Cerebral Vasospasm

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CHAPTER 364 Cerebral Vasospasm

Cerebral vasospasm is a prolonged, sometimes severe, but ultimately reversible narrowing of the cerebral arteries that begins days after subarachnoid hemorrhage (SAH). The risk for vasospasm depends mainly on the thickness of blood clots in the subarachnoid space and ventricles. Bleeding significant enough to cause vasospasm is usually due to rupture of a saccular aneurysm, but vasospasm can complicate traumatic SAH and, rarely, vascular malformations or brain tumors that bleed heavily into the subarachnoid space at the base of the brain.

Angiographic vasospasm is arterial narrowing seen on vascular imaging; it begins several days after SAH and peaks in severity about 1 week later. Clinical or symptomatic vasospasm is narrowing causing cerebral ischemia with corresponding symptoms and signs and is sometimes referred to as delayed ischemic neurological deficits. Progression to symptomatic vasospasm depends on a number of factors but most importantly the degree and distribution of arterial narrowing. Vasospasm can be focal or diffuse in distribution and mild, moderate, or severe in degree. Vasospasm affects only the intradural arteries and primarily, but not exclusively, arteries and arterioles located outside the brain. The pathogenesis of vasospasm is clearly encasement of cerebral arteries by blood clots, but the complex extracellular and intracellular responses to contact between the arterial wall and hematoma are still being explored and defined.

The delayed onset and predictability of vasospasm provide a unique therapeutic window of opportunity not found with other types of ischemic stroke. Over the past several decades, improvements in our understanding and ability to manage vasospasm have led to a major decline in patient morbidity and mortality from vasospasm, although it still remains one of the more important determinants of outcome after aneurysm rupture.

Minimizing harm caused by vasospasm by avoiding hypovolemia, ensuring adequate blood pressure, use of cerebroprotectants such as nimodipine, and prompt intervention with endovascular treatments such as balloon angioplasty for symptomatic and medically refractory ischemia is the most important goal of SAH management after repair of ruptured cerebral aneurysms. Determining the exact pathogenesis of this condition and development of a corresponding single pharmacologic means of prevention remain ongoing pursuits of neurosurgical research.

Vasospasm in Conditions Other Than Aneurysm Rupture

Vasospasm has been observed in head-injured patients both with and without subarachnoid blood clots in the basal subarachnoid cisterns, although the diagnosis has sometimes relied on transcranial Doppler (TCD) blood velocity measurements, which are difficult to interpret in the setting of brain injury.^1,² The clinical significance of posttraumatic vasospasm is debated, and there is not yet any proven value of either monitoring cerebral arterial diameters or routine treatment with calcium channel blockers in the setting of traumatic brain injury associated with SAH.^3,⁴

Vasospasm rarely complicates rupture of arteriovenous malformations, brain tumor surgery, and surgery for unruptured intracranial aneurysms because significant bleeding into the subarachnoid space is uncommon with these conditions.

Epidemiology of Vasospasm

Angiographic vasospasm is common after rupture of an aneurysm, with an overall incidence of 50% to 90%.⁵ Still useful but rough estimates are that at least moderate vasospasm in at least one cerebral artery will develop in two thirds of patients with ruptured aneurysms, half of these patients will become symptomatic as a result of ischemia, and a cerebral infarct will develop in about half of these patients. An analysis of 2741 patients entered into SAH trials in the 1990s found that cerebral infarction (all causes) had developed in 26% at 6 weeks, which correlated strongly with poor outcome.⁶ Cerebral infarction was significantly associated with increasing patient age, worse neurological grade on admission, history of hypertension or diabetes mellitus, larger aneurysm, induced hypertension, fever, and a diagnosis of symptomatic vasospasm. With modern SAH management routines, the combined risk for death and permanent disability from vasospasm alone has shrunk to less than 10%, but it still remains one of the leading causes of preventable poor outcome after rupture of an aneurysm (Figs. 364-1 and 364-2).⁷^–⁹

FIGURE 364-1 A 51-year-old woman, a cigarette smoker but otherwise healthy, collapsed at work and was intubated and unresponsive when brought to the hospital by ambulance. A, Computed tomographic scanning showed extensive and thick subarachnoid hemorrhage, intraventricular clots, hydrocephalus, and an underlying anterior communicating artery aneurysm. B, The aneurysm was repaired microsurgically, and the patient improved enough to be extubated on the first postoperative day with a Glasgow Coma Scale score of 13 and no lateralizing neurological signs. C, Delayed-onset deterioration began on the eighth postoperative day when left middle cerebral artery transcranial Doppler testing showed velocities in the left middle cerebral artery higher than 200 cm/sec. D, Within 12 hours and despite hypertensive treatment, she required reintubation and continued to be hemiparetic on the right side of her body. Angiography showed severe left-sided internal carotid, middle cerebral, and anterior cerebral artery vasospasm (arrow).

FIGURE 364-2 A, Balloon angioplasty was performed to dilate the left-sided vessels as shown. B, Severe distal and bilateral anterior cerebral artery vasospasm persisted (arrow). C, Despite continued hypertensive treatment, bilateral medial frontal lobe infarcts developed, and 12 months later the patient was completely dependent with spastic right hemiparesis and abulia.

Prediction of Vasospasm

A large volume of persistent subarachnoid clot is the most important risk factor predictive of vasospasm after SAH.^10,¹¹ The original Fisher grading scale in which clot volume and distribution on admission computed tomography (CT) are related to risk for vasospasm has been modified and in one single-center study found to have greater predictive value for delayed ischemia and prognosis.¹² This modified Fisher scale (Table 364-1) scores hemorrhage noted on CT from 0 to 4: 0, no SAH or intraventricular hemorrhage (IVH) (very low risk for vasospasm); 1, focal or diffuse thin layer of SAH, no IVH (low risk for vasospasm); 2, focal or diffuse thin layer of SAH, IVH present (moderate risk for vasospasm); 3, focal or diffuse thick layer of SAH, no IVH (high risk for vasospasm); and 4, focal or diffuse thick layer of SAH, IVH present (highest risk for vasospasm). A slower rate of subarachnoid clot clearance has also been shown to be an independent predictor of vasospasm, although this is not an easy measurement in clinical practice.¹¹

TABLE 364-1 Modified Fisher Scale and Risk for Vasospasm

0	No SAH or IVH: very low risk
1	Focal or diffuse thin layer of SAH, no IVH: low risk
2	Focal or diffuse thin layer of SAH, IVH present: moderate risk
3	Focal or diffuse thick layer of SAH, no IVH: high risk
4	Focal or diffuse thick layer of SAH, IVH present: very high risk

IVH, intraventricular hemorrhage; SAH, subarachnoid hemorrhage.

Other risk factors for the development of vasospasm have been identified, including poor neurological grade or loss of consciousness on admission, cigarette smoking, and preexisting hypertension (Table 364-2).¹³ Factors studied but found to have either an unclear or unlikely relationship with risk for vasospasm include gender, patient age, and aneurysm location. There has been a suggestion that Japanese people may be more susceptible to vasospasm.¹⁴ In addition, a small study suggested that cocaine use is an independent risk factor for vasospasm.¹⁵

TABLE 364-2 Risk Factors for Vasospasm

Thick subarachnoid clots

Intraventricular hematoma

Persistent subarachnoid clots (slow clearance)

Poor neurological condition on admission

Loss of consciousness associated with rupture

History of cigarette smoking

Preexisting hypertension

Cocaine use

Spontaneous perimesencephalic or prepontine SAH (or both) unassociated with aneurysm rupture is typically a low-volume hemorrhage that clears quickly with a low risk for the development of vasospasm.¹⁶ Thick and persistent nonaneurysmal SAH, however, is still associated with a risk for vasospasm.

There is some evidence that endovascular coiling, as opposed to microsurgical repair of ruptured aneurysms, is associated with a lower risk for the subsequent development of vasospasm,¹⁷ although the difference was not large and a rigorous comparison has not yet been made.

Pathogenesis

Smooth Muscle Contraction

Vasospasm is prolonged cerebral arterial constriction caused by vascular smooth muscle contraction. The hemoglobin released from subarachnoid blood clots triggers the entry and release of calcium and subsequent activation of calcium/calmodulin-dependent myosin light-chain kinase, which in turn leads to phosphorylation of the myosin light chain and induces actin and myosin cross-linkage and mechanical shortening (smooth muscle contraction). Such contraction requires adenosine triphosphate and calcium, and vascular smooth muscle relies more on extracellular than intracellular calcium stores, which enter through voltage-gated and receptor-operated calcium channels. Although myofilament activation depends on calcium and high-energy phosphates, chronic vasospasm, which ensues days later and lasts up to several weeks, does not. The contractile proteins protein kinase C, Rho kinase, and protein tyrosine kinase and their corresponding signal transduction pathways have been implicated in vasospasm models when their activation shifts the contractile mechanism toward increased shortening in the absence of high intracellular calcium levels.^18,¹⁹ This contiguous and second-phase “chronic” vasospasm is less reversible with pharmacologic vasodilators both in animal models²⁰ and in humans undergoing intra-arterial, pharmacologic vasodilation treatment.

Sustained vasoconstriction is associated not only with functional impairment of the vessel but also with ultrastructural damage to the vascular wall layers, including vacuolization of endothelial cells and loss of tight junctions, breakage of the internal elastic lamina, and patchy myonecrosis in the tunica media.²¹

Endothelial Injury, Nitric Oxide, and Endothelin-1

Auto-oxidation of the oxyhemoglobin contained in blood clots encasing cerebral arteries produces methemoglobin and superoxide anion radical, which in turn lead to lipid peroxidation.^22,²³ Harmful hydroxyl radicals and lipid peroxides permeate the vessel wall and injure endothelial and smooth muscle cells.^24,²⁵ Damage to the endothelium in particular is thought to play a key role in the establishment of vasospasm, either through the loss of endothelial nitric oxide (NO) synthesis, an important vasodilator and regulator of vascular tone, or through the overproduction of endothelin, a powerful vasoconstrictor peptide.²⁶ These two endothelial-derived substances and the possible imbalance in their production after SAH are at the center of experimental vasospasm research at the present time.

Decreased availability of the simple molecule NO may contribute to the development of vasospasm in the following ways: (1) endothelial NO synthase (eNOS) dysfunction in vasospastic vessels, (2) NO scavenging by oxyhemoglobin; (3) reversal of vasospasm by NO donors, (4) disappearance of neuronal NO synthase (nNOS) activity from the adventitia of vasospastic vessels, and (5) decreased cerebrospinal fluid (CSF) nitrite levels along with increased levels of asymmetric dimethyl-L-arginine, the endogenous inhibitor of NO synthase.²⁷^–³⁵

Endothelin-1 (ET-1) is the predominant isoform of endothelin and has the greatest role in vasoconstriction. ET-1 is a 21–amino acid cleavage product of a 212–amino acid peptide precursor, the final step mediated by endothelin-converting enzyme. It is released on the abluminal side of the tunica media, acts on neighboring vascular smooth muscle ET_A receptors, and causes profound and sustained vasoconstriction.³⁶ ET-1 levels have been found to be elevated in the CSF of patients in whom vasospasm and brain ischemia develop,³⁷^–³⁹ and either inhibition of ET-1 production or antagonism of its effect has prevented vasospasm in animal models.³⁶

It seems possible that derangements in either or both NO or ET-1 production by cerebral vascular endothelium may play a critical role in the pathogenesis of vasospasm, and these mechanisms are being investigated in new vasospasm treatments to be discussed.

Inflammation, Vessel Remodeling, and Vasospasm

Although it has become clear that vasospasm is not a type of vasculitis, there is evidence that inflammatory mechanisms are activated after SAH and may therefore be involved in the development of vasospasm, possibly by contributing to vasocontraction or modifying the vessel wall extracellular matrix and smooth muscle cell phenotype—a process known as vascular “remodeling.”⁴⁰ Inflammatory cytokines,^41,⁴² intercellular adhesion molecules (ICAMs),^43,⁴⁴ and genetic upregulation of inflammatory, proliferative, and extracellular matrix–regulating genes⁴⁵^–⁴⁷ have been examined. In humans, elevations of plasma complement C3a and soluble ICAM-1 have been associated with poor outcome and the development of vasospasm, respectively,^48,⁴⁹ and increased intrathecal levels of the cytokine interleukin-6 predicted vasospasm in another small study.⁵⁰

Although the precise pathogenesis of vasospasm is still the subject of investigation, a prolonged, biphasic vasoconstrictive process in which the second, chronic phase is mechanistically distinct from the first seems most consistent with what has been seen experimentally and in humans. It remains possible that additional processes, including inflammation, may contribute to the pathogenesis of this condition (Table 364-3).

TABLE 364-3 Theories on the Pathogenesis of Vasospasm

Prolonged, mechanistically distinct biphasic vasoconstriction:

Endothelin-1 overproduction (vasoconstrictor)

Nitric oxide underproduction (vasodilator)

Inflammation-mediated “remodeling” and narrowing of the arterial wall

Combined processes

Clinical Features and Investigation

Symptoms, Signs, and Differential Diagnosis

Coincident with its delayed onset, symptoms of ischemia resulting from cerebral vasospasm most commonly appear 1 week after aneurysm rupture but often occur later; accordingly, it is important to remain vigilant for this complication for at least 2 weeks after SAH. Regular and careful bedside examination remains the simplest and most effective means of detecting early ischemia in awake, examinable patients; one should concentrate on subtle findings such as diminished attention, changes in verbal output, or a slight but new pronator drift of the upper extremity. Symptomatic vasospasm usually has a gradual onset, sometimes heralded by increased headache and either agitation or somnolence—a change in patient behavior. It then follows a progressive course if untreated. A smaller group of patients will experience precipitous deterioration.⁵¹ Signs of symptomatic vasospasm are referable to the territory that has become ischemic and are most easily distinguished when they lateralize to a middle cerebral artery (MCA) territory with monoparesis or hemiparesis and, when the dominant hemisphere is affected, aphasia. Anterior cerebral artery vasospasm can be marked by leg weakness, but because it is often bilateral in distribution, confusion, drowsiness, poverty of speech, and eventually abulia are characteristic signs. Vertebrobasilar vasospasm can also cause a more generalized deterioration, with a reduced level of consciousness being an early sign.

Vasospastic ischemia is difficult to detect in patients who remain in poor neurological condition after SAH, and monitoring of comatose patients with ancillary techniques is particularly important.

Delayed neurological deterioration after aneurysmal SAH has a number of causes, including increased edema surrounding intracerebral hematomas, contusions, or infarcts; rebleeding of the aneurysm or aneurysmal remnant; hydrocephalus; sepsis, including meningitis and ventriculitis; hyponatremia; hypoxia; and hypotension (Table 364-4). One or more of these conditions can magnify even a focal neurological deficit and therefore easily be mistaken for vasospasm, which has a tendency to be overdiagnosed in the setting of SAH. Conversely, it is recognized that there is a subgroup of patients who suffer a delayed and often global decline in neurological status for which no single underlying cause can be identified. “Cortical spreading depression” has been one proposed mechanism at work in these patients.¹⁹

TABLE 364-4 Causes of Delayed Deterioration after Subarachnoid Hemorrhage

Increased edema surrounding hematomas, contusions, or infarcts

Rebleeding of aneurysms or aneurysmal remnant

Hydrocephalus

Infection, including ventriculitis

Hyponatremia

Hypoxemia

Cerebral vasospasm causing cerebral ischemia

Diagnosis

Diagnosis of symptomatic vasospasm requires that the other causes of delayed worsening listed earlier be ruled out with CT and appropriate laboratory investigations. If vasospasm remains the most likely cause of deterioration and treatment by induced hypertension reverses the deficit, the diagnosis can safely be assumed without further testing. Failure to respond in this scenario, as well as evaluation of comatose patients, requires additional testing (Table 364-5).

TABLE 364-5 Diagnosis of Vasospasm

CBF, cerebral blood flow; CT, computed tomography; MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography; TCD, transcranial Doppler.

Transcranial Doppler

TCD works on the principle that as an artery narrows, blood flow velocity within it increases. Because examinations are noninvasive, are carried out at the bedside, and can easily be performed on a daily basis, TCD is frequently used to monitor patients with SAH for increases in intracranial blood flow velocity suggestive of incipient vasospasm. There is good general correlation between TCD velocities and vasospasm, with velocities in the MCA greater than 120 cm/sec indicative of some degree of vasospasm and those greater than 200 cm/sec consistent with severe vasospasm. Because other factors can influence velocity, including blood pressure and overall cerebral blood flow (CBF), distinguishing vasospastic from hyperemic increases in blood velocity has been reported to be facilitated by measuring cervical internal carotid artery (ICA) velocity in addition to intracranial blood velocity.⁵² A “Lindegaard ratio” of V_MCA/V_ICA greater than 3 is consistent with vasospasm (hyperemia is associated with increased velocity in both the MCA and ICA, so the ratio is the same). A similar velocity ratio between the basilar artery and the extracranial vertebral artery has been proposed to improve the sensitivity and specificity of detecting basilar artery vasospasm.⁵³

The clinical utility of TCD is best when MCA values are clearly low (<120 cm/sec) or very high (>200 cm/sec), and the respective negative and positive predictive values for significant angiographic vasospasm in the MCA trunk are close to 90%.⁵⁴^–⁵⁶ For values in the intermediate range, additional maneuvers may improve its accuracy in detecting vasospasm, such as testing for hyperemic autoregulatory responses to transient, manual carotid compression^57,⁵⁸ or combining the TCD information with CBF measurements.⁵⁹ TCD does not reliably detect vasospasm in more peripheral branches,⁶⁰ which may account for its failure to always correlate with perfusion deficits detected on CBF studies.⁶¹ Regular surveillance of SAH patients with TCD ultrasonography by skilled technicians is considered helpful in many neurosurgical units, but the results must be considered in the context of the individual patient along with all other information available.

Cerebral Blood Flow and Perfusion

Single-photon emission CT,⁶² quantitative stable xenon–enhanced CT,⁵⁹ and positron emission tomography⁶¹ can be used to detect cerebral ischemia after SAH, but none are practical investigations that can be easily performed or repeated in critically ill patients. Magnetic resonance imaging to look for either perfusion deficits⁶³ or ischemia on diffusion-weighted images^64,⁶⁵ has the same limitation.

Perfusion CT has been used in patients with SAH ^66,⁶⁷ and with greater experience will probably find more widespread use and validation for predicting or diagnosing vasospasm.

Thermal diffusion flowmetry has been used as bedside monitoring in SAH patients to detect vasospasm causing significant reductions in CBF.⁶⁸ Provided that the white matter location into which the thermal diffusion microprobe is inserted (usually the frontal lobe) is representative of the territory at risk, continuous measurement of CBF values could be particularly useful in patients with high-grade SAH who cannot be assessed neurologically.

Microdialysis Monitoring

Cerebral microdialysis catheters allow continuous bedside measurement of extracellular concentrations of glutamate, lactate, pyruvate, glucose, and glycerol in brain tissue, thereby screening for excitotoxic cell injury characterized by elevations in lactate with respect to glucose and pyruvate levels and an increase in the glycerol concentration. This somewhat demanding monitoring technique provides chemical information about a very small region of the brain, but it has been used, along with cerebral oximetry, to detect ischemia in patients with SAH.⁶⁹^–⁷¹

Vascular Imaging

The most practical method of imaging large and medium-sized cerebral arteries is digital subtraction angiography or high-definition CT angiography.⁷² Catheter-based angiography is best in patients in whom balloon angioplasty is being considered and can accompany the procedure.

Angiographic vasospasm is a concentric narrowing that can be focal, segmental, or diffuse. It is commonly graded as mild (<25%), moderate (25% to 50%), or severe (>50%) in comparison to baseline, prevasospasm imaging. “Early” vasospasm on admission angiography and within 48 hours of aneurysm rupture has been described in a small percentage of SAH patients, although without baseline angiography it is not clear how this diagnosis can be made accurately in all cases.⁷³ Its detection has been associated with the development of cerebral infarction and poor outcome.

Along with TCD and CBF measurements (if available), properly timed and sometimes repeated cerebral angiography is important in patients who are in poor neurological condition and in whom physical examination is difficult or inaccurate. If discovered, significant large-vessel vasospasm can then be treated as described in later sections of this chapter.

Prevention of Vasospasm and Cerebral Protection

General Measures: Fluid Management and Medical Treatment

Patients have a tendency toward volume contraction in the acute stage of SAH,⁷⁴ and hypovolemia should be carefully avoided. It is not clear that a deliberate attempt to induce hypervolemia with volume expansion therapy is beneficial in terms of prevention of vasospasm or ischemia or even possible in patients with normal renal function.⁷⁵^–⁷⁸ Patients should be hydrated with at least 3 L of isotonic fluids daily, and there is some evidence that additional colloid infusions (such as albumin) are beneficial.⁷⁹ Some SAH patients experience excessive natriuresis and are susceptible to the development of hyponatremia during this time (usually related to elevations in brain natriuretic peptide), an electrolyte disturbance that may increase the risk for vasospasm.⁸⁰ It has been reported that fludrocortisone administration (0.3 mg/day) may help avert this complication.⁸¹

Blood transfusion has been associated with a higher likelihood of both vasospasm and poor outcome in SAH patients,^12,⁸² thus suggesting that anemia is a marker for other factors that contribute to SAH-associated morbidity. The optimal hemoglobin concentration in patients with SAH in terms of hematocrit, blood viscosity, and oxygen delivery to the brain is not known with certainty, but is generally accepted to be higher than 9 g/dL.

Systemic blood pressure should be maintained in the normotensive to slightly hypertensive range, provided that the aneurysm has been repaired. In patients with external ventricular drains, cerebral perfusion pressure (CPP) is a more important parameter to monitor and maintain at 70 mm Hg or greater in poorer grade patients.⁸³

Nimodipine, administered orally or via a nasogastric tube, 60 mg every 4 hours and continued for 3 weeks (for patients requiring that length of hospitalization), is standard treatment of patients with aneurysmal SAH because it has a modest but statistically significant beneficial impact on clinical outcome.⁸⁴ Nimodipine prevents increases in intracellular calcium by blocking dihydropyridine-sensitive (L-type) calcium channels, but its mechanism of effect in patients with SAH is unknown. It can cause temporary depression of blood pressure, in which case the dose can be reduced and, if possible, given more frequently (i.e., 30 mg every 2 hours) (Table 364-6).

TABLE 364-6 Prevention of Vasospasm and Cerebral Protection

General Measures

Maintain euvolemia (at least 3 L of isotonic fluids daily)

Prevent anemia (hemoglobin <9 g/dL)

Maintain normal to high systemic blood pressure

Prevent high ICP (and maintain CPP) with external ventricular drainage as necessary

Nimodipine, 60 mg by mouth or nasogastric tube every 4 hr

Investigational Treatments

Endothelin receptor antagonists

HMG-CoA inhibitors (statins)

Magnesium sulfate (intravenous infusion)

Intrathecal vasodilators (slow-release implants)

Augmentation of Subarachnoid Clot Clearance

Clot lysis

Lamina terminalis fenestration

Lumbar CSF drainage

“Head shaking”

Combined treatment

CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid; HMG-CoA, 3-hydroxyl-3-methylglutaryl coenzyme A; ICP, intracranial pressure.

Investigational Preventive Treatments

It is beyond the scope of this chapter to review the countless number of pharmacologic agents that have been tested in experimental models of SAH and vasospasm, many of which, by targeting a specific pathologic process, were intended to explore a particular pathogenetic theory for vasospasm. The following are preventive strategies that have been tested clinically, some under ongoing investigation.

Prophylactic Balloon Angioplasty

Based on the experimental observation that angioplasty of canine carotid arteries prevented the development of vasospasm when the arteries were subsequently encased in blood clots,⁸⁵ prophylactic transluminal balloon angioplasty (TBA) was tested in a phase II multicenter, randomized trial.⁸⁶ One hundred seventy patients with thick subarachnoid clots were enrolled and 85 were randomized to undergo percutaneous TBA within 96 hours of SAH; the major cerebral arteries targeted included the supraclinoid ICA, MCA M1 segments, and the basilar artery. Although there was a trend toward reduced vasospasm in the patients treated prophylactically by percutaneous TBA, outcome was no different from that in the control group, and the safety of this treatment was questionable; 4 patients had a procedure-related vessel perforation, 3 of whom died.

Clot Clearance

Intracisternal thrombolysis with either recombinant tissue plasminogen activator (rt-PA) or urokinase speeds clearance of subarachnoid clots, and there is evidence that this is associated with prevention of vasospasm and less cerebral ischemia.⁸⁷ However intuitive and hopeful this approach appears, safety concerns about introducing a thrombolytic agent into the subarachnoid space in a recently injured brain has precluded wide acceptance of this approach. “Head shaking” with cisternal thrombolysis⁸⁸ or with lumboventricular lavage⁸⁹ has been reported to be beneficial in terms of prevention of vasospasm in single-center studies, as has simple lumbar drainage.⁹⁰ Finally, one report has suggested that fenestration of the lamina terminalis at the time of aneurysm clipping reduces the incidence of not just subsequent hydrocephalus but also vasospasm from 55% to 30% in patients with thick subarachnoid clots, the proposed mechanism being increased CSF flow and clot clearance in the basal subarachnoid cisterns.⁹¹

Intrathecal Vasodilators

Prolonged-release nicardipine implants placed in the subarachnoid space of patients with thick clots and undergoing surgical clipping appeared to significantly prevent vasospasm and ischemia in a single-center, nonrandomized cohort study,⁹² results similar to those in a previous study in which papaverine pellets were used.⁹³

Magnesium

Magnesium sulfate (MgSO₄) has neuroprotective and vasodilatory properties and has therefore been tested for the prevention of vasospasm and ischemia in patients with SAH. One study found no benefit from intravenous MgSO₄ infusions,⁹⁴ another showed various trends toward benefit,⁹⁵ and a third suggested efficacy equivalent to nimodipine in preventing ischemic damage.⁹⁶ Larger randomized trials are required.

Endothelin Receptor Antagonists

As discussed earlier, ET-1 overproduction from cerebral endothelial cells damaged by SAH is one of the leading theories behind the pathogenesis of cerebral vasospasm. The ET_A/B receptor antagonist TAK-044 was found to reduce delayed ischemia with an acceptable safety profile in a phase II randomized controlled trial, but with no apparent effect on outcome.⁹⁷ The ET_A receptor antagonist clazosentan, which showed promising results in a multicenter phase IIa study,⁹⁸ has now been studied in a randomized, double-blind, placebo-controlled, phase II dose-finding trial (CONSCIOUS-1).⁹⁹ Treatment with either 1, 5, or 15 mg/hr of intravenous clazosentan was started within 56 hours of SAH and continued up to 14 days. The primary end point, moderate to severe angiographic vasospasm, was significantly reduced in a dose-dependent fashion from 66% in the placebo group to 23% in the 15-mg/hr clazosentan group (risk reduction, 65%; 95% confidence interval, 47% to 78%; P < .0001). There was no clear effect on infarction or outcome, and clazosentan was associated with increased rates of pulmonary edema, hypotension, and anemia. CONSCIOUS-2 is presently under way (fall 2008), a multicenter placebo-controlled phase III study examining the effect of clazosentan, 15 mg/hr given for 14 days after aneurysm clipping, on clinical outcome.

Statins

Statin agents inhibit 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is the rate-limiting enzyme in the mevalonate pathway of cholesterol synthesis. In addition to their hypolipidemic activity of lowering cholesterol levels, they have other salutary effects on the cardiovascular system, including improving endothelial function, modulating inflammatory responses, maintaining the stability of atherosclerotic plaque, and preventing thrombus formation. Perhaps important as they relate to SAH, statins also improve CBF by upregulation of eNOS.

In a pilot randomized clinical trial, simvastatin (80 mg) given once daily for 14 days appeared to decrease the incidence of radiographic vasospasm and delayed ischemia.¹⁰⁰ Reduced vasospasm and cerebral infarction were also found in several cohort studies comparing SAH outcomes in statin users and nonusers at the time of hospital admission.^101,¹⁰² A phase II placebo-controlled trial of 80 patients randomized to receive either placebo or 40 mg of oral pravastatin for up to 14 days found that statin use reduced vasospasm and severe vasospasm by 32% and 42%, respectively, and reduced vasospastic infarcts and mortality by 83% and 75%, respectively (all significant P values).¹⁰³ The improvement in early outcome proved durable at 6 months.¹⁰⁴ Even though there has been a single negative retrospective statin study, the evidence in total suggests that statins are safe and quite possibly effective in preventing vasospasm, infarction, and poor outcome after aneurysmal SAH. A large, international phase III study investigating the use of simvastatin for aneurysmal subarachnoid hemorrhage (STASH) is currently under way (fall 2008).

Tirilazad Mesylate

Tirilazad, an inhibitor of iron-dependent lipid peroxidation and free radical scavenger, was tested in a series of large-scale randomized controlled trials and became licensed for use in several countries, although not in North America. An analysis of all tirilazad results showed decreased mortality associated with treatment, but nonmortality end points of good outcome did not show benefit except in a post hoc analysis of poor-grade patients.¹⁰⁵ Because of gender-specific pharmacokinetics, higher dosages were necessary in women, who appeared to benefit less than men.

Reversal of Vasospasm and Cerebral Ischemia: Rescue Treatments

Augmentation of CBF through and via collaterals around vasospastic vessels by elevating systemic blood volume and pressure can reverse cerebral ischemia, and either pharmacologic or balloon dilation of narrowed arteries can reverse vasospasm itself. When and how these two “reversal” or “rescue” treatments should be implemented and combined is subject to some variation.

Triple-H Therapy: Hypervolemia, Hypertension, and Hemodilution

This combination is intended to improve cardiac output, increase CPP, and optimize hemorheology for oxygen transport. A degree of hemodilution accompanies any deliberate volume expansion, and reduced viscosity may contribute to an improvement in oxygen delivery, provided that the hematocrit (i.e., the oxygen-carrying capacity) does not fall below 30 and the hemoglobin concentration is maintained higher than 9 g/dL.

When symptomatic vasospasm is diagnosed or strongly suspected, hemodynamic treatment can commence by additional volume expansion with an isotonic crystalloid infusion, which in euvolemic patients raises CBF in vasospastic territories without a significant change in cardiac indices.¹⁰⁶ A replete intravascular volume beyond which additional expansion is probably of no further benefit corresponds to a central venous pressure between 8 and 10 mm Hg or a pulmonary capillary wedge pressure in the range of 14 to 16 mm Hg. Unless patients have a complicated cardiopulmonary status (because of myocardial infarction, heart failure, or pulmonary edema, for example), a pulmonary artery catheter (PAC) is unnecessary.^107,¹⁰⁸

Induced hypertension is more effective than aggressive hypervolemia in improving cerebral oxygenation in patients with vasospasm and has fewer complications.¹⁰⁹ Provided that the ruptured aneurysm has been repaired, symptomatic vasospasm should be treated by the administration of dobutamine or dopamine, which at low to moderate doses have mainly β-agonist, inotropic effects. Another cardiac inotrope, milrinone, has also been used after SAH.¹¹⁰ Blood pressure rises with elevations in cardiac output, which increases CPP. If a prompt blood pressure response does not occur (i.e., to dopamine administered at 10 to 15 µg/kg per minute), a more purely α-agonist vasopressor, such as norepinephrine (titrated to a maximum dose of 20 µg/kg per minute), phenylephrine (titrated to a maximum dose of 180 µg/kg per minute), or a combination of the two, should be added. At high doses, dopamine also causes α-adrenergic agonism; however, it is accompanied by unwanted tachycardia because of β₂ receptor activity, which norepinephrine does not possess. In some centers, vasopressors are used before inotropes; the key aspect of treatment is elevating blood pressure, regardless of the agent chosen. Systolic blood pressure of 200 mm Hg or higher or CPP greater than 80 mm Hg is sometimes required, but if ischemic signs persist at systolic pressures greater than 220 mm Hg or CPP higher than 120 mm Hg, hypertensive treatment should be considered to have failed.

It should be noted that hypertension and hypervolemia do not seem to increase the risk for hemorrhage from unsecured, unruptured aneurysms in the acute setting or in their short-term natural history.¹¹¹

The significant risks of triple-H therapy are cardiac failure and infarction, pulmonary edema, the complications associated with either central venous catheter or PAC placement, and possibly cerebral edema and raised intracranial pressure (ICP).¹¹²^–¹¹⁴ Risks are greatest in the elderly and patients with intrinsic, preexisting cardiopulmonary disease.

Intra-aortic Balloon Counterpulsation

Originally designed for the management of cardiogenic shock, placement of a transfemoral aortic balloon that inflates on aortic valve closure with each cardiac cycle and augments diastolic flow proximally to the coronary and cranial arteries and distally to the peripheral circulation has been reported to be feasible and effective in patients with combined severe vasospasm and cardiac failure.^115,¹¹⁶

Endovascular Reversal of Vasospasm

If the hemodynamic goals of triple-H therapy are not easily met in a patient with persistent signs of cerebral ischemia, if the signs do not reverse within several hours of hypertension induced into the target range, or if a patient has a fragile cardiopulmonary status, it is appropriate to proceed directly to endovascular treatment of vasospasm. It is important to first rule out a large cerebral infarct with CT because dilation therapy is both futile and dangerous in this situation.

Chemical Angioplasty

There has been considerable experience with superselective intra-arterial infusion of the vasodilator papaverine for the management of vasospasm. Although demonstrated to sometimes be effective in dilating spastic arteries, its effect is short-lived and inconsistently associated with clinical improvement. There have been reports of toxicity and other adverse effects, including elevations in ICP.¹¹⁷

Other agents have also been administered intra-arterially for vasospasm, including the calcium channel blocker verapamil (≈3 mg per vessel or ≈20 mg per patient),¹¹⁸ the intracellular calcium antagonist fasudil hydrochloride,¹¹⁹ and the phosphodiesterase inhibitor milrinone.^120,¹²¹ The calcium antagonists nicardipine and nimodipine have likewise been administered intra-arterially. Although experience with these various agents remains preliminary, most appear to be quite well tolerated in terms of blood pressure and ICP at the doses used. There have been reports of verapamil administration and seizures.¹²² Although intra-arterial vasodilators are able to reach more distal vessels, the response of vessels exhibiting chronic vasospasm is often blunted, and the duration of their effect is usually temporary.

Balloon Angioplasty

Percutaneous TBA results in reliable and durable dilation of any artery that can be reached and treated. Second- and third-order branches cannot generally be dilated because of their small size, although dilation of proximal arteries is sometimes sufficient to improve flow into these vessels, especially with continued triple-H treatment. Because of its angle of departure from the ICA, the anterior cerebral artery is in particular more difficult to treat. Severe bilateral anterior cerebral artery vasospasm is a difficult condition to treat and carries a significant risk for medial frontal lobe infarction. In addition to the ability to reach target vessels, the other key to clinical success with TBA is its performance before progression to cerebral infarction.

In vitro and in vivo experiments in dogs indicate that TBA results in arterial stretching with an immediate and profound functional impairment in vascular smooth muscle ^123,¹²⁴ that lasts several weeks.¹²⁵

Clinical series suggest that approximately two thirds of patients will show some clinical improvement after TBA, and its risks include vessel perforation, dissection, and occlusion, which complicate between 5% and 10% of procedures.^117,¹²⁶^–¹²⁹ Good results with this technique depend on appropriate timing and expertise (Fig. 364-3).

FIGURE 364-3 A 22-year-old otherwise healthy woman arrived at the hospital after a sudden-onset, severe headache caused by rupture of an anterior communicating artery aneurysm (A-C). After successful endovascular coiling of the aneurysm the patient became weak on the right side of her body 5 days later, which failed to reverse with induced hypertension. Balloon angioplasty was able to reverse the left internal carotid and middle cerebral artery vasospasm as shown (arrow) (D and E), after which the patient recovered and avoided cerebral infarction as seen on delayed computed tomographic scanning (F).

Other Reversal Therapies

In patients with severe and medically refractory vasospasm, sodium nitroprusside, an NO donor, has been administered into the lateral ventricles, either as single injections or as a continuous infusion via a ventriculostomy catheter, but the results have not been consistent or promising.^130,¹³¹ Cervical sympathetic blockade with regional anesthesia appeared to result in improvement of mild to moderate symptoms of vasospasm, but without reversal of angiographic vasospasm.¹³²

Practical Approach to the Prevention and Treatment of Cerebral Vasospasm

Ruptured aneurysms are treated early in our unit, and for microsurgical cases in which there is a large volume of subarachnoid clot and clipping is confirmed to be complete by visual inspection, aneurysm opening, or intraoperative angiography (or any combination of the three), I still administer 5 to 10 mg of rt-PA for lysis of subarachnoid clots. Excellent overnight clot lysis is often observed on CT, and such patients are at much lower risk for proximal, circle of Willis vasospasm.

Patients are kept well hydrated with isotonic crystalloid and intermittent albumin infusions (at least 3 L/day, combined), ICP is kept normal with the liberal use of external ventricular drainage, and CPP is optimized to levels higher than 70 mm Hg. No attempt is made to control mild or moderate hypertension (Table 364-7). Daily TCD examination is carried out by a dedicated technician, and values in excess of 200 cm/sec in the MCA are considered indicative of significant angiographic vasospasm in that segment. Regular clinical assessment to search for subtle changes in mentation, verbal output, and arm and hand control is most important. Obtunded or sedated patients being ventilated undergo direct vascular imaging on day 5 as a matter of routine and then again several days later if considered necessary.

TABLE 364-7 Reversal of Vasospasm and Cerebral Ischemia: Stepped-Care Approach

1 Ensure adequate intravascular volume with additional isotonic crystalloid, colloid (albumin), or red blood cell infusions as appropriate (target CVP, 8-12 mm Hg; hemoglobin, >9 g/dL)

2 Induce hypertension with one or more of the following agents (target systolic blood pressure, >200 mm Hg within 2 hr):

a Dobutamine, 5-20 µg/kg/min

b Dopamine, 5-15 µg/kg/min

c Milrinone, 0.50-0.75 µg/kg/min

d Norepinephrine, 5-20 µg/kg/min

e Phenylephrine, up to 150 µg/min

3 Percutaneous TBA:

a Consider early for patients with severe deficits or fragile cardiopulmonary status (i.e., before maximum “triple-H” therapy)

b First rule out cerebral infarction with CT scanning

c May require ongoing hypertensive treatment of distal or untreated vasospastic territories

4 Chemical angioplasty (i.e., intra-arterial verapamil, ≈3 mg per vessel):

a When TBA is unavailable

b For vasospasm in territories untreatable by TBA

c May have to be repeated

5 Intra-aortic balloon counterpulsation:

a Consider in patients with refractory vasospastic ischemia and heart failure (and endovascular treatment is not feasible or successful)

CT, computed tomography; CVP, central venous pressure; TBA, transluminal balloon angioplasty; triple-H therapy, hypervolemia, hypertension, and hemodilution.

All patients receive nimodipine, 60 mg every 4 hours per os or via a nasogastric tube for 21 days or as long as they remain in the hospital, and 40 mg of pravastatin per day; phenytoin is avoided unless the patient has a documented seizure, and corticosteroids are also not prescribed. Every effort is made to avoid hyponatremia, fever, and hypoxia, and patients are fed enterally as soon as possible.

Symptomatic vasospasm detected in examinable patients and moderate to severe angiographic vasospasm in comatose, unexaminable patients is treated by infusion of a vasopressor. We prefer central venous catheters to PACs, and euvolemia or slight hypervolemia is ensured. If signs do not respond quickly and completely or a target blood pressure and CPP is difficult to reach, we move quickly to endovascular treatment with TBA for all spastic and reachable arteries. A CT scan is always performed first to rule out a large, established infarction or a new hemorrhage. In general, we do not wait until medical treatment of symptomatic vasospasm has utterly failed over a period of many hours before opting for endovascular treatment because under these circumstances, TBA is more often inconvenient, dangerous, and unsuccessful.

We await the results of further clinical trials of the statin agent pravastatin and the endothelin receptor antagonist clazosentan.