CRITICAL CARE ISSUES FOR THE NEPHROLOGIST Current Diagnosis and Management of Hypertensive Emergency Andrew R. Haas and Paul E. Marik Division of Critical Care, Pulmonary, Allergy and Immunologic Disease, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania ABSTRACT The appropriate and timely evaluation and treatment of patients with severely elevated blood pressure is essential to avoid serious adverse outcomes. Most importantly, the distinction between a hypertensive emergency (crisis) and urgency needs to be made. A sudden elevation in systolic (SBP) and/or diastolic blood pressure (DBP) that is associated with acute end organ damage (cardiovascular, cerebrovascular, or renal) is defined as a hypertensive crisis or emergency. In contrast, acute elevation in SBP and/or DBP not associated with evi- dence of end organ damage is defined as hypertensive urgency. In patients with a hypertensive emergency, blood pressure control should be attained as expeditiously as possible with parenteral medications to prevent ongoing and potentially permanent end organ damage. In contrast, with hypertensive urgency, blood pressure control can be achieved with the use of oral medications within 24–48 hours. This paper reviews the management of hypertensive emergencies. Hypertension is one of the most common chronic medical conditions in the United States affecting close to 30% of the population over the age of 20 years (1,2). While chronic hypertension is an established risk factor for cardiovascular and cerebrovascular mortality and end-stage renal disease, accelerated elevations in blood pressure from various etiologies can result in acute end organ damage and dysfunction. These acute blood pressure elevations are likely to be encountered by a wide variety of clinicians and recognition and prompt evaluation and treatment are crucial to prevent permanent end organ damage. Unfortunately, the impact of these clinical situations is often underappreciated such that appropriate and timely evaluation and treatment is delayed leading to potentially serious adverse outcomes. ciated with evidence of end organ damage is defined as hypertensive urgency (7,8,11). To simplify the categorization of acute elevations in blood pressure, the term ‘‘malignant hypertension,’’ used to describe a syndrome characterized by elevated blood pressure with encephalopathy or acute nephropathy, has been removed by the National and International Blood Pressure Control Guidelines and should be referred to as hypertensive emergency or crisis instead (1,12). Several points should be considered when distinguishing hypertensive emergency from hypertensive urgency. The presence of end organ damage, not the absolute blood pressure, is the differentiating factor between hypertensive emergency and urgency. This differentiation is critical, as how quickly and aggressively the quest for blood control is pursued is dictated by the presence of end organ damage. Specifically, in hypertensive emergency, blood pressure control should be attained as expeditiously as possible with parenteral medications to prevent ongoing and potentially permanent end organ damage. In contrast, with hypertensive urgency, blood pressure control can be achieved with the use of oral medications within 24–48 hours (7,8,11). This review will focus on the management of hypertensive emergencies. Table 1 lists those clinical conditions regarded as a hypertensive emergency. The classification and approach to hypertension undergoes periodic review by the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure with the most recent report (JNC VII) having been released in 2003 (see Table 2) (1,12). Within this report, the classification of blood pressure was simplified compared with previous JNC reports with the recognition of two stages Definitions The terminology applied to the clinical situations associated with acute elevations in blood pressure has been confusing and often misused. Most authorities concur that a sudden elevation in systolic (SBP) and/or diastolic blood pressure (DBP) that is associated with acute end organ damage (cardiovascular, cerebrovascular, or renal) is defined as hypertensive crisis or emergency (3– 11). In contrast, acute elevation in SBP or DBP not assoAddress correspondence to: Paul E. Marik, MD, Division of Pulmonary and Critical Care Medicine, 834 Walnut Street, Suite 650, Philadelphia, PA 19107, or e-mail: paul.marik@ jefferson.edu. Seminars in Dialysis—Vol 19, No 6 (November–December) 2006 pp. 502–512 502 HYPERTENSIVE EMERGENCY TABLE 1. Hypertensive emergencies Hypertensive encephalopathy Acute aortic dissection Acute myocardial infarction Acute coronary syndrome Pulmonary edema with respiratory failure Severe pre-eclampsia, HELLP syndrome, eclampsia Acute renal failure Microangiopathic hemolytic anemia HELLP, Hemolysis, elevated liver enzymes, low platelets. TABLE 2. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure categorization of blood pressure (JNC VII) (1,12) Blood Pressure Class Systolic BP (mmHg) Diastolic BP (mmHg) Normal Prehypertension Stage I Stage II <120 121–139 140–159 >160 <80 80–89 90–99 >100 of hypertension (compared with the previous four stages in JNC VI), but a new category called prehypertension was added (13). Addition of this category was deemed important to recognize that progression from this category to hypertension is often encountered, which subsequently puts patients at increased risk for the various complications associated with chronic hypertension. As mentioned previously, hypertension is an extremely common medical problem in the United States with an ever-increasing incidence given increasing obesity rates and the metabolic syndrome affecting the nation (14–16). A striking increase in hypertension in young adults and children because of obesity and sedentary lifestyles is also occurring (17,18). Most of these patients have essential hypertension; however, only 68.9% were reported to be aware of their blood pressure problem, only 58.4% were under pharmacologic treatment, and adequate blood pressure control was achieved in only 30–50% of patients depending on the population studied (2,19–25). Interestingly, even with these poor statistics on blood pressure recognition, treatment, and control, only 1% of these patients will develop a true hypertensive emergency (26,27). As would be expected, most patients who present with hypertensive emergency have previously received a diagnosis of hypertension with many of them having inadequate blood pressure control on oral therapy. Of note, because of many factors including access to healthcare, economic demographics, and age and ethnic responses to various medications, the elderly and African Americans are at higher risk of developing a hypertensive emergency (11,28–30). Pathophysiology The pathophysiology of hypertensive emergency is multifactorial and includes such factors as mechanical stress and injury, endothelial damage, renin–angiotensin system activation, and oxidative stress. The initial insult is often difficult to ascertain, but abrupt release of 503 humoral vasoconstrictors increase systemic vascular resistance (31,32). The subsequent increase in blood pressure generates mechanical stress and endothelial injury leading to increased permeability, activation of the coagulation cascade and platelets, and deposition of fibrin. This process results in ischemia and the release of additional vaso-active mediators generating a vicious cycle of ongoing injury. The renin–angiotensin system is often activated leading to further vasoconstriction and the production of proinflammatory cytokines such as IL-6 (33,34). Furthermore, NADPH oxidase activity is increased and generates reactive oxygen species (35). These collective mechanisms can culminate in end organ hypoperfusion, ischemia, and dysfunction that manifest as hypertensive emergency. Initial Diagnostic Evaluation Patients with hypertensive emergency usually present for evaluation as a result of a new symptom complex related to their elevated blood pressure. Patient triage and physician evaluation should proceed expeditiously to prevent ongoing end organ damage. A focused medical history that includes the use of any prescribed or over-the-counter medications should be obtained. If the patient is known to have hypertension, their hypertensive history, previous control, current antihypertensive medications with dosing, compliance, and time from last dose are important facts to know as subsequent treatment decisions are made. Inquiry into use of recreational drugs (amphetamines, cocaine, and phencyclidine) or monoamine oxidase inhibitors should be made. Confirmation of the blood pressure should be obtained in both arms by a physician using a blood pressure cuff of appropriate size. The appropriate size cuff is particularly important as the use of a cuff too small for the arm size has been shown to artificially elevate blood pressure readings in obese patients (36,37). As mentioned previously, it is important to note that the rate of blood pressure elevation may be more important than the absolute value (38– 41). Patients with long-standing hypertension may tolerate SBP > 200 mmHg or DBP > 150 mmHg without developing clinical signs or symptoms of end organ damage; however, in postoperative or pregnancy patients a much lower but more rapidly progressive increase in blood pressure may result in end organ damage. The physical examination should attempt to identify evidence of end organ damage by assessing pulses in all extremities, auscultating the lungs for evidence of pulmonary edema, the heart for murmurs or gallops, the renal arteries for bruits, and performing a focused neurologic and fundoscopic examination. Headache and altered levels of consciousness are the usual manifestations of hypertensive encephalopathy (38,42). Focal neurological findings, especially lateralizing signs, are uncommon in hypertensive encephalopathy, being more suggestive of a cerebrovascular accident. Subarachnoid hemorrhage should be considered in patients with a sudden onset of a severe headache. The ocular examination may show evidence of advanced retinopathy with 504 Haas and Marik arteriolar changes, exudates, hemorrhages, or papilledema assisting in the identification of hypertensive encephalopathy. Cardiac evaluation should aim to identify angina or myocardial infarction with the focus on clarifying any atypical symptoms such as dyspnea, cough, or fatigue that may be overlooked (28,43). Severe renal injury may result in hematuria or oliguria. On the basis of this evaluation, the clinician should be able to distinguish between a hypertensive emergency and an urgency and to formulate the subsequent plan for further diagnostic tests and treatment. Initial objective evaluation should include a metabolic panel to assess electrolytes, creatinine, and blood urea nitrogen; a complete blood count (and smear if microangiopathic hemolytic anemia is suspected); a urinalysis to look for proteinuria or microscopic hematuria; and an electrocardiogram to assess for cardiac ischemia (27). Supportive radiographic studies such as a chest radiograph in a patient with dyspnea or chest pain or a head computed tomography scan in a patient with neurologic symptoms should be obtained in the appropriate clinical scenario. If the physical examination or clinical picture is consistent with aortic dissection (unequal pulses and widened mediastinum), a contrast-computed tomography scan or MRI of the chest should be obtained promptly to rule out aortic dissection. Although trans-esophageal echocardiography has excellent sensitivity and specificity for aortic dissection, this study should not be performed until adequate blood control has been achieved. In patients presenting with pulmonary edema it is important to obtain an echocardiogram to distinguish between diastolic dysfunction, transient systolic dysfunction, or mitral regurgitation (44). Many patients, particularly the elderly, have a normal ejection fraction and in such patients heart failure is caused by isolated diastolic dysfunction (44). The management of these patients differs from those patients with predominant systolic dysfunction and those with transient mitral regurgitation (see Table 3). The unique clinical situation of pregnancy and eclampsia is worth noting. Pre-eclampsia can range from mild to life threatening, with features in severe disease consistent with multiorgan damage (45,46). Patients may have severe headache, seizures, acute delirium, visual defects, right upper quadrant pain, oliguria, and congestive heart failure. Intracerebral hemorrhage is a devastating and often fatal complication (45,47). While antihypertensive agents are used to control blood pressure, rapid assessment and decisions regarding risk to mother and fetus need be considered as the only definitive therapy is delivery of the fetus (45,46). Initial Management The majority of patients in whom severe hypertension (SBP > 160, DBP > 100 mmHg) is identified on initial evaluation will not have evidence of end organ damage and thus have hypertensive urgency. As no acute end organ damage is present, these patients may present for evaluation of another complaint, and the elevated blood pressure may represent an acute recognition of chronic hypertension. In these patients, utilizing oral medications to lower the blood pressure gradually over 24–48 hours is the best approach to management (7,8,11). In fact, rapid reduction of blood pressure may be associated with significant morbidity in hypertensive urgency because of a rightward shift in the pressure/flow auto-regulatory curve in critical arterial beds (cerebral, coronary, and renal) (48). Rapid correction of severely elevated blood pressure below the autoregulatory range of these vascular beds can result in a marked reduction in perfusion causing ischemia and infarction (39,49–51). Therefore, although the blood pressure must be reduced in these patients, it must be lowered in a slow and controlled fashion to prevent this impaired autoregulatory hypoperfusion problem. This autoregulatory problem also occurs in patients with hypertensive emergency; and as end organ damage is already present, rapid and excessive correction of the blood pressure can further reduce perfusion and propagate the ongoing injury. Therefore, patients with a hypertensive emergency are best managed with a continuous infusion of a short-acting, titratable antihypertensive agent. Because of unpredictable pharmacodynamics, the sublingual and intramuscular route should be avoided. Patients with a hypertensive emergency should be managed in an intensive care unit with close monitoring. For those patients with the most severe clinical manifestations or with the most labile blood pressure, intra-arterial blood pressure monitoring may be prudent. TABLE 3. Recommended antihypertensive agents for hypertensive crises Condition Acute pulmonary edema-systolic dysfunction Acute pulmonary edema-diastolic dysfunction Acute myocardial ischemia Hypertensive encephalopathy Acute aortic dissection Pre-eclampsia, eclampsia Acute renal failure/microangiopathic anemia Sympathetic crisis/cocaine overdose Preferred antihypertensive agent Nicardipine, fenoldopam, or nitroprusside in combination with nitroglycerin and a loop diuretic Esmolol, metoprolol, labetalol, or verapamil in combination with low-dose nitroglycerin and a loop diuretic Labetalol or esmolol in combination with nitroglycerin Labetalol, nicardipine, or fenoldopam Labetalol or combination of nicardipine or fenoldopam and esmolol or combination of nitroprusside with either esmolol or IV metoprolol Labetalol or nicardipine Fenoldopam or nicardipine Verapamil, diltiazem, or nicardipine in combination with a benzodiazepine 505 HYPERTENSIVE EMERGENCY There are a variety of rapid-acting intravenous agents that are available for use in patients with hypertensive emergency, and the agent of choice depends on which manifestation of end organ damage is present and the available monitored setting (see Table 3). As mentioned previously, rapid-acting intravenous agents should not be used outside of an intensive care unit monitored setting to prevent a precipitous reduction of blood pressure, which may have significant morbidity or mortality. The immediate goal is to reduce DBP by 10–15% or to about 110 mmHg over a period of 30–60 minutes. In aortic dissection, this goal should be achieved within 5–10 minutes. Once there is a stable blood pressure with intravenous agents and end organ damage ceased, oral therapy can be initiated as the intravenous agents are slowly titrated down. One very important consideration prior to initiating intravenous therapy is to assess the patient’s volume status. Because of pressure natriuresis, patients with hypertensive emergencies may be volume depleted and restoration of intravascular volume with intravenous saline will serve to restore organ perfusion and prevent a precipitous fall in blood pressure when antihypertensive regimens are initiated. Pharmacologic Agents Available for Treatment of Hypertensive Emergency Given the aforementioned problem related to an abnormal autoregulatory response in many patients with hypertensive emergency, the ideal agent for these situations would be fast acting and rapidly reversible to allow for optimal titration of blood pressure control. Intravenous antihypertensive agents available for the management of hypertensive emergencies fall into the broad categories of arterial vasodilators (hydralazine, fenoldopam, nicardipine, clevidipine, and enalaprilat); venous vasodilators (nitroglycerin); mixed venous and arterial vasodilators (sodium nitroprusside); negative inotropic/chronotropic agents with (labetalol) or without vasodilator properties (esmolol); and alpha-adrenergic receptor blockers for increased sympathetic activity (phentolamine). At this time the preferred agents for the management of hypertensive emergency include labetalol, esmolol, nicardipine, and fenoldopam. Phentolamine and trimethaphan camsylate are less commonly used today; however, they may be useful in particular situations such as catecholamine-induced hypertensive crises (i.e., pheochromocytoma) (26,38–40,52,53). The preferred antihypertensive for each hypertensive emergency is listed in Table 3. The antihypertensive agents that have been used for the treatment of a hypertensive emergency are reviewed individually and alphabetically below. The dosage and adverse effects of these agents are summarized in Table 4. Clevidipine. Clevidipine is a relatively new agent under investigation for management of postanesthesia hypertension and possibly hypertensive emergencies (54). It is an ultrashort acting vaso-selective calcium channel antagonist with rapid onset and very short halflife (<1 min). Similar to esmolol, it is rapidly metabolized by red blood cell esterases; thus its metabolism is not affected by renal or hepatic function. Clevidipine reduces blood pressure by a direct and selective effect on arterioles, thereby reducing afterload without affecting cardiac filling pressures or causing reflex tachycardia (54). In fact, it increases stroke volume and cardiac output. Moreover, it has been shown to protect against ischemia/reperfusion injury in an animal model of myocardial ischemia and to maintain renal function and splanchnic blood flow when compared with nitroprusside (55–57). Several small trials have compared clevidipine with nitroprusside in the management of anesthetized patients with postoperative hypertension. These studies report similar findings: clevidipine is as effective at blood pressure control as nitroprusside, but it has less effect on cardiac filling pressures and heart rate (58,59). Although no studies have investigated the role of clevidipine in hypertensive emergency, its profile of excellent blood pressure control, fewer hemodynamic and cardiac side effects, and a short half-life, make it a potentially ideal drug for the treatment of hypertensive emergency. At TABLE 4. Recommended antihypertensive agents for hypertensive crises dosage and adverse effects of commonly used parenteral antihypertensive medications Agent Enalaprilat Esmolol Fenoldopam Labetalol Nicardipine Nitroglycerin Nitroprusside Phentolamine Dosage 1.25 mg over 5 min every 4–6 hr, titrated by 1.25 mg increments at 12- to 24-hr intervals to a maximum of 5 mg every 6 hr 500 lg/kg loading dose over 1 min, infusion at 25–50 lg/kg/min, increased by 25 lg/kg/min every 10–20 min to maximum of 300 lg/kg/min 0.1 lg/kg/min initial dose, 0.05–0.1 lg/kg/min increments to a maximum of 1.6 lg/kg/min 20 mg initial bolus, 20–80 mg repeat boluses or start infusion at 2 mg/min with a maximum 24 hr dose of 300 mg 5 mg/hr, increased at 2.5 mg/hr increments every 5 min to a maximum of 15 mg/hr 5 ug/min, titrated by 5 ug/min every 5–10 min to a maximum of 100 ug/min 0.5 lg/kg/min, increased to a maximum of 2 lg/kg/min to avoid toxicity 1–5 mg boluses, maximum 15-mg dose Adverse effects Variable response, potential hypotension in high rennin states, headache, dizziness Nausea, flushing, first degree heart block, infusion site pain Nausea, headache, flushing Hypotension, dizziness, nausea/vomiting, paresthesias, scalp tingling, bronchospasm Headache, dizziness, flushing, nausea, edema, tachycardia Headache, dizziness, tachyphylaxis Thiocyanate and cyanide toxicity, headache, nausea/vomiting, muscle spasm, flushing Flushing, tachycardia, dizziness nausea/vomiting 506 Haas and Marik this time clevidipine is not available in the United States for use outside of clinical trials. Enalaprilat. As the intravenous form of the oral angiotensin converting enzyme (ACE) inhibitor enalapril, enalaprilat has gained popularity in use in some hypertensive emergencies. It has an onset of action within 15 minutes, but its peak effect may not be seen for up to 4 hours and its duration of action can last from 12 to 24 hours. The response to enalaprilat can be variable and unpredictable as a result of variable plasma volume and plasma rennin activity present in patients with hypertensive emergency (60). Hypovolemic patients with high plasma rennin activity may have an excessive and deleterious hypotensive response. Because of these factors, the delayed peak effect, and its long duration of action, enalaprilat is not ideal for rapid titration of blood pressure in hypertensive emergency. Importantly, this agent is contraindicated in pregnancy (61,62). Esmolol. Esmolol is a cardioselective, beta-adrenergic blocking agent with an almost immediate onset of action, a short half-life of approximately 9 minutes, and a duration of action of 10–30 minutes (63–65). Its short half-life is because of rapid hydrolysis by red blood cell esterases and thus is not dependent on renal or hepatic function for metabolism. These pharmacokinetic and dynamic properties make esmolol an ideal agent for use in critically ill patients with supraventricular dysrhythmias, patients with postoperative hypertension, and in patients with hypertensive emergency (66,67). Esmolol can be administered via bolus or continuous infusion. The recommended bolus dose is 0.5–1.0 lg/kg with an infusion rate at 50–200 lg/kg/min. Because of its short duration of action, the main side effects of bradycardia and excessive hypotension because of negative chronotropic and inotropic effects are rapidly reversed by slowing or discontinuing the infusion. For hypertensive emergency, esmolol often must be combined with a vasodilating agent to achieve optimal blood pressure control. Fenoldopam. Fenoldopam is unique among the parenteral blood pressure agents as it mediates peripheral vasodilation by acting on peripheral dopamine-1 receptors. Interestingly, it has the distinct advantage of mediating renal arterial vasodilation by activating dopamine receptors on the proximal and distal tubules (10 times more potent than dopamine), and it inhibits sodium reabsorption, thereby promoting natriuresis and diuresis (68). The onset of action is within 5 minutes with a maximal response achieved by 15 minutes (69– 71). The duration of action is 30–60 minutes without rebound hypertension when the infusion is discontinued. It is quickly and extensively metabolized by conjugation in the liver without the participation of the P450-cytochrome complex. After a starting dose of 0.1 lg/kg/min, the dose can be titrated every 15 minutes depending on the blood pressure response. It has been demonstrated to have a dose-dependent decrease in blood pressure in the infusion range of 0.03–0.3 lg/kg/min (72). No adverse effects have been noted with its use. In a prospective, randomized, open-label, multicenter clinical trial, fenoldopam was as effective as nitroprusside for the treatment of hypertensive emergency. However, fenoldopam has been demonstrated to improve creatinine clearance, urine flow rates, and sodium excretion in severely hypertensive patients with both normal and impaired renal function (73–75). Consequently, fenoldopam may be particularly beneficial in patients with impaired renal function with hypertensive emergency (76). Of note, fenoldopam is contraindicated in patients with glaucoma. Hydralazine. Hydralazine is a direct arteriolar vasodilator with little or no effect on the venous circulation and often causes reflex sympathetic stimulation. Hydralazine should therefore be used with caution in patients with coronary artery disease or aortic dissection unless a beta-blocking agent is used concomitantly. Furthermore, although hydralazine has a rapid onset within 5–15 minutes, there can be an unpredictable and often precipitous drop in blood pressure that can last up to 12 hours. Therefore, it can be very difficult to titrate the blood pressure response, and it is best to avoid hydralazine for the management of hypertensive emergency. Traditionally, because of limited crossing of the uteroplacental circulation, hydralazine has been the drug of choice for the treatment of pre-eclampsia or eclampsia. Labetalol. Labetalol is a combined selective alpha-1 and nonselective beta-adrenergic receptor blocker with an alpha- to beta-blocking ratio of 1:7 (77). Labetalol is metabolized by the liver to form an inactive glucuronide conjugate (78). Of note, labetalol reduces afterload without reducing cerebral, coronary, or renal blood flow (79–82). Labetalol has a rapid onset of action (5 min or less), reaches it peak action by 5–15 minutes, and persists for 2–4 hours (78,83). The initial bolus dose is 20 mg followed by repeat doses of 20–80 mg at 10-minute intervals to a total dose of 300 mg until the therapeutic blood pressure goal is achieved. Alternatively, after the initial oral loading dose of 20 mg, an infusion of 0.5–2 mg/min of labetalol could be commenced and titrated to achieve blood pressure goals. Labetalol is safe in patients with acute coronary syndromes with systemic hypertension, but should be avoided in patients with asthma, chronic obstructive pulmonary disease (COPD), systolic heart failure, bradycardia, or greater than first degree heart block. Labetalol has been used in pregnancy-related hypertensive emergency as little placental transfer occurs (79). The drug is effective and well-tolerated in patients with all grades of hypertension, but is of particular value in special subgroups such as black patients, the elderly, and patients with renal hypertension. Nicardipine. Nicardipine is a second generation dihydropyridine calcium channel blocker with high vascular selectivity and strong cerebral and coronary vasodilatory activity; consequently, it has been shown to reduce both cardiac and cerebral ischemia in patients with a hypertensive emergency (84). It can be given as an intravenous infusion and is readily titratable. Its HYPERTENSIVE EMERGENCY onset of action is between 5 and 15 minutes, with a duration of action of 4–6 hours. The initial dose is 5 mg/hr increasing the infusion rate by 2.5 mg/hr every 5 minutes to a maximum of 15 mg/hr until the desired blood pressure is attained. Several studies have investigated the role of nicardipine when administered to patients with severe hypertension (85,86). In two multicenter, prospective randomized trials comparing nicardipine with nitroprusside in patients with severe postoperative hypertension, Halpern et al. and Neuteal et al. reported that nicardipine is as effective as nitroprusside (87,88). In a recent prospective study comparing nicardipine with nitroprusside in patients who presented to the emergency department with hypertensive emergency and acute pulmonary edema, nicardipine, and nitroprusside were equally effective at controlling blood pressure without significant differences in heart rate, respiratory rate, or oxygen saturation, but there were greater declines in serum norepinephrine levels in the nicardipine group compared with nitroprusside (89). This fact may suggest that nicardipine may be advantageous over nitroprusside to prevent the cycle of perpetual vascular injury by decreasing norepinephrine levels. A useful therapeutic benefit of nicardipine is that the agent has been demonstrated to increase both stroke volume and coronary blood flow with a favorable effect on myocardial oxygen balance (84,90–93). This property is useful in patients with coronary artery disease and systolic heart failure. In addition, nicardipine has been shown to reduce cerebral ischemia (84). Nifedipine. Oral or sublingual nifedipine has been widely used in many clinical situations associated with elevated blood pressure. Although it is not absorbed through the buccal mucosa, it is rapidly absorbed through the gastrointestinal tract after the capsule is dissolved and causes direct arteriole vasodilation (94). A rapid and significant decrease in blood pressure occurs within 5–10 minutes, peaks at 30–60 minutes, and lasts up to 6 hours (95). As effective as nifedipine is at vasodilation, sudden and dramatic declines in blood pressure may precipitate cerebral, renal, and cardiac ischemic events that have been associated with fatal outcomes (84,94,95). Because of the difficulty in controlling the response to nifedipine, this drug should not be used for blood pressure control in hypertensive emergencies. Nitroglycerin. For blood pressure control, nitroglycerin is administered as an intravenous infusion mediating its blood pressure effect primarily by causing venodilation and decreased preload and cardiac output. It is an ineffective arteriolar vasodilator and as such is not an effective agent for use in hypertensive emergency; however, it is a valuable therapy for patients with severe hypertension and symptomatic acute coronary syndromes or pulmonary edema and in postcoronary artery bypass surgery. The initial dose of nitroglycerin is 5 lg/ min, which can be titrated to a maximum of 100 lg/min. The onset of action is 2–5 minutes with a duration of action of 5–10 minutes. Headache because of cerebral vasodilation and tachycardia resulting from reflex sympathetic activation are the primary side effects. 507 Phentolamine. Phentolamine is a pure alphaadrenergic antagonist utilized for the management of catecholamine-induced hypertensive emergencies (e.g., pheochromocytoma or tyramine ingestion in a patient being treated with a monoamine oxidase inhibitor) (26,38–40,52,53). It is administered intravenously in 1–5 mg boluses with an immediate effect that can last up to 15 minutes. Continuous infusion can be done if necessary, but phentolamine may cause tachydysrhythmias or angina. Once initial catecholamine-induced hypertension is under control, oral phenoxybenzamine, a long-acting alpha-adrenergic antagonist should be administered. Sodium Nitroprusside. Sodium nitroprusside is considered by many to be the most effective parenteral drug for the treatment of most hypertensive emergencies as it is an effective arterial and venous vasodilator, thereby decreasing afterload and preload. It has an extremely rapid onset (within seconds) and a duration of action of 1–2 minutes with a plasma half-life of 3–4 minutes. Consequently, abrupt cessation of infusion will cause blood pressure to rise almost immediately and return to preinfusion levels within 1–10 minutes. Even though nitroprusside has an ideal pharmacokinetic and pharmacodynamic profile for the treatment of hypertensive emergency, it has many limitations. It is light sensitive and requires special handling to prevent drug degradation (72). It requires intra-arterial monitoring to prevent excessive blood pressure correction. Cerebral blood flow may decrease in a dose-dependent manner and both clinical and experimental evidence has demonstrated that it may increase intracranial pressure (98–101). Furthermore, in patients with coronary artery disease, the significant afterload reduction may reduce coronary arterial flow (coronary steal phenomenon) (102). Interestingly, in a randomized, placebo-controlled trial, nitroprusside increased mortality (mortality at 13 weeks, 24.2% vs. 12.7%) when infused in early hours after acute myocardial infarction (103). The greatest limitation to the prolonged use of nitroprusside is the risk of developing fatal cyanide or thiocyanate toxicity. Nitroprusside contains 44% cyanide by weight, which is released nonenzymatically in a dosedependent manner from nitroprusside. Cyanide is then metabolized in the liver in a reaction that requires thiosulfate to generate thiocyanate, which is 100 times less toxic than cyanide and is excreted largely by the kidney. Therefore, cyanide removal requires the bioavailability of thiosulfate and adequate liver and renal function (104,105). Coma, encephalopathy, convulsions, unexplained cardiac arrest, and irreversible neurologic abnormalities have been documented as a result of cyanide toxicity (106,107). The current methods of monitoring for cyanide toxicity are insensitive and not widely available and the clinical manifestations of cyanide toxicity often present too late for effective treatment to be initiated (104). Data suggests that infusion rates of 4 lg/kg/ min for as little as 2–3 hours may lead to toxic cyanide levels (104). Given the potential for potentially fatal toxicity with nitroprusside, this drug should only be used when 508 Haas and Marik other parenteral antihypertensive agents are not available. As the risk of developing cyanide toxicity is increased with higher doses (>2 lg/kg/min), longer infusion times (>24–48 hr), and with liver and renal insufficiency, treatment should be as brief as possible with the lowest dose (should not exceed 2 lg/kg/min) and in patients with normal liver and renal function. If doses between 4 and 10 lg/kg/min are being used, an infusion of thiosulfate should be used to prevent the accumulation of cyanide (105). Similarly, it has been shown that a continuous infusion of hydroxycobalamin is safe and effective in preventing and treating cyanide toxicity associated with nitroprusside (108). Considering the limitations associated with the use of nitroprusside, its use should be avoided if other agents are available. Special Circumstances Regarding Management Acute Aortic Dissection. Patients who present to the emergency department with the presumptive diagnosis of aortic dissection should be started on parenteral antihypertensives as soon as possible. The objective of treatment is to lower the pulsatile load and aortic stress by lowering cardiac output and blood pressure in the hopes of retarding the propagation of dissection and preventing aortic rupture. A vasodilator alone is not ideal as this can promote reflex tachycardia, increase aortic ejection velocity, and promote dissection propagation; therefore, the combination of a beta-adrenergic antagonist and a vasodilator is the standard approach to treatment. Esmolol is the beta-adrenergic antagonist of choice with metoprolol as a suitable alternative (109,110). Although nitroprusside has traditionally been used as the vasodilator of choice, nicardipine or fenoldopam are less toxic, equally effective alternatives (110,111). All patients with aortic dissection require cardiovascular surgical consultation to determine if surgical management is necessary. Unless significant medical comorbidities are present, surgery is indicated for all patients with ascending aorta type A dissection (112,113). Patients with type B dissections and distal aortic dissections can be managed with aggressive blood pressure control as outcomes have been shown to be the same with either medical or surgical treatment unless complications such as leak, rupture, or impaired flow to vital organs supervene (114). Stroke. Stroke is the number one cause of permanent disability in adults in the United States. Most patients who present with acute ischemic or hemorrhagic stroke will present with elevated blood pressure likely as an adaptive mechanism to maintain blood flow to the affected area (115). In these clinical situations, the elevated systemic blood pressure is not a manifestation of hypertensive emergency, but rather a protective physiologic response to maintain cerebral perfusion pressure to the vascular territory affected by ischemia. Because of impaired cerebral autoregulation from chronic hypertension, rapid blood pressure correction can reduce cerebral perfusion and extend the ischemic penumbra to the entire arterial territory with catastrophic consequences. There is no evidence that this elevated blood pressure affects the outcome during the acute phase of an ischemic stroke (39,116,117). The American Heart Association currently recommends that hypertension in the setting of acute ischemic stroke be treated ‘‘rarely and cautiously’’ (118,119). Most experts agree that a 10–15%, but not greater than 20%, reduction in blood pressure during the first 24 hours is an acceptable goal in patients with severe elevations of blood pressure (DBP > 120 mmHg) following an acute ischemic stroke (39,116,117,120). Interestingly, Semplicini et al. demonstrated a better neurologic outcome in patients with higher presenting systemic blood pressure, suggesting that lowering the blood pressure could be harmful in these situations (121). Furthermore, induced hypertension may be beneficial in patients with an acute ischemic stroke. In fact, Rordorf et al. used phenylephrine to increase the SBP by 20% (but not to exceed 200 mmHg) in patients with an acute stroke and demonstrated signs of neurologic improvement in seven out of 13 patients (122). In the setting of hemorrhagic stroke with intracerebral hematoma, blood pressure control is recommended when SBP is greater than 200 mmHg and/or DBP is greater than 110 mmHg (116,117,123). However, a rapid decline in blood pressure within 24 hours of presentation has been demonstrated to be independently associated with increased mortality in patients with intracranial hemorrhage (124). Judicious restraint in controlling blood pressure in the setting of ischemic or hemorrhagic stroke is therefore warranted. Pre-eclampsia and Eclampsia. The presentation of a patient with pregnancy-induced hypertension may range from a mild to a life-threatening disease process (46). Most pre-eclamptic patients are vasoconstricted and hemoconcentrated. Initial therapy of pre-eclampsia includes volume expansion, magnesium sulfate (MgSO4) for seizure prophylaxis, and blood pressure control (125–127). Delivery is the definitive treatment for pre-eclampsia and eclampsia. Magnesium sulfate is usually given as a loading dose of 4–6 grams in 100 cc D5 1/4 NS over 15–20 minutes followed by a constant infusion of 1–2 g of MgSO4 per hour depending on urine output and deep tendon reflexes, which are checked on an hourly basis. The next step in the management of pre-eclampsia is to reduce the blood pressure to a safe range being diligent to avoid significant hypotension. The objective of treating severe hypertension is to prevent intracerebral hemorrhage and cardiac failure without compromising cerebral perfusion or jeopardizing uteroplacental blood flow, which is already reduced in many women with eclampsia (46). Most authorities and the current guidelines from the American College of Obstetricians and Gynecologists recommend keeping the SBP between 140 and 160 mmHg and the DBP between 90 and 105 mmHg (45,46,128,129). This recommendation is supported by a recent study, which demonstrated that a SBP > 160 mmHg was the most important factor associated with a cerebrovascular accident in patients 509 HYPERTENSIVE EMERGENCY with severe pre-eclampsia and eclampsia (47). This would suggest that a SBP between 155 and 160 mmHg should be the primary trigger to initiate antihypertensive therapy in a patient with severe pre-eclampsia or eclampsia (47,130). Hydralazine has been recommended as the drug of choice to treat severe pre-eclampsia and eclampsia since the early 1970s (131). However, hydralazine has a number of properties that make it unsuitable for this indication. Its side effects (such as headache, nausea, and vomiting) are common and mimic symptoms of deteriorating pre-eclampsia. Most importantly, however, it has a delayed onset of action, an unpredictable hypotensive effect, and a prolonged duration of action. These properties may result in a precipitous hypotensive overshoot compromising both maternal cerebral blood flow and uteroplacental blood flow. Indeed, in a meta-analysis published by Magee et al. hydralazine was associated with an increased risk of maternal hypotension, which was associated with an excess of cesarean sections, placental abruptions, and low APGAR scores (132). Based on the available data, we suggest that hydralazine should not be used as first line treatment of severe hypertension in pregnancy. Similarly, sublingual or oral nifedipine should be avoided in this setting. Our preference is intravenous labetalol or nicardipine, which are easier to titrate and have a more predictable dose response than hydralazine. Both agents appear to be safe and effective in hypertensive pregnant patients (133–137). Sympathetic Crises. The most commonly encountered sympathetic crises revolve around the recreational use of sympathomimetic drugs such as cocaine, amphetamine, or phencyclidine. Rarely, these crises may be seen with pheochromocytoma, a patient taking a monoamine oxidase inhibitor who ingests a tyraminecontaining food, or patients who abruptly stop antihypertensive medications such as clonidine or beta-adrenergic antagonists. In the clinical situations characterized by sympathetic overstimulation, beta-adrenergic antagonists should be avoided to prevent vascular beta-receptor antagonism resulting in unopposed alpha-adrenergic activity and potential increase in blood pressure. In fact, in cocaine-induced hypertensive emergency, the use of beta-adrenergic blockade can increase coronary vasoconstriction, fail to control heart rate, increase blood pressure, and decrease survival (138–140). Interestingly, although labetalol is traditionally considered as the ideal agent because of its alpha- and beta-adrenergic antagonism, experimental studies do not support its use in this clinical setting (63,141–144). Blood pressure control is best achieved with nicardipine, fenoldopam, or verapamil in combination with a benzodiazepine (140,145,146). Phentolamine is an alternative agent (147). Conclusions Hypertensive emergency represents a serious medical condition with the potential for permanent end organ damage and significant morbidity and mortality. Recognition of elevated blood pressure with evidence of end organ damage should prompt initiation of timely and appropriate parenteral antihypertensive regimens to prevent on-going end organ damage. 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