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.
Table 63–1. Inclusion and Exclusion Criteria from the NINDS t-PA Stroke Trial ||Download (.pdf)
Table 63–1. Inclusion and Exclusion Criteria from the NINDS t-PA Stroke Trial
Age 18 through 80 years.
Clinical diagnosis of ischemic stroke causing a measurable neurologic deficit, defined as impairment of language, motor function, cognition, and/or gaze or vision, or neglect. Ischemic stroke is defined as an event characterized by the sudden onset of an acute focal neurologic deficit presumed to be due to cerebral ischemia after computed tomography (CT) has excluded hemorrhage.
Time of onset well established to be less than 180 minutes before treatment would begin.
Prior to treatment, the following must be known or obtained: complete blood cell count, platelet count, prothrombin time (if the patient has a history of oral anticoagulant therapy in the week prior to treatment initiation), partial thromboplastin time (if the patient has received heparin within 48 hours of treatment initiation), blood glucose, and CT scan (noncontrast).
Minor stroke symptoms or major symptoms that are improving rapidly.
Evidence of intracranial hemorrhage on CT scan.
Clinical presentation that suggests subarachnoid hemorrhage even if initial CT scan is normal.
Female patient who is lactating or known or suspected to be pregnant.
Platelet count less than 100,000/μ L; prothrombin time greater than 15 seconds; heparin has been given within 48 hours and partial thromboplastin time is greater than the upper limit of normal for laboratory; anticoagulants currently being given.
Major surgery or serious trauma, excluding head trauma, in the previous 14 days, or head trauma within the previous 3 months.
History of gastrointestinal or urinary tract hemorrhage in the previous 21 days.
Arterial puncture at a noncompressible site or a lumbar puncture within the previous 7 days.
On repeated measurement, systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg at the time treatment is to begin, or patient requires aggressive treatment to reduce blood pressure to within these limits.
Patient has had a stroke in the previous 3 months or has ever had an intracranial hemorrhage considered to put the patient at an increased risk for intracranial hemorrhage.
Serious medical illness likely to interfere with this trial.
Abnormal blood glucose (<50 or >400 mg/dL).
Clinical presentation consistent with acute myocardial infarction or suggesting post–myocardial infarction pericarditis.
Patient cannot, in the judgment of the investigator, be followed for 3 months.
Seizure occurred at onset of stroke.
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.
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
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.
Table 63–2. The Hunt-Hess, the World Federation of Neurologic Surgeons, and the Fisher Scales ||Download (.pdf)
Table 63–2. The Hunt-Hess, the World Federation of Neurologic Surgeons, and the Fisher Scales
|I||Asymptomatic or mild headache|
|II||Moderate to severe headache, nuchal rigidity, with or without cranial nerve deficits|
|III||Confusion, lethargy, or mild focal symptoms|
|IV||Stupor and/or hemiparesis|
|V||Comatose and/or extensor posturing|
|WORLD FEDERATION OF NEUROLOGIC SURGEONS SCALE|
|Grade||Glasgow Coma Scale Score||Motor Deficits|
|IV||12–7||Present or absent|
|V||6–3||Present or absent|
|FISHER SCALE (BASED ON INITIAL CT APPEARANCE AND QUANTIFICATION OF SUBARACHNOID BLOOD)|
No subarachnoid hemorrhage on computed tomography
Broad diffusion of subarachnoid blood, no clots and no layers of blood greater than 1 mm thick
Either localized blood clots in the subarachnoid space or layers of blood greater than 1 mm thick
Intraventricular and intracerebral blood present, in absence of significant subarachnoid blood
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.
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 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 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 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 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.
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.
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
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.
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