O A Busari, MBBS, FMCP, Consultant Physician and Cardiologist, Federal Medical Centre, Ido-Ekiti, Nigeria; O G OPADIJO, MBBS, FWACP, Senior Lecturer, Consultant Physician and Cardiologist, University of Ilorin Teaching Hospital, Ilorin, Nigeria; and A B O OMOTOSO, MBBS, FWACP, Professor of Medicine, Consultant Physician and Cardiologist, University of Ilorin Teaching Hospital, Ilorin, Nigeria

Because of advances in the management of hypertension, malignant hypertension is now relatively rare and its prognosis has improved. When it does present, prompt and proper management is essential to prevent serious injury to the central nervous system, cardiovascular system and kidneys. This article discusses the management of malignant hypertension, highlighting important markers in patient evaluation and appropriate pharmacological therapy.

INTRODUCTION 
Hypertension [or high blood pressure (HBP)] is now a global epidemic and a major risk factor for coronary artery disease, stroke, congestive heart failure, end-stage renal disease and peripheral vascular disease. HBP has become a public health issue worldwide and particularly in sub-Saharan Africa.1
Malignant hypertension (MHT) occurs when severely elevated blood pressure (diastolic blood pressure often greater than 120 mmHg) is associated with acute or ongoing end-organ damage.2 Attempts were once made to discriminate between malignant and accelerated hypertension, according to retinal changes of Grade IV and III, respectively. However, it is now clear that the prognosis is the same and the terms ‘malignant’ and ‘accelerated’ can be considered synonymous.3
MHT is one of the hypertensive emergencies and should be distinguished from hypertensive urgency. In the latter, there is no acute or ongoing end-organ damage. MHT occurs at an average age of 40 years but within a wide age range.4 Men are more often affected than women, and MHT is commoner among Blacks than among Caucasians.1,4

CAUSES AND PATHOPHYSIOLOGY
About 1% of patients with HBP develop the malignant phase, which can occur in the course of both essential and secondary hypertension.5,6 Table 1 lists agents that can precipitate MHT.
The pathogenesis of MHT is not well understood. However, at least two independent processes are known to contribute to the associated signs and symptoms.4 First, there is characteristic generalised fibrinoid necrosis (necrotising arteriolitis) of arterioles and small arteries,4,7 these changes leading in the glomerular vessels to rapidly progressive renal failure associated with proteinuria and haematuria. The fibrin deposited in the damaged vessels obstructs and damages red blood cells, resulting in microangiopathic haemolytic anaemia.8
Second, there is a loss of cerebral blood flow autoregulation. In normal autoregulation, the cerebral vessels constrict and dilate when the mean arterial pressure is increased or decreased, respectively. When the mean arterial pressure rises above the autoregulatory range in severe HBP, cerebral arterial vasodilation occurs with resultant hyperperfusion and cerebral oedema.4 This mechanism is more common in HBP that has developed over a relatively short period of time without the presence of protective vascular hypertrophy.

CLINICAL EVALUATION
History 
Symptoms related to severe elevation in blood pressure, particularly those that suggest impending or ongoing end-organ damage, should be rapidly assessed. Table 2 shows some of these symptoms. The history should include information about previously diagnosed HBP, including duration, severity and general level of control. Patients should also be asked about: pre-existing end-organ damage (renal insufficiency or failure, congestive heart failure, stroke); use of prescription, over-the-counter and illicit drugs; and compliance with previous medical therapy.9

Physical examination
A quick and thorough physical examination should be performed, with special focus on the cardiovascular and central nervous systems and the retinas.
Cardiovascular examination should concentrate on evidence of heart failure or aortic dissection. Evidence of heart failure includes tachycardia, elevated jugular venous pressure, a third or fourth heart sound and pulmonary rales. Diagnostic clues for aortic dissection are asymmetric pulses, asymmetric blood pressure measurements, a new diastolic murmur and progression or development of new bruits over major peripheral arteries.
A complete and careful neurological examination can reveal signs of impending or ongoing neurological compromise. The presence of focal signs mandates screening for cerebral haemorrhage, infarct or presence of a mass.10
Fundoscopic findings may reveal changes consistent with chronic hypertension. Acute changes include flame-shaped haemorrhages, soft-tissue exudates and papilloedema.9,10

INVESTIGATIONS
The initial and principal goal of investigation is to detect acute or ongoing end-organ damage. Other aims are to discover secondary causes of HBP and complications.
Initial laboratory studies include complete blood count, serum electrolytes, serum urea and creatinine, coagulation studies, complete urinalysis and blood glucose estimations. The blood count may confirm the presence of microangiopathic haemolytic anaemia. Serum chemistry may reveal elevated urea and creatinine, electrolytic abnormalities and metabolic acidosis. Urinalysis may demonstrate proteinuria, microcytic haematuria and red blood cells or casts. Further laboratory investigations are guided by the initial workup and individual cases, and may include plasma and urinary catecholamines, 24-hour urinary vanillylmandelic acid, plasma aldosterone and renin levels, thyroid hormones and thyroid stimulating hormone.
Chest radiography can reveal evidence of pulmonary oedema or the presence of a widened mediastinum, which may indicate aortic dissection. Computed tomography of the head, echocardiography, renal angiography and other advanced imaging may be indicated.
Electrocardiography is a very useful investigation, as it may detect changes consistent with left ventricular hypertrophy, ischaemia or infarction. The presence of a normal electrocardiogram does not rule out MHT.

TREATMENT 
MHT is a medical emergency, and patients should be admitted to an intensive care unit. An intravenous line is started for fluid and medications. The goals of therapy are the correction of medical complications and the reduction of mean arterial pressure by about 25%, or of diastolic blood pressure to 100-110 mmHg, over the first several minutes to several hours.9,11 In cases of acute HBP (particularly involving children and pregnant women) and ongoing end-organ damage with modest hypertension, it may be necessary to reduce blood pressure to normal levels.11 Careful observation is very important, as too rapid reduction of blood pressure can cause end-organ ischaemia or infarction. Drugs for the treatment of MHT can be divided into two groups according to onset of action (Table 3). The choice of drug is often based on clinical situation, rapidity of action, ease of administration and potential side effects.

Drugs used in malignant hypertension
Nitroprusside, a direct arterial and venous dilator, is used most often because of its almost immediate onset of action and very short half-life. Its administration requires an intravenous infusion pump and an arterial line for continuous measurement of blood pressure, which can be titrated to desired levels. However, nitroprusside carries a risk of cyanide or thiocyanate toxicity when used for more than a few days.12 Toxicity can result in venous hypoxaemia, acidosis, mental status change and death.
Nitroglycerin is predominantly a venodilator. It is particularly useful in MHT following coronary bypass surgery, acute coronary syndromes or left ventricular failure.
Fenoldopam mesylate is a selective dopamine-1 receptor agonist. It increases renal blood flow and glomerular filtration rate, which often improves renal function in cases presenting with renal insufficiency.13 Fenoldopam provides an alternative to sodium nitroprusside for patients with renal insufficiency, without the threat of cyanide toxicity.13,14 It can be safely administered without invasive monitoring; side effects include headache, hypo­kalaemia and increased intraocular pressure.14
Hydralazine is a direct arterial vasodilator which causes severe hypotension, and slow administration is required. It is reserved for use in pregnancy, where it improves uterine blood flow, and should be avoided in acute coronary syndrome and aortic dissection.15
Enalaprilat is an intravenous form of the angiotensin-converting enzyme, enalapril. It is effective in MHT, particularly in cases of acute left ventricular failure.
Labetalol has both a- and b-blocking effects. Intravenous labetalol may be very useful in acute coronary syndrome. It is contraindicated in obstructive airway disease and advanced heart block.16
Phentolamine is a direct vasodilator and reversible b1- and b2-receptor blocker. It is primarily used in acute hypertensive crises secondary to catecholamine excess, such as occur in phaeochromocytoma.11

Complications 
The treatment of certain complications of MHT requires careful consideration of a particular antihypertensive agent or combination of agents.
In hypertensive encephalopathy, the agent of choice should have few or no central nervous system side effects.17 Centrally acting agents should be avoided as much as possible, because of their potential to affect mental status. Diazoxide should also be avoided, because it can reduce cerebral blood flow precipitously.
Aortic dissection requires a reduction in the shearing force on the aorta. The agent of choice is nitroprusside, almost always in conjunction with a b-receptor blocker such as esmolol.
Acute coronary syndromes are best treated with vasodilators, mainly nitroglycerin. A b-receptor blocker such as esmolol or labetalol should be added.
In acute left ventricular failure, intravenous loop diuretics, particularly furosemide, should be added to the conventional medications.

FOLLOW-UP AND PROGNOSIS
Close outpatient follow-up is the best way to prevent further episodes of MHT. Adequate lifestyle modification, compliance with medication and regular clinic visits are all central to the survival of the patient. Before the availability of effective treatment, life expectancy was less than 2 years, and the survival rates at 1 year and 5 years were less than 25% and 1%, respectively.2 With the advent of effective antihypertensive therapy, including haemodialysis, the survival rates at 1 year and at 5 years are now about 90% and 80%, respectively. The most common causes of death are cardiac complications.2