The differential diagnosis of acute cerebrovascular disease is quite broad, encompassing thrombosis, dissection, vasculitis, and occlusion of the brain’s arterial and venous systems. The cerebrovascular diseases most commonly seen in the acute care setting are ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Together, these 3 conditions represent approximately 780,000 cases annually in the United States. A total of 600,000 of these cases will be new; 87% will be ischemic strokes, 10% will be intracerebral hemorrhages, and 3% will be subarachnoid hemorrhages.1 Risk factors for cerebrovascular disease are similar to those for coronary artery disease and include smoking, hyperlipidemia, heavy alcohol consumption, and diabetes mellitus. The primary risk factor for cerebrovascular disease, however, is systemic arterial hypertension.2 Hypertension is also a prominent presenting feature with all 3 types of cerebrovascular emergencies. It behooves the physician, therefore, to understand the pathophysiologic rationale for managing blood pressure (BP) in patients with acute neurologic deterioration. This is especially important for patients presenting to an emergency department (ED) in a hospital that is not a stroke center or does not have expert consultation services immediately available. In that case, the physician must stabilize the patient and appropriately manage the BP while arranging transfer to an appropriate facility.
Acute cerebrovascular diseases (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) affect 780,000 Americans each year. Physicians who care for patients with these conditions must be able to recognize when acute hypertension requires treatment and should understand the principles of cerebral autoregulation and perfusion. Physicians should also be familiar with the various pharmacologic agents used in the treatment of cerebrovascular emergencies. Acute ischemic stroke frequently presents with hypertension, but the systemic blood pressure should not be treated unless the systolic pressure exceeds 220 mm Hg or the diastolic pressure exceeds 120 mm Hg. Overly aggressive treatment of hypertension can compromise collateral perfusion of the ischemic penumbra. Hypertension associated with intracerebral hemorrhage can be treated more aggressively to minimize hematoma expansion during the first 3 to 6 hours of illness. Subarachnoid hemorrhage is usually due to aneurysmal rupture; systolic blood pressure should be kept <150 mm Hg to prevent rerupture of the aneurysm. Nicardipine and labetalol are recommended for rapidly treating hypertension during cerebrovascular emergencies. Sodium nitroprusside is not recommended due to its adverse effects on cerebral autoregulation and intracranial pressure. Hypoperfusion of the injured brain should be avoided at all costs. J Clin Hypertens (Greenwich). 2011;13:205–211. © 2010 Wiley Periodicals, Inc.
Principles of BP Management (Table I)
|Hypotension, regardless of cause||MAP ≥70 mm Hg|
SBP ≥90 mm Hg
|Cerebral perfusion depends on adequate systemic BP and should be maintained at all costs!|
|Subarachnoid hemorrhage||MAP 90–110 mm Hg|
SBP 120–150 mm Hg
|SBP spikes above 150 mm Hg, increase the risk of rerupture of the aneurysm, which carries a 75% risk of mortality|
|Intracerebral hemorrhage||MAP 100–120 mm Hg|
SBP 140–160 mm Hg
|Cerebral perfusion needs to be maintained, but BP should be rapidly lowered to prevent expansion of the hematoma|
|Acute ischemic stroke||Don’t lower BP unless SBP exceeds 220 mm Hg or DBP exceeds 120 mm Hg, unless thrombolytics have been given||After an ischemic stroke, a “penumbra” of viable, but threatened, brain tissue exists around the infarcted area. This penumbra depends on collateral circulation and adequate perfusion, and dropping BP can lead to death of this tissue. So, while the temptation to lower BP is there, RESIST!|
|Post-thrombolysis for stroke||MAP 100–130 mm Hg|
SBP 140–180 mm Hg
|After tPA, the balance is between adequate perfusion of the penumbra and the risk of hemorrhage with higher BPs|
The two most important principles in the treatment of any patient with acute cerebrovascular disease are to avoid hypoxemia and hypoperfusion. Most patients who arrive in the ED with cerebrovascular emergencies are hypertensive and physicians focus on lowering the systemic arterial pressure. However, an overly aggressive reduction in BP can result in worsening cerebral ischemia. At minimum, the systolic BP (SBP) should be kept above 90 mm Hg.3
Cerebral perfusion pressure (CPP) is defined as the difference between the mean arterial pressure (MAP) and the intracranial pressure (ICP). Normal cerebral blood flow is approximately 50 mL/100 g brain tissue per minute and remains constant, despite fluctuations in systemic BP, via cerebral autoregulation. This is maintained between a CPP of 50 mm Hg and 150 mm Hg.3 When the CPP falls below 50 mm Hg, cerebral blood flow falls in a linear fashion. Likewise, when the CPP exceeds 150 mm Hg, arteriolar vasoconstriction is exhausted and cerebral edema occurs. Chronic hypertension shifts this curve to the right, so cerebral autoregulation may be lost at a higher CPP than in normal patients. Acute cerebrovascular disruption, such as that seen with massive stroke, intracerebral hemorrhage, or aneurysmal rupture, severely impairs cerebral autoregulation. In these cases, cerebral perfusion follows a linear relationship with CPP (Figure).
Since most hospitals do not have the capability to routinely place intracranial pressure monitors, the treating physician must rely on the MAP and their clinical examination of the patient to make decisions regarding BP management. Rapid lowering of the systemic BP has been associated with neurologic deterioration in several smaller studies and case series, although large randomized control trials examining this are lacking.4,5 In patients in whom there is suspicion of cerebral hypoperfusion, intravenous fluid boluses, followed by vasopressor therapy, are indicated to augment cerebral blood flow.
Acute Ischemic Stroke
Acute ischemic stroke results in two types of neuronal injury. The core, or central part of the infarction, consists of cellular necrosis and irreversibly damaged brain tissue. Unfortunately, this area of the brain is beyond salvage with current therapies. The second type is the penumbra, which varies in size and surrounds the core.3 The penumbra represents ischemic, but not infarcted, neuronal tissue and is the focus of most interventions for acute stroke. This area is not usually evident on computed tomography scanning but can be detected using magnetic resonance imaging. The typical pattern is one of mismatch between diffusion-weighted images (which represent the infarcted core) and perfusion-weighted images (which represent ischemic, but potentially viable, tissue).6
The majority of patients who present to the ED with acute stroke will be hypertensive,7,8 but it is not known whether this represents a natural compensatory mechanism. It has been shown that without treatment, the hypertension present at the time of admission will decline over the next 24 hours and this decline may continue for up to 7 days after the stroke.7,8 The American Heart Association/American Stroke Association (AMA/ASA) Scientific Statement on the early treatment of stroke recommends that arterial hypertension not be treated in the acute phase unless the SBP exceeds 220 mm Hg, the diastolic BP (DBP) exceeds 120 mm Hg, or if there is evidence of other acute end-organ damage due to hypertension, such as cardiac ischemia, pulmonary edema, aortic dissection, or acute renal failure.9
Severe hypertension is considered a contraindication to the use of thrombolytics in acute ischemic stroke9 due to the increased risk of hemorrhagic conversion. If thrombolytic therapy is given, the BP should be more tightly controlled than if the patient were treated conservatively. The SBP should be treated if it exceeds 180 mm Hg, and the DBP should be treated if it exceeds 105 mm Hg.10,11
The role of induced hypertension in the treatment of stroke for patients who are not eligible for thrombolytic therapy is still being investigated. Several smaller studies, totaling 152 patients, have looked at augmenting the MAP to improve cerebral blood flow to the penumbra.12–17 Phenylephrine has been the agent most commonly used, since it is a peripheral α-agonist and there are few α1 receptors in the cerebral vasculature. This allows for systemic vasoconstriction without impairing cerebral blood flow.18 While this treatment has theoretical promise and is supported by these trials, it is not recommended as routine therapy until larger studies assessing its efficacy and safety have been performed.9
Intracerebral hemorrhage (ICH) is defined as nontraumatic bleeding into the parenchyma of the brain or into the cerebral ventricles. The most common sites for ICH are the basal ganglia, thalamus, cerebellum, and brainstem.19 Hemorrhage occurs when small penetrating arteries rupture. Pathologic studies show that there is often medial and smooth muscle degeneration of these vessels. In elderly patients, β-amyloid deposition in smaller arteries leads to amyloid angiopathy; lobar ICH and recurrent bleeding is seen in this condition.19 Hypertension has been identified as the biggest risk factor for ICH.20
Formerly, it was believed that ICH was a monophasic event and that the bleeding was complete by the time the patient arrived to the hospital. Computed tomography studies of patients with ICH have shown that this is not true, and that there is progression in the size of the hematoma for up to 6 hours following the initial hemorrhage.21,22 Expansion of the volume of the hematoma may be due in part to uncontrolled hypertension and a localized coagulopathy related to consumption of clotting factors.23 Mortality from ICH is directly correlated to hematoma volume and the Glasgow Coma Score (GCS) at the time of admission. Patients with a GCS of <9 and a hematoma volume of >60 mL were found by Broderick and colleagues to have a 30-day mortality of 90%, while those with a hematoma volume of <30 mL and a GCS of 9 or better had a 30-day mortality of 17%.24 Controlling hematoma expansion may represent the best therapeutic option for the patient, but whether persistent hypertension after ICH leads to hematoma expansion is debatable and the ideal target BP is not known. The vast majority of patients with ICH will be hypertensive, and this may in fact be a protective reflex to maintain cerebral perfusion if there is brainstem compression (the Cushing-Kocher response).25
The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage (INTERACT) trial compared standard BP control (180 mm Hg SBP) with intensive control (140 mm Hg SBP) and found no difference in 90-day mortality or neurologic outcome. There was a trend toward lower hematoma volume with the intensive group, but this did not reach statistical significance.26 To date, this is the largest randomized study examining the effect of BP control on ICH. The National Institutes of Health–sponsored Antihypertensive Therapy in Acute Cerebral Hemorrhage (ATACH) study compared 3 tiers of BP regulation, keeping the SBP between 170 mm Hg and 200 mm Hg (tier one), 140 mm Hg to 170 mm Hg (tier two), and 110 mm Hg to 140 mm Hg (tier three). This study showed that tighter BP control was safe and feasible, but the small size (n=60) of ATACH was not powered to detect a mortality benefit or reduction in size of hematoma expansion.27 Together with INTERACT, the results of the phase I ATACH study should serve as a basis for future studies designed to investigate the possibility of a mortality benefit with a reduction of systemic BP in ICH.
BP control in the management of ICH can be more aggressive than with acute ischemic stroke, mainly because of the lack of an ischemic penumbra with ICH.25,28 The rim of the hematoma may be vulnerable to impaired cerebral perfusion, however, and any BP reduction should be moderate.29 Currently, the AHA/ASA recommends modest reduction of BP to a target of 160/90 mm Hg, with a MAP of 110 mm Hg, if there is no suspicion of intracranial hypertension.30 If there is concern for elevated intracranial pressure, early intracranial pressure monitoring and therapy directed toward maintaining a cerebral perfusion pressure of 60 mm Hg to 80 mm Hg is recommended.30
Nontraumatic subarachnoid hemorrhage (SAH) most commonly results from rupture of a large artery aneurysm. Arteriovenous malformations and perimesencephalic arterial rupture cause a minority of cases of SAH. The major risk factors are hypertension, cigarette smoking, and heavy alcohol consumption.31 The mortality from SAH related to aneurysmal rupture approaches 50%, and between 20% and 30% of survivors will have significant neurologic impairment.32
Rebleeding of the ruptured aneurysm has an incidence of 4% in the first 24 hours after SAH. The incidence falls to 1% each day thereafter until the aneurysm is secured.33 While a direct link between hypertension following SAH and rebleeding has not been established,34 most neurosurgeons and intensivists will treat elevated BP. Higher rates of rebleeding have been observed when the SBP exceeds 160 mm Hg,35 so a target SBP of 120 mm Hg to 150 mm Hg seems prudent. With SAH in particular, attention should be paid to both the MAP (and its relationship with cerebral perfusion) and the SBP, since larger cerebral arteries—the site of most aneurysms—will be more sensitive to wide fluctuations in the pulse pressure.
Pharmacologic Therapy (Table II)
|Drug||Dose||Mechanism: Pros and Cons|
|Nicardipine||5- to 15-mg/h infusion||Calcium channel antagonist with no suppression of the atrioventricular node; acts as a cerebral arterial vasodilator. Very titratable with few side effects and preferred for most neurocritical care patients|
|Labetalol||20- to 40-mg intravenous bolus, or 0.5- to 2.0-mg/min infusion||Combined α- and β-receptor antagonist; especially useful in hyperadrenergic conditions (cocaine intoxication, subarachnoid hemorrhage). Can cause bradycardia and bronchospasm.|
|Esmolol||500 μg/kg intravenous bolus, followed by a 25- to 300-μg/kg/min infusion||Selective β1-receptor antagonist; has very short half-life. Effect of the drug is lost 10 to 20 min after the infusion is stopped.|
|Fenoldopam||0.1- to 1.6-μ/kg/min infusion||DA1 receptor agonist; lowers systemic blood pressure while increasing renal blood flow, so it can be useful when there is evidence of acute renal failure|
|Phenylephrine||40- to 200-μg/min infusion||α-Receptor agonist. Causes peripheral vasoconstriction while maintaining cerebral perfusion. Tachyphylaxis is common.|
|Norepinephrine||4- to 30-μg/min infusion||α- and β1-receptor agonist. Predominant effect is peripheral vasoconstriction, but it also has inotropic and chronotropic effects. Tachydysrhythmias may occur with higher doses.|
|Sodium nitroprusside||Doesn’t matter||Sodium nitroprusside dilates both arterioles and veins, which increases cerebral edema and intracranial pressure. It also worsens cerebral autoregulation and has no place in neurocritical care|
The ideal drug for managing BP in acute cerebrovascular emergencies would be rapidly titratable, have a short half-life, and have a minimal number of side effects. As with any treatment, the pharmacologic regimen prescribed for each patient must be individualized, taking into account comorbid conditions and the goal of therapy. Antihypertensives most commonly used in cerebrovascular emergencies include nicardipine, labetalol, and esmolol. Vasopressors that are useful when BP augmentation is desirable include phenylephrine and norepinephrine.
Nicardipine. Nicardipine is a dihydropyridine-derived calcium channel blocker that produces peripheral arterial vasodilatation without affecting cardiac conduction pathways.36 This effect allows for BP reduction without the risk of bradydysrhythmias. It can be given intravenously with a usual dose of 5 mg/h to 15 mg/h. Nicardipine has been shown to reduce both cerebral and coronary ischemia in the setting of uncontrolled hypertension37 and is considered a first-line agent.
Labetalol. Labetalol blocks α-, β1-, and β2-adrenergic receptors. Due to the combined blockade of both α- and β-receptors, cardiac output is maintained while the systemic BP is lowered.37 Cerebral blood flow is not compromised with labetalol, making it a desirable agent in the treatment of uncontrolled hypertension during cerebrovascular emergencies.38 Bradycardia may occur and labetalol is generally not given if the heart rate is <60 beats per minute. Labetalol can be given intermittently in 20- to 40-mg intravenous boluses until BP targets are achieved. Alternatively, a continuous infusion starting at 0.5 mg/min can be administered (with or without a loading dose of 20–40 mg) and titrated to keep the BP in the desired range.
Esmolol. Esmolol is a selective antagonist of β1-adrenergic receptors. Its duration of action is only 10 to 20 minutes, compared with 4 to 6 hours for labetalol. This effect makes esmolol very attractive for the treatment of hemodynamically unstable patients.39 In the event of significant bradydysrhythmias or hypotension, the drug can be stopped and the effect will quickly disappear. A loading dose of 500 μg/kg, followed by an infusion of 25 μg/kg/min to 300 μg/kg/min, is the usual regimen.
Fenoldopam. Fenoldopam is a dopaminergic (DA1-receptor) agonist. Its primary mechanism of action is in the proximal and distal renal tubules.37 It lowers systemic BP while augmenting renal blood flow, so it is an attractive agent for patients with both a cerebrovascular emergency and accelerated hypertensive nephropathy. Its effects on the cerebral vasculature are not well-known, so it is not used as commonly as other agents are. The dose is 0.1 μg/kg/min by continuous infusion, titrated upward as necessary to achieve the target BP.
Phenylephrine. Phenylephrine is a selective α1-adrenergic receptor agonist and can be used to augment BP in patients with hypotension and cerebral hypoperfusion. The lack of β-receptor agonism reduces the rate of tachydysrhythmias compared with dopamine and norepinephrine. Since α1-receptors are relatively rare in the cerebral vasculature, phenylephrine infusion leads to peripheral vasoconstriction without compromising cerebral perfusion.18 The usual starting dose is 40 μg/min, titrated upward as needed.
Norepinephrine. Like phenylephrine, norepinephrine is a potent α1-adrenergic receptor agonist; however, it is also a β1-receptor agonist. This effect can be useful in the setting of bradycardia due to increased intracranial pressure (the Cushing reflex) or with myocardial systolic dysfunction. The starting dose is 4 μg/min, titrated upward to maintain adequate cerebral perfusion.
Sodium Nitroprusside. Sodium nitroprusside (SNP) has long been considered a mainstay in the treatment of hypertensive emergencies, but there is evidence that SNP may be deleterious in patients with cerebrovascular emergencies and uncontrolled hypertension. SNP is a potent dilator of both arterioles and veins, which can lead to increased cerebral edema and intracranial pressure.40 In addition, renal or hepatic dysfunction can lead to impaired metabolism and accumulation of toxic levels of cyanide and thiocyanate.11,37 Given the ready availability of safer alternatives, sodium nitroprusside should not be used in the treatment of hypertension associated with cerebrovascular disease.
Acute cerebrovascular diseases are common events, and physicians should be comfortable with managing BP derangements in these patients. Above all, the treating physician should ensure that hypoxemia and cerebral hypoperfusion are avoided, as this can result in significant secondary brain injury. When uncontrolled hypertension is present, the physician must decide two things: one, what is the optimal BP for this patient; and two, what is the best pharmacologic agent to reach this goal. Prompt treatment, while avoiding exacerbating cerebral ischemia, is an integral part of the care of patients with acute cerebrovascular disease.
Disclosures: The author reports no financial or proprietary interests in any of the subject matter discussed in this manuscript. No financial support for this paper has been obtained.