 (Fig. 1). Prognostic indicators Early mortality, generally defined as that in the first 30 days postictus, is higher in ICH than in ischemic stroke. Previous studies indicate the 30 day mortality rate in ICH ranges from 13 to 56%.5;70;71 The mortality rate has steadily decreased in subsequent investigations, largely due to the recognition of smaller ICHs which were often undiagnosed prior to the increased availability of CT imaging.71;72 It has been estimated that 24% of ICH cases were diagnosed as ischaemic infarcts in the pre-CT era and that many of these cases were less severe with better outcomes.73;74 Recent studies with CT confirmation of all cases of ICH indicate that ICH has a 30 day mortality rate between 34 and 50% (Table 1).5 While early mortality is higher, survivors of ICH appear more likely than ischaemic stroke patients to be functionally independent at one year. In the Oxfordshire stroke project, although 62% of ICH patients were dead after 1 year, 68% of the survivors were independent.2 Helweg-Larsen followed 108 spontaneous ICH patients with CT scans and neurologic examination (median 4.5 years after ictus) and found that 30% made a complete recovery.71 Although it is not possible to predict individual patient outcome with complete accuracy, some knowledge of the relevant prognostic indicators is desirable, as the probability for a meaningful recovery invariably dictates future management. The two most significant predictors of mortality are haematoma volume and level of consciousness at admission. Increasing patient age, infratentorial location of the ICH, midline shift and the presence of intraventricular blood have all been associated with poor outcome (Table 2).71 In addition, intubation has been shown to be an independent predictor of mortality in ICH.75;76 Broderick found that an admission Glasgow Coma Scale of 8 or less and ICH haematoma volume of 60 mL or more predicted a mortality of 91% at 30 days.77 Other investigators have reported that a haematoma volume of >50 mL was associated with a mortality rate of 90%.71 A rating system known as the ICH score has been developed.78 It is based on GCS, age, haematoma volume, location and presence of intraventricular blood. The ICH score was recently externally validated.79 It is important that clinicians not become overly didactic in their approach to patients with large haemorrhage volumes and low Glasgow Coma Scale scores, but this information can be very helpful in assisting families and health care providers in man-

Table 2

Prognostic factors in intracerebral hemorrhage

Indicator

Predictors of favorable outcome

Predictors of unfavorable outcome

Glasgow Coma Scale Intubation Haematoma volume

P9 Required O60 mL= O50 mL (see text) Absent Absent Supratentorial (lobar > deep) Absent Younger

O8 Not required P61 mL=P51 mL

Intraventricular blood Expansion of haematoma Location of haematoma Mass effect Patient agea

161

agement decisions. It has been pointed out that therapeutic nihilism can affect the outcome of patients who might otherwise do well. Becker determined in a retrospective analysis that the decision to withdraw treatment was the biggest predictor of mortality.80 This was most often based on initial GCS and haematoma volume. In the small portion of patients with haematoma volumes P 60 mL and GCS scores 6 8, in whom treatment was maintained, the majority were discharged to rehabilitation. MANAGEMENT Treatment of stroke patients begins with assessment and management of airway, respiration and circulation. This is followed by rapid assessment of the level of consciousness, generally accomplished with the Glasgow Coma Scale. Individuals presenting with ICH should be admitted to an acute observation ward, preferably a stroke unit or ICU with neurological expertise at hand. Specialised neurological units have been shown to have improved outcomes relative to general ICUs.81 Airway management in ICH calls for endotracheal intubation more frequently in ICH than ischaemic stroke.75 The decision to intubate should be based on the individuals level of consciousness, ability to protect their airway and arterial blood gas levels, rather than an arbitrary GCS score.66 Intravenous therapy should be aimed at maintaining euvolemia with an isotonic fluid, such as normal saline. Potassium supplementation is often necessary, although glucose should be avoided, except in rare cases of hypoglycemia. Elevated intracranial pressure Patients with ICH may develop signs and symptoms of raised intracranial pressure (ICP), which is often asymmetric resulting in herniation.82 Initial treatment measures include elevation of the head of the bed. The acutely deteriorating patient, with signs of herniation, should be hyperventilated with positive pressure ventilation and intubated. Precautions against elevating the ICP should be undertaken during intubation, including sedation and short acting paralytics. Mechanical ventilation parameters should be adjusted to keep PCO2 30–35 mmHg. This is generally accomplished by increasing the ventilation rate, while maintaining a constant tidal volume. Most patients being hyperventilated will require sedation, usually provided with combinations of benzodiazepines and narcotic analgesics, although propofol is used increasingly in the intensive care setting. In addition to hyperventilation, osmotherapy in the form of intravenous mannitol should also be administered acutely, at a dose of 1 g/kg over approximately 20 min.83 The authors recommend surgical consultation at this point. Mannitol is sometimes used repeatedly in lower doses to control elevated ICP, when surgery is not considered appropriate. Routine use of hyperventilation and osmotherapy in ICH patients without signs of elevated ICP is discouraged. Barbiturates should be considered a last resort in the treatment of refractory increased ICP. Barbiturates make neurologic assessment impossible and can result in systemic hypotension.

Intracranial pressure monitoring Present Present Infratentorial Midline shift, herniation Older

a Caution: older age may serve as a proxy for concomitant illness in prognostic studies and should not be used as a prognostic indicator in isolation.

ª 2003 Elsevier Science Ltd. All rights reserved.

While clinical and radiological examinations provide some estimation of elevated ICP, this can only be accurately determined by direct measurement, either through intraventricular, intraparenchymal or epidural devices. Accurate measurement of ICP in combination with mean arterial pressure allows the calculation of cerebral perfusion pressure (CPP). This makes it possible to titrate treatment ensuring that ICP is kept below 20 mmHg, while Journal of Clinical Neuroscience (2003) 10(2), 158–167

162 Butcher and Laidlaw

maintaining CPP above 70 mmHg. In the patient with radiological signs of intraventricular blood, obstructive or impending hydrocephalus, this is a straightforward management decision, as treatment will require placement of an external ventricular drainage (EVD) catheter, which also allows measurement of ICP. In patients not requiring an EVD for treatment of hydrocephalus, the need for ICP monitoring is less clear. Although the American Heart Association Stroke Council recommends monitoring in patients with a GCS < 9 or in whom deterioration is thought to be secondary to elevated ICP, there is currently no evidence that this alters outcome.84 ICP measurements have not been shown to be useful in prognostication. Generalised and progressive increases in ICP are seen only with massive ICH, which is already known to have a poor prognosis.85 In addition, herniation can occur in patients with normal or mildly elevated ICP. At this time the decision to implement ICP monitoring is as dependent on the experience, skills and resources of the treating physician, as it is on the condition of the patient. Hydrocephalus Hydrocephalus in ICH can result from external compression of the ventricular drainage system by the expanding haematoma or by occlusion of flow by intraventricular blood clotting. Both conditions are associated with a high mortality rate and urgent EVD catheter placement is recommended.86 There is some evidence that outcome may be unaffected by EVD catheter placement, as control of ICP is often not accompanied by a clinical improvement.87;88 The presence of intraventricular blood appears to reduce the effectiveness of EVD catheters, suggesting there may be a role for thrombolytic instillation. A pilot study of urokinase injection via EVD catheter in 20 patients with intraventricular haemorrhage revealed promising results.89 A multi-center randomised doubleblind placebo controlled trial of intraventricular tissue plasminogen activator is currently underway.90 Blood pressure Management of blood pressure in ICH is somewhat controversial. At present, the only guidelines for blood pressure management in ICH are provided by the AHA Stroke Council, which suggests acutely lowering mean arterial pressures P130 mmHg.66 These guidelines are based on non-randomised retrospective and anecdotal trials. Traditionally, physicians have been reluctant to decrease mean arterial pressures acutely in ICH. This approach is predicated on the belief that there is a degree of ischaemia or at least impaired autoregulation within the brain of a patient who has suffered an ICH. The concern has therefore been that pharmacological lowering of arterial pressures may decrease cerebral perfusion pressure further, ultimately producing or exacerbating ischaemia and adversely affecting outcome.91 A second reason for a conservative approach to blood pressure has been the previously widely held belief that ICH forms rapidly and ceases expansion within a number of minutes. Reduction of blood pressure in an effort to limit the size of the ICH has therefore been thought to be pointless. In addition to the fact that haematomas do enlarge in a significant portion of ICH cases, systolic blood pressure P200 mmHg has been shown to predispose to this growth.49 Furthermore, secondary clinical deterioration is associated with haematoma expansion.48 This raises the possibility that carefully reducing arterial pressure may provide therapeutic benefit by preventing this growth. In addition, the concept of exacerbating secondary neuronal injury in peri-haematomal and more remote regions by decreasing blood pressure is also beginning to appear less plausible. Cerebral blood flow

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measurements are not changed following reduction of blood pressure in an animal model of ICH.92 One small clinical trial randomised 14 patients with small to moderate sized supratentorial ICH to treatment with either placebo or intravenous anti-hypertensives.93 This study demonstrated no significant changes in cerebral blood flow, using PET, in the peri-haematomal region or elsewhere. This trial was quite small and the safety of acutely reducing blood pressure needs to be assessed in the context of a larger trial. It has also been pointed out, that while reduction of arterial pressure in ICH may be safe, there is as yet no evidence that it will have any effect on outcome.94 The only way to address this question is a large multi-center randomised controlled trial of blood pressure reduction in acute ICH. Other medical therapies While ICH patients do suffer higher early mortality rates due to the effects of the haemorrhage itself, the other medical complications are those seen in all stroke types. Deep vein thrombosis, pulmonary embolism and pneumonia are the major non-central complications of stroke.70;95 The use of pneumatic compression devices and elastic stockings has been shown to decrease the incidence of venous thrombosis in neurosurgical patients.96 The efficacy of elastic stockings specifically in stroke is being tested in a randomised controlled trial.97 Subcutaneous heparin use in acute ICH was tested in a randomised controlled trial in which 5000 U TID was started at 2, 4 and 10 days post-ictus.98 Treatment initiation on day 2 significantly reduced the frequency of deep venous thrombosis, with no concomitant increase in haematoma expansion. As in ischaemic stroke, ICH patients should not be fed orally until proper assessment of swallowing is performed. In cases where dysphagia is present, alternative diets or feeding routes are recommended as required. Nutrition should not be withheld for a prolonged period. Gastric cytoprotection should also be considered, as the frequency of peptic ulceration is increased acutely. Aspiration pneumonia develops in a high percentage of patients, even when alternative feeding methods are used. Intravenous antibiotics are recommended in the event of this complication. All fevers should be treated aggressively with acetaminophen. Iatrogenic ICH management Although warfarin associated ICH is a form of secondary intracerebral haemorrhage, it is a relatively common admission diagnosis on acute neurological wards. The main therapeutic consideration is reversal of the coagulopathy. In patients anticoagulated for prophylaxis of stroke secondary to atrial fibrillation, this is a straightforward decision. The risk of an embolic event acutely is relatively low, estimated at 5% per year in most patients. The concern that reversal or abrupt discontinuation of anticoagulant therapy results in a rebound phenomenon of hypercoagualibility, does not appear to be supported by the available evidence.99 Failure to normalise the clotting profile acutely however, has been shown to be associated with continued intraparenchymal bleeding, expansion of the haematoma and worse outcome.28 These patients should therefore be treated acutely with intravenous fresh frozen plasma and vitamin K until the INR is normalised. Patients with metallic cardiac valves have presented more of a dilemma to treating physicians. Phan described 52 patients with mechanical aortic and/or mitral cardiac valves who were admitted with ICH and treated with fresh frozen plasma and vitamin K.100 The median time off anticoagulation was 10 days and the probability of an ischaemic event in the first 30 days post-ictus was

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Current intracerebral haemorrhage management

found to be 2.9%. Thus, while no recommendation or guideline exists for management of ICH in these patients, reversal and discontinuation of anticoagulation for 10–14 days appears relatively safe. In view of the evidence that failure to discontinue warfarin in ICH is detrimental, the authors recommend temporary reversal and suspension of anticoagulation. Seizures Seizures are a more frequent complication of haemorrhagic versus ischaemic stroke. The largest and most rigorous investigation of post-stroke seizures and epilepsy was the prospective multi-center Seizures After Stroke Study Group.101 Seizures occurred in 10.6% of patients with ICH. The majority of seizures after ICH occurred Ôearly,Õ which is arbitrarily defined as within the first 2 weeks postictus, and 57% were seen in the first 24 h. The only independent predictor of seizures was a cortical location. This has been confirmed in other studies.102;103 Seizures were equally divided between partial and generalised. Seizures are most often associated with cortical haemorrhages, particularly those in the temporal and parietal lobes. Although seizures may theoretically exacerbate ICH, outcome has not been shown to be affected to date.102 The use of prophylactic anticonvulsants is recommended by the AHA Stroke Council. One month of phenytoin therapy is suggested, although this recommendation is based on anecdotal evidence only.66 Deep sub-cortical and cerebellar ICH pose very little risk for seizures and the authors do not use prophylactic anticonvulsants in these patients. EEG may be helpful in cases of altered level of consciousness. The majority of patients with ICH do not suffer recurrent seizures, i.e., epilepsy. There are no known predictors of epilepsy following ICH, although late seizures more commonly recur following stroke in general.101;104 Surgery for ICH does not appear to increase the risk of epilepsy. Patients treated with anticonvulsants who remain seizure free for 1 year following the resolution of ICH may attempt a trial of anti-epileptic medication discontinuation. Unhelpful therapies Corticosteroids have been used in the past for treatment of ICH. The rationale was that the edema surrounding the haematoma was at least partially vasogenic in origin and should therefore be responsive to steroids. Dexamethasone has been tested in ICH in two randomised controlled trials.105;106 In neither case were steroids shown to decrease morbidity or mortality. In addition, steroids were associated with an excess number of infections in one trial, leading to its premature termination. Therefore, steroids are not recommended in the treatment of ICH. Glycerol is an osmotic diuretic that has been used in the treatment of ICH in the past. Theoretical benefits of this therapy were thought to be decreases in vasogenic oedema, as well as improved blood flow via a decrease in haematocrit. A randomised double-blind control study demonstrated no difference in any outcome measure between patients treated with intravenous glycerol and those given normal saline infusions.107 This lack of efficacy was consistent irrespective of the presence or absence of elevated intracranial pressure. Hemodilution with phlebotomy and dextran infusion was also found to be unhelpful in acute ICH.108

Surgical intervention MacEwan reported the first surgical successful evacuation of ICH in 1888, and as early as 1932 the standard technique of evacuation through a craniotomy was described by Penfield.109;110 To this day, ª 2003 Elsevier Science Ltd. All rights reserved.

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however, the uncertainty regarding the indications for surgery in ICH and the effect on outcome remain.111 There are 7 reported prospective randomised series specifically considering the role of surgery for ICH, the largest being reported by McKissock in 1961, which indicated surgical intervention was actually harmful.112 That study is now more than 40 years old and was performed prior to the CT era, although its importance remains because of the absence of any subsequent reported series of comparable size.84;113;114 Of the remaining 6 modern CT-era studies, only the endoscopic procedure reported by Auer showed a statistical benefit on outcome, which was most notable for lobar rather than deep ICH.84;113–117 Meta-analyses of the above trials have generally indicated that surgery is unhelpful, although removal of the pre-CT era study did suggest a trend for surgical intervention to improve outcome.118–120 This issue is currently being addressed by the international surgical treatment of intracerebral haemorrhage (ISTICH) multi-centre trial, which is actively recruiting 1000 ICH patients for randomisation to surgical evacuation within 24 h or medical therapy.121 None of these trials specifically addresses the issue of timing of surgery, which may be a major determining factor in outcome. There remains a significant controversy between potential benefits of early clot evacuation versus the increased re-bleed rate observed with very early surgery.111;116;122–125 The preoperative clinical state is considered to be the most important prognostic factor following ICH, and there has long been general acceptance that surgical evacuation of ICH is rarely required in patients with a relatively normal state of consciousness (GCS 13–15).126 Similarly, because of presumed extensive brain damage and therefore poor prognosis, there has been marked reluctance to perform surgery on deeply comatose patients (GCS 3– 5).127 Although there is some published data regarding surgical outcome for comatose ICH patients supporting this conservative approach, it is limited and does not yet reliably validate a nonsurgical strategy.114 Surgery is therefore usually considered to have the most potential benefit for the group of patients with GCS 6–12, particularly deteriorating patients.111;123;127;128 The pre-morbid condition and co-existing illnesses of the patient also influence the surgical decision making process.111 As stated above, patient age may only be a marker for inter-current illness and should not be a contraindication to surgical treatment. There is widespread neurosurgical bias toward more aggressive surgery for non-dominant hemispheric intracerebral haemorrhage. Over 70% of British neurosurgeons indicate that dominant hemisphere involvement is a significant factor in their decision making process when considering ICH evacuation.111 Outcome studies indicate that despite language disability associated with dominant hemispheric lesions, functional outcome is not necessarily worse than in non-dominant injury. A rehabilitation study of 236 hemiparetic stroke patients (129 left, 107 right), reported that patients with dominant hemisphere involvement progressed more rapidly in all stages of ambulation.129 In a recent study of patients with unilateral brain damage it was observed that right hemisphere affected patients were significantly impaired relative to patients with left hemisphere involvement in terms of identification of verbally based emotional stimuli.130 The visuospatial neglect and anosagnosia associated with non-dominant hemisphere stroke also interferes with rehabilitation and is a significant cause of disability.131 Therefore, despite current biases, there is little rational basis for selecting patients for surgery or other aggressive management based on the hemisphere affected by ICH. Cerebellar ICH is well recognised to have a more variable clinical course and is notorious for rapid secondary deterioration.19 This risk of secondary deterioration and the relatively good Journal of Clinical Neuroscience (2003) 10(2), 158–167

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rehabilitation prospects following cerebellar ICH have resulted in this condition being much more aggressively considered for surgical treatment than ICH elsewhere. The secondary deterioration is usually due to re-bleeding or swelling causing brainstem compression and/or hydrocephalus. Although it most commonly occurs in the first 48 h after the initial cerebellar ICH, it can be seen up to 2 weeks.132 Increased risk of secondary deterioration is somewhat more common with vermian haemorrhage.66 CT findings of distortion or significant asymmetry of the fourth ventricle, effacement or obliteration of the cisterna ambiens, and early hydrocephalus all indicate the necessitate for extremely close neurological monitoring and preparedness for emergency intubation and surgery in the event of deterioration. Surgical intervention is recommended for haematomas >3 cm in diameter or when clinical deterioration with radiological signs of ventricular obstruction is present.66 Sub-occipital craniotomy and haematoma evacuation is the definitive surgical treatment,133 commonly incorporating a ventricular drainage procedure also. Rarely an external ventricular drain alone is sufficient in some cases of small haematoma with hydrocephalus. The success of operating is dependent on the level of consciousness prior to surgery and the delay in surgery. Once patients have become comatose, the prognosis is poor,132 but not uniformly hopeless if urgent surgery is available.134 The surgical procedures available for evacuation of ICH include craniotomy, burr hole aspiration, and endoscopic aspiration.84;114;115;123;135 Additional localisation techniques such as stereotaxy and ultrasonic guidance provide allow more precise approach, particularly for deep lesions. Thrombolytic agents (urokinase or tissue plasminogen activator) have been used as an adjunct for clot removal, particularly with aspiration techniques, as have mechanical methods including ultrasonic aspirators, augers, modified nucleotomes and water-jet techniques.126;135–141 The optimal surgical technique is not known, although craniotomy remains the most common technique.111 Attention to microsurgical principles, including precise localisation, non-eloquent cerebrotomy and approach, minimal brain retraction, magnification and optimal haemostasis, is well known to improve neurosurgical outcome in general, and is probably of more importance than the actual technique chosen.

SECONDARY PREVENTION ICH has been thought of as a one-time event with a low probability of recurrence. More recent studies have reported recurrence rates from 1.8 to 5.3%.146 A meta-analysis of 10 studies reported a recurrent stroke rate of 4% per year in survivors of ICH. The most common type of stroke was another ICH, which was seen in 75% of cases. A Japanese study retrospectively evaluated the blood pressures of patients with recurrent ICH. While the overall recurrence rate was 2% per year, the risk increased to 10% per year in patients with diastolic blood pressures >90 mmHg.147 No secondary prevention trials specific to this condition have been published. A recent secondary stroke prevention study included ICH as a qualifying event and in the reported outcome measures (PROGRESS).148 This large trial indicated that treatment of blood pressure with an angiotensin converting enzyme inhibitor, either alone or in combination with a low dose diuretic, reduced the risk of ICH by 50%. A reduction in ICH incidence was also seen in patients classified as normotensive, suggesting that aggressive management of blood pressure is an effective strategy. CONCLUSIONS ICH is a common neurological condition with relatively high morbidity and early mortality. Haematoma volume and initial GCS score are valuable in predicting early outcome, although decisions regarding treatment aggressiveness need to be individualised. Early expansion of ICH and secondary neuronal injury may provide future therapeutic options. An important first step is a randomised controlled trial of acute blood pressure control in ICH. Conservative medical management continues to be the standard of care in ICH for the time being. Surgical haematoma removal is effective in reducing mass effect and can be lifesaving, although the optimal patient selection criteria remain unclear. Primary and secondary prevention of ICH should be aimed at treatment of hypertension. ACKNOWLEDGEMENTS Dr. Butcher is a Fellow of the Canadian Institute of Health Research and the Alberta Heritage Foundation for Medical Research.

Future therapies REFERENCES

Ongoing bleeding and expansion of the haematoma presents a potential for therapeutic intervention. Theoretically, either potentiation of clotting mechanisms or inhibition of fibrinolysis may limit haematoma growth in ICH. Possible complications of such therapies are those of hypercoagulability, specifically venous thrombosis and pulmonary embolism. Intravenous recombinant factor VIIa given within 4 h of symptom onset in ICH is currently being tested in a phase II safety analysis, the results of which are pending.142 The discovery that neuronal compromise occurs in the perihaematomal region raises the possibility that a ÔpenumbraÕ of potentially salvageable tissue exists in ICH. Although ischaemia does not appear to be the aetiology of this secondary neuronal degeneration, many of the mechanisms may be similar, i.e., excitotoxicity and inflammation. This has prompted investigations of putative neuroprotective agents in ICH. In addition, some neuroprotective trials have included haemorrhagic arms, mainly in an effort to confirm safety of these medications in ICH.143;144 To date, none of these agents has demonstrated efficacy in either ischaemic or haemorrhagic stroke. Currently, the effectiveness of citicholine, a phosphatidylcholine precursor with membrane stabilizing properties, given within 24 h of ICH onset is being evaluated in a randomised controlled trial.145 Journal of Clinical Neuroscience (2003) 10(2), 158–167

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