March 2001
Michael A. Lucia, M.D.
University of Nevada School of Medicine
Hypertension is a ubiquitous condition among the US population, afflicting nearly one third of all adult Americans. As the US population ages and continues to become more obese, this proportion is expected to increase even further. Despite this prevalence and the frequency with which primary care providers are confronted with management of this disease, hypertensive emergencies are relatively rare. Approximately 1% of all hypertensives will present with severe elevations of blood pressure at some point in their lives. While rare, this condition is associated with significant morbidity and mortality if not properly treated. The most important principle is prompt recognition of the condition and distinguishing hypertensive urgencies from emergencies. Appropriate initiation of therapy and degree of blood pressure reduction, along with proper drug selection become the next clinical challenge. Finally, one must tailor therapy for specific clinical scenarios to maximize outcomes.
Definitions and Terminology
The literature is replete with confusing terminology regarding severe elevations of blood pressure. The simplest and most clinically useful terms are hypertensive emergency and hypertensive urgency.
Hypertensive emergency has been reserved for those patients with SBP> 180 or DBP> 120 mmHg and evidence of end-organ damage, primarily to the kidneys, heart or CNS. Examples would include acute hypertension in the setting of active process such as CHF, angina, encephalopathy or aortic dissection that require immediate lowering to prevent further morbidity or mortality (Table 1). Hypertensive urgency refers to the same elevation of blood pressure without signs of end-organ damage that requires BP lowering over 24-48 hours. Hypertensive crisis is a more generic and less precise term for any acute elevation of blood pressure, usually in the setting of chronic hypertension.
Accelerated-Malignant hypertension is a related term often used in reference to severe hypertension associated with small vessel damage which can be seen as retinal changes (papilledema, hemorrhages, or exudates). When BP reaches a certain critical level (a mean arterial pressure of about 150 mmHg in experimental animals), pathological changes begin to occur in the vessel wall. Endothelial injury from increased arterial wall tension leads to the release of prostaglandins and other inflammatory mediators, which causes a subsequent myointimal proliferation (referred to as fibrinoid necrosis). Other vasoactive compounds such as angiotensin II are usually involved as well. This appears to be a non-specific response which can appear with any form of hypertension. If untreated the course of accelerated-malignant hypertension is rapidly progressive; one-year survival rates are only 10-20% without therapy.
Patients at Risk
Hypertensive urgencies and emergencies most often occur in patients with known hypertension. Often, they are poorly controlled despite being prescribed multiple medications and frequently there is a history of poor compliance. There is also an independent association with age and African-American lineage. Frequently, there is an associated inciting stress such as surgery, pregnancy, or drug use. Withdrawal from certain medications such as clonidine or MAO inhibitors can also precipitate this condition. Parenchymal renal disease or renovascular disease are common predisposing conditions. Other systemic conditions such as vasculitis and collagen vascular disease, or excess catecholamine states such as pheochromocytoma are uncommon causes (Table 2). Rare is the patient with no known risk factors, and illicit drug use should be ruled out in that setting.
Cerebral Autoregulation
Tissue perfusion to the human brain remains relatively constant over a wide range of mean arterial pressures in both normal and hypertensive patients. Cerebral perfusion remains constant because cerebral blood vessels have the capacity to dilate or constrict to retain a relatively constant level of cerebral blood flow. This process is known as “autoregulation”.
When arterial pressure exceeds the upper range of autoregulation, cerebral blood vessels are no longer able to maintain the necessary degree of constriction; they begin to stretch and dilate, and cerebral blood flow increases. This breakthrough vasodilation leads to cerebral edema and subsequent encephalopathy. Conversely, when blood pressure falls beneath the lower range of autoregulation relative cerebral ischemia can develop.
In the setting of chronic hypertension, the entire autoregulatory curve is shifted upwards. Chronic hypertensives have permanent hypertrophy of the cerebral arterioles and therefore autoregulate at a higher pressure (Figure 1). As such, a normotensive patient may become encephalopathic at a level of blood pressure where a chronic hypertensive might be asymptomatic. Similarly, a poorly controlled chronic hypertensive may actually develop evidence of relative cerebral ischemia when blood pressure is lowered into the “normal” range. This has important implications for the management of hypertensive urgency and emergency as will be shown below.
Clinical Evaluation
In addition to a targeted history for potential risk factors or inciting causes, the duration, severity and control of hypertension should be assessed. Similar to the management of sodium derangements, the rate of rise of the blood pressure is more important than the absolute value. Pre-existing end-organ damage such as renal insufficiency, CHF or prior cerebrovascular events should be ascertained.
Blood pressure should be checked in all four limbs to rule out aortic dissection. Careful funduscopic exam for hemorrhages, exudates or papilledema is essential. Signs and symptoms of CHF or angina should be elicited, as well as any new murmurs. Volume status should be determined as patients are often intravascularly depleted from a pressure-induced diuresis and natriuresis and may become profoundly hypotensive with therapy as a result. Orientation, mental status and level of consciousness are essential measures of encephalopathy.
Laboratory analysis should include: a CBC and peripheral smear (for signs of microangiopathic hemolytic anemia), electrolytes (hypokalemia is common due to secondary hyperaldosteronism), BUN and creatinine (assess renal function and volume status), urinalysis (looking for protein and/or red cells), ECG (assessing for left ventricular hypertrophy, strain, or ischemia), cardiac enzymes (rule-out myocardial infarction) and chest x-ray (observing heart size and evidence of congestive heart failure). Echocardiography is often a useful to guide therapy. CT of the chest or brain is usually unnecessary unless aortic dissection or cerebral hemorrhage is suspected, and should not delay initiation of therapy. In addition, a spot urine for the metabolites of pheochromocytoma (metanephrines, catecholamines, and VMA), peripheral renin, and serum aldosterone may be useful if a secondary cause of hypertension is suspected.
Immediate Management & Goals of Therapy
For hypertensive emergencies, all patients should be managed in an ICU setting with intra-arterial monitoring. Most textbooks and review articles recommend a 10-15% reduction in blood pressure or a target diastolic pressure of 110 mmHg over the first 30-60 minutes with IV therapy. In cases of aortic dissection, reduction of blood pressure should be within 5-10 minutes, as shear forces on the arterial wall directly correlate with extension. Once signs and symptoms of end-organ damage improve, oral therapy should be initiated for long-term treatment. If patients develop any signs of hypoperfusion (e.g. worsening angina, declining mental status) therapy should be reduced. The majority of the complications seen in the management of hypertensive emergency are actually from overly aggressive blood pressure reductions. The use of short-acting and easily titratable intravenous drug therapy is essential in this situation. Specific agents are reviewed below.
For hypertensive urgencies, control should be achieved over 24-48 hours with oral therapy. Once again, the goal of initial therapy is not normalization of blood pressure in this timeframe. Blood pressure should be decreased gradually over months to avoid side-effects and symptoms of hypoperfusion. As long as the patient is improving on an oral agent in the first several hours, outpatient management is acceptable. Preferred agents include oral labetalol, ACE-inhibitors, calcium channel blockers, other than short-acting nifedipine, and clonidine. Except in the setting of volume overload, diuretics should be avoided as patients are usually volume-contracted secondary to compensatory pressure natriuresis. The use of short-acting calcium channel blockers such as sublingual nifedipine should be avoided since these agents can cause rapid and profound systemic vasodilation leading to an increased risk of myocardial ischemia and cardiac death.
Drug Selection: Pros & Cons
The ideal anti-hypertensive agent for the management of hypertensive emergency would have all of the following properties: parenteral administration, rapid onset and offset, easy titratability, reliability, safety across a wide range of patient populations, ease of use, and cost-effectiveness. While none of the available agents meet this ideal, some come closer than others (Table 3).
Nitroprusside is a commonly used, potent agent that acts primarily as an arterial and venous dilator. Given IV it provides smooth, immediate BP reduction. Its use is limited by the potential for severe toxicity from cyanide poisoning, especially in patients with liver or renal disease. Co-administration of hydroxycobalamine may decrease the risk of cyanide poisoning. Since it is such a potent vasodilator, nitroprusside may also cause coronary steal syndrome and increase intracranial pressure due to dilation of the large intracerebral arteries. If used, limited infusion rates and times are recommended. Newer, less toxic agents are usually preferred.
Labetalol is a commonly used combined alpha- and beta-blocker with rapid onset of action (5 min) and easily titratable to the desired effect. In patients with normal left ventricular function, cardiac output is maintained, and no reduction in cerebral, renal, or coronary blood flow is seen. It can be used in almost any hypertensive emergency except when left ventricular dysfunction may worsen due to its predominant beta-blockade. Labetalol is safe and effective with easy conversion to oral therapy.
Esmolol is a cardioselective B-blocker with extremely rapid onset of action (1 min) and immediate clearance. Total duration of action is approximately 30 minutes. Esmolol is especially useful in the setting of acute MI, arrhythmia, or hemodynamically labile patients. It may cause bronchospasm in susceptible individuals.
Fenoldopam is a newer agent with purely dopamine-1 receptor agonist activity. In contrast to other available agents, since dopamine- 1 receptors are found in large quantities in the afferent arteriole of the kidney, fenoldopam maintains or increases renal blood flow. Fenoldopam has a unique mechanism of action with no active metabolites or adjustments for renal disease. It has a rapid onset of action (5 min) with rapid clearance. In published studies, adverse effects are rare, and there is evidence of improved renal outcomes. This agent is expensive, otherwise it may be the drug of choice in many situations if available. A number of studies have found that fenoldopam has efficacy equal to that of nitroprusside (Table 4).
Hydralazine is an older agent which acts as a direct vasodilator. Response to its administration is variable when given IV, and may result in prolonged hypotension. It is no longer considered a preferred agent. It has traditionally been the drug of choice in eclampsia.
Enalaprilat is an intravenous angiotensin converting enzyme (ACE) inhibitor with moderate onset (15 min) and prolonged duration (12 hours) of action, but no adverse effects or hypotension. It is particularly useful in patients with congestive heart failure or suspected activation of the renin-angiotensin system. Contraindications include pregnancy and acute renal failure.
Nicardipine is an effective arterial vasodilator from the dihydropyridine class of calcium channel blockers with gradual onset & duration of action. Outcomes in post-operative hypertensive patients have been comparable to nitroprusside in several studies.
Nitroglycerin is a direct venodilator which is primarily useful the setting of coronary ischemia or CHF. Like nitroprusside, the use of nitroglycerine can reduce both cerebral and renal perfusion. Cardiac output may also decrease due to decreases in preload.
Special Clinical Situations
Congestive Heart Failure: Useful agents include enalaprilat, diuretics, and nitroglycerine. Except in the setting of coronary ischemia, beta-blockers should usually be avoided.
Coronary Ischemia: Nitroglycerine and beta-blockers are usually the drugs of choice. Medications which cause reflex tachycardia (nitroprusside, hydralazine, or short-acting dihydropyridine calcium channel blockers) should be avoided unless beta-blockers are given in sufficient doses.
Acute & Chronic Renal Failure: Fenoldopam has become the preferred agent due to relative increases renal blood flow from stimulation of dopamine-1 receptors on the afferent arteriole. ACE inhibitors and nitroglycerin should generally be avoided. In contrast to most other forms of hypertensive emergency, patients with acute renal failure are often volume overloaded and may benefit from diuretics. There is no contraindication to nicardipine, labetolol, or esmolol.
Aortic Dissection: Nitroprusside in conjunction with a beta-blocker agent remains the standard of care. Immediate control is paramount, as well as acute surgical consultation. Fenoldopam, nicardipine, or ACE-inhibitors may also be safe and effective.
Drug overdose or withdrawal: Nicardipine and fenoldopam are the preferred agents as this usually represents an excess catecholamine state. Beta-blockers, including labetalol, should be avoided due to unopposed alpha activity and increased risk of seizures. Withdrawal from antihypertensive medication is best treated with restarting prior therapy.
Cerebrovascular events: In the setting of acute stroke, cerebral autoregulation is lost, and patients are dependent on high MAP to perfuse the “border-zone” and prevent further ischemia. Most patients should not be treated in this situation due to increased morbidity and mortality from hypoperfusion. Goals of therapy, if initiated, should be a very gradual reduction to DBP<110 or SBP<220 mmHg. Short-acting agents such as fenoldopam, nicardipine or labetalol are preferred agents. Nitroprusside should be avoided due to increased intracranial pressure and poor ability to monitor for toxicity.
Summary & Conclusions
Hypertensive crisis is a relatively uncommon complication, usually of long-standing hypertension, that occurs when patients present with severely elevated blood pressures. Generally blood pressure is > 240/120 mmHg, but depending on the duration an severity of hypertension, hypertensive urgencies and emergencies can be seen in patients with lower blood pressures. The most important diagnostic goal is a rapid evaluation for evidence of acute end-organ damage. Under-treatment or delayed treatment of such a hypertensive emergency can result in significant morbidity and mortality. Patients without evidence of acute ongoing target organ injury have hypertensive urgency, which can be treated with oral medications, often as outpatients. For hypertensive emergencies, intravenous agents should be used initially, but overly-aggressive blood pressure reduction is associated with poor outcomes, especially in the setting of an acute cerebrovascular event. Short-acting calcium channel blockers such as nifedipine have no role in current therapy. The drug chosen for therapy should be rapid in onset, easily titratable, with a low incidence of adverse events such as hypotension or reduced cerebral or renal blood flow. Due to its lack of toxicity and maintenance of regional blood flow, the dopamine-1 receptor agonist, fenoldopam, is quickly becoming one of the most preferred agents.
Selected References:
Bales A. Hypertensive crisis. Postgrad Med 1999; 105:119-130
Grossman E, Messerli FH, Grodzicki T, et al. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA 1996; 276:1328-1331
The sixth report of the Joint National Committee of Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1997; 157:2413-2446
Varon J, Marik PE. The diagnosis and management of hypertensive crisis. Chest 2000; 118:214-227.
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