Chapter 63. Cerebrovascular Disease

• Nonarteriosclerotic causes of stroke occur more commonly in patients admitted to the ICU and should be carefully sought by appropriate diagnostic tests.
• In patients with acute ischemic stroke, reduction of systemic blood pressure may carry a risk of producing further neurologic deterioration.
• Intravenous tissue plasminogen activator improves outcome in carefully selected patients with acute ischemic stroke when treatment is instituted within 3 hours of onset.
• Clinical trials of anticoagulation with heparin or heparin-like drugs in patients with acute cerebral ischemia or infarction have shown no benefit. If other indications for acute anticoagulation are present, these drugs may be given safely.
• Emergency neurosurgical intervention should be strongly considered in patients with cerebellar infarction or hemorrhage and consequent brain stem compression.
• Early surgical clipping or coiling of ruptured aneurysms removes the risk of rebleeding and facilitates the effective management of delayed vasospasm and hydrocephalus.

Cerebrovascular diseases can be divided into three categories: cerebral ischemia and infarction, intracerebral hemorrhage, and subarachnoid hemorrhage.

Cerebral ischemia and infarction are caused by processes that reduce cerebral blood flow. Reductions in whole brain blood flow due to systemic hypotension or increased intracranial pressure (ICP) may produce infarction in the distal territories or border zones of the major cerebral arteries. More prolonged global reductions cause diffuse hemispheric damage without localizing findings, or at its most severe produce brain death. Prolonged regional reductions can lead to focal brain infarctions. Local arterial vascular disease accounts for approximately 65% to 70% of all ischemic strokes. In most cases, arterial disease serves as a nidus for local thrombus formation with or without subsequent distal embolization. Focal arterial stenosis in combination with systemic hypotension is a rare cause of focal brain infarction. Atherosclerosis is the most common cause of local disease in the large arteries supplying the brain. Disease of smaller penetrating arteries may cause small deep (lacunar) infarcts; it is unclear how often these lacunar infarcts are caused by atherosclerosis, some other arteriosclerotic process of small vessels, or by small emboli arising from more proximal sources. While emboli arising from the heart cause approximately 30% of all cerebral infarcts in a general population, they assume more importance in ICU patients.1 Atrial fibrillation is the most common cause. Atherosclerotic emboli following heart surgery, infective endocarditis, nonbacterial thrombotic endocarditis, and ventricular mural thrombus secondary to acute myocardial infarction or cardiomyopathy should all be considered in appropriate circumstances. Rarer causes of cerebral infarction must also be considered in the ICU. These include dissections of the carotid or vertebral artery after direct neck trauma, “whiplash” injuries or forced hyperextension during endotracheal intubation, intracranial arterial or venous thrombosis secondary to meningeal or parameningeal infections, and paradoxical embolization from venous thrombosis via a patent foramen ovale.1

Hemorrhages into the basal ganglia, thalamus, and cerebellum in middle-aged patients with long-standing hypertension are the most common type of intracerebral hemorrhage. In hypertensive patients with hemispheric lobar hemorrhages and patients without hypertension, other causes should be sought, such as arteriovenous malformations or saccular aneurysms.2 Amyloid angiopathy becomes increasingly important in patients in the seventh, eighth, and ninth decades; these hemorrhages usually occur in the subcortical hemispheric white matter and may be multiple. Hemorrhage due to anticoagulant and thrombolytic drugs can affect any part of the brain. Rarer causes of intracerebral hemorrhage occurring in patients with other systemic diseases include thrombocytopenia, hemophilia, and disseminated intravascular coagulation (DIC).

Nontraumatic spontaneous subarachnoid hemorrhage (SAH) is almost always due to ruptured saccular aneurysms. Aneurysms may also rupture into the brain parenchyma, producing intracerebral hemorrhage as well. Saccular aneurysms are most commonly located on the large arteries at the base of the brain. Both congenital and acquired factors appear to play a role in the development of aneurysms. Acquired contributing factors include atherosclerosis, hypertension, and hemodynamic stress. In patients with infective endocarditis, mycotic aneurysms of more distal arteries may form and sometimes rupture. Other causes of SAH include ruptured arteriovenous malformations (cerebral and spinal) and fistulae, cocaine abuse, pituitary apoplexy, and intracranial arterial dissection.3 In some cases, particularly SAH ventral to the midbrain, the cause cannot be determined.

The initial diagnostic evaluation of the patient with suspected stroke serves (1) to determine whether neurologic symptoms are due to cerebrovascular disease or to some other condition, such as peripheral nerve injury, intracranial infection, tumor, subdural hematoma, multiple sclerosis, epilepsy, or hypoglycemia; and (2) to distinguish among different types of cerebrovascular disease that require different treatments. The clinical history and examination remain the cornerstone of this process. Cerebrovascular disease typically produces focal brain dysfunction of sudden onset in a single location. The primary exception to this is aneurysmal SAH, which usually presents as a sudden onset of severe headache, with or without nausea, vomiting, or loss of consciousness. In some cases, a less severe aneurysmal hemorrhage may present as a headache of moderate intensity, neck pain, and nonspecific symptoms. A high index of suspicion is needed in order to avoid missing the diagnosis of SAH. Focal brain dysfunction may not always include an obvious hemiparesis. Neurologic deficits such as neglect, agnosia, aphasia, visual field defects, or amnesia may be the only manifestations of brain infarction or hemorrhage. The clinical distinction between cerebral infarction and intracerebral hemorrhage is unreliable. Both produce sudden focal deficits. Large hemorrhages may produce vomiting or unconsciousness, but so may infarcts in the vertebrobasilar circulation. Multiple small brain infarcts may produce impaired consciousness with minimal or no focal neurologic deficits, thus mimicking metabolic or toxic encephalopathy. The initial neurologic examination provides information about the location of the brain dysfunction and provides a baseline for monitoring the subsequent clinical course. A thorough medical evaluation is necessary to detect systemic diseases that may be the cause of the cerebrovascular problem. Careful examination of the heart is imperative to detect conditions that might predispose to embolization, particularly atrial fibrillation, recent myocardial infarction, and more rarely, infective endocarditis.

X-ray computed tomography (CT) is the diagnostic neuroimaging test of choice for patients with acute stoke. It is rapid and can be performed easily on acutely ill patients. Acute intracerebral hemorrhage is easily identified by noncontrast CT. Intravenous contrast administration increases the sensitivity for detecting diseases that may mimic stroke, such as tumor, chronic subdural hematoma, and abscess. Cerebral infarction may not be demonstrated by CT for several days. If the infarct is small enough, it may never be apparent. Magnetic resonance diffusion weighted imaging is more sensitive than CT for lesion detection in the early period following ischemic infarction. Due to its superior resolution, magnetic resonance imaging (MRI) is also superior for detecting small infarcts (especially those in the posterior fossa) at any time. However, MRI is more cumbersome to perform in acutely ill patients because of longer imaging times, the need for special nonferromagnetic life support equipment, and the necessity of putting the entire body in the scanner. Demonstration of cerebral infarction by neuroimaging is rarely necessary, since the diagnosis can be made reliably by the clinical presentation together with a negative CT scan to exclude hemorrhage and other conditions. Cerebral infarction is most commonly misdiagnosed when there is no clear history of an abrupt onset.

Diagnosis of border zone infarction due to systemic arterial hypotension is almost entirely dependent on the pattern of infarction shown by CT or MRI. Border zone infarctions are often asymmetrical and patchy; rarely is the entire border zone territory between the middle cerebral artery and posterior or anterior cerebral artery involved. Furthermore, the actual location of the border zone varies from person to person.4 When more than one area of acute infarction has occurred and all infarcted areas are within the border zones, systemic hypotension should be considered as a cause of infarction.

MRI has no advantage over CT in the demonstration of acute intracerebral hemorrhage, but it does have superior sensitivity for detecting subacute or chronic hemorrhage. Noncontrast CT has a sensitivity of >90% for detecting SAH when performed within 24 hours of hemorrhage. There is no role for standard MRI in the initial diagnosis of acute SAH since it is difficult to perform in an acutely ill agitated patient and it does not increase the likelihood of detecting SAH.

In the patient who is awake and alert with acute focal brain dysfunction in whom noncerebrovascular causes can be excluded, the immediate distinction between cerebral infarction and cerebral hemorrhage may not be necessary if no emergent treatment of the stroke is planned. In certain situations, however, differentiation between infarction and hemorrhage may be critical. Patients with ischemic stroke whose time of onset can be determined to be less than 3 hours earlier and whose other medical problems do not preclude thrombolytic therapy, will benefit from treatment with intravenous tissue plasminogen activator (t-PA).5 In this circumstance, emergency CT to exclude cerebral hemorrhage is imperative, or t-PA cannot safely be given (see the section on treatment below). In the patient with decreased consciousness and a new focal neurologic deficit, emergency CT may be critically important in identifying an intracranial mass lesion that requires emergency neurosurgical intervention.

Except in patients with cerebral venous thrombosis, hematologic evaluation of patients with ischemic stroke is rarely of value. Antiphospholipid antibodies are found in a high percentage of patients with arterial stroke, but they confer neither a worse prognosis nor is there a benefit of long-term anticoagulation.6 Acquired or hereditary hypercoagulable disorders have not been clearly linked to arterial ischemic stroke, whereas they are clearly of etiologic importance in cerebral venous thrombosis. In patients with intracranial hemorrhage, especially in the ICU, acquired hemorrhagic diatheses (e.g., anticoagulant or thrombolytic drugs, DIC, thrombocytopenia) should always be considered and should be sought by appropriate laboratory testing when clinical suspicion indicates.

Lumbar puncture with cerebrospinal fluid (CSF) examination can be an extremely important test in the evaluation of the patient with apparent stroke, especially in patients with acquired immune deficiency syndrome (AIDS) or when there is infection elsewhere. Meningitis may cause stroke by producing thrombosis of arteries or cortical veins. CSF pleocytosis is common following septic embolism from infective endocarditis and can serve as a valuable clue to its presence. Lumbar puncture is the most sensitive test for detection of SAH; it should be reserved for cases in which there is a strong clinical suspicion and a negative CT scan, or when CT is not available or feasible. CSF xanthochromia can help differentiate SAH from traumatic lumbar puncture. In most patients, conditions that cause increased ICP can be excluded by a careful history and neurologic examination; lumbar puncture can then be performed safely at the bedside without a prior neuroimaging study.

Electrocardiographic monitoring detects previously unsuspected atrial fibrillation in 2% of patients with acute cerebral ischemia.7,8 This information is clinically useful, since the superiority of oral anticoagulation over aspirin for secondary stroke prevention in this circumstance has been demonstrated.9 Transthoracic echocardiography can provide evidence of poor left ventricular function, and rarely left ventricular thrombi. In patients without clinical cardiac disease (no previous history or signs or symptoms of cardiac disease, no electrocardiographic [ECG] abnormalities, and normal cardiac silhouette on chest x-ray), significant left ventricular dysfunction is vanishingly rare. Transesophageal echocardiography has made it possible to identify atherosclerosis of the ascending aorta hitherto detectable only by cardiac catheterization, surgery, or autopsy. Large aortic arch lesions are associated with an increased risk of stroke. The most common lesion detected by echocardiography in patients with stroke who have no other evidence of heart disease is patent foramen ovale with or without atrial septal aneurysm. Although echocardiography can detect these lesions in patients with ischemic stroke, the treatment implications are problematic (see below). ECG abnormalities are extremely common in patients with SAH. However, the clinical relevance of these abnormalities is questionable since they often do not correlate with echocardiographic abnormalities, histopathologic abnormalities, or serum markers of cardiac injury. Approximately 20% of patients with SAH have elevated serum troponin-I levels. Patients with elevated troponin-I levels should undergo echocardiography, as elevated troponin-I levels have been shown to be 100% sensitive and 86% specific for the detection of left ventricular dysfunction by echocardiography.10

Cerebral arteriography provides high-resolution images of both extracranial and intracranial vessels, which may occasionally be useful in the identification of causes of cerebral infarction, such as arterial dissection or vasculitis. Magnetic resonance arteriography (MRA), although widely used, is not reliable and can overestimate the degree of stenosis, sometimes even portraying normal vessels as abnormal. In addition, MRA lacks the high resolution of conventional arteriography and cannot be used to exclude small aneurysms or abnormalities in distal arterial branches. In contrast, magnetic resonance venography has supplanted conventional catheter arteriography for the detection of sagittal and lateral sinus venous thrombosis. In hypertensive patients with lobar intracerebral hemorrhage and in nonhypertensive patients with intracerebral hemorrhage in any location, arteriography may demonstrate vascular malformations or aneurysms.2 Cerebral arteriography plays an important role in the evaluation of the patient with SAH by confirming the existence of an aneurysm and providing the necessary information to plan a surgical approach. If a CT scan demonstrates SAH, a four-vessel angiogram should be performed as soon as possible. A complete study is necessary to look for multiple aneurysms. If arteriography does not reveal a cause for SAH, it should be repeated in 1 to 2 weeks. CT angiography is sometimes used to provide detailed three-dimensional reconstruction of the aneurysm and surrounding vessels to allow precise interventional planning.

Doppler ultrasound of the carotid arteries is useful to prevent subsequent stroke in screening for severe carotid stenosis at the cervical bifurcation in patients who are candidates for carotid endarterectomy. It is important to remember that the reliability of this technique varies from center to center, and that it is insensitive to stenosis above the carotid bifurcation. Patients with transient ischemic attacks (TIAs) who are good surgical candidates should be evaluated immediately since the risk of stroke following TIA can be as high as 1 in 20 within the first 2 days.11 On the other hand, in patients with a completed stroke, there is usually no urgency in obtaining this information since carotid endarterectomy does not play a role in the management of acute stroke. Transcranial Doppler (TCD) studies can detect stenosis of intracranial vessels, but the value of this information in management decisions remains to be demonstrated.12 TCD can also detect increases in flow velocity in most patients with arteriographic vasospasm of the middle cerebral artery following SAH (see below). The value of regional cerebral blood flow measurements with positron emission tomography (PET), single photon emission computed tomography (SPECT), stable xenon CT, or MRI in the diagnosis and treatment of patients with cerebrovascular disease remains to be demonstrated. Since the diagnosis of cerebral infarction can be made reliably by means of the clinical picture and a CT scan, it is rarely if ever necessary to demonstrate a defect on a cerebral blood flow study. Furthermore other conditions also may produce focal regional reductions of cerebral blood flow. Cerebral blood flow measurement as an adjunct in deciding the appropriate therapeutic intervention in patients with stroke has not been shown to result in improved outcome. The combination of diffusion weighted imaging (DWI) and perfusion weighted imaging (PWI) in patients with acute ischemic stroke often reveals a central area of restricted diffusion surrounded by a larger area of low perfusion. The diffusion abnormality increases with time. These observations have led to the hypothesis that the area of perfusion-diffusion mismatch indicates tissue destined for infarction that may be salvaged by thrombolytic therapy. This hypothesis remains unproven. Clinical trials are currently under way to determine if treatment decisions based on DWI-PWI magnetic resonance scans lead to better patient outcome.

Atherothrombotic Infarction

Immediate supportive care of the patient with atherothrombotic infarction requires attention to the patient's airway, breathing, and circulation. Although most patients have preserved pharyngeal reflexes, those with brain stem infarction or depressed consciousness may require intubation for airway protection. Coexisting heart and lung disease is common in patients with atherothrombotic stroke. Respiratory and cardiac function should be assessed fully, and appropriate interventions should be performed to maintain perfusion and oxygenation. The use of supplemental inspired oxygen is rational only if the arterial oxygen content of the blood is decreased. At the time of hospital admission, some patients may have mild intravascular volume depletion. In addition to normal maintenance requirements, careful fluid supplementation may be required. The composition of the intravenous fluid (normal saline solution, one-half normal saline solution, or 5% glucose) makes no difference as long as serum electrolyte and glucose concentrations remain normal. Care should be taken to avoid hypo-osmolarity, which potentially could exacerbate brain edema.

Systemic arterial hypertension is common following acute ischemic stroke. In most cases, blood pressure returns to baseline levels without treatment in a few days. It remains controversial what treatment is appropriate. During the period following acute cerebral infarction, the normal mechanism of cerebral autoregulation of blood flow in response to changes in cerebral perfusion pressure is impaired. Any reduction in systemic blood pressure may cause a decrease in cerebral blood flow, causing further damage in marginally perfused areas adjacent to the infarct. There are no known hazards to the brain from this spontaneous transient elevation in systemic blood pressure. When systemic hypertension causes organ damage elsewhere (e.g., myocardial ischemia, congestive heart failure, or dissecting aortic aneurysm), careful and judicious lowering of the blood pressure with constant monitoring of neurologic status is indicated. Unfortunately, there are insufficient data to permit designation of any target blood pressure levels as either safe or effective.13

The NINDS t-PA Stroke Trial demonstrated that intravenously administered t-PA improves outcome in carefully selected patients with acute ischemic stroke when instituted within 3 hours of onset.5 Inclusion and exclusion criteria used in this trial are listed in Table 63-1. Owing to the strictness of these criteria, less than 5% of patients initially screened were enrolled. Patients received 0.9 mg/kg (90 mg maximum) of alteplase, 10% given as an initial bolus over 1 minute, followed by a continuous intravenous infusion of the remainder over 60 minutes. The infusion was discontinued if intracranial hemorrhage was suspected. All patients were admitted to a neurology special care area or ICU. Anticoagulant or antiplatelet drugs were not allowed for 24 hours. Blood pressure was monitored every 15 minutes for 2 hours, every 30 minutes for 6 hours, and then every 60 minutes for 16 hours. Blood pressure was kept below 185/110 mm Hg with labetalol or sodium nitroprusside. Symptomatic cerebral hemorrhage occurred more commonly in the group treated with t-PA (6%) than in the control group (<1%). Even taking into account the increased risk of intracerebral hemorrhage, there was no difference in mortality, and more t-PA–treated patients demonstrated an excellent neurologic outcome at 3 months by each of four separate outcome scales.

The use of intravenous t-PA in acute ischemic stroke has been questioned because proof of its efficacy is based only on a single well-conducted trial. Retrospective analysis of small subgroups of patients enrolled <3 hours postevent in other trials have provided supporting evidence, and there are no data to indicate that patients who meet the eligibility criteria for the NINDS trial do not benefit.14,15 Therefore at this time, t-PA can be recommended for patients who meet the strict inclusion and exclusion criteria of the NINDS trial.16 The diagnosis of ischemic stroke in this situation rests on clinical evidence; it should be made by a physician experienced in the evaluation of acute neurologic problems to avoid unnecessary administration of an expensive and dangerous drug to patients who will not benefit. If the time of stroke onset cannot accurately be established to be less than 3 hours, t-PA should not be given. For patients who awaken from sleep with a stroke, the time of onset must be taken to be the last time they were awake and known to be in their premorbid state, not the time of awakening. CT signs of early infarction should prompt careful reconsideration of the time of onset, as they rarely occur within 3 hours of onset, but they are not a contraindication to treatment.17 Facilities must be available for closely monitoring blood pressure and maintaining it below 185/110 mm Hg. Recommended treatment of symptomatic intracerebral hemorrhage following t-PA includes cryoprecipitate and platelet transfusion.18 In spite of this treatment, mortality at 3 months was 75% in the NINDS trial.19

The value of any thrombolytic agent delivered after 3 hours either intravenously or directly by an intra-arterial catheter is not supported by current data.16 A single trial of intra-arterial pro-urokinase in patients with middle cerebral artery stem occlusion showing a barely statistically significant benefit was not sufficient proof for the drug to be approved for use in the United States.20 The use of MRI (DWI, PWI, or MRA) or CT (CT angiography or perfusion studies) to identify patients beyond the 3 hour window who might benefit from thrombolytic therapy is the subject of active investigation, but lacks evidence to demonstrate that patient outcome is improved. Owing to its poor safety profile, streptokinase cannot be used as a substitute for t-PA.

Two large studies have shown that 160 or 300 mg/d of aspirin begun within 48 hours of the onset of ischemic stroke results in a net decrease in further stroke or death of 9/1000.21 Data from several randomized controlled trials have shown that anticoagulation with heparin, low-molecular-weight heparins, or heparinoids in patients with acute ischemic stroke provides no net short- or long-term benefit in general or in any subgroup.22,23 Ticlopidine, clopidogrel, and the combination of low-dose aspirin and extended-release dipyridamole (Aggrenox) all have been demonstrated to be modestly effective in the long-term prevention of recurrent ischemic stroke, but there are no data regarding their value during the acute period.24

Many drugs aimed at ameliorating ischemic neuronal damage in patients with acute stroke are currently undergoing clinical trials. Physicians treating patients with acute ischemic stroke should be aware of the results of these trials on an ongoing basis.

Cerebral edema is the major cause of early mortality following cerebral infarction; no treatment has been shown by randomized controlled trials to be effective in improving outcome. Mannitol and hyperventilation can temporarily reduce intracranial pressure. They may be of value to the patient with brain stem compression from an edematous cerebellar infarct for whom craniotomy and removal of the edematous tissue may be life-saving. Both hypothermia and hemicraniectomy are sometimes used to treat massive edema from hemispheric infarction. The value of these treatments is unproven, and the proper selection of patients is problematic.16

No clinical evidence or pathophysiologic rationale supports routine restriction to bed of patients with acute brain infarction. Prolonged bed rest carries an increased risk of iliofemoral venous thrombosis, pulmonary embolism, and pneumonia. Patients should be out of bed and walking as soon as possible after a stroke. Occasionally, orthostatic hypotension with worsening of neurologic deficits will occur. In these cases, a more gradual program of ambulation should be instituted. In hemiplegic patients, subcutaneous heparin should be administered to prevent iliofemoral venous thrombosis. Alternating pressure antithrombotic stockings may provide benefit as well. In the case of pulmonary embolism or deep venous thrombosis, full anticoagulation with heparin or heparin-like drugs may be instituted without risk to the brain. Fever may occur due to infection or other systemic causes. Central fevers due to hypothalamic disease are an exceedingly uncommon event and the search for other causes should be vigorously pursued. Animal studies have shown that even minor elevations in temperature of a few degrees poststroke can lead to worse brain damage. Maintaining normothermia through the use of antipyretics and cooling blankets makes good sense but is of unproven value. Trials of induced hypothermia with both external and internal cooling are now underway. It is important to remember that dysphagia occurs commonly, even with unilateral hemispheric lesions. Before oral feeding is instituted, each patient's ability to swallow should be carefully checked. Incontinence is also common following acute stroke. Careful attention must be given to the prevention of decubitus ulcers in bedridden patients.

Cardioembolic Infarction

The basic supportive care of the patient with cardioembolic brain infarction is the same as for atherothrombotic infarction. Intravenous t-PA instituted within 3 hours is effective in selected patients with nonhemorrhagic cardioembolic stroke as well.5 Patients with ischemic stroke and a cardioembolic source, including atrial fibrillation, do not benefit from acute anticoagulation.25–27

Other Causes of Cerebral Infarction

In general, the principles of general care discussed above are applicable to patients with other causes of cerebral infarction. Specific causes may require specific definitive treatments, such as exchange transfusions for cerebral infarction due to sickle cell anemia. The major therapeutic question that arises in dealing with these unusual causes is whether acute anticoagulation will be of benefit. In most cases, this is unknown. Cerebral venous thrombosis can present a particularly difficult situation because of the presence of hemorrhage. Two small controlled trials have demonstrated that anticoagulation improves outcome even in patients with hemorrhagic infarction, although many of those enrolled did not receive anticoagulation within the first few days.28

Patent foramen ovale (PFO) is detected more commonly in patients with ischemic stroke than in nonstroke controls and is often the only abnormality found. Based on this finding, it is often concluded that the cause of stroke is paradoxical embolization from deep venous thrombosis. However, in contrast to pulmonary embolization, it is unusual to find a deep venous source in these patients. The risk of recurrent stroke is low and anticoagulation with warfarin does not reduce the risk of long-term recurrence.29,30 Studies of acute anticoagulation are not available. Acute anticoagulation of spontaneous or traumatic dissections of the carotid or vertebral arteries is often recommended. Data to support this approach are derived only from small nonrandomized, nonblinded studies, and even these data are weak.31

Intracerebral Hemorrhage

Supportive care of patients with primary intracerebral hemorrhage (ICH) requires attention to the same basic factors as for patients with cerebral infarction. Any underlying coagulopathy should be corrected as rapidly as possible. Prophylaxis for deep venous thrombosis with low-dose subcutaneous heparin may be instituted safely on the second day after the hemorrhage.32 Seizures are more common with lobar ICH compared to basal ganglia hemorrhage. While seizures in the acute setting warrant treatment with anticonvulsants, antiepileptic medication should be discontinued after 1 month if seizures do not recur. Prophylactic antiepileptic medications are not recommended.33

Systemic blood pressure is often elevated acutely, sometimes to very high levels. Whether acute treatment of hypertension following ICH is beneficial remains to be determined.13 In patients with small to medium sized hematomas, reductions in blood pressure down to a mean arterial pressure (MAP) of 110 mm Hg or about 20% of the admission MAP do not affect cerebral blood flow in the brain as a whole or in the region around the clot. If ICP is elevated due to large hematomas or hydrocephalus, this lower limit of autoregulation may be shifted to a higher value. Calcium channel blockers and β-blockers have an equivalent minimal effect on CBF within the autoregulatory range of MAP; ganglionic blockers may have a more profound effect on cerebral blood flow.34 In patients with increased ICP, the use of systemic antihypertensive agents that cause intracranial vasodilation (e.g., sodium nitroprusside) may further increase ICP. If the ICH is large enough to increase ICP, cerebral perfusion pressure will be reduced, making the rationale for lowering systemic blood pressure problematic. Although rebleeding is now known to occur in up to one third of patients within the first 24 hours, there is no relationship to early arterial hypertension.13

The value of ICP monitoring and treatment remains unknown. Corticosteroids do not reduce morbidity and mortality due to edema.33 Ventriculostomy is of unknown value. In our experience, patients with ventricular enlargement due to intraventricular blood do not appear to benefit from ventriculostomy.35 Mannitol and hyperventilation can be used effectively to reduce ICP temporarily. This tactic is particularly useful if a definitive surgical intervention is planned.

The primary goal of surgery is to alleviate the effects of the hematoma acting as an intracranial mass lesion, not to reverse the effects of local tissue destruction. Thus surgery has no role in the treatment of small hemorrhages. The value of surgery is best accepted for cerebellar hemorrhages resulting in brain stem compression, although no data other than anecdotal reports are available. Ideally such surgical intervention should be undertaken before brain stem damage occurs. Patients with small cerebellar hematomas (<2 cm) may do well without surgical intervention, or simply with ventricular drainage for hydrocephalus. Those with larger cerebellar hematomas usually undergo surgical evacuation, although no prospectively validated criteria for the necessity and the timing of cerebellar hematoma evacuation are available. Patients with large, deep hematomas arising from the basal ganglia or thalamus do not benefit from surgical intervention. Those with more superficial hematomas and signs of increased ICP may show improvement after surgical evacuation.35 Intracerebral hematomas due to arteriovenous malformations or ruptured aneurysms require special consideration and careful angiographic studies prior to any surgical approach.

Subarachnoid Hemorrhage Due to Ruptured Intracranial Aneurysm

Aneurysmal SAH remains a devastating neurologic problem, with up to 25% of patients dying within 24 hours with or without medical attention. Of those patients that survive, more than half are left with neurologic deficits as a result of the initial hemorrhage or delayed complications. SAH presents the intensivist with a unique and challenging series of management issues. SAH usually presents as an acute neurologic event which triggers a predictable series of processes that lead to delayed central nervous system and systemic complications. Patients who are minimally affected by the initial hemorrhage can, over the course of hours to weeks, deteriorate due to rebleeding, hydrocephalus, or delayed ischemic deficits caused by vasospasm. Management can be complicated by spontaneous volume contraction, cardiac dysfunction, electrolyte abnormalities, infections, and a catabolic state. The treatment team should include neurosurgeons, radiologists, anesthesiologists, intensivists, and nurses experienced in the management of SAH patients. Because of the complicated nature of their surgical and medical management, SAH patients are best cared for in centers that specialize in this care.

The management of patients following rupture of intracranial aneurysms has changed significantly over the past decades. The calcium channel blocker nimodipine is now routinely used to reduce the impact of vasospasm. Attempts at early obliteration of the ruptured aneurysm with surgical clipping or endovascular placement of detachable coils within the aneurysm have become routine. Hypertensive therapy is now the cornerstone of the management of vasospasm with adjunctive endovascular treatment employed in selected cases. Several new interventions to prevent or to reduce injury from vasospasm are currently under investigation.36

Initial Stabilization and Evaluation

Initial evaluation should assess airway, breathing, circulation, and neurologic function. Patients with a diminished level of consciousness often have impaired airway reflexes. In general, patients with a Glasgow Coma Scale score of 8 or less should be intubated. This should be performed under controlled conditions by experienced personnel. Premedication with short-acting agents such as thiopental or etomidate should be used to prevent elevations in blood pressure (BP) with tracheal stimulation so the risk of rebleeding can be minimized.

As soon as the patient is stabilized, a complete neurologic examination, CT, and if indicated, lumbar puncture should be performed. Patients are graded on the basis of clinical and radiographic criteria. The two common clinical grading scales are the Hunt-Hess scale and the World Federation of Neurological Surgeons scale (Table 63-2). The Fisher grade is based on the amount of blood visible on CT scan.37 These scales predict the likelihood of vasospasm and death.

Routine management of SAH patients usually includes anticonvulsants, steroids, and prophylaxis against deep vein thrombosis (DVT). Anticonvulsants are frequently used in patients with SAH. However, the majority of seizures in these patients occur prior to presentation, and the efficacy of anticonvulsants in preventing subsequent seizures is not conclusively established.38 Steroids are thought to reduce meningeal irritation and headache and to make the brain less swollen at surgery; however, there are no clear data on their effectiveness. DVT is common in SAH patients, and pneumatic compression stockings are preferred to heparin for prophylaxis because of the risk of intracranial bleeding. Patients require close neurologic and cardiopulmonary monitoring to detect the early complications of hypertension, rebleeding, acute hydrocephalus, pulmonary edema, cardiac arrhythmias, and left ventricular dysfunction.

Routine treatments to reduce the impact of vasospasm include preventing volume contraction and administering nimodipine. Patients should be hydrated with 3 to 5 L of isotonic saline per day. Indicators of volume status should be monitored closely (fluid balance, weight, and in selected cases, central venous pressure or pulmonary capillary wedge pressure) and fluids adjusted accordingly. Several large, prospective, placebo-controlled studies have demonstrated that nimodipine reduces the incidence and severity of delayed ischemic deficits and improves outcome in SAH.39 It remains uncertain whether this drug acts by causing vasodilation or by exerting direct neuroprotective effects. The recommended dose is 60 mg every 4 hours for 21 days from the time of hemorrhage. At this dose, nimodipine can sometimes reduce systemic BP, an effect that is undesirable in patients with vasospasm (see below). This effect can be ameliorated by increasing fluid administration and by altering the dose to 30 mg every 2 hours, but pharmacologic blood pressure support is necessary in some patients.

Early Complications

Hypertension

Elevated BP often initially accompanies acute SAH. Several factors may contribute to increased BP, including headache, elevated ICP in patients with hydrocephalus, increased sympathetic nervous system activity, and pre-existing hypertension. The rationale for treating hypertension is to reduce the risk of aneurysmal rebleeding. There are few compelling reasons not to treat the elevated BP before the onset of vasospasm. As definitive data on optimal BP are lacking, it seems prudent to take the patient's usual BP as a target. When the patient's usual BP is not known, it is probably better to overtreat than to undertreat. There is one important exception—comatose patients in whom CT shows marked hydrocephalus. In such cases BP should be treated very cautiously until the ICP is known, to avoid causing a critical reduction in cerebral perfusion pressure. In patients who present several days after hemorrhage and are at risk for vasospasm, the appropriate management of hypertension is less clear. The benefit of preventing rebleeding must be weighed against the risk of worsening neurologic symptoms by lowering blood pressure in the presence of vasospasm.

The first step in treating elevated BP is to administer analgesics such as morphine or fentanyl. Patients are routinely given nimodipine to prevent vasospasm, and it alone may be adequate to control BP. Otherwise, short-acting agents are preferred, since BP may be labile. Labetalol administered in intermittent intravenous boluses is frequently used, since it appears to have little effect on ICP and is easily titrated. Other useful agents include intravenous hydralazine and enalapril. Sodium nitroprusside is usually avoided because of its tendency to increase ICP and thus reduce the cerebral perfusion pressure. Intravenous nicardipine is becoming more popular in the management of SAH patients.

Rebleeding

Rebleeding is most common in the first 24 hours after the initial hemorrhage. The cumulative risk after 1 week is ∼20%, and the risk remains elevated for several weeks.40 About one half of patients who rebleed die. Measures employed in the hope of preventing rebleeding include avoidance of hypertension, cough, the Valsalva maneuver, and excessive stimulation. Treatment may involve the administration of antitussives, stool softeners, and sedatives when indicated. Antifibrinolytic medications can reduce the risk of rebleeding, but do so at the cost of an increased incidence of hydrocephalus and vasospasm. With the increasingly wide use of early surgery, the use of antifibrinolytics has largely been abandoned.

The timing of surgical obliteration of the aneurysm has changed considerably. Up to the 1970s, surgery was routinely delayed because of reluctance to operate on an edematous brain. Several factors have resulted in a shift to early surgery (days 1 to 3) for patients who have a grade of I to III on the Hunt-Hess scale. These include improved surgical techniques, better results with early surgery in North America,41 and the necessity that the aneurysm be clipped before hypertensive therapy for vasospasm is administered. The timing of surgery in poor-grade patients (Hunt-Hess grades IV or V) remains controversial, but early surgery is routinely performed in some centers.42

In recent years, endovascular techniques for the occlusion of intracranial aneurysms have become possible, allowing craniotomy to be avoided. Electrolytically detachable coils can be placed directly in the aneurysm, where they induce thrombosis. This technique is currently considered appropriate treatment for patients with an aneurysm unsuitable for surgical clipping and those considered to be at high risk for craniotomy.43 In a recent multicenter randomized trial, 20% of all assessed patients had a ruptured aneurysm that was considered to be amenable to treatment with either surgical clipping or endovascular coiling. Among this subgroup of patients (predominantly of good clinical grade with small ruptured aneurysms of the anterior circulation) the risk of death or dependency at 1 year was significantly lower with endovascular coiling.44 The long-term risk of rebleeding with this technique and the need for repeated procedures are still under investigation.

Acute Hydrocephalus

Acute hydrocephalus can develop very quickly after SAH. It is most common in patients with intraventricular blood, but can occur in the absence of this factor. The hallmark of symptomatic hydrocephalus is a diminished level of consciousness, sometimes accompanied by downward deviation of the eyes and poorly reactive pupils. The diagnostic evaluation can be complicated if the patient has received sedative drugs; it is important that analgesics be administered in doses that provide adequate relief from pain, but not excessive sedation. If sedatives are required for agitated patients, judicious administration of short-acting agents is prudent.

Hydrocephalus can be diagnosed reliably with CT and treated effectively with external ventricular drainage. Since less than half of patients with CT evidence of hydrocephalus will deteriorate clinically, ventriculostomy is usually reserved for patients with a diminished level of consciousness.

Cardiac Complications

Cardiac arrhythmias and electrocardiographic abnormalities are common in the first 24 to 48 hours after SAH. Most arrhythmias are benign. More serious arrhythmias include supraventricular and rarely ventricular tachycardia and are associated with hypokalemia.

A significant number of patients have ventricular dysfunction, which can manifest as pulmonary edema or hypotension. Increased serum levels of troponin-I and Swan-Ganz catheter recordings showing elevated pulmonary artery occlusion pressure and decreased cardiac output can serve as surrogate markers of left ventricular dysfunction and should prompt the physician to order definitive tests such as echocardiography or radionuclide ventriculography. Electrocardiographic abnormalities do not always correlate with ventricular dysfunction. Subendocardial myocardial lesions (myofibrillar degeneration and contraction-band necrosis) are seen in patients dying from SAH. These lesions are thought to be due to high levels of circulating catecholamines and/or to cardiac nerve hyperactivity and not to reflect coronary insufficiency. Cardiac pump failure is often transient, hence this condition has been called “stunned myocardium.” Though catecholamines have been implicated in the pathogenesis, patients have been successfully treated with inotropes such as dobutamine.45

Pulmonary Complications

Pulmonary complications are seen in almost one fourth of all patients with SAH.46,47 They include pneumonia (arising from acute or subacute aspiration, commonly with nosocomial organisms), cardiogenic pulmonary edema, neurogenic pulmonary edema, and pulmonary embolism. Neurogenic pulmonary edema is thought to be secondary to massive catecholamine release leading to systemic vasoconstriction and a relative shift of the intravascular volume to the pulmonary vasculature. Other possibilities include direct endothelial damage mediated by the sympathetic system and transient cardiac dysfunction. Management of severe pulmonary edema usually involves positive pressure ventilation and diuretics; however, diuretics may not be appropriate for neurogenic pulmonary edema if there is relative intravascular volume depletion.45 A pulmonary artery catheter often helps guide therapy in such cases.

Postoperative Management

Knowledge of the intraoperative surgical and anesthetic course facilitates the postoperative care of SAH patients. Large doses of mannitol may have been administered to shrink the brain and facilitate retraction. This measure can result in postoperative hypovolemia. If temporary clipping of cerebral vessels is required, hypothermia and/or large doses of barbiturates may be employed. These maneuvers may delay emergence from anesthesia and add to the systemic complications of hypothermia. The decision to extubate a postoperative patient must take these factors into consideration. If the aneurysm is successfully clipped, many practitioners will accept higher blood pressures in the postoperative period in anticipation of vasospasm (see below).

Hyponatremia and Intravascular Volume Contraction

A total of 30% to 50% of SAH patients develop intravascular volume contraction and a negative sodium balance (referred to as cerebral salt wasting) when given volumes of fluids intended to meet maintenance needs. Low intravascular volume is associated with symptomatic vasospasm. Hyponatremia develops in 10% to 34% of patients following SAH. Administration of large volumes (5 to 8 L per day) of isotonic saline prevents hypovolemia, but patients may still develop hyponatremia. The degree of hyponatremia appears to be related to the tonicity rather than the volume of fluids administered.48 Thus administration of large volumes of isotonic saline and restriction of free water are usually effective at limiting hyponatremia and preventing hypovolemia. In SAH patients with hyponatremia, the volume of fluids should never be restricted; instead only free water intake should be limited.

Vasospasm

The term vasospasm was originally used to refer to segmental or diffuse narrowing of large conducting cerebral vessels. Recently, this term has taken on multiple meanings. It may refer to angiographic findings, to increased transcranial Doppler velocities, or to delayed ischemic deficits. Angiographic and transcranial Doppler vasospasm occurs in 60% to 80% of patients, whereas clinical vasospasm (or delayed ischemic deficit) occurs in 20% to 40% of patients.

The pathogenesis of vasospasm is complex. Sustained exposure of vessels to extraluminal oxyhemoglobin appears to play an important role in initiating vasospasm. In animal models of vasospasm, vessels demonstrate enhanced responses to vasoconstrictors, as well as structural changes that physically reduce luminal diameter. These changes develop in a delayed fashion after exposure to subarachnoid blood and are self-limited. In addition to changes in the large conducting cerebral vessels that traverse the subarachnoid space, small-vessel reactivity may be impaired as well.49

Monitoring for Vasospasm

Serial neurologic assessments are essential in monitoring for vasospasm. These must be performed frequently by physicians and nurses well versed in neurologic examination and the recognition of subtle deficits. The patients with the highest incidence of vasospasm are those with Hunt-Hess grades III through V and Fisher grade 3. These patients are often monitored in the ICU or another special care area during the period of highest risk for onset of vasospasm (days 5 to 10). Clinically vasospasm presents as a decline in the global level of function or a focal neurologic deficit. Patients may initially appear “less bright” and then become progressively less alert and finally comatose. The focal deficits mimic those seen in ischemic stroke. Middle cerebral artery vasospasm can produce hemiparesis, and if left-sided, aphasia. Anterior cerebral artery vasospasm often manifests as abulia or lower extremity weakness. The focal deficits wax and wane and therefore are not reported by all observers. The symptoms are exacerbated by hypovolemia or hypotension.

Transcranial Doppler ultrasonography detects changes in the blood flow velocity in the proximal portion of the major cerebral vessels. Very high flow velocities (>200 cm/s) in the middle cerebral and intracranial carotid arteries are closely correlated with angiographic vasospasm, while low flow velocities (<120 cm/s) suggest a low likelihood of vasospasm.50 Patients with rapidly rising velocities are considered to be at highest risk for developing clinical vasospasm. Transcranial Doppler has several limitations. High flow velocities can be due to increased blood flow rather than narrowing of the blood vessel. Distal segments of the major arteries cannot be evaluated. The technique is also operator dependent and adequate “acoustic windows” are required. Therefore, transcranial Doppler velocities should not be used in isolation as an indication for the initiation of aggressive treatments—the clinical course must be considered as well. Angiography may be used to confirm the clinical diagnosis of vasospasm and for endovascular treatment (see below), but it has a limited role in monitoring for vasospasm.

Treatment of Vasospasm

Hemodynamic Augmentation

Hemodynamic augmentation for the treatment of vasospasm has been referred to as hemodilution hypervolemic hypertensive therapy (“triple H therapy”) or as hypervolemic hypertensive therapy (HHT). The pathophysiologic rationale is based on the high rate of spontaneous hypovolemia, the association of hypovolemia with delayed ischemic deficits, and the loss of autoregulation of cerebral blood flow in this population.

Most centers continue aggressive hydration during the period of vasospasm risk. Some will increase the rate of fluid administration if transcranial Doppler velocities are rising. The indication for starting aggressive hemodynamic augmentation is usually the onset of clinical symptoms of delayed ischemic deficit. Early descriptions of this therapy emphasized the role of volume expansion, as many of these patients had not been aggressively hydrated before the onset of symptoms. However, if intravascular volume has been maintained before the onset of symptoms, further volume expansion may not be helpful.51 The optimal intravascular volume is unknown, and achieving cardiac filling pressures that optimize cardiac output has been advocated.

When symptoms persist despite optimal intravascular volume, vasoactive drugs are administered, usually to raise mean arterial pressure (MAP). In most cases, patients will be monitored with an arterial line and a pulmonary artery catheter. The most commonly used agents are dopamine and phenylephrine. Caution must be employed when using dopamine alone, because of a high incidence of tachyarrhythmias. When dopamine is combined with phenylephrine, this is less of a problem. It is best to monitor MAP rather than systolic pressure, because MAP more accurately reflects cerebral perfusion pressure. MAP also varies less than systolic BP with the use of different techniques for measuring blood pressure.

When therapy is initiated, the MAP should be raised to 15% to 20% above baseline rather than to an arbitrary value. If after 1 to 2 hours the delayed ischemic deficit has not resolved, the MAP should be raised further. The MAP is increased progressively until the neurologic deficit is completely resolved or the risk of systemic toxicity becomes unacceptable. Some patients may require a MAP of 150 to 160 mm Hg to completely reverse the neurologic symptoms. Often extremely high doses of vasopressors are required to produce the degree of hypertension desired. The neurologic status should be re-evaluated several times a day to determine MAP goals. Recently, the use of dobutamine to augment cardiac output has been proposed as an alternative to raising blood pressure. Both approaches are reported to produce neurologic improvement. It has not yet been determined whether the optimal therapy is to enhance cardiac output, MAP, or both.

Once instituted, the therapy is generally continued for 3 to 4 days before attempts are made to wean the patient from it. Weaning should be done gradually, with very close monitoring of neurologic status. If the initial attempt at weaning is unsuccessful, a second attempt should be made after 1 to 2 days. The patient usually is weaned from vasoactive drugs first, aggressive hydration being continued for several more days.

Hemodynamic augmentation is not without complications. Early reports indicated high rates of fluid overload, heart failure, and myocardial ischemia. A more recent study indicated that this therapy is safe when administered in a closely monitored setting, even in patients with pre-existing cardiac disease.52 Cardiovascular monitoring should include continuous display of the electrocardiogram, peripheral oxygen saturation, MAP, and frequent measurements of pulmonary capillary wedge pressure and cardiac output. In patients with a history of ischemic heart disease, daily electrocardiograms and cardiac enzyme measurements may be helpful. Close monitoring of potassium, magnesium, and phosphate levels is important because of large losses in the urine.

Endovascular Therapies: Percutaneous Transluminal Angioplasty and Papaverine

Balloon angioplasty can be used to dilate proximal segments of intracranial vessels, but it is not well suited for use in the distal vasculature. The dilatation achieved appears to be long-lasting. Complications that have been reported include artery rupture and displacement of aneurysm clips. In most cases there is clear-cut angiographic improvement, but the clinical efficacy of angioplasty has not been clearly established.36

Papaverine is a potent vasodilator that has been used in superselective intra-arterial infusions as an adjunct to angioplasty. The vasodilator effects of papaverine persist for less than 2 hours.53 Radiographic improvement is usually evident, but the clinical effect is less clear. Complications of papaverine treatment are increased intracranial pressure, tachycardia, arrhythmias, and transient neurologic deficits. These therapies are usually reserved for patients who do not tolerate or do not respond to hemodynamic augmentation.

Other Potential Therapies

Prevention rather than treatment of the consequences of vasospasm would significantly reduce the morbidity, mortality, and cost of SAH. Intracisternal instillation of thrombolytic agents has been employed in an attempt to dissolve clots around the circle of Willis and thereby decrease vasospasm. A multicenter, randomized, blinded, placebo-controlled study found trends towards reduction of angiographic vasospasm, reduced delayed neurologic worsening, lower 14-day mortality, and improved 3-month outcome that did not achieve statistical significance in patients treated with intracisternal t-PA. Patients with thick subarachnoid clots had a significant reduction in the incidence of severe vasospasm with intracisternal t-PA.54

The degradation of blood deposited during an SAH involves the conversion of oxyhemoglobin to methemoglobin, which releases an activated form of oxygen that catalyzes free radical reactions, including lipid peroxide formation. The 21-aminosteroid, tirilazad mesylate, a potent scavenger of oxygen free radicals, inhibits lipid peroxidation and reduces vasospasm in animal models. A European-Australian multicenter study showed that tirilazad was associated with better outcomes compared to control patients, but this was not confirmed in a subsequent North American study.55,56 In a multicenter, randomized, double-blind, placebo-controlled trial, nicaraven, a hydroxyl radical scavenger, significantly reduced the incidence of severe vasospasm and poor outcome at 1 month but not at 3 months.57 Ebselen, another lipid peroxidation inhibitor, did not lower the incidence of symptomatic vasospasm in a controlled study.58 Other potential therapies being studied include cyclosporine A, high-dose methylprednisolone, serine protease inhibitors, thromboxane A2 inhibitors, endothelin-1 receptor antagonists, nitric oxide donors, potassium channel activators, and delivery systems capable of slow subarachnoid release of papaverine and calcitonin gene-related peptide.36