American Journal of Therapeutics 14, 135139 (2007)

Management of Hypertensive Crises

Carlos Feldstein, MD*

Hypertensive emergencies are life-threatening conditions because their course is complicated with acute target organ damage. They can present with neurological, renal, cardiovascular, microangiopathic hemolytic anemia, and obstetric complications. After diagnosis, they require the immediate reduction of blood pressure (in ,1 hour) with intravenous drugs such as sodium nitroprusside, administered in an intensive care unit. These patients present with a mean arterial pressure .140 mm Hg and grade III to IV retinopathy. Only occasionally do they have hypertensive encephalopathy, reecting cerebral hyperperfusion, loss of autoregulation, and disruption of the blood-brain barrier. In hypertensive emergencies, blood pressure should be reduced about 10% during the rst hour and another 15% gradually over the next 2 to 3 hours to prevent cerebral hypoperfusion. The exception to this management strategy is aortic dissection, for which the target is systolic blood pressure ,120 mm Hg after 20 minutes. Oral antihypertensive therapy can usually be instituted after 6 to 12 hours of parenteral therapy. Hypertensive urgencies are severe elevations of blood pressure without evidence of acute and progressive dysfunction of target organs. They demand adequate control of blood pressure within 24 hours to several days with use of orally administered agents. The purpose of this review is to provide a rational approach to hypertensive crisis management. Keywords: hypertensive crisis, hypertensive emergencies, management

INTRODUCTION
The majority of cases of severe hypertension characterized by diastolic blood pressure (BP) .120 mm Hg or systolic BP .180 mm Hg can be controlled with drugs given orally. However, in some patients hypertension is life-threatening because there is evidence of rapid failure of vital organs; these patients require immediate reduction of BP, usually in ,1 hour, by means of intravenous drugs.18 These conditions, called hypertensive emergencies, can occur at any age, and their more frequent causes are listed in Table 1. Although hypertensive emergencies have become less common, it is estimated that about 1% of hypertensive patients will develop a hypertensive crisis.1,2 It has been estimated that hypertensive emergencies
Hypertension Program, Hospital de Clinicas Jose de San Martn, Buenos Aires University and Instituto Universitario de Ciencias de la Salud, Buenos Aires, Argentina. *Address for correspondence: Av Rivadavia 4243, 6P, Buenos Aires (1205), Argentina. E-mail: carlfel@yahoo.com 10752765 2007 Lippincott Williams & Wilkins

account for .25% of all patients visits to the medical section of an emergency department, with hypertensive emergencies detected in one-third of these cases.3 Most patients presenting with hypertensive emergency have had previously inadequately controlled or unknown chronic hypertension, although the disorder can present in previously normotensive individuals, particularly when associated with preeclampsia or acute glomerulonephritis.47 Hypertensive emergencies also may develop in the course of secondary hypertension, particularly that associated with renovascular disease, pheochromocytoma, and (less frequently) primary aldosteronism. Critically elevated BP without evidence of acute and progressive dysfunction of target organs is called hypertensive urgency.18 Such patients require adequate control of BP within 24 hours to several days by means of orally administered agents in a closely monitored outpatient setting. The purpose of this review is to describe a rational approach toward and appropriate therapy for hypertensive crises.

136 Table 1. Causes of hypertensive emergencies. Uncontrolled essential hypertension Cerebrovascular conditions Hypertensive encephalopathy Ischemic stroke Intracerebral hemorrhage Eclampsia, pre-eclampsia Renal Diseases Acute glomerulonephritis Renovascular hypertension Renal crises from systemic sclerosis Post-renal transplantation Renal malformation Endocrine Diseases Pheochromocytoma Cushing syndrome Primary aldosteronism Aortic dissection Aortic coarctation Drug-induced hypertension Cocaine Amphetamine SSRI MAOI in combination with certain foods or drugs Rebound hypertension Abrupt withdrawal of clonidine, ACEI, or b-blockers Postoperative hypertension Burns Head injuries and CNS trauma Autonomic hyperactivity (Guillain-Barre syndrome) Vasculitis
SSRI, selective serotonin reuptake inhibitors; ACEI, angiotensinconverting enzyme inhibitors; MAOI, monoamine oxidase inhibitors; CNS, central nervous system.

Feldstein

status, and examination for focal or lateralizing neurologic signs that are infrequent in hypertensive encephalopathy and usually suggest some other cerebrovascular disease (hemorrhage, embolism, or atherosclerotic thrombosis). Laboratory studies and electrocardiography should be performed immediately after presentation and may provide crucial clues to underlying conditions. Imaging should be performed for presumptive diagnosis of the primary cause of the hypertensive crisis. Management of hypertensive crisis The distinctions between hypertensive emergencies and urgencies are often ambiguous. It appears to be better to institute immediate antihypertensive treatment for all patients, with the agent and route of administration chosen on the basis of clinical criteria and available resources.8 The rst consideration in BP management in the setting of a life-threatening condition is that BP level is not the most critical factor in determining the existence of a hypertensive emergency. Prehospital treatment may include furosemide when there is clear evidence of volume expansion, as in heart failure or acute nephritis. On the other hand, the use of loop diuretics may worsen hypertension that is secondary to increased renin production by causing further volume contraction. Nitrates and oxygen administration may be used in conditions where they are indicated. In hypertensive emergencies, sublingual or oral nifedipine is absolutely contraindicated because it produces a nonpredictable reduction of BP, accompanied by heart and brain ischemia. Clonidine is also contraindicated because it is a strong sedative and causes hypertensive rebound when it is withdrawn. After hospital admission the hypertensive emergency should be managed with one of the parenteral drugs listed in Table 2, according to etiology. The main objective is to reverse end-organ damage, which is accomplished by reducing mean arterial pressure by up to 25% over minutes to a few hours. Once the patients condition has stabilized, an oral medication can be substituted and the physician should discuss long-term follow-up plans. The following are the drugs of choice in the treatment of hypertensive emergencies. Sodium nitroprusside is a rst-choice agent for the majority of hypertensive emergencies.10,11 This agent is a potent arterial and venous vasodilator with a very rapid onset of action (within seconds of beginning an infusion) and a very short duration of effect; it is easily titratable. It is administered as an intravenous infusion, with intra-arterial line BP monitoring. Nitroprusside reduces preload, afterload, and myocardial oxygen requirements. Because it is light-sensitive, the containers

Clinical evaluation Medical history should include previous treatments (antihypertensive agents and compliance), illicit drug use (cocaine and others), cardiovascular manifestations (heart failure, angina, aortic disection), and neurologic symptoms (headache, blurred vision, changes in mental status, nausea, vomiting, weakness, and renal symptoms such as hematuria and oliguria). Information about other medical conditions such as thyroid disease, Cushing syndrome, systemic lupus, systemic sclerosis, abdominal pain, and dyspnea and the date of most recent menstruation should be ascertained. Physical examination must be directed toward the cardiovascular and neurological systems. BP must be measured in both arms to detect any signicant differences. Other tests include peripheral pulse exploration for absence or delay (which would suggest aortic dissection), fundoscopy (searching for soft exudates, hemorrhages, and papilledema), cardiac and lung auscultation (S3, rales), assessment of mental
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Hypertensive Crisis Table 2. Agents for management of hypertensive crises. Drug Sodium nitroprusside Nitroglycerin Fenoldopam Nicardipine Hydralazine Dose 0.2510 mg/kg/min as IV infusion; maximal dose for 10 minutes only 5100 mg/min as IV infusion 0.10.3 mg/kg/min as IV infusion 515 mg/hr as IV infusion 1020 mg as IV bolus or intramuscularly; repeat every 46 hours (maximum dose: 40 mg) Onset of action Seconds to 2 minutes after beginning of infusion 25 minutes 515 minutes 15 minutes 1020 minutes

137

Duration of action 13 minutes 510 minutes 30 minutes to 4 hours 15120 minutes 38 hours

IV, intravenous.

and tubings must be light-resistant. Sodium nitroprusside doses can be carefully adjusted for a controlled reduction of BP. Its main indications are hypertensive crises complicated with hypertensive encephalopathy, heart failure, aortic dissection, and adrenergic crisis. The most important adverse effect of sodium nitroprusside include intoxication with thiocyanate (a metabolite of nitroprusside), which can occur when this agent is administered for more than 48 to 72 hours, particularly in patients with renal or liver dysfunction. Thiocyanate intoxication presents with nausea, vomiting, tinnitus, muscle cramps, hyperreexia, disorientation, and psychosis.12 Treatment of thiocyanate toxicity includes administration of hydroxycobalamin and sodium thiosulfate infusions, and in chronic renal failure dialysis may be indicated. Nitroprusside in high doses may increase intracranial pressure, which could limit its usefulness in patients with central nervous system complications. Extravasation can cause local tissue necrosis. Nitroglycerin is a powerful venodilatator that reduces preload, increases coronary blood ow through collateral coronary vessels dilation, suppresses coronary vasospasm, and decreases cardiac oxygen demands. Higher doses are required to produce arteriolar vasodilatation. Nitroglycerin is the best agent in hypertensive crises that are complicated with ischemic heart disease and after coronary bypass.10,12 Tolerance to nitroglycerine develops if it is administered continuously for 24 to 48 hours. Glass containers must be used because polyvinyl chloride containers and tubing may absorb it in an unpredictable manner. This agent is contraindicated for cerebral hemorrhage, because it may increase intracranial pressure, and for closedangle glaucoma. Nicardipine is a dihydropyridine calcium antagonist with intermediate onset and duration of effect and a prolonged half-life, which has been used for the control

of perioperative hypertension in cardiac surgery patients. Nicardipine also reduces cerebral ischemia. Its adverse effects include reex tachycardia, headache, nausea, and vomiting. This agent potentiates curare effects and has interaction with inhalant anesthetics. Nicardipine contraindications are heart block, acute myocardial infarction, and renal failure.2,7 Fenoldopam is a selective agonist of dopaminergic-1 receptors, which produces arterial vasodilatation and increased renal blood ow and natriuresis that is benecial in patients with renal failure.13 This agent has a rapid onset of action and ease of BP titration. Fenoldopam must be administered as an intravenous infusion and not as a bolus; the increments must not exceed 0.1 mg/kg/min at 20-minute intervals, and the highest dose should not exceed 1.7 mg/kg/min. It does not cause rebound hypertension, and therefore it can be withdrawn by tapering off or stopping its administration abruptly. The efcacy of fenoldopam is similar to that of nitroprusside, but it has the advantage of not requiring a line for intra-arterial BP monitoring. However, it is expensive and not readily available in some places. Its main indications are severe hypertension with renal failure and acute heart failure. Fenoldopam is contraindicated for glaucoma. Side effects include headache, ushing, dizziness, tachycardia or bradycardia, hypokalemia, and local phlebitis. Labetalol is a nonselective b- and a1-blocker (in the ratio of 37:1) with a rapid onset of action, sustained effect, and low toxicity.12,14 It reduces peripheral vascular resistance without a reex increase in systolic volume. Labetalol administration does not require intra-arterial BP monitoring. Its main indications are hypertensive encephalopathy and adrenergic crisis. This agent is contraindicated for heart failure, heart block, and chronic obstructive pulmonary disease. Esmolol is an ultrarapid, short-acting b-1 selective adrenergic blocker with no intrinsic sympathomimetic
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138

Feldstein

activity; it has been approved by the U.S. Food and Drug Administration only for perioperative hypertensive emergencies. Esmolol administration requires a line for intra-arterial BP monitoring. Adverse reactions include thrombophlebitis and extravasation of this agent, resulting in local necrosis. It is contraindicated for cocaine toxicity when used alone and in heart failure, chronic obstructive pulmonary disease/asthma, and atrioventricular block. Hydralazine is a direct arterial vasodilator. It also has the property of improving uterine blood ow. The adverse effects include signicant reex sympathetic stimulation, sodium and water retention, ushing, headache, and increase of intracranial pressure. It is indicated only for pre-eclampsia and eclampsia and is contraindicated for patients with coronary atherosclerosis.1,2,49 Phentolamine is a competitive, nonselective a-blocker and is the drug of choice only for adrenergic crisis (drug-induced or secondary to pheocromocytoma). After administration of an intravenous bolus injection of 5 to 10 mg, BP decreases within several minutes.68 Management of specic conditions In general, BP should be reduced about 10% during the rst hour and another 15% gradually over the next 2 to 3 hours. The exception is aortic dissection, for which the target is systolic BP ,120 mm Hg after 20 minutes. In the elderly, use of lower doses of drugs is recommended, and the BP should not be reduced as much as in younger patients. Because many patients with hypertensive crisis are volume-depleted as a result of pressure-induced natriuresis, the use of loop-diuretics should be avoided initially unless there is clear evidence of volume overload. Because of the same reason, potent vasodilators such as nitroprusside should be avoided because it may cause a sudden decrease in BP below a safe target level. Oral antihypertensive therapy can usually be instituted after 6 to 12 hours of parenteral therapy.15 Hypertensive encephalopathy The main goal of treatment is to decrease mean arterial pressure by 20% or diastolic BP to 100 to 110 mm Hg in the rst hour. In general, the drug of choice is sodium nitroprusside. Nevertheless, sometimes it may reduce cerebral blood ow in areas with a xed arterial narrowing and thus lead to cerebral steal phenomenon and focal ischemia. It has been proposed that labetalol or nicardipine may be a better choice, because these drugs are less likely to decrease cerebral blood ow. Lack of improvement in neurologic symptoms suggests a stroke. Cerebral blood ow autoregulation is disrupted in the setting of acute brain ischemia. This results when
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cerebrovascular resistance fails to respond to changes in cerebral perfusion pressure. When BP is suddenly reduced in these conditions, cerebral blood ow may be strongly decreased and neurologic decits may worsen. There is consensus that BP must not be reduced in ischemic stroke patients unless they are candidates for thrombolytics.16 When thrombolytic treatment is planned for ischemic stroke, the BP must be #180/105 mm Hg. If the BP is .220/120 it would be acceptable to gradually reduce the BP in 24 to 48 hours. When diastolic BP is .140 mm Hg, sodium nitroprusside should be administered in order to decrease diastolic BP 10% to 15% in 12 to 24 hours. There is no evidence that hypertension increases the risk of intracerebral hemorrhage or of a new hemorrhage. Vasospasm and reduction of brain perfusion are common in areas adjacent to an intracerebral hematoma. Furthermore, in ischemic stroke the sudden reduction of mean arterial pressure may aggravate brain ischemia. In some cases, hypertension may be a secondary phenomenon and BP may spontaneously decrease in a few hours. Heart failure When the patient has pulmonary edema, nitroglycerin or nitroprusside is the drug of choice, and the target is to reduce BP to normal or near-normal levels. Coronary insufciency Nitroglycerin is the drug of choice and should be rapidly titrated to the desired effect. One alternative to the intravenous route is to administer 1.25 mg of isosorbide dinitrate aerosol upon arrival.17 If BP does not decrease with use of nitroglycerin, then nitroprusside should be added to the regimen. Nevertheless, the adverse reactions of nitroprusside may include baroreex activation, causing tachycardia, and coronary steal phenomenon, with worsening of ischemia in areas with xed coronary stenosis. Other agents that can be used when there is no concomitant heart failure are b-blockers. Aortic dissection In this condition, systolic BP must be reduced to 100 to 120 mm Hg as soon as possible, by means of a combined treatment with sodium nitroprusside and a b-blocker (esmolol appears to be more useful than propranolol). b-blockade must be established rst, before starting the nitroprusside infusion. An alternative agent is labetalol, which may be used as the only treatment because it has both b- and a-blocking effects. Heart rate must be maintained between 60 and 80 beats/minute.

Hypertensive Crisis

139 4. Jackson RE. Hypertension in the emergency department. Emerg Med Clin North Am. 1988;6:173196. 5. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet. 2000;356:411417. 6. Vidt DG. Emergency room management of hypertensive urgencies and emergencies. J Clin Hypertens. 2001;3:158164. 7. Tuncel M, Ram CV. Hypertensive emergencies: etiology and management. Am J Cardiovasc Drugs. 2003;3:2131. 8. Kaplan NM, ed. Clinical Hypertension. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2002:339356. 9. Blumenfeld JD, Laragh JH. Management of hypertensive crises: the scientic basis for treatment decisions. Am J Hypertens. 2001;14:11541167. 10. Murphy C. Hypertensive emergencies. Emerg Med Clin North Am. 1005;13:9731007. 11. Gifford RW Jr. Management of hypertensive crises. JAMA. 1991;266:829835. 12. Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest. 2000;118:214227. 13. Murphy MB, Murray C, Shorten GD. Fenoldopam: a selective peripheral dopamine-receptor agonist for the treatment of severe hypertension. N Engl J Med. 2001;345: 15481557. 14. Chamontin B, Amar J, Chollet F, et al. Acute blood pressure elevations [in French]. Arch Mal Coeur Vaiss. 2000;93(11 Suppl):14411447. 15. Elliott WJ. Clinical features and management of selected hypertensive emergencies. J Clin Hypertens. 2004;6:587592. 16. Klijn CJ, Hankey GJ. American Stroke Association and European Stroke Initiative. Management of acute ischaemic stroke: new guidelines from the American Stroke Association and European Stroke Initiative. Lancet Neurol. 2003;2:698701. 17. Rubio-Guerra AF, Vargas-Ayala G, Narvaez-Rivera JL, et al. Comparison between isosorbide dinitrate in aerosol and in tablets for the treatment of hypertensive emergencies. Angiology. 2001;52:131135. 18. Henry CS, Biedermann SA, Campbell MF, Guntupalli JS. Spectrum of hypertensive emergencies in pregnancy. Crit Care Clin. 2004;20:697712. 19. Gregg AR. Hypertension in pregnancy. Obstet Gynecol Clin North Am. 2004;31:223241. 20. Duley L. Pre-eclampsia and the hypertensive disorders of pregnancy. Br Med Bull. 2003;67:161176.

Adrenergic crises The drug of choice is phentolamine, and another option is the combination of sodium nitroprusside and a b-blocker. It has to be taken into account that b-blockers can exacerbate hypertension in patients with adrenergic crisis and thus should not be used until adequate a-receptor blockade is achieved. Labetalol is relatively contraindicated because it produces more b- than a-blocking effects, allowing a paradoxical increase in BP from the absence of opposition to the a effect of catecholamines (or cocaine, amphetamines, or tyramine in those receiving monoamine oxidase inhibitors). Pre-eclampsia This condition, either mild or severe, is managed best with a policy of delivery at or beyond 37 or 34 weeks gestation, respectively.19 Even though no single antihypertensive drug has been proven to be better than another, intravenously administered hydralazine is probably the initial agent of choice.20 The aim is to decrease diastolic BP to 80 to 100 mm Hg. Severe preeclampsia should be treated with intravenous magnesium to prevent progression to eclampsia. It must be emphasized that nitroprusside is relatively contraindicated in pregnancy. Hypertensive emergencies in the perioperative setting The drugs of choice are esmolol, nitroglycerin (after coronary bypass surgery), nicardipine, nitroprusside, and fenoldopam.

REFERENCES
1. Calhoun DA, Oparil S. Treatment of hypertensive crisis. N Engl J Med. 1990;25;323:11771183. 2. Elliott WJ. Management of hypertension emergencies. Curr Hypertens Rep. 2003;5:486492. 3. Zampaglione B, Pascale P, Marchisio M, et al. Hypertensive urgencies and emergencies: prevalence and clinical presentation. Hypertension. 1996;27:144147.

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