A 57-year-old male with hypertension and end-stage renal disease is brought into the ED by his family for evaluation of headache, nausea, blurry vision, and confusion. Blood pressure is 235/130 mmHg. He is somnolent but arousable and oriented only to person; the remainder of his neurologic exam is nonfocal. A fundoscopic exam shows retinal hemorrhages, exudates, and papilledema. How should this patient be managed?
Hypertension (HTN) is a medical problem that affects an estimated 1 in 3 adults in the U.S. and more than 1 billion people worldwide. The Joint National Committee (JNC) 7 Report defines hypertensive emergency as severe hypertension with evidence of impending or progressive end-organ dysfunction.1 Systolic blood pressure (SBP) in these settings often is >180 mm Hg with diastolic blood pressure (DBP) >120 mm Hg. The JNC 7 Report defines hypertensive urgency as severe HTN without acute end-organ dysfunction. Whereas hypertensive urgencies can be treated with oral antihypertensive agents with close outpatient follow-up, hypertensive emergencies require immediate BP reduction to halt the progression of end-organ damage.
Severe HTN causes shear stress and endothelial injury, leading to activation of the coagulation cascade, fibrinoid necrosis, and tissue ischemia.2 Due to adaptive vascular changes, pre-existing hypertension lowers the probability of a hypertensive emergency developing at a particular BP. The rate of BP rise, rather than the absolute level, determines most end-organ damage.3 In previously normotensive patients, end-organ damage can occur at BPs >160/100 mm Hg; however, organ dysfunction is uncommon in chronically hypertensive individuals, unless BP >220/120 mm Hg.
Clinical manifestations of hypertensive emergency depend on the target organs involved (see Figure 1, right). When a patient presents with severe hypertension, a focused evaluation should attempt to identify the presence of end-organ damage. If present, these patients should be admitted to an ICU for close monitoring, and administration of parenteral antihypertensive agents should be started. (Online Exclusive: View a chart of “Parenteral Antihypertensive Agents Used in Hypertensive Emergencies”)
Review of the Data
General principles: The initial therapeutic goal in most hypertensive emergencies is to reduce the mean arterial pressure (MAP) by no more than 25% within the first hour. Precipitous or excessive decreases in BP might worsen renal, cerebral, or coronary ischemia. Due to pressure natriuresis, patients with primary malignant hypertension might be volume-depleted. Restoration of intravascular volume with intravenous (IV) saline can prevent precipitous falls in BP when antihypertensive agents are started.
After the patient stabilizes, the BP can be lowered about 10% per hour to 160/100-110 mm Hg. A gradual reduction to the patient’s baseline BP is targeted over the ensuing 24 to 48 hours. Once there is stable BP control and end-organ damage has ceased, patients can be transitioned to oral therapy.
No large clinical trials have investigated optimal drug therapy in patients with hypertensive emergencies. The choice of pharmacologic agent should be individualized based on drug properties, patient comorbidities, and the end-organ(s) involved.
Selected pharmacologic agents: Sodium nitroprusside (SNP) is a short-acting, potent arterial and venous dilator that has been used extensively in the treatment of hypertensive emergencies. Despite its familiarity, there are several important limitations to its use. SNP can increase intracranial pressure (ICP), worsen myocardial ischemia through coronary steal, and is associated with cyanide and/or thiocyanate toxicity. Although used broadly across many types of hypertensive emergencies, SNP should be considered a first-line agent in acute left ventricular (LV) failure and, when combined with beta-blockers, in acute aortic dissection.
Labetalol is an alpha-1 and nonselective beta-blocker that reduces systemic vascular resistance while preserving cerebral, renal, and coronary blood flow. It is considered a first-line agent in most hypertensive emergencies, with the exception of acute LV failure.
Esmolol is a short-acting, selective beta-blocker that decreases heart rate, myocardial contractility, and cardiac output.
Nicardipine is a second-generation dihydropyridine calcium channel blocker. Although it has a longer duration of action, excess hypotension has not been seen in clinical trials comparing it with SNP.4 Nicardipine is used safely in such hypertensive emergencies as hypertensive encephalopathy, cerebral vascular accidents, and postoperatively.
Fenoldopam creates vasodilation by acting on peripheral dopamine type 1 receptors. It improves creatinine clearance and urine output, and is most useful in acute kidney injury.5 It is a well-tolerated and highly effective agent for use in most hypertensive crises, although is expensive and has limited hard outcome data.
Nitroglycerin is a potent venodilator that is used as an adjunct to other anti-hypertensives in the treatment of acute coronary syndromes and acute pulmonary edema.
Immediate-release nifedipine and clonidine are not recommended; they are long-acting and poorly titratable, with unpredictable hypotensive effects.
Hydralazine may be used in LV failure and in pregnancy.
Specific emergencies: Aortic dissection is the most rapidly fatal complication of severe HTN. Untreated, approximately 80% of patients with acute type-A dissections die within two weeks.6 In this specific setting, SBP should be decreased as rapidly as possible to <110 mm Hg in order to halt propagation of the dissection prior to surgery. Therapy should aim to reduce the shear stress on the aortic wall by decreasing both BP and heart rate. This can be accomplished with a combination of esmolol and SNP. Nicardipine and fenoldopam are effective alternatives to SNP. Labetalol is a good single-agent option, provided adequate heart rate suppression is achieved.
LV failure and acute pulmonary edema are associated with high systemic vascular resistance and activation of the Renin Angiotensin Aldosterone (RAAS) system. First-line therapy should consist of arterial vasodilators (e.g., SNP, nicardipine, fenoldopam) in combination with a loop diuretic. Nitroglycerin can be used as an adjunct to reduce LV preload.
In hypertensive encephalopathy, blood pressure exceeds the cerebral autoregulatory threshold, leading to breakthrough vasodilation and the development of cerebral edema. Characteristic symptoms include the insidious onset of headache, nausea, vomiting, and nonlocalizing neurologic signs (e.g., lethargy, confusion, seizures). It is important to exclude stroke, as treatment strategies differ. SNP is used widely in the treatment of hypertensive encephalopathy; it may increase ICP and should be used with caution. Nicardipine and labetalol are effective alternatives with favorable cerebral hemodynamic profiles.
Malignant HTN is characterized by neuroretinopathy: cotton wool spots, flame hemorrhages, and papilledema. Encephalopathy and other evidence of end-organ dysfunction might not be present, although renal disease is common. Preferred drugs are SNP and labetalol, although fenoldopam has been used successfully.
Appropriate BP management following acute ischemic stroke remains controversial. Elevated BP often is a protective physiologic response to maintain cerebral perfusion. The American Heart Association (AHA) recommends initiating IV antihypertensive therapy for thrombolysis candidates when SBP >185 or DBP >110 mm Hg. For those who are not thrombolysis candidates, the recommended threshold for initiating IV antihypertensives is SBP >220 or DBP >120 mm Hg.7 The goal is to lower the BP by 15% to 25% within the first 24 hours. These goals are less aggressive than in patients with hypertensive encephalopathy without stroke.
Spontaneous intracerebral hemorrhage causes a rise in ICP with reflex systemic hypertension. Although a correlation between HTN and hematoma expansion exists, there is no evidence that shows lowering BP is protective. Two clinical trials are evaluating the effects of BP reduction to specified target levels.8 Pending those results, the AHA recommends BP reduction for patients with SBP >200 or MAP >150 mm Hg, or for patients with SBP >180 or MAP >130 mm Hg and evidence of elevated ICP.7 In both ischemic and hemorrhagic stroke, nicardipine and labetalol are appropriate first-line agents.
Most sympathetic crises are related to the recreational use of sympathomimetic drugs, pheochromocytoma, abrupt antihypertensive withdrawal, or concurrent ingestion of monoamine-oxidase inhibitors and tyramine-containing foods. Selective beta-blockers can increase BP and worsen HTN through unopposed alpha effects.
Although labetalol traditionally has been considered the ideal agent—due to its alpha and beta antagonism—studies have failed to support its use in this clinical setting.9 Phentolamine, nicardipine, and fenoldopam are reasonable selections.
Hypertension is common in the early postoperative period following cardiothoracic, vascular, head and neck, and neurosurgical procedures. No consensus exists regarding the treatment of noncardiac surgery patients, but treatment is recommended for BP >140/90 or MAP >105 mmHg in cardiac surgery patients. Nicardipine, clevidipine, and esmolol are proven agents. All three have been shown more effective than SNP in maintaining target BP, and each is associated with less BP variability.10
In patients with pregnancy-induced hypertension, initial therapy for preeclampsia includes magnesium sulfate for seizure prophylaxis and BP control until delivery of the fetus can be safely undertaken. The FDA does not recommend any specific antihypertensive agents; however, ACE inhibitors and SNP are contraindicated. Although hydralazine is used extensively in this setting, a meta-analysis showed increased risk of maternal hypotension, Cesarean section, placental abruptions, and low Apgar scores.11 Labetalol and nicardipine appear to be safe and effective in pregnant hypertensive patients.
Back to the Case
This case represents a classic presentation of malignant hypertension with hypertensive encephalopathy, which is reversible with timely and appropriate management. The patient’s MAP is approximately 165 mmHg, well above the upper threshold of cerebral vascular autoregulation in most patients with chronic hypertension. A brain MRI should be obtained to definitively rule out stroke, as management goals would be considerably different.
If the scan is negative, treatment should be initiated immediately with a goal of reducing the MAP by no more than 25% within the first hour. Nicardipine or labetalol would be appropriate therapeutic choices, administered in an ICU with close hemodynamic monitoring.
Given the patient’s end-stage renal disease and evidence of intracranial hypertension, SNP would be a suboptimal choice. Over hours two through six, BP could be lowered gradually to 160/100, then to his baseline BP over the ensuing 24 to 48 hours, monitoring closely for signs of neurologic deterioration. Once BP is stable and there is no evidence of worsening end-organ damage, he can be safely transitioned to oral agents.
The therapeutic goal in hypertensive emergencies is to immediately and safely lower BP to halt end-organ damage. Drug selection should be individualized. TH
Dr. Shanahan is a hospitalist and assistant professor at the Denver VA Medical Center. Dr. Linas is professor of medicine in the division of renal diseases and hypertension at the University of Colorado Denver School of Medicine. Dr. Anderson is associate professor and chief of the hospital medicine section at the Denver VA Medical Center.
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- Adams HP Jr., del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation. 2007;115(20):e478-534.
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- Aronson S, Dyke CM, Stierer KA, et al. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg. 2008;107(4):1110-1121.
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