Hypertensive Encephalopathy

Acute elevations in systemic arterial BP can lead to HE, resulting from a failure of the upper level of cerebral vascular autoregulation. The most common clinical manifestations include headache, nausea and vomiting, visual disturbances, focal neurologic findings, or seizures. If left untreated, the condition can progress to coma and death. The majority of patients with HE will have a MAP significantly above the patient’s baseline BP, although not always in the range typically associated with hypertensive emergency. Retinal findings including arteriolar spasm, exudates, hemorrhages, and papilledema are often present but are not required to establish the diagnosis. Magnetic resonance imaging (MRI) studies show a characteristic edema pattern involving the subcortical white matter of the parietooccipital regions; this finding is termed posterior leukoencephalopathy.¹¹ Best appreciated on T₂-weighted images, posterior structures including the cerebellum, brainstem, and occasionally the cortex also can be affected. The findings typically are bilateral but can be asymmetric. The electroencephalogram (EEG) can show loss of the posterior dominant alpha rhythm, generalized slowing, and posterior epileptiform discharges, which resolve after appropriate therapy.¹²

In general, the neurologic symptoms of stroke or intracranial hemorrhage have a more acute onset than those associated with HE. The diagnosis of HE is confirmed by the absence of other conditions and the prompt resolution of symptoms and neuroimaging abnormalities with effective BP control. No improvement within 6 to 12 hours of BP reduction should prompt a search for an alternative cause of the mental status changes. In the majority of cases, the condition is entirely reversible with no observable adverse outcomes.

Acute Stroke

Hypertension is present in as many as 80% of patients with acute stroke, particularly in patients with preexisting hypertension. The incidence is higher among patients with primary intracerebral hemorrhage as compared to ischemic disorders.¹³ The acute high systemic arterial BP most frequently declines to normal within 48 hours of presentation. The relationship between BP and mortality in patients with stroke may be “U-shaped.” According to this notion, systolic BP (SBP) values above or below 140 to 180 mm Hg are associated with increased mortality. In the International Stroke Trial, SBP above 200 mm Hg was associated with an increased risk of recurrent ischemic stroke (50% greater risk of recurrence), while low BP (particularly <120 mm Hg) was associated with an excess number of deaths from coronary heart disease.¹⁴

A number of important clinical features complicate the management of hypertension in acute stroke. First, during acute stroke, cerebral autoregulation may be compromised in ischemic tissue, and lowering of BP may further compromise CBF and extend ischemic injury. Second, medications used to treat hypertension can lead to cerebral vasodilation, augmenting CBF and leading to progression of cerebral edema.¹⁵ Ideally a “correct” level of MAP should be maintained in each patient to maintain CPP without risking worsening cerebral edema or progression of the lesion, but the clinical determination of this “ideal” value is often difficult.

A Cochrane review of 12 trials comparing an active intervention to placebo/control with 1153 total participants concluded that insufficient evidence existed to favor altering BP in acute stroke.¹⁶ Using available information, most consensus guidelines recommend that BP not be treated acutely in patients with ischemic stroke unless the hypertension is extreme (SBP >220 mm Hg or DBP >120 mm Hg) or the patient has active end-organ dysfunction in other organ systems.¹⁷ When treatment is indicated, cautious lowering of BP by approximately 15% during the first 24 hours after stroke onset is suggested. Antihypertensive medications are restarted approximately 24 hours after stroke onset in patients with preexisting hypertension who are neurologically stable, unless a specific contraindication to restarting treatment exists. Requiring special consideration are patients with extracranial or intracranial arterial stenosis and candidates for thrombolytic therapy. The former group is dependent on perfusion pressure so BP therapy may be further delayed. In contrast, before lytic therapy is started, treatment is recommended so that SBP is 185 mm Hg or less and DBP is 110 mm Hg or less. Blood pressure should be stabilized and maintained below 180/105 mm Hg for at least 24 hours after intravenous lytic therapy.¹⁷

The natural history for stroke is for BP to begin falling shortly after the onset of the acute event and to stabilize within the first 24 hours. Agents that allow titration of therapy (i.e., intravenous (IV) medications) may be preferred over oral agents when treatment is necessary, provided the patient can be carefully monitored in a stroke unit.

Patients with hemorrhagic strokes provide an additional challenge. Severe elevations in BP may worsen intracranial hemorrhage by creating a continued force for bleeding. However, the increase in arterial pressure also may be necessary to maintain cerebral perfusion in this setting, and aggressive BP management could lead to worsening cerebral ischemia. Current guidelines advise aggressive BP reduction for patients with SBP above 200 mm Hg or MAP above 150 mm Hg, using IV titration of medications and continuous monitoring. For patients with suspected elevated intracranial pressure (ICP), ICP monitoring may be indicated to help maintain CPP during therapeutic interventions. For patients with SBP above 180 mm Hg or MAP above 130 mm Hg and no evidence or suspicion of elevated ICP, a more modest reduction of BP is suggested, using intermittent dosing or continuous infusion of IV medications.

Two recent clinical trials have suggested aggressive BP reduction limits hematoma expansion without clear benefit on mortality.^18,19

Subarachnoid Hemorrhage

The patient with subarachnoid hemorrhage (SAH) provides the challenge of an acute neurologic syndrome secondary to an initial insult, followed by the ongoing risk of additional insults over time, including hydrocephalus, rebleeding, and vasospasm. The clinician faces the competing goals of lowering BP to minimize the rebleeding risk, and elevating BP to minimize the risk of cerebral vasospasm and infarction. In general, hypertension is not aggressively treated in this population for fear of precipitating cerebral ischemia. Treatment is guided by the neurologic condition. In the neurologically intact patient, small reductions in BP can be accomplished to minimize the risk of rebleeding. For the neurologically impaired patient, aggressive control of BP is avoided to maintain CPP.

Acute Coronary Syndrome

Patients presenting with acute myocardial ischemia and/or infarction frequently suffer from elevated systemic arterial pressure. This increased afterload raises myocardial oxygen demand. A reduction in myocardial work, achieved by decreasing heart rate and BP, will favorably reduce myocardial oxygen demand and infarct size in these patients. However, a reduction of high systemic arterial pressure in this setting should be done cautiously. Excessive systemic vasodilation without coronary vasodilation can lead to a reduced coronary artery perfusion pressure and infarct extension. For this reason, nitroglycerin (NTG), a potent coronary vasodilator, is often the antihypertensive agent of choice in acute coronary syndromes. In combination with beta-blocker therapy, this approach can reduce cardiac workload significantly in the setting of ischemia. Careful monitoring of hemodynamic indices during treatment is paramount.

Acute Left Ventricular Dysfunction

The vast majority of patients presenting with acute heart failure are hypertensive on initial assessment.²⁰ Hypertension can be the inciting event, with secondary myocardial dysfunction; or alternatively, hypertension can be a secondary component of acute pulmonary edema due to the sympathoadrenal response to hypoxemia, increased work of breathing, and anxiety. Efforts to control elevated systemic arterial pressure in this setting are essential because high systemic arterial BP in the patient with acute pulmonary edema contributes to increased myocardial workload and diastolic dysfunction. In contrast, the use of vasodilators in patients with acute pulmonary edema and normal to low BP can have deleterious effects.^21,22 Similar to the patient with cerebrovascular disease, a U-shaped blood pressure/mortality relationship is expected.

For the hypertensive patient with acute heart failure, IV vasodilators such as NTG and sodium nitroprusside (SNP) permit rapid titration of BP and are preferred. Patients with acute pulmonary edema may be hypertensive secondary to high circulating catecholamine levels. With effective treatment or control of hypoxemia and anxiety, BP can decrease rapidly, especially in the setting of concomitant diuresis. Thus, longer-acting medications such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) should be avoided early in the treatment period. Patients with hypertensive emergencies, in particular, may have undergone excessive natriuresis, resulting in elevated levels of renin production by the kidney and, hence, increased circulating levels of the potent endogenous vasoconstrictor, AT II. Further reduction in intravascular volume and renal perfusion can lead to a further increase in circulating AT II levels. Therefore, aggressive diuresis prior to BP control is generally not a good idea. Medications that increase cardiac work (e.g., hydralazine) or impair cardiac contractility (e.g., labetalol) are contraindicated as primary therapy for hypertension in the setting of acute LV dysfunction.

In addition to the more traditional IV vasodilators, IV calcium channel antagonists have demonstrated efficacy in the treatment of acute hypertension in the setting of LV dysfunction. The dihydropyridine calcium channel antagonists nicardipine and clevidipine can reduce systemic arterial pressure while preserving coronary blood flow.²³ Fenoldopam, a dopamine-1 receptor antagonist, also has been has been shown to preserve coronary blood flow during treatment to reduce systemic arterial pressure in this setting.²⁴ Despite their demonstrated efficacy in the treatment of hypertensive emergency, limited data exist with these newer agents to suggest superiority over NTG or nitroprusside. Agent selection should first be influenced by the adverse risk profile associated with the individual agents (Table 5-1). When not contraindicated by specific risk, the agents with a more favorable cost profile (i.e., NTG, nitroprusside) should be used based upon equivalent efficacy.

Acute Aortic Dissection

Aortic dissection results from an intimal tear in the aortic wall. The primary morbidity and mortality results from extension of the tear. This extension is promoted by factors that increase the rate of change of aortic pressure (dp/dt), including elevation in BP, heart rate, and myocardial stroke volume. Blood pressure should be reduced promptly to near-normal levels. Aggressive control of BP with a vasodilator can trigger reflex tachycardia, leading to increased dp/dt. Combined modality therapy to promote vasodilation (SNP) and control cardiac contractility (beta-blocker) is advocated for this disorder.

Scleroderma Renal Crisis

Scleroderma renal crisis is characterized by the development of acute renal failure associated with moderate to severe hypertension and a normal to minimally abnormal urine sediment. The most significant risk factor for scleroderma renal crisis is the presence of diffuse skin involvement characteristic of the disease and recent treatment with high-dose corticosteroids.²⁵ The disorder results in marked activation of the renin-angiotensin system. Aggressive control of BP using ACE inhibitors, particularly early in the disease process, can control BP in up to 90% of patients and promote a greater rate of recovery in renal function.²⁶

Post Kidney Transplantation

Hypertension following renal transplantation occurs in the majority of patients.²⁷ In the immediate posttransplantation period, hypertension can be a manifestation of volume overload, graft rejection, ischemia, or toxic effects of calcineurin inhibitors used for immunosuppression. Treatment is directed primarily at the underlying mechanism. Renal artery stenosis can also complicate allograft function and should be evaluated in any patient with resistant hypertension. This complication can occur at any time within 1 month or up to 3 years after transplantation.²⁸ In the immediate posttransplant period, BP should be regulated at the upper limits of normal to preserve graft function. In the later postoperative period, more strict control of BP is favored.²⁹ Calcium channel blockers (CCBs) are frequently used to treat hypertension after renal transplantation, based upon their antagonism of cyclosporine-induced renal vasoconstriction. CCBs also have been studied extensively in renal transplant hypertension and are associated with preservation of allograft function in comparison to placebo.²⁹ ACE inhibitors have the potential to exacerbate renal dysfunction and augment hyperkalemia induced by calcineurin inhibitors.

Pheochromocytoma

Pheochromocytoma can result in the production of circulating mediators, leading to catecholamine excess. These mediators result in hypertension, diaphoresis, tachycardia, and paresthesias of the hands and feet. These attacks can last from minutes to days and occur as frequently as several times a day or as infrequently as once a month.³⁰ Operative manipulation of the tumor can result in perioperative hypertension. The treatment of hypertension in this disorder must avoid the use of isolated therapy with a beta-blocker, a strategy that can lead to unopposed alpha-adrenergic stimulation, with the risk of further vasoconstriction and BP elevation. The preferred agent for treatment is phentolamine, a potent alpha-adrenergic antagonist. If needed, this medication can be combined with a beta-blocker, or a combined alpha/beta-blocker such as labetalol also can be used safely.

Pharmacologically Mediated

A broad range of medications have been associated with the development of hypertension or alternatively may limit the effectiveness of treatment for primary hypertension. A detailed medical history is required to evaluate patients with high systemic arterial BP. Attention should be paid to prescription medications as well as herbal supplements and substance abuse.³¹ Both administration of exogenous substances and abrupt withdrawal of substances can be associated with hypertensive crises. As an example, clonidine withdrawal can mimic the crisis of pheochromocytoma. Clonidine is a centrally acting stimulant of alpha-adrenergic receptors that reduces peripheral adrenergic system activation. Rapid withdrawal or tapering of clonidine produces a hyperadrenergic state characterized by hypertension, diaphoresis, headache, and anxiety.³² The syndrome is best treated by restarting treatment with clonidine. Extreme symptoms can be treated as outlined for the patient with pheochromocytoma. Hypertension also can occur during the withdrawal phase of alcohol abuse.

Monoamine oxidase (MAO) inhibitors are associated with marked elevations of systemic arterial BP if the patient consumes foods or medications containing tyramine or other sympathomimetic amines. Tyramine-containing foods include champagne, avocados, smoked or aged meats, and fermented cheeses. The MAO inhibitor interferes with degradation of tyramine in the intestine, leading to excess absorption of the amine and tyramine-induced catecholamine activity in the circulation.

Other medications, including metoclopramide, a dopamine agonist, the calcineurin inhibitors, cyclosporine and tacrolimus, and drugs of abuse such as cocaine, phenylpropanolamine, phencyclidine, and methamphetamine all must be considered as possible factors in the evaluation of elevated systemic arterial pressure.

Following spinal cord injury, hypertensive states may occur, particularly with stimulation of dermatomes and muscles below the level of the spinal cord injury. Patients with hypertension in this setting typically have lesions above the level of the thoracolumbar sympathetic neurons. The BP elevation is believed to result from excessive stimulation of sympathetic neurons. Hypertension is accompanied by bradycardia through stimulation of the baroreceptor reflex. Treatment is focused on minimizing stimulation and providing medical therapy as necessary. Patients with Guillain-Barré syndrome can present with a similar clinical picture.

Preeclampsia/Eclampsia

Preeclampsia/eclampsia remains the second most common cause of maternal death in the United States, following thromboembolic disease. Hypertension occurs as one manifestation of preeclampsia in the pregnant patient; the other key features are proteinuria and edema. Hypertension in pregnancy also can be seen secondary to chronic hypertension and transient or gestational hypertension. New onset of hypertension following 20 weeks of gestation is most characteristic of the patient with preeclampsia.

When possible, the optimal treatment of preeclampsia is delivery of the fetus, an approach that prevents progression to eclampsia. However, BP should be regulated to prevent end-organ damage. Hydralazine is considered the antihypertensive agent of choice in pregnant patients. SNP (fetal defects), ACE inhibitors (renal dysfunction in the fetus), and trimethaphan (meconium ileus) should be avoided in pregnant patients. Alternatives to hydralazine to control hypertension in pregnant patients include labetalol and nicardipine.

Postoperative Hypertension

Poorly controlled hypertension pre- and intraoperatively is associated with an increased rate of postoperative complications. Postoperative hypertension occurs in as many as 75% of patients, and the risk appears to be greater for vascular surgical procedures, including abdominal aortic aneurysm repair, carotid endarterectomy, and coronary artery revascularization. Postoperative hypertension in these patients can lead to complications including bleeding from suture lines, intracerebral hemorrhage, and LV dysfunction. Postoperative hypertension can be caused by elevated systemic vascular resistance in response to circulating stress hormones, renin-angiotensin-aldosterone system activation, or altered baroreceptor function.

Patients with postoperative hypertension must be thoroughly investigated to rule out reversible causes prior to the institution of drug therapy. Factors such as pain, anxiety, hypervolemia, hypoxemia, hypercarbia, and nausea can contribute to the disorder. Postoperative hypertension is often limited in duration (i.e., 2-12 hours), and aggressive attempts to acutely lower BP can lead to delayed hypotension.

Postoperative hypertension is typically treated with administration of vasodilators, including SNP and NTG or beta-blockers as needed.

Nitric Oxide Vasodilators

SNP is an NO donor that activates endovascular guanylyl cyclase, leading to the formation of the second messenger, cyclic guanosine monophosphate (cGMP) and ultimately smooth muscle relaxation. SNP has been the gold standard for the treatment of hypertensive emergencies, owing to its short duration of action, allowing careful titration. SNP acts as a direct vasodilator of arterioles and veins. The BP response to SNP is rapid and mandates the use of this medication in a well-monitored environment. The infusion must be provided by a calibrated pump, with frequent BP recordings. Typically, intraarterial BP monitoring is preferred because of the need for rapid and frequent dosage adjustments, particularly during initial titration of the medication. However, an accurate noninvasive system may be sufficient in some cases.

SNP’s arteriolar and venous vasodilating activity may not be uniform, however. Redistribution of oxygenated blood flow from unresponsive ischemic regions to vasodilated nonischemic coronary arteries can reduce coronary perfusion pressure, resulting in a “coronary steal” syndrome.³³ A similar “cerebral steal” syndrome has been suggested with SNP as a result of preferential vasodilation in systemic vascular beds versus cerebral vessels.¹⁵ Additional concerns have been raised with the use of SNP in patients with increased ICP; dilatation of large-capacitance vessels by SNP can lead to an increase in CBF and ICP.¹⁵

In rare instances, SNP administration can lead to cyanide or thiocyanate toxicity. Cyanide intoxication is manifested by alterations in mental status, gastrointestinal (GI) complaints, arrhythmias, seizures, and/or lactic acidosis. The latter finding occurs in association with a reduced systemic oxygen uptake and a narrow arterial-venous oxygen gradient. Cyanide is liberated during the combination of nitroprusside with sulfhydryl groups in red cells and tissues. Cyanide is converted in the liver to thiocyanate, with subsequent excretion by the kidney.

Cyanide toxicity from SNP is uncommon and occurs primarily in patients receiving infusions for more than 24 to 48 hours, in the setting of underlying renal insufficiency, and/or the use of doses that exceed the capacity of the body to detoxify cyanide (>2 µg/kg/min). The treatment of cyanide intoxication involves the administration of sodium thiosulfate. Sodium thiosulfate donates its sulfane sulfur atom in a reaction catalyzed by the enzyme, rhodanese, to convert cyanide to the much less toxic thiocyanate ion, which is then excreted in the urine. For severe cases, sodium nitrite may also be administered. Sodium nitrite oxidizes hemoglobin (Hb) in the blood to methemoglobin, which binds cyanide with high affinity. Thus, methemoglobin competes with other cellular targets for cyanide, notably cytochrome a-a3 in mitochondria, and thereby decreases the toxic effects of cyanide ion. The onset of action of sodium nitrite is rapid, but the induction of methemoglobinemia decreases the oxygen-carrying capacity of blood and therefore can be harmful in patients with anemia or significant carboxyhemoglobinemia. Hydroxocobalamin (vitamin B_12a), is another safe and effective antidote for cyanide intoxication. Hydroxyocobalamin administration does not affect the oxygen-carrying capacity of the blood, so this harmless agent may be preferable to sodium nitrite. Hydroxyocobalamin reacts with circulating cyanide to form cyanocobalamin, with subsequent urinary excretion. Hydroxocobalamin has been demonstrated to minimize the risk of cyanide accumulation during nitroprusside use in surgery.³⁴

Thiocyanate toxicity in association with SNP infusion is also rare. The clinical manifestations include fatigue, GI complaints, and mental status changes. The symptoms most typically appear when plasma thiocyanate levels are over 5 to 10 ng/dL, and occur with higher-dose SNP infusion in the setting of renal impairment.

Nitroglycerin is a vasodilator known to promote coronary vascular dilation. The drug acts as a systemic venodilator, acting to reduce myocardial preload. It demonstrates arterial smooth muscle effects only at higher infusion rates. The drug is contraindicated in patients with significant volume depletion; venodilation in these patients will further lower preload, reduce cardiac output, and compromise overall systemic perfusion. When administered by the IV route, NTG has a relatively short duration of action. The drug has favorable effects for patients with acute coronary syndromes, including reducing myocardial oxygen demand via its effects on preload and afterload and augmenting myocardial oxygen delivery through its effects on the coronary circulation.

Headache is the most common adverse effect of NTG, and methemoglobinemia is a rare complication of prolonged NTG therapy. Tolerance to the medication is recognized and may limit the overall effectiveness in longer-term infusions.

Calcium Channel Blockers

Calcium channel blockers are a heterogenous class of medications used in the treatment of hypertension emergencies. A specific class of CCB called the dihydropyridines (e.g., nicardipine, clevidipine) are selective for vascular smooth muscle over the myocardium, having little if any activity on cardiac muscle or the sinoatrial node.³⁵ Because these drugs act to promote vascular smooth muscle relaxation without associated cardiac effects, they are attractive for the treatment of hypertensive emergencies. In contrast, CCBs from other pharmacologic classes, such as diltiazem and verapamil, affect the cardiac conduction system and myocardial calcium channels, making them less optimal choices for the treatment of hypertension.

Nicardipine hydrochloride is a dihydropyridine CCB that acts primarily as a systemic, cerebral, and coronary artery vasodilator. The greater water solubility of this drug, in comparison to other CCBs such as nifedipine, allows IV administration with a short onset and duration of action and therefore easy titration to therapeutic effect. The medication has no significant effect on cardiac inotropy and promotes afterload reduction. Nicardipine readily crosses the blood-brain barrier and relaxes vascular smooth muscle, especially in regions of ischemic tissue. The medication acts as a vasodilator of small-resistance cerebral arterioles but does not change intracranial volume or ICP; thus, cerebral oxygenation is preserved.³⁶

Nicardipine has been studied as an alternative agent to SNP in the management of hypertension for patients with intracranial or subarachnoid hemorrhage. In comparison to SNP, nicardipine offers equal efficacy in terms of BP control. But nicardipine, avoiding problems related to the toxic metabolites of SNP, requires less frequent dose adjustments and carries less risk of increasing ICP.³⁷ Comparative investigations of nicardipine and nitroprusside in postoperative patients with hypertension suggest therapeutic equivalency.^38,39 Nicardipine is metabolized by the liver, and excretion can be impaired in patients with abnormal hepatic function.

Clevidipine is the first third-generation dihydropyridine CCB approved in the United States. It is supplied as a racemic mixture in a lipid emulsion for IV infusion. Clevidipine is an ultrafast arteriolar vasodilator that reduces afterload without affecting cardiac filling pressures or causing reflex tachycardia. Clevidipine has a rapid onset (~2-4 minutes) and offset of action (~5-15 minutes). It undergoes rapid ester hydrolysis by arterial blood esterases to form inactive metabolites, which makes clearance of this medication independent of renal or hepatic function.

Clevidipine has been most extensively investigated in adult patients (>18 years of age) with acute perioperative or postoperative hypertension in the setting of cardiac surgery. The antihypertensive efficacy of IV clevidipine was compared with that of SNP and NTG for perioperative hypertension, and with nicardipine for postoperative hypertension.⁴⁰ All agents were administered by IV infusion. The primary endpoint was the incidence of death, stroke, MI, or renal dysfunction from study drug initiation to 30 days after surgery. BP control was a secondary endpoint evaluated; using the area under the curve (AUC) of SBP excursions above or below predetermined limits (65-135 mm Hg, intraoperatively; 75-145 mm Hg, pre- and postoperatively).

There was no difference in the incidence of MI, stroke, or renal dysfunction for clevidipine-treated patients compared with the other treatment groups. There was no difference in mortality rates between the clevidipine, NTG, or nicardipine groups. Mortality was significantly higher, however, for SNP-treated patients compared with clevidipine-treated patients. Clevidipine was more effective compared with NTG (P <0.0006) or SNP (P <0.003) in maintaining BP within the prespecified BP range. Clevidipine was equivalent to nicardipine for keeping patients within a prespecified BP range; however, when the BP range was narrowed, clevidipine was associated with fewer BP excursions beyond these BP limits compared with nicardipine.

The antihypertensive efficacy of IV clevidipine in patients with acute severe hypertension has also been assessed in a large, noncomparative, open-label, multicenter, phase III study.⁴¹ Clevidipine was administered as a non–weight-based dose of 2 mg per hour for patients with acute severe hypertension with or without end-organ injury. The medication provided rapid, predictable BP control, and the majority of patients reached the target BP within 30 minutes. Prolonged administration (>18 hours) was well tolerated.

Clevidipine is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products. Clevidipine is also contraindicated in patients with defective lipid metabolism. Owing to lipid-load restrictions, no more than 1000 mL or an average of 21 mg/h of clevidipine infusion is recommended per 24-hour period. Clinicians must account for the calories infused from the lipid emulsion and adjust the nutrition regimen as needed and monitor triglyceride levels during prolonged administration.