Nontraumatic Intracerebral and Subarachnoid Hemorrhage

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35 Nontraumatic Intracerebral and Subarachnoid Hemorrhage

Allyson R. Zazulia, Michael N. Diringer

Intracerebral Hemorrhage

Spontaneous (nontraumatic) intracerebral hemorrhage (ICH) accounts for approximately 10% of all strokes in North America and about 20% to 30% in East Asia. It is associated with greater mortality and more severe neurologic deficits than any other stroke subtype.¹^–³ Nearly half of all patients die within the first 30 days; survivors often have significant residual disability.⁴

Pathophysiology

The pathophysiologic mechanisms of brain injury due to ICH are complex. The primary injury is one of local tissue destruction as rupture of a cerebral blood vessel introduces a sudden stream of blood into the brain parenchyma. In over one third of patients, continued bleeding or rebleeding results in hematoma enlargement and further mechanical injury within the first few hours after onset.⁵ The mass of the hematoma produces tissue shifts within the intracranial cavity.

In addition to the primary mechanical injury, further damage is believed to occur after the bleeding stops. The mechanisms underlying this secondary injury are unknown, but ischemia, edema, and toxic effects of parenchymal blood have been implicated. While each of these processes has been demonstrated in animal models, the clinical importance of any of them remains unsettled.

Experimental models of ICH consistently suggest that ischemia is an important part of the pathophysiology of ICH.^6,⁷ In clinical studies, peri-clot and ipsilateral hemispheric hypoperfusion have been demonstrated,⁸^–¹⁰ but the hypoperfusion does not appear to represent ischemia.^11,¹² Positron emission tomography (PET) studies in humans performed 5 to 22 hours after symptom onset showed that perihematomal cerebral metabolism was reduced to a greater degree than cerebral blood flow (CBF), suggesting that the hypoperfusion reflects reduced metabolic demand of the damaged tissue surrounding the hematoma rather than ongoing ischemia.¹² Magnetic resonance imaging (MRI) studies within 6 hours after symptom onset demonstrate hypoperfusion without restricted diffusion, findings that are inconsistent with ischemia.¹³

Cerebral edema has been demonstrated to occur within hours of experimental ICH, variably thought to result from the toxic effects of blood-derived enzymes, from increased osmotic pressure exerted by clot-derived serum proteins, or from ischemia.¹⁴^–¹⁶ The presence, time course, and importance of edema formation in humans are debated, however. Signal changes on radiographic studies after ICH indicate increased water content in the area surrounding the clot, but the clinical and pathophysiologic significance of this is not known. Edema does not appear to contribute to early increases in mass effect¹⁷ and is not associated with worsened functional outcome or increased mortality.^18,¹⁹

Hemostasis after hemorrhage is initially achieved at the site of vascular injury by the formation of a platelet-fibrin plug. After several days, red blood cells within the clot begin to lyse, cellular infiltrates appear, and the process of reabsorption begins. Months later, a residual collapsed cavity is all that remains.

Causes and Risk Factors

The leading risk factor for ICH, occurring in over half of all cases, is chronic hypertension.²⁰ Long-term adequate treatment of chronic hypertension significantly reduces this risk.²¹ Increasing age is another risk factor, with a doubling of the rate of hemorrhage with each decade of life until age 80, when the incidence plateaus at nearly 25 times that of the previous decade.²² In the United States, ICH is 2 to 3 times more common in African Americans and Hispanics than in Caucasians (incidence rates of 32, 35, and 10 to 15 per 100,000 population, respectively).^23,²⁴ The incidence in Asian countries is considerably greater (61 per 100,000 population).²⁵

Low serum cholesterol has been implicated in a number of studies,²⁶ and use of high-dose statins appears to increase the risk of ICH, particularly in those with prior history of ICH.²⁷ The impact of smoking,²⁸ alcohol abuse,^29,³⁰ and diabetes^31,³² on the risk of ICH is disputed.

Hypertensive Hemorrhage

Hypertensive ICH predominantly occurs deep in the cerebral hemispheres, most often in the putamen ³³ (Figure 35-1). Other frequently involved sites include the thalamus, lobar white matter, cerebellum, and pons. The common link between these sites is that they are all supplied by small penetrating arteries,³⁴ perpendicular branches directly off major arteries that are subject to high sheer stress and that have no collaterals. These features make them vulnerable to the effects of increased blood pressure. Chronic hypertension damages the tunica media, resulting in lipohyalinosis, fibrinoid necrosis, and microaneurysms (Charcot-Bouchard aneurysms). Although Charcot-Bouchard aneurysms have been demonstrated in the weakened vessel walls of patients with ICH, their pathogenetic role in vascular rupture is uncertain.³⁵ The occurrence of ICH in an atypical location, in multiple locations, or in association with subarachnoid hemorrhage raises the suspicion of a non-hypertensive etiology, such as a cerebral vascular anomaly, blood dyscrasia, or trauma.

Figure 35-1 Typical moderate-sized putamenal hemorrhage.

Intracranial Aneurysms and Vascular Malformations

Although aneurysmal rupture is most commonly associated with hemorrhage in the subarachnoid space, the blood may also be directed into the substance of the brain if the aneurysm is adherent to the brain parenchyma. Rarely, aneurysms located at the middle cerebral artery bifurcation can produce hemorrhages that appear identical to hypertensive hemorrhage into the basal ganglia, and anterior communicating artery aneurysms can produce flame-shaped hemorrhages in the base of the frontal lobes.

Approximately half of intracranial AVMs in adults present with hemorrhage.³⁶ In 60% of cases, the hemorrhage is parenchymal, involving virtually any location within the cerebrum, brainstem, or cerebellum.³⁷ The majority of AVMs become symptomatic by age 40; thus hemorrhage due to AVM occurs in a younger population than that due to aneurysms or hypertension. Multiple calcified vascular channels may be seen within the hematoma on CT scan, suggesting the presence of an AVM. MRI and four-vessel cerebral angiography are useful adjuncts in the diagnosis of these lesions.

Other Causes

Cerebral amyloid angiopathy (CAA) is an important cause of predominantly lobar, often recurrent, ICH in the elderly. Histopathologic studies in CAA demonstrate the deposition of beta-amyloid protein in the media and adventitia of small meningeal and cortical vessels; deposition in the typical sites for hypertensive hemorrhage is rare but has been reported in the cerebellum.³⁸ The prevalence of amyloid in cerebral vessels increases dramatically with age^39,⁴⁰ and may partially account for the exponential rise in the risk for ICH with increasing age. There is an overrepresentation of the apolipoprotein E ε2 and ε4 genotypes in CAA-related hemorrhage, and these alleles are associated with an earlier age of onset of first hemorrhage and a higher risk of early recurrence.^41,⁴² Although neuropathologic examination remains the only means of definitively diagnosing CAA, the presence of multiple or recurrent lobar ICH (including asymptomatic microhemorrhages detected on gradient-echo MRI) in individuals 55 years or older without other known causes of hemorrhage strongly suggests the diagnosis.⁴³ Recent PET studies with ¹¹C-Pittsburgh compound B (PIB) suggest an occipital predominant increase in amyloid in such patients.⁴⁴ Neuropathologic correlation remains to be demonstrated, but PIB-PET appears to be a promising tool for in vivo diagnosis of CAA.

Hematologic causes of ICH include the use of antithrombotic and thrombolytic agents as well as systemic disease (e.g., thrombocytopenia, leukemia, and hepatic and renal failure) and congenital or acquired factor deficiencies. The incidence of oral anticoagulant (OAC)-associated ICH has been increasing in parallel with the increased use of warfarin following pivotal trials in atrial fibrillation in the 1990s. A recent population-based study in the greater Cincinnati area identified a fivefold increased incidence of OAC-associated ICH between 1988 and 1999, such that this condition now accounts for 17% of all ICH cases.⁴⁵ The incidence is anticipated to rise further in the coming years as the population ages. Although the risk of ICH is greater in the setting of very elevated international normalized ratio (INR), a significant number of hemorrhages occur when the INR is within the therapeutic range.⁴⁶ Hematoma expansion may be more common in OAC-associated ICH and occur over a longer time frame because of persistent coagulopathy, contributing to the doubling of mortality rate compared to spontaneous ICH.⁴⁷

The relationship between antiplatelet agent use and hematoma size, hematoma expansion, and outcome in ICH are active areas of investigation. Most studies suggest that antiplatelet use at ICH onset is not associated with larger hematoma size, hematoma growth, or poor clinical outcome ⁴⁸; however, an association has been demonstrated between reduced platelet activity and hematoma growth and poor outcome.⁴⁹ Whether platelet transfusion is beneficial in this situation is unknown.

Hemorrhage from an underlying neoplasm is rare but occasionally occurs with malignant primary CNS tumors such as glioblastoma multiforme and lymphoma and with metastatic tumors such as melanoma, choriocarcinoma, renal cell carcinoma, and bronchogenic carcinoma.⁵⁰ Benign tumors are almost never associated with ICH.

ICH may also occur in association with infection (e.g., infiltration of vessel wall by fungal organisms,⁵¹ necrotizing hemorrhagic encephalitis with herpes simplex,⁵² vasculitis,⁵³ venous sinus occlusion,⁵⁴ in a delayed fashion after head trauma,⁵⁵ following reperfusion (e.g., after carotid endarterectomy or acute thrombolysis),⁵⁶ and with the use of various drugs, particularly sympathomimetics (e.g., cocaine, amphetamines, pseudoephedrine, and phenylpropanolamine).⁵⁷ Finally, some degree of hemorrhagic transformation of acute cerebral infarcts is common,⁵⁸ though symptomatic ICH in this setting is rare in the absence of anticoagulation or thrombolytic therapy.

Clinical Features

The clinical presentation of ICH is often indistinguishable from that of ischemic stroke but more commonly includes altered level of consciousness, headache, and vomiting, reflecting the presence of increased intracranial pressure (ICP).³³ Blood pressure is elevated in the majority of patients (see later discussion). Seizures occur in nearly one-third of patients at onset or within the first few days, particularly in those with lobar hemorrhages or underlying vascular or neoplastic lesions, and may be purely electrographic.⁵⁹ Symptoms are maximal at onset or develop over minutes to hours. Neurologic deterioration within 48 hours after hospital admission has been reported to occur in 22% of patients with ICH.⁶⁰ The cause for clinical worsening is not always evident, but it is predicted by clinical and biological markers of inflammation on admission and commonly associated with increased hematoma size and intraventricular bleeding.

Diagnostic Studies

Noncontrast computed tomography (CT) scanning has been the traditional gold standard for diagnosis of acute ICH. The typical CT appearance of an acute hematoma consists of a well-defined area of increased density surrounded by a rim of decreased density. Over time, the borders of both the high- and low-attenuation regions become increasingly indistinct such that the hematoma is isodense with adjacent brain parenchyma by 2 to 6 weeks.⁶¹ Peripheral contrast enhancement can often be seen at this time.⁶² By 2 to 6 months, there may be no CT evidence of previous hemorrhage or there may be an area of hypodensity or a slit-like scar.⁶³

Recent studies have suggested that MRI has high sensitivity and specificity for the diagnosis of acute ICH.⁶⁴^–⁶⁶ These studies have been criticized, however, for major methodological limitations including the basing of sensitivity estimates on only a small fraction of patients investigated, lack of CT comparator in many patients, and both incorporation and spectrum bias (highly selected patient sample) that may have overestimated diagnostic accuracy of MRI.⁶⁷ In addition, MRI may not be feasible in a substantial number of patients with acute ICH because of impaired consciousness, hemodynamic compromise, or vomiting.⁶⁸ The benefits of MRI over CT are its superior performance in the identification of associated vascular malformations, greater accuracy in determining the approximate age of a hematoma (because each hemoglobin oxidation state during evolution of the hematoma produces a predictable pattern of MR signal intensity),⁶⁹ and its utility in demonstrating the iron-containing deposits of previous asymptomatic hemorrhages.⁷⁰

Angiography is useful in evaluating the cause of ICH if an underlying aneurysm or vascular malformation is suspected, but the yield of such studies is extremely low when the patient has chronic hypertension and the hemorrhage is in one of the typical sites associated with hypertensive hemorrhage.⁷¹ Multidetector CT angiography is evolving as an alternative to conventional angiography. In a retrospective review of 623 patients, multidetector CT angiography identified a vascular etiology for ICH in 91 (15%), with a sensitivity of 96% and a specificity of 99%. The yield was higher in patients who were younger than 46 (47%), had lobar (20%) or infratentorial (16%) ICH locations, had lobar hemorrhages with intraventricular extension (25%), and had neither hypertension nor impaired coagulation (33%).⁷² In another study of 78 patients, CT angiography identified all but one of the 22 lesions seen on conventional angiography, with a sensitivity of 96% and a specificity of 100%.⁷³

Multidetector CT angiography can also be used to identify the presence of active contrast extravasation into the hematoma, an indicator of active hemorrhage. Termed the “spot sign,” these foci of intralesional enhancement are seen in up to one third of patients with acute ICH ⁷⁴ and are associated with an increased risk of hematoma expansion, in-hospital mortality, and poor outcome in survivors.⁷⁵

Treatment

Initial Stabilization

Acute ICH is a medical emergency requiring considerable attention to airway and respiratory management, hemodynamic status, and correction of any underlying coagulopathy. As many as half of all patients with ICH undergo mechanical ventilation.⁷⁶ Blood pressure is often elevated at presentation, sometimes markedly so. Finally, given the frequency of hematoma enlargement over the first few hours, aggressive correction of coagulopathies might be helpful.

Airway and Respiratory Management

Airway difficulty in ICH may occur for two reasons. First, with diminished consciousness, the pharyngeal and tongue musculature relax, and cough and gag reflexes are inhibited. In ICH involving the posterior fossa, there may be complete loss of pharyngeal tone, resulting in early obstruction of the upper airway.

Initial airway management includes proper positioning, frequent suctioning, and placement of an oral or nasal airway. Frequent assessments for sonorous respiration, inability to manage oral secretions, or decreased oxygen saturation are necessary. If conservative measures are ineffective, intubation may be necessary. Intubation of patients with ICH requires adequate sedation and jaw relaxation as well as prevention of elevation of ICP. Several factors may conspire to raise ICP during intubation: hypoxia, hypercarbia, and direct tracheal stimulation causing systemic and intracranial hypertension. Intravenous (IV) lidocaine (1-1.5 mg/kg) has been recommended to block this response,⁷⁷ although data supporting its use are lacking.⁷⁸ Short-acting IV anesthetic agents (thiopental, 1-5 mg/kg; or etomidate, 0.1-0.5 mg/kg) also block this response⁷⁹ and additionally suppress brain metabolic rate,⁸⁰ theoretically improving tolerance of a transient fall in cerebral perfusion pressure (CPP) should it occur. Etomidate is generally preferred over thiopental, since it is less likely to lower blood pressure. Paralytic agents are usually unnecessary but, if needed, short-acting agents should be used.

Noninvasive ventilation offers a potential alternative to intubation; it can be used to overcome mild upper airway obstruction and support oxygenation but may compromise management of secretions. It is difficult to provide adequate suctioning when a mask is present.

Hemodynamics

Arterial blood pressure is elevated on admission in the majority of patients with ICH, even in the absence of a history of hypertension.³³ Mean arterial pressure (MAP) is greater than 120 mm Hg in over two-thirds of patients and greater than 140 mm Hg in over one-third.⁸¹ Although this acute increase in blood pressure is often implicated as the cause of the hemorrhage, it may simply be a reflection of chronic hypertension, the brain’s attempt to maintain CPP in response to the sudden increase in ICP, pain and anxiety, and sympathetic activation. Even without pharmacologic intervention, blood pressure tends to decline to premorbid levels during the first 7 to 10 days after hemorrhage.⁸²

There is substantial controversy over if and when to lower blood pressure after acute ICH and how aggressive any intervention should be.⁸³ Proponents of rapid treatment of acute hypertension argue that high blood pressure may predispose to hematoma enlargement and may exacerbate vasogenic edema by increasing capillary hydrostatic pressure, especially in areas with a damaged blood-brain barrier. Yet, an association between hypertension and edema has never been demonstrated, and data on the effect of hypertension on hematoma enlargement have been inconsistent.^84,⁸⁵ Another potential reason to lower blood pressure is that hypertension during the acute phase of ICH has been shown to correlate with a poor prognosis in some studies.^86,⁸⁷ One compelling reason to consider lowering blood pressure in ICH patients with moderate to severe hypertension is the potential for end-organ damage. Such patients are at risk for systemic complications of elevated blood pressure, including myocardial ischemia, congestive heart failure, and acute renal failure.

The major argument against the treatment of elevated blood pressure is that lowering blood pressure might exacerbate ischemic damage in the tissue surrounding the hematoma by impairing blood flow.⁸⁸ Chronic hypertension shifts the cerebral autoregulatory curve to the right such that a higher CPP is required to maintain adequate CBF.^89,⁹⁰ Lowering the blood pressure to “normal” levels in these patients might thus lead to inadequate CBF. Similarly, since CPP is equal to the difference between MAP and ICP, lowering blood pressure may reduce CPP below the autoregulatory limit in patients in whom ICP is elevated due to a large space-occupying clot or hydrocephalus.

Seeking to address the issue of whether lowering blood pressure produces cerebral ischemia in acute ICH, several studies of CBF autoregulation in patients with recent ICH and elevated blood pressure (MAP > 130-140 mm Hg) have been carried out.⁹¹^–⁹³ Taken together, these studies demonstrate that regional and global autoregulation are preserved after ICH down to a lower MAP limit that averages 110 mm Hg or about 80% of the admission MAP.

These observations set the stage for the INTERACT trial,⁹⁴ a prospective trial of blood pressure management beginning within 6 hours of symptom onset in 404 patients with spontaneous ICH and elevated systolic blood pressure (150-220 mm Hg). Patients were randomized to an early intensive blood pressure–lowering strategy that targeted a reduction in systolic blood pressure to below 140 mm Hg within 1 hour, or control, with a target systolic pressure of less than 180 mm Hg. The primary efficacy endpoint was hematoma growth at 24 hours. After the first hour of treatment, mean blood pressure was 13.3 mm Hg lower (95% confidence interval [CI] 8.9-17.6 mm Hg; P <0.0001) in the intensive blood pressure–lowering group. Hematoma growth at 24 hours was 36.3% in the control group and 13.7% in the intensive treatment group, a 22.6% difference (95% CI 0.6%-44.5%; P=0.04). After adjusting for initial hematoma volume and time from onset to CT, median hematoma growth at 24 hours differed by 1.7 mL (95% CI 0.5-3.9, P=0.13). Intensive blood pressure–lowering treatment did not increase the risk of adverse events or improve 90-day clinical outcome. A much larger follow-on trial is currently underway.

If the decision is made to treat hypertension in acute ICH, the most appropriate antihypertensive agent would have a short half-life and minimal cerebrovascular effects and would be administered in such a way as to avoid sudden large reductions in blood pressure. Vasodilators, especially those that dilate veins, can raise ICP by increasing cerebral blood volume and hence should be avoided. Sodium nitroprusside and nitroglycerin increase ICP and lower CBF in patients with reduced intracranial compliance. Ganglionic blockers may also lower CBF. Calcium channel blockers, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors have minimal effect on CBF within the autoregulatory range of MAP and do not alter ICP. Therefore, popular treatment options in the setting of acute ICH include intermittent boluses of labetalol, enalapril, and/or hydralazine or continuous infusion of nicardipine.

Prevention of Hemorrhage Extension

Because hemorrhage extension occurs within the first few hours after symptom onset in about one-third of patients (Figure 35-2), it seems appropriate that any coagulopathy should be corrected as rapidly as possible. Patients taking warfarin should receive IV vitamin K and enough fresh frozen plasma (FFP) to normalize the coagulation profile. Prothrombin complex concentrate may be a useful alternative. Care must be taken not to precipitate congestive heart failure, however, and diuretics may be required. Additionally there is risk of transfusion-related acute lung injury with the administration of fresh frozen plasma, which can complicate the process considerably. Correcting coagulopathy associated with thrombolytic-induced ICH is discussed later.

Figure 35-2 Example of hematoma enlargement. Computed tomography (CT) on left was obtained 2 hours after onset of left hemiparesis and shows right putamenal hemorrhage. CT on right was obtained 1 hour later when patient acutely deteriorated and shows expansion of hematoma, with intraventricular extension, midline shift, and enlarging ventricles.

Even in those patients without coagulopathy, promoting early hemostasis might limit ongoing bleeding and decrease hematoma volume. Factor VIIa is a coagulation factor that interacts with tissue factor exposed in the wall of a damaged blood vessel to drive a burst of thrombin that initiates platelet aggregation and accelerates formation of a stable fibrin clot. A phase IIb placebo-controlled dose-ranging proof-of-concept study found that treatment with recombinant factor VIIa (rFVIIa) given as a single IV bolus within 4 hours of ICH onset decreased hematoma growth and improved clinical outcome despite a small increase in thromboembolic events. A much larger phase III trial comparing placebo to 20 and 80 µg/kg of rFVIIa followed. This study confirmed the ability of rFVIIa to reduce hematoma growth; however, at 90 days there was no difference in clinical outcome.⁹⁵ A post hoc exploratory analysis suggested that a subgroup of younger patients who present earlier and have no significant intraventricular hemorrhage might benefit from rFVIIa, but this has not been tested.⁹⁶

Intraventricular Hemorrhage and Hydrocephalus

In approximately 40% of patients with ICH, blood extends into the ventricular system (intraventricular hemorrhage [IVH]).⁹⁷ Mortality in these patients is high.^98,⁹⁹ IVH may contribute to poor outcome by blocking cerebrospinal fluid (CSF) pathways, with resultant hydrocephalus and increased ICP. In addition, intraventricular blood and/or its breakdown products may exert direct chemical irritative effects on periventricular structures. Hydrocephalus may develop after ICH either in association with IVH or because of direct mass effect on a ventricle (e.g., on the third ventricle with a thalamic hemorrhage) (Figure 35-3). External ventricular drainage (ventriculostomy) is frequently used to treat hydrocephalus and IVH, but its efficacy has never been established. Ventriculostomy in the setting of IVH is difficult to manage because the catheter frequently becomes obstructed with thrombus, interrupting drainage and raising ICP. Flushing the system helps remove thrombus from the catheter but increases the risk of ventriculitis. Recently, investigators have attempted to facilitate removal of blood from the ventricles via direct intraventricular administration of thrombolytic agents. Preliminary studies have been promising,¹⁰⁰ and a multicenter randomized trial is currently underway.

Figure 35-3 Example of a small thalamic hemorrhage with blood obstructing the foramen of Monro, causing hydrocephalus.

Intracranial Hypertension

The incidence, impact, and appropriate management of intracranial hypertension in ICH are not well understood. Factors likely to contribute to elevated ICP in this population include large hematoma size, minimal degree of underlying cerebral atrophy, hydrocephalus, and edema, but the true incidence of intracranial hypertension is unclear, since routine ICP monitoring is not performed. Because the hematoma is localized and the increase in volume it produces can be compensated for to some degree by reduction in the size of the ventricles and subarachnoid space, a global increase in ICP may not be seen unless the hemorrhage is very large or is associated with marked hydrocephalus. However, mass effect from the hematoma and local tissue shifts can compress the brainstem or result in herniation in the absence of a global increase in ICP.^101,¹⁰² Thus the utility of ICP monitoring has never been established.

Invasive ICP monitoring devices with implantable transducers can be placed in extradural, subdural, intraparenchymal, and intraventricular locations, but external ventricular drains (EVD) have the added capacity to remove CSF and thus lower ICP. The appropriate time to use an EVD is uncertain; however, patients who have progressive deterioration in level of consciousness and enlarging ventricles on serial imaging are most likely to benefit. Those with very large parenchymal hematomas are least likely to benefit, and overdrainage of the contralateral ventricle could worsen tissue shifts and lead to deterioration.

Elevated ICP is often treated with osmotic agents (mannitol, hypertonic saline) and, if the ventricles are enlarged, CSF drainage. A recent case series suggested that rapid reversal of clinical transtentorial herniation (decreased level of consciousness and dilated pupil) with hyperventilation and osmotic agents improved long-term outcome.¹⁰³ There are only a few small clinical trials of osmotic agents in ICH, which do not provide sufficient data to support their routine use.¹⁰⁴ The best available data on corticosteroids in ICH indicate that they do not provide any benefit and increase the rate of complications.¹⁰⁵

Surgical Evacuation

The rationale for surgical evacuation of a hematoma is that reducing mass effect and removing neurotoxic clot constituents should minimize injury to adjacent brain tissue and hence improve outcome. Unfortunately, several randomized controlled trials of surgery for supratentorial ICH dating back to 1961 have all failed to show a benefit of the intervention.¹⁰⁶^–¹⁰⁹ A meta-analysis of three of these trials reported that patients undergoing surgical evacuation via open craniotomy had a higher rate of death or dependency at 6 months compared to those managed medically (83% versus 70%).¹¹⁰ Criticisms of these trials are that the surgical techniques used were outdated, patient selection was inadequate, and surgery was delayed too long.

Because open craniotomy is complicated by tissue damage sustained during the approach to the hematoma, a variety of new techniques for clot removal have been proposed, including an Archimedes screw, ultrasonic aspirator, modified endoscope, modified nucleotome, double track aspirator, intraoperative CT monitoring, and instillation of thrombolytics. However, the recurrence of bleeding due to the loss of tamponade effect on adjacent tissue that occurs in 10% of patients treated with open craniotomy remains an issue with the newer techniques. In addition, because the newer techniques involve limited surgical exposure, concern exists that rebleeding will be more difficult to control than with open craniotomy. One study comparing endoscopic aspiration to medical management found a better outcome in the surgical group (74% death or disability compared to 90%), but the benefit was limited to patients with lobar hematomas.¹¹¹ Three studies addressed the feasibility of early craniotomy for ICH. In one,¹¹² 34 patients were treated within 12 hours of ICH. Mortality was 18% in the surgical group and 23% in the medical group. In another study,¹¹³ 20 patients were randomized, with a median time to surgery of 8.5 hours from onset. Good outcome (Glasgow Outcome Scale score > 3) was 56% with surgery and 36% in the medically treated group (P = NS). The third, a study of ultra-early surgery (<4 hours), found a disturbingly high rate of postoperative rebleeding.¹¹⁴

A lack of benefit of surgery in ICH was also shown in a recently completed multicenter trial in which 1033 patients were randomized within 72 hours of ICH onset to surgical hematoma evacuation (open craniotomy or stereotactic aspiration, at surgeon’s discretion) or initial conservative management. Favorable outcome occurred in 26.1% in the surgery group and 23.8% in the initial conservative treatment group, a nonsignificant difference (odds ratio 0.89; 95% CI 0.66-1.19). There was also no difference in mortality (surgery 62.6% versus conservative treatment 63.7%). Subgroup analysis suggested a possible benefit of surgery in patients with superficial hematomas (less than 1 cm from cortical surface).¹¹⁵ A trial comparing surgical and medical management of superficial hematomas is currently underway.

Cerebellar hemorrhages were excluded from the randomized trials of surgery, but nonrandomized case series report good outcomes for surgically treated patients with cerebellar hemorrhages that are large or associated with brainstem compression or obstruction of the fourth ventricle. Recommended criteria for when to evacuate a cerebellar hematoma have thus included diminished level of consciousness, large size of the hematoma (>3 cm³), midline location, compression of basal cisterns and/or brainstem, and presence of hydrocephalus (Figure 35-4).¹¹⁶^–¹¹⁸ Patient selection is important as many patients with smaller hemorrhages do well with medical management.¹¹⁹

Figure 35-4 Typical cerebellar hemorrhage with effacement of basal cisterns and early hydrocephalus manifest by enlargement of temporal horns of lateral ventricles.

Management of Thrombolytic-Induced Ich

Associated with considerable morbidity and mortality, symptomatic ICH is a feared complication of thrombolytic therapy. Symptomatic ICH occurs after thrombolytic treatment of acute ischemic stroke in approximately 6% of patients.¹²⁰ It is substantially less common after thrombolytic treatment of extracerebral thrombosis (myocardial infarction, pulmonary embolism, deep venous thrombosis, and arterial and graft occlusion)¹²¹ but results in a similarly poor outcome.¹²² Factors that increase the risk of symptomatic ICH include intraarterial versus IV route of administration, early ischemic changes on pretreatment CT, greater symptom severity, and elevated serum glucose or history of diabetes mellitus.^123,¹²⁴

In the setting of thrombolytic therapy, any new neurologic deficit, especially with a decline in consciousness, should be assumed to be due to hemorrhage. Management of a suspected ICH should begin with stopping the thrombolytic infusion, reassessing the patient’s airway, and obtaining an emergent CT scan. Blood studies (prothrombin time, partial thromboplastin time, thrombin, and fibrinogen levels) should be performed to assess fibrinolytic state. Preparations for giving FFP, cryoprecipitate, and platelets should be initiated at the first suspicion of hemorrhage so that they will be ready if needed; however, no reliable data are available to guide the choice of blood product. The NINDS rt-PA study ¹²⁵ stipulated 6 to 8 units of cryoprecipitate or FFP and 6 to 8 units of platelets, but only rarely was this amount of blood product given to an individual patient during the study. Although neurosurgical consultation was frequently obtained in patients with symptomatic ICH in the NINDS trial, only one patient in the study underwent surgery, and that patient died.

Management of Seizures

Although seizures may theoretically exacerbate ICH, they have not been demonstrated to alter outcome. Prophylactic anticonvulsants may reduce the risk of early seizures in patients with lobar ICH but do not affect the risk of developing epilepsy.¹²⁶ Thus reasonable approaches include either a brief period of prophylaxis or treating only if seizures occur. As for any hospitalized patient, the treatment of clinical seizures typically begins with an IV benzodiazepine such as lorazepam followed by an IV agent such as fosphenytoin.

Supportive Care

Patients with ICH are prone to the same medical complications seen in patients with ischemic stroke, including fever, deep venous thrombosis (DVT), pulmonary embolism, and pneumonia.^127,¹²⁸ Given the association between fever and worsened outcome in experimental models of brain injury, it is reasonable for antipyretic medications to be administered in febrile patients with ICH. The use of pneumatic sequential compression devices and elastic stockings has been shown to significantly decrease the incidence of DVT in patients with acute ICH relative to elastic stockings alone.¹²⁹ Subcutaneous heparin at a dose of 5000 U three times daily when initiated on day 2 after hemorrhage has been shown to significantly reduce the frequency of DVT relative to treatment begun on day 4 or 10, with no concomitant increase in hematoma expansion.¹³⁰ In another study, subcutaneous enoxaparin (40 mg daily) initiated at 48 hours after ICH was also safe. A benefit of enoxaparin over compression stockings could not been detected because of the low incidence of DVT in both treatment groups.¹³¹

Early mobilization and rehabilitation are generally recommended for clinically stable patients with ICH.

Prognostic Factors and Causes Of Mortality

Mortality following ICH is high (25%-50%), with over half of the deaths occurring in the first 48 hours. Although patients who have small hemorrhages and mild deficits may recover completely, the majority of ICH survivors have significant residual disability.^4,^132,¹³³ A variety of clinical, laboratory, and radiographic predictors of poor outcome have been identified, the most consistent being impaired level of consciousness and large hematoma size on admission. Other predictive clinical features variably include increasing age, elevated admission blood pressure on admission, rapid decline in blood pressure over the first 24 hours, history of diabetes, antecedent OAC use, male gender, and in-hospital neurologic deterioration. Laboratory parameters identified in at least one study include hyperglycemia, elevated troponin level, elevated plasma S100B level, elevated plasma D-dimer level, elevated INR, low serum cholesterol and triglyceride levels, and apolipoprotein E ε2 or ε4 allele. Radiographic features include infratentorial hematoma location, intraventricular spread of blood, midline shift, hydrocephalus, hematoma growth, and presence of the spot sign on CT angiography. A number of prognostic models of varying complexity have been developed to allow risk stratification upon presentation with ICH. One easy to use model is the ICH score,¹³⁴ which is based on point assignments for Glasgow Coma Scale score, ICH volume, presence of intraventricular hemorrhage, infratentorial location, and patient age and has been validated to accurately predict 30-day mortality. It has been demonstrated, however, that withdrawal of support in patients felt likely to have a poor outcome biases predictive models in ICH and negates the predictive value of all other variables.¹³⁵ Thus, the most frequent cause of death after ICH is withdrawal of care, followed by early (within 48 hours) transtentorial herniation with progression to brain death. Medical complications of immobility (pulmonary embolism, pneumonia, sepsis) account for most of the other deaths.¹³³ For survivors of ICH, the risk of recurrent stroke is approximately 4% per year. Recurrent ICH occurs about twice as often as ischemic stroke, especially in those with previous lobar hemorrhage.¹³⁶

Subarachnoid Hemorrhage

Although it is the least common form of stroke, subarachnoid hemorrhage (SAH) has great impact on its sufferers. One-quarter of patients die before reaching medical attention,¹³⁷ and because of the consequences of secondary insults—rebleeding, hydrocephalus, and delayed ischemia due to vasospasm—more than half of those that reach medical attention either die or are left with neurologic deficits.

Pathophysiology

In SAH, the primary site of bleeding is within the subarachnoid space, but may also involve hemorrhage into the brain parenchyma, ventricular system, or subdural space. Rupture of an intracranial saccular aneurysm (Figure 35-5) is by far the most common cause of spontaneous SAH. Saccular or berry aneurysms are small, rounded protrusions of the arterial wall occurring predominantly at bifurcations of the large arteries of the circle of Willis at the base of the brain. The most common sites of ruptured aneurysms are the distal internal carotid artery and its posterior communicating artery junction (41%); anterior communicating artery/anterior cerebral artery (34%); middle cerebral artery (20%); and vertebrobasilar arteries (4%).¹³⁸ About 20% of patients have multiple aneurysms.

Figure 35-5 Autopsy specimen of intracranial aneurysm filled with pressurized blood to simulate subarachnoid hemorrhage.

The pathogenesis of aneurysms remains controversial, especially in regard to the relative important of developmental versus acquired factors. Proponents of the congenital theory suggest that aneurysms arise at sites of faulty fusion between muscular segments within the arterial wall. Supporters of the acquired-degenerative theory focus on the role of vascular damage caused by hemodynamic stress.¹³⁹ The third possibility is that aneurysms develop at sites harboring congenital defects with superimposed degenerative changes.

What leads to aneurysmal growth and rupture is also debated. Hemodynamic stress and other factors intrinsic to the involved vessels may play a role. The time course over which aneurysms grow and subsequently rupture is unknown, although some aneurysms appear to grow rapidly over weeks, whereas others grow slowly over years.

Most aneurysms rupture at the dome, where the wall may be as thin as 0.3 mm. Tension on the aneurysm wall is determined by the radius of the aneurysm and the pressure gradient across the wall (law of La Place). The probability of rupture is related to size; aneurysms less than 5 millimeters in diameter have a very low rate of rupture. Aneurysm rupture causes local tissue damage due to the jet of blood under high pressure, as well as a transient increase in ICP.

Causes and Risk Factors

Genetic conditions that predispose to aneurysm formation include polycystic kidney disease, connective tissue disorders, and coarctation of the aorta. Recently it has become clear that in some patient populations, genetic factors play a role in aneurysm formation, without other associated conditions.¹⁴⁰ There is a familial form as well.¹⁴¹ Other types of aneurysms that less commonly cause SAH include atherosclerotic, mycotic, and traumatic aneurysms.

Trauma is the most common cause of non-aneurysmal SAH. Arteriovenous malformations, cocaine and stimulant abuse, neoplasia, and vasculitis account for the bulk of the remainder. Bleeding into the subarachnoid space may accompany ICH, particularly in the setting of CAA. In 10% to 15% of cases of SAH, no source of bleeding is identified.

The risk of SAH increases with age, peaking at 55 to 60 years. There is a slight male predominance in younger age groups and a slight female predominance among older patients.¹⁴² Potentially reversible risk factors for SAH include cigarette smoking, oral contraceptive use, alcohol abuse, and hypertension.¹⁴³ Prospective cohort studies have reported a relative risk of SAH as high as 5.7 for female and 4.7 for male smokers,¹⁴⁴ but no increased risk in former smokers. Oral contraceptive use, in addition to being an independent risk factor for SAH, dramatically increases the risk among smokers.¹⁴⁵ A dose-response relationship exists between alcohol consumption and incidence of SAH.

Clinical Features

Presentation

The most common initial symptom of SAH, occurring in over 90% of patients, is a sudden severe headache. Less severe warning (“sentinel”) headaches ¹⁴⁶ may precede the presenting event in as many as half and are thought to represent minor leaks. In about half of patients, loss of consciousness accompanies the headache.¹⁴⁷ The mechanisms thought to be responsible for the loss of consciousness are the sudden surge in ICP at the moment of hemorrhage or cardiac arrhythmias. Vomiting can be a prominent symptom. Seizure activity may be reported,¹⁴⁸ but it is unclear whether this represents true epileptic seizures or reflex posturing related to the sudden rise in ICP. Focal deficits at the onset of hemorrhage occur in less than 10% of cases. After a few hours, a stiff neck can develop, reflecting the sterile meningeal inflammation induced by the presence of blood in the subarachnoid space.

Complications

A worsening of neurologic status often indicates one of the three major complications of SAH: rebleeding, hydrocephalus, or vasospasm. An understanding of the timing and nature of the deterioration facilitates rapid diagnosis and treatment. It must be emphasized that systemic perturbations such as infection, hyponatremia, fever, hypoxia, and hypotension may produce similar symptoms and should be sought and corrected as part of the evaluation process.

Early Complications

Rebleeding

Rebleeding is heralded by a sudden worsening of headache, vomiting, blood pressure elevation, development of a new neurologic deficit, or arrhythmia. It occurs in up to one-third of patients and is often fatal. The risk of rebleeding is greatest during the first 24 hours, declining rapidly over the next 2 weeks.¹⁴⁹ Rates of rebleeding are highest in women, those who are a poor clinical grade, those in poor medical condition, and those with elevated systolic blood pressure.

Hydrocephalus

Hydrocephalus occurs after SAH because of disturbances of CSF flow or reabsorption: subarachnoid blood may impair CSF reabsorption at the arachnoid granulations, and ventricular blood may obstruct its flow. Acute hydrocephalus can develops within hours of SAH,¹⁵⁰ often in the absence of intraventricular blood. It usually manifests as a gradual decline in level of consciousness and can easily be treated by placement of an external ventricular drain. Delayed hydrocephalus may also develop gradually days to weeks later. Hydrocephalus must be distinguished from metabolic derangements, infection, and vasospasm. CT scan is essential in making the diagnosis. The natural history of untreated acute hydrocephalus is that about one third of patients progress, one-third spontaneously improve, and one third remain static.¹⁵¹

Delayed Complications

Vasospasm

The term vasospasm refers to complex changes in intracerebral vessels, with segmental or diffuse narrowing of the lumen due to arterial wall thickening, vasoconstriction, and impaired relaxation that reduce CBF. If the reduction in flow is severe enough, ischemia and infarction follow. The term delayed cerebral ischemia (DCI) describes the clinical situation where these and other factors conspire to produce ischemia. Other factors that may contribute to DCI include impaired autoregulation, hypovolemia, and microthrombosis.¹⁵² DCI is a leading cause of morbidity and mortality following SAH.

Arterial narrowing can be detected angiographically (Figure 35-6) in up to 70% of patients,¹⁵³ of whom almost half become symptomatic. The pathogenesis of arterial vasospasm is complex and not fully understood, but sustained exposure of vessels to extraluminal blood constituents and catecholamines is thought to play a role. It involves structural changes in the vessel walls and in adrenergic nerve fibers. The onset of vasospasm is delayed, most commonly developing 5 to 10 days after initial hemorrhage, and may persist for up to 3 weeks. The strongest predictor of vasospasm is the amount of subarachnoid blood on the initial CT scan, with the greatest risk occurring in those having thick subarachnoid clots and intraventricular blood (graded using Fisher Scale and modified Fisher Scale; Table 35-1).^154,¹⁵⁵ Focal neurologic deficits resulting from vasospasm may appear abruptly or gradually and may fluctuate, exacerbated by hypovolemia or hypotension. If untreated, infarction may occur.

Figure 35-6 Baseline angiogram obtained shortly after subarachnoid hemorrhage (left) and repeat angiogram obtained 7 days later (right) showing severe vasospasm of basilar artery, with reduced distal flow.

TABLE 35-1 Fisher Grade of Subarachnoid Hemorrhage on Initial Computed Tomography

1 No blood detected

2 Diffuse or vertical layers <1 mm thick

3 Localized subarachnoid clot and/or vertical layers ≥1 mm thick

4 Intraparenchymal or intraventricular clot with diffuse or no SAH

Modified Fisher CT Rating Scale

1 Minimal or diffuse thin SAH without IVH

2 Minimal or thin SAH with IVH

3 Thick cisternal clot without IVH

4 Thick cisternal clot with IVH

CT, computed tomography; IVH, intraventricular hemorrhage; SAH, subarachnoid hemorrhage.

Medical Complications

Blood pressure is often elevated after SAH and is associated with a greater risk of rebleeding and vasospasm as well as higher mortality. Multiple factors may underlie the rise in blood pressure, including increased sympathetic outflow, agitation, and pain. Early on, blood pressure management focuses on preventing re-rupture of the aneurysm. Following repair of the aneurysm, the risk of rebleeding is virtually eliminated, and spontaneous elevations in blood pressure should be allowed to occur without intervention, since now the risk of vasospasm is the primary concern.

Disturbances in sodium and water balance occur in approximately one-third of patients, and hyponatremia and volume depletion after SAH are correlated with an increased risk of symptomatic vasospasm and poor outcome.¹⁵⁶ Although hyponatremia was previously attributed to inappropriate secretion of antidiuretic hormone (SIADH) and was therefore treated with fluid restriction, later evidence suggested that both sodium and water are lost. In fact, when administered normal “maintenance” volumes of fluid (2-3 L/day), as many as half of patients develop intravascular volume contraction.¹⁵⁷

Cardiac abnormalities are common in the first 48 hours after SAH. Electrocardiographic (ECG) changes (Figure 35-7) including tall peaked T waves (“cerebral T waves”), diffuse T-wave inversion, ST-segment depression, and prolonged QT segments¹⁵⁸ occur frequently and have been linked to elevated levels of circulating catecholamines. It appears that these changes usually do not represent myocardial ischemia, as the myocardial lesions reported are pathologically distinct from ischemia. Cardiac enzymes may be mildly elevated.¹⁵⁹ Cardiac rhythm disturbances occur in about 30% to 40% of patients, especially on the day of hemorrhage or in the postoperative period. Arrhythmias are typically benign but can be life threatening in about 5%.^160,¹⁶¹ In rare cases, “stunned myocardium” may occur, with impairment of myocardial contractility leading to a fall in cardiac output, hypotension, and pulmonary edema.¹⁶² This phenomenon can be dramatic but is transient, usually lasting 2 to 3 days, after which cardiac function returns to baseline.¹⁶³ Management is the same as with other causes of cardiogenic shock.¹⁶⁴ During hemodynamic treatment for vasospasm, pulmonary edema may occur in up to one-quarter of patients,¹⁶⁵ though its incidence is lower with careful monitoring.¹⁶⁶

Figure 35-7 Electrocardiogram in a patient with acute subarachnoid hemorrhage, demonstrating diffuse T-wave inversions.

In a review of over 450 patients with SAH, Solenski et al.¹⁶⁷ reported some degree of hepatic dysfunction in 24%. The majority had only mild abnormalities of hepatic enzymes without clinical accompaniment, but severe hepatic dysfunction occurred in 4%. Thrombocytopenia was found in 4% of patients, usually occurring in the setting of systemic sepsis. Renal dysfunction occurred in 7% of patients.

Fever, anemia, hyperglycemia, pneumonia, and hypertension occur frequently after SAH. Potential treatments include maintaining normothermia with antipyretics and possibly systemic cooling devices, administration of erythropoietin to prevent anemia, and preserving normoglycemia.¹⁶⁸

Diagnostic Studies

CT is the imaging modality of choice in screening for SAH, having a sensitivity of better than 90%.¹⁶⁹ Blood appears as high attenuation within the perimesencephalic and interpeduncular cisterns surrounding the brainstem (the basal cisterns), Sylvian fissure, and sulci (Figure 35-8).

Figure 35-8 Computed tomography scan of acute subarachnoid hemorrhage, with a thick layer of hyperdense blood filling basal cisterns.

CT may fail to demonstrate SAH if the volume of blood is very small, if the hemorrhage occurred several days prior to the CT scan, or if the hematocrit is extremely low.¹⁷⁰ Lumbar puncture for CSF analysis is indicated if CT is negative and clinical suspicion is high. Red blood cells in the CSF are indicative of SAH but can also be seen with traumatic puncture. The common technique of comparing cell counts in the first and last tubes collected is not reliable; however, the presence of yellow pigment (xanthochromia), resulting from red cell breakdown, can be helpful in distinguishing between the two.¹⁷¹ Xanthochromia develops 2 to 6 hours after hemorrhage and persists for 1 to 4 weeks. It can also be seen in the setting of high protein levels due to diabetes, renal failure or infection, in which case spectrophotometric analysis to identify hemoglobin breakdown products improves diagnostic accuracy.¹⁷²

Once SAH has been diagnosed, cerebral angiography should be performed as soon as possible to identify the responsible vascular lesion, search for other lesions (multiple aneurysms are found in 20% to 30% of patients with aneurysmal SAH), and assist in operative management. Angiography does not identify a source of bleeding in 10% to 15% of patients with nontraumatic SAH. In some cases, this may be due to vasospasm or inadequate views to detect a subtle aneurysm, especially in the region of the anterior communicating artery or in the posterior circulation. Repeat angiography in about one week is recommended.¹⁷³ There is a subset of patients in whom the blood on CT is localized to the perimesencephalic cisterns. In these cases, angiography is usually negative, and the bleeding is thought to be venous in origin; the prognosis is excellent, and repeat angiography is almost always negative.¹⁷⁴

With its wide availability, ease of use, and safety profile, CT angiography is increasingly being used as the initial diagnostic tool in the investigation of SAH. Overall sensitivity is 90% or greater compared to conventional angiography but is notably lower for aneurysms smaller than 5 mm ¹⁷⁵; thus, a negative CT angiogram should be followed by conventional catheter angiography. A negative CT angiogram alone may be sufficient in the case of perimesencephalic SAH.¹⁷⁴ Magnetic resonance angiography (MRA) has good sensitivity for detecting medium and large aneurysms, but sensitivity falls to less than 40% for small aneurysms. In addition, MRA is impractical for many acutely ill patients with SAH because of logistics, movement artifact, need for sedation, and difficulty in monitoring clinical status in the scanner.

MRA and CT angiography may also be of assistance in planning surgical or endovascular approaches to aneurysm treatment.

Treatment

Initial Stabilization

The initial steps in the evaluation of a patient with suspected SAH should include assessment of airway, hemodynamic status, and the level of neurologic function. The Hunt and Hess Scale ¹⁷⁶ and the World Federation of Neurological Surgeons Scale¹⁷⁷ provide standardized measures of the patient’s clinical condition (Tables 35-2 and 35-3).

TABLE 35-2 Hunt & Hess Clinical Classification of Subarachnoid Hemorrhage

I Asymptomatic or mild headache and neck stiffness

II Moderate to severe headache and neck stiffness ± cranial nerve palsy

III Mild focal deficit, lethargy, or confusion

IV Stupor, moderate to severe hemiparesis

V Deep coma, extensor posturing

TABLE 35-3 World Federation of Neurologic Surgeons Clinical Classification of Subarachnoid Hemorrhage

Grade	Glasgow Coma Scale	Motor Deficits
I	15	Absent
II	13-14	Absent
III	13-14	Present
IV	7-12	Present or absent
V	3-6	Present or absent

As in ICH, some patients with SAH may be unable to protect their airway because of diminished consciousness. If the patient is lethargic or agitated, elective intubation should be considered prior to angiography. This is because sedation is often necessary for angiography and may result in unrecognized hypoventilation or airway obstruction.

Routine Care and Monitoring

The routine monitoring of all patients with acute SAH should include serial neurologic examinations, continuous ECG monitoring, and frequent determinations of blood pressure, electrolytes, body weight, and fluid balance. The role of prophylactic anticonvulsants in patients who have not had a seizure is controversial. Initial use of anticonvulsants is generally recommended; however, the duration of administration should be limited to several days during the periprocedural period.¹⁷⁸ Recent retrospective studies have suggested that routine use of anticonvulsants for a longer duration is associated with worse neurologic outcome.¹⁷⁹ Dexamethasone is widely used to reduce meningeal irritation and intra- and postoperative edema, but there is no convincing evidence documenting its efficacy.

Fluid Management

A stable intravascular volume should be maintained by hydration with isotonic saline and daily monitoring of fluid balance, body weight, and hematocrit. Monitoring of fluid balance alone may not be adequate to prevent hypovolemia, and combining multiple clinical indicators of volume status are needed.^180,¹⁸¹ In some patients with severe cerebral salt wasting, large volumes of fluid are required to prevent intravascular volume contraction.¹⁸² Hyponatremia can often be managed with restriction of free water by administering only isotonic IV fluids, minimizing oral liquids, and using concentrated enteral feedings. It is important to adjust the tonicity of the fluid, not the volume of fluids administered. Fludrocortisone is of marginal benefit in treating salt wasting^183,¹⁸⁴; however, one study suggested that hydrocortisone may be helpful.¹⁸⁵ Persistent hyponatremia can be treated by using mildly hypertonic solutions (1.25%-2% saline) as the sole IV fluid. There may be a role for ADH antagonists such as conivaptan, but since they increase urine volume, extreme caution must be exercised to avoid hypovolemia.¹⁸⁶

Management of Secondary Complications

Rebleeding

Multiple clinical trials have demonstrated that antifibrinolytic agents such as epsilon aminocaproic acid and tranexamic acid reduce the risk of rebleeding, but this benefit is offset by an increased incidence of vasospasm and hydrocephalus.^197,¹⁹⁸ With the advent of early surgery and now endovascular treatment of aneurysms, the use of these agents has declined dramatically. More recently, there has been interest in a shorter course of antifibrinolytic therapy while awaiting surgery or endovascular treatment. Tranexamic acid begun immediately upon SAH diagnosis and continued only until the aneurysm was secured (always within 72 hours) reduced the risk of rebleeding from 10.8% to 2.4% and did not increase risk of DCI.¹⁹⁹

Other measures directed at prevention of rebleeding include avoiding situations that produce sudden changes in the transmural pressure across the wall of the aneurysm (i.e., sudden increases in arterial or venous pressure or decreases in ICP). Patients are placed on bed rest with minimal stimulation. In the agitated patient, sedation is indicated, though care must be taken to preserve the ability to assess the patient’s responsiveness to stimulation. Opiates are a good choice for sedation, since they also provide analgesia for treating headache. Because of the risk of impairing the ability to evaluate for clinical deterioration, long-acting sedative agents such as phenobarbital should be avoided. Measures should be taken to minimize cough and Valsalva maneuvers. In intubated patients, frequent coughing should be suppressed prior to aneurysm repair. Stool softeners are administered to avoid straining. If lumbar puncture or ventriculostomy is performed, rapid drainage of a large volume of CSF should be avoided so as not to induce sudden changes in the transmural pressure and rebleeding.

The definitive way to prevent rebleeding is to repair the aneurysm by surgical or endovascular means. Endovascular techniques involving electrolytically detachable platinum coils that thrombose the aneurysm are now routinely used to repair acutely ruptured aneurysms (Figure 35-9).

Figure 35-9 Angiogram demonstrating middle cerebral artery aneurysm before (A) and after placement of detachable coils to thrombose the aneurysm (B).

The International Subarachnoid Aneurysm Trial was a multinational, prospective, randomized trial that compared surgical clipping with endovascular coiling of acutely ruptured intracranial aneurysms. Participating centers were required to treat at least 60 SAH patients per year and offer both treatment modalities. Patients were eligible to be enrolled only if there was clinical equipoise regarding the best method to repair the aneurysm. Initial results favored endovascular coiling, with 23.7% dead or dependent at 1 year compared to 30.6% in the surgery group.²⁰⁰ Long-term follow-up indicated an increased risk of recurrent bleeding from a coiled aneurysm compared with a clipped aneurysm. At 5 years, the risk of death remained significantly lower in the coiled group than in the clipped group, but the proportion of survivors who were independent did not differ between the two groups.²⁰¹

Hydrocephalus

The decision to treat hydrocephalus is usually based on the CT appearance of enlarging ventricles in a patient whose level of consciousness is deteriorating. During placement of an external ventricular drain, the CSF pressure must be reduced slowly to lessen risk of aneurysmal re-rupture. CSF drainage may be needed for many days to clear intraventricular blood before it can be determined if a permanent shunt is required.

Vasospasm

Monitoring for vasospasm involves serial neurologic exams, serial transcranial Doppler (TCD) measurement of blood flow velocities,^202,²⁰³ and catheter angiography. Neurologic signs may be vague, such as a global decline in responsiveness, or consist of focal deficits such as hemiparesis or language disturbance. Symptoms may wax and wane, being exacerbated by hypovolemia or hypotension. Vasospasm can be identified on TCD by an increase in linear blood flow velocity (LBFV): mild (>120 cm/sec), moderate (>160 cm/sec), or severe (>200 cm/sec) vasospasm.²⁰⁴ Alternatively, the rate of rise in the LBFV is used to define the onset of vasospasm. The sensitivity of TCD in detecting vasospasm is about 80% when compared to angiography, at least partly because TCD samples only a small segment of the vasculature.²⁰⁵ It has a very high negative predictive value, and the presence of normal velocities usually indicates the absence of vasospasm. Newer CT and MRI techniques including angiography and perfusion may have a role in assessing for delayed ischemia in the future.

When making a clinical diagnosis of vasospasm, alternative causes of neurologic changes such as sedatives, rebleeding, hydrocephalus, cerebral edema, metabolic derangements and infections should be promptly excluded using radiographic, clinical and laboratory assessments. Detection of clinical signs of vasospasm is particularly difficult in poor grade patients because of the limited exam that is possible.

Prevention

Routine measures taken to prevent or ameliorate the effects of vasospasm include mechanical removal of subarachnoid blood at the time of aneurysm surgery or by CSF drainage, administration of the centrally acting calcium channel antagonist nimodipine, and avoidance of intravascular volume contraction (see earlier) and hypotension. Nimodipine (60 mg orally every 4 hours) for 3 weeks after SAH reduces the impact of symptomatic vasospasm and improves outcome.^206,²⁰⁷ It is not clear whether this beneficial effect is due to action on the cerebral vessels or to prevention of calcium influx into ischemic neurons. Any hypotension developing with nimodipine administration can usually be managed with fluids or adjusting the dosage schedule to 30 mg every 2 hours. In patients receiving hemodynamic augmentation for symptomatic vasospasm, nimodipine may have to be discontinued if it interferes with maintenance of blood pressure goals.

While there is general agreement that hypovolemia must be avoided, the use of prophylactic hypervolemia is more controversial.²⁰⁸^–²¹⁰ In a prospective controlled study, prophylactic volume expansion with albumin failed to reduce the incidence of clinical or TCD-defined vasospasm, did not improve CBF, and had no effect on outcome.²¹¹ Costs and complications may be higher with the use of prophylactic hypervolemia.

Prophylactic use of transluminal balloon angioplasty has recently been evaluated.²¹² Although it reduced the need for therapeutic angioplasty and reduced ischemic deficits, these benefits were offset by procedure-related vessel complications.

Treatment of Delayed Ischemic Deficits

The trigger for instituting more aggressive interventions varies widely. Some centers actively intervene in the setting of rising TCD velocities ²¹³ or angiographic vasospasm in asymptomatic patients,²¹⁴ whereas others institute aggressive measures in the setting of clinical deterioration. Aggressive measures include both hemodynamic and endovascular manipulations.²¹⁵^–²¹⁷ The goal is to improve CBF in ischemic regions. Since patients with SAH tend to become hypovolemic and lose pressure autoregulation,²¹⁸ it has been inferred that hypervolemia, induced hypertension, and augmentation of cardiac output would accomplish that goal.

Hemodynamic Augmentation

Hemodynamic manipulations aiming to improve cerebral perfusion include hypervolemia, hypertension, and hemodilution, or “triple-H therapy.” Because of the risk of rebleeding with hemodynamic augmentation, triple-H therapy is reserved for patients who have had repair of the ruptured aneurysm. The presence of other small untreated aneurysms does not exclude use of this therapy. Support for the benefit of hemodynamic augmentation is based on case series. The relative contribution of each component is debated.

Data supporting the use of hypervolemia are scant. As described earlier, prophylactic hypervolemia had no impact on CBF, vasospasm, or outcome.²¹¹ In one study of patients with symptomatic vasospasm, hypervolemia was reported to improve CBF, but a proper control group was not used.²¹⁹ Other studies question whether hypervolemia adds further benefit beyond correction of hypovolemia and report that the impact of volume expansion on CBF is modest compared to induced hypertension.²²⁰

Hemodilution is perhaps the least understood component of triple-H therapy. The rationale is to augment CBF by reducing blood viscosity. The tradeoff is that oxygen-carrying capacity is reduced, reducing oxygen delivery. It has been suggested that a hematocrit of 30% provides the optimal balance between oxygen-carrying capacity and viscosity; however, one study found that despite a rise in CBF, oxygen delivery fell with hemodilution.²²¹

Blood pressure augmentation may be the most effective hemodynamic intervention. Studies have demonstrated a consistent rise in CBF in response to blood pressure elevation with dopamine and phenylephrine, although the optimal target has not yet been identified.²²⁰ Under normal conditions, cardiac output does not influence CBF; however, with cerebral ischemia or impaired autoregulation, changes in cardiac output may alter CBF. Dobutamine or milrinone may be effective in improving cardiac output and CBF in some patients.

The initial step is to rapidly correct any possible hypovolemia with isotonic crystalloid or colloid fluids. If there is no immediate response to fluid administration, vasoactive agents are instituted—vasopressors (phenylephrine, norepinephrine) or, alternatively, inotropes (dobutamine, milrinone).

Recently there has been a decline in the use of Swan-Ganz catheters to manage hemodynamic augmentation. The arbitrary pulmonary capillary wedge pressure goals used in the past have largely been abandoned. If alternative means of monitoring cardiac output are available, fluid administration should be adjusted to optimize cardiac output. Goals for blood pressure should be defined as a percent change from baseline (beginning with an approximately 15% change) rather than prespecified levels. While defining such goals is useful to guide therapy, the degree of hemodynamic augmentation should be titrated continuously to the patient’s neurologic status; thus, if a goal is reached but there is no neurologic improvement, the goal should be modified. Once the optimal goals have been reached, they are usually maintained for 2 to 3 days. Hemodynamic augmentation is then weaned gradually over several days, guided by neurologic status. If neurologic deterioration occurs during weaning of therapy, the blood pressure goals should be returned to higher levels, and attempts to wean therapy should be delayed for 1 or 2 days.

Endovascular Treatments

The endovascular approach to vasospasm involves treatment of constricted vessels with either balloon angioplasty or intraarterial infusion of vasodilating agents.^180,²²² Angioplasty on the proximal segments of vasospastic cerebral vessels yields impressive angiographic changes (Figure 35-10) that appear to be long lasting.^223,²²⁴ Vasoconstriction in more distal vessels usually cannot be reached by angioplasty catheters and can be treated with intraarterial infusion of vasodilators.

Figure 35-10 Example of severe distal internal carotid and proximal middle cerebral artery vasospasm (arrows) before (A) and after (B) angioplasty.

Intraarterial papaverine has an immediate and dramatic effect on blood vessels, but reversal of clinical deficits is inconsistent.²²⁵^–²²⁷ The use of papaverine has largely been abandoned because of its short-lived effect and complications including increased ICP, apnea, worsening of vasospasm, neurologic deterioration and seizures.²²⁸ It has been replaced by nicardipine, verapamil, nimodipine, and milrinone.²²⁹^–²³¹

The timing of when to initiate endovascular therapy is debated. It is generally used if after a few hours, the response to hemodynamic augmentation is inadequate, but it may be the initial therapy in patients with poor cardiac function who are at high risk of complications of hemodynamic augmentation.²³²