Special Feature
Pharmacologic Treatment of Hypertensive Emergencies
By Maged Botros, MD, and David J. Karras, MD, FAAEM, FACEP
Hypertensive emergencies generally are defined as situations that require immediate blood pressure reduction in order to prevent or limit damage to target organs.1 The decision to treat an elevated blood pressure as a hypertensive emergency is independent of the actual blood pressure value, but rather depends on evidence of acute end-organ damage. Examples of acute end-organ dysfunction related to hypertension include encephalopathy, intracranial hemorrhage, renal dysfunction, unstable angina pectoris, myocardial ischemia, acute left ventricular failure with pulmonary edema, aortic dissection, and eclampsia. Although the diagnosis of hypertensive emergency hinges on the presence of end-organ damage, most authorities agree that it needs to occur in conjunction with a diastolic blood pressure greater than 110 mmHg.2 The primary pathophysiologic abnormality in hypertensive emergencies is an alteration in autoregulation, in which important vascular beds are unable to constrict appropriately to maintain perfusion. Frank arteritis and ischemia usually follow this process.
The initial goal of therapy in hypertensive emergencies is a reduction in mean arterial pressure (MAP) of no more than 25% within the first minutes to two hours,1 although the rate and degree of reduction vary somewhat depending upon the site of end-organ damage. Rapid drops in pressure should be avoided, as they may precipitate renal, cerebral, or coronary ischemia. Medical intensivists have traditionally preferred the use of sodium nitroprusside to accomplish this task; its rapidness of onset, short duration of action, and ease in titration have made it a convenient medication to use. However, given its extensive side effect profile, newer medications are being investigated to treat hypertensive emergencies with an emphasis on directly improving the function of the target end organ with evidence of damage.
Nitroprusside
Nitroprusside is a potent vasodilator that decreases both preload and afterload. Its onset of action is within seconds and duration of action is 1-2 minutes. Nitrocysteine is formed when nitroprusside reacts with the body’s own cysteine and activates guanylate cyclase, which, in turn, stimulates the formation of c-GMP, a potent smooth muscle relaxant. Although nitroprusside achieves excellent blood pressure control, its side effect profile is of concern. In a large, randomized, placebo-controlled trial, nitroprusside was shown to increase mortality when infused in the early hours after a myocardial infarction (mortality at 13 weeks, 24.2% vs 12.7%).3 This effect is believed to be due to a "cardiac steal" phenomenon, resulting in a significant reduction in cardiac blood flow in patients with significant coronary artery disease.
Furthermore, both clinical and experimental evidence demonstrate that nitroprusside increases intracranial pressure,4-7 which may result in decreased cerebral blood flow. This phenomenon may have deleterious effects on patients presenting to the emergency department (ED) with hypertensive encephalopathy. Finally, cyanide is released nonenzymatically from nitroprusside in a dose-related manner. Cyanide is metabolized in the liver by thiosulfate-sulfurtransferase into the less toxic metabolite thiocyanate, which is excreted via the kidneys. Cyanide removal therefore requires adequate liver function, adequate kidney function, and adequate bioavailability of thiosulfate. The possibility of cyanide toxicity therefore must be considered in all patients receiving nitroprusside.
Considering the potential side effects, nitroprusside should be used with caution in patients presenting with renal, hepatic, or coronary artery impairment. Fortunately, a few therapeutic options have been developed and marketed in the past few years for the ED treatment of hypertensive emergencies.8
Fenoldopam
Fenoldopam is a selective DA1 receptor agonist which has shown significant promise in the treatment of hypertensive emergencies, especially in patients exhibiting evidence of renal impairment. While fenoldopam is available in both oral and intravenous preparations, its serum half-life of only 10 minutes limits its utility as an oral agent. Dopamine acts at low doses by stimulating specific peripheral dopaminergic receptors that are classified into subgroups. DA1 receptors are located post-synaptically on the smooth muscle of the renal, coronary, cerebral, and mesenteric arteries.9 Stimulation of DA1 receptors causes vasodilatation of those arteries. Intravenous fenoldopam is a potent DA1 vasodilator that has 6-9 times the vasodilatory effect of dopamine. This vasodilatory effect tends to be strongest in the renal arteries, where renal blood flow can be increased by up to 77% in patients with impaired renal function.10 In addition, recent evidence also suggests that DA1 receptors also are located in the renal tubules, which, when stimulated, seem to be directly responsible for the natriuresis usually seen with dopamine administration.10
Although other antihypertensive agents produce a reduction in blood pressure by vasodilatory effects, the additional advantage of fenoldopam is its maintenance of renal perfusion combined with its natriuretic and diuretic effect. In addition, fenoldopam does not carry the added risk of cyanide toxicity seen in nitroprusside. In a prospective, randomized, multicenter, clinical trial, Panacek and colleagues compared fenoldopam to nitroprusside in the treatment of acute hypertension.11 Both agents were found to have equivalent efficacy in reducing blood pressures; however, fenoldopam demonstrated improved creatinine clearance, urine flow rates, and sodium excretion.
In addition, DA1 receptor agonists may have an added benefit on cardiac function. By providing a direct vasodilatory effect on myocardial vessels, the "cardiac steal" phenomenon is avoided and an increase in myocardial blood flow is noted.12 In conclusion, because of fenoldopam’s rapid onset (usually within five minutes), short half-life (duration of action once discontinued is 30-60 minutes), and renal/cardiac effects, it is an excellent alternative for the treatment of hypertensive emergencies, especially in patients with impaired renal function. The dose of fenoldopam is based on body weight and titrated to desired effect with a starting point of 0.1 mg/kg/min.
Nicardipine
Nicardipine is a dihydropyridine-derivative calcium channel blocker that differs from nifedipine by the addition of a tertiary amine structure. Although very similar in structure, these changes make nicardipine 100 times more water-soluble than nifedipine, and therefore it can be administered intravenously. The onset of action of nicardipine is 5-15 minutes, with a duration of action of roughly 4-6 hours; thus, this drug is an excellent candidate for the treatment of hypertensive emergencies.8
Multiple studies comparing the effects of nicardipine with nitroprusside on patients presenting with severe hypertension have demonstrated equivalent efficacy for lowering blood pressure. Intravenous nicardipine, however, has been shown to reduce both cardiac and cerebral ischemia.8 Studies of both dogs and baboons also have demonstrated a significant cardioprotective effect of nicardipine on animal hearts with induced ischemia.13 Nicardipine appears to be a good alternative for patients presenting with hypertensive emergency and evidence of acute myocardial ischemia.
Nicardipine’s side effect profile is relatively safe, with headache, dizziness, flushing, reflex tachycardia, and excessive hypotension reported. The currently recommended dosage is 5 mg/hr, increasing the infusion by 2.5 mg/hr every five minutes (to a maximum of 15 mg/hr) until the required blood pressure reduction is achieved.
Summary
The management of hypertensive emergencies has advanced over the past couple of decades, due to a better understanding of its pathophysiology and an improved pharmacologic armamentarium. Given the significant side effect profile of sodium nitroprusside, physicians need to aggressively seek alternative treatment modalities that will be dictated by the organ system most in jeopardy. Doing so will perhaps contribute to decreasing mortality and morbidity in this disease.
(Dr. Botros is an Assistant Professor of Emergency Medicine at Temple University School of Medicine, and serves as the Assistant Research Director for Sponsored Projects within the Department of Emergency Medicine at Temple University Hospital.)
References
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3. Cohn JN, et al. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure: Results of a Veterans Administration cooperative study. N Engl J Med 1982;306:1129-1135.
4. Hartmann A, et al. Alteration of intracranial pressure, cerebral blood flow, autoregulation and carbon dioxide-reactivity by hypotensive agents in baboons with intracranial hypertension. Neurochirurgia 1989;32:37-43.
5. Kondo T, et al. Effect of intra-arterial sodium nitroprusside on intracranial pressure and cerebral autoregulation. Jpn Heart J 1984;25:231-237.
6. Griswold WR, et al. Nitroprusside-induced intracranial hypertension [letter]. JAMA 1981;246: 2679-2680.
7. Anile C, et al. Sodium nitroprusside and intracranial pressure. Acta Neurochir 1981;58:203-211.
8. Varon J. The diagnosis and management of hypertensive crisis. Chest 2000;118:214-227.
9. Frishman WH. Selective and nonselective dopamine receptor agonist: an innovative approach to cardiovascular disease. Am Heart J 1996;132:861-870
10. Lee MR: Dopamine and the kidney, 10 years on. Clin Sci 1993;84:357-375.
11. Panacek EA, et al. Randomized, prospective trial of fenoldopam vs sodium nitroprusside in the treatment of acute severe hypertension: Fenoldopam Study Group. Acad Emerg Med 1995;2:959-965
12. Shi Y, et al. Selective dopamine1 receptor agonist augments regional myocardial blood flow: Comparison of fenoldopam and dopamine. Am Heart J 1992; 124:418-423.
13. Alps BJ, et al. Nicardipine in models of myocardial infarction. Br J Clin Pharmacol 1985; 20(suppl 1): 29S-49S.
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