16.17.5 Hypertensive urgencies and emergencies 380

16.17.5 Hypertensive urgencies and emergencies 3800 Gregory Y.H. Lip and Alena Shantsila

section 16  Cardiovascular disorders 3800 the measurement of plasma renin activity and plasma aldosterone. If the aldosterone is significantly elevated, then the differential diag- nosis lies between the various forms of Conn’s syndrome and GRA. Diagnosis of GRA would be supported by the finding of elevated 18-​hydroxycortisol and 18-​oxocortisol in the urine, and a positive dexamethasone suppression test, suppression of plasma aldosterone levels to less than 4 ng/​dl with 0.75 to 2.0 mg/​day for at least 2 days being reported to have a greater than 90% specificity and sensitivity for the diagnosis, and GRA can now also be relatively easily con- firmed by finding a chimeric gene fragment with DNA testing. If the aldosterone level is suppressed, then finding an in- creased ratio of cortisol/​cortisone metabolites in the urine would support a diagnosis of AME. The presence of hyperkalaemia, hyperchloraemia, and metabolic acidosis would suggest a diagnosis of Gordon’s syndrome. No biochemical abnormalities specifically support a diagnosis of Liddle’s syndrome, but it typically presents with hyporeninaemic hypoaldosteronism. Ultimately, diagnosis of AME, Liddle’s syndrome, and Gordon’s syndrome also requires DNA analysis, but this is not as straightforward as it is with GRA since several different mutations can give rise to each syndrome. FURTHER READING Boyden LM, et al. (2012). Mutations in kelch-​like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature, 482(7383), 98–​102. Geller DS, et al. (2000). Activating mineralocorticoid receptor muta- tion in hypertension exacerbated by pregnancy. Science, 289, 119–​23. Lifton RP, et  al. (1992). A chimaeric 11β-​hydroxylase/​aldosterone synthase gene causes glucocorticoid-​remediable aldosteronism and human hypertension. Nature, 355, 262–​65. Lifton RP, et al. (2001). Molecular mechanisms of human hyperten- sion. Cell, 104, 545–​56. Maass PG, et al. (2015). PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nat Genet, 47, 647–53. Mune T, et al. (1995). Human hypertension caused by mutations in the kidney isozyme of 11β-​hydroxysteroid dehydrogenase. Nat Genet, 10, 394–​9. Shimkets RA, et al. (1994). Liddle’s syndrome: heritable human hyper- tension caused by mutations in the β subunit of the epithelial so- dium channel. Cell, 79, 407–​14. Wilson FH, et al. (2001). Human hypertension caused by mutations in WNK kinases. Science, 293, 1107–​12. 16.17.5  Hypertensive urgencies
and emergencies Gregory Y.H. Lip and Alena Shantsila ESSENTIALS Hypertensive urgencies and emergencies occur most commonly in patients with previous hypertension, especially if inadequately managed. About 40% of cases have an underlying cause, most com- monly renovascular disease, primary renal diseases, phaeochromo- cytoma, and connective tissue disorders. Hypertensive emergencies occur when severely elevated or sudden marked increase in blood pressure is associated with acute end-​organ damage. The key pathophysiological process is intense peripheral vasocon- striction, resulting in a rapid rise in blood pressure and a vicious circle of events, including ischaemia of the brain and peripheral organs. Hypertensive urgencies Malignant phase hypertension is a rare condition (1–​3 per 100 000 per year, more common in black people) characterized by very high blood pressure, with bilateral retinal haemorrhages and/​or exudates or cotton wool spots, with or without papilloedema. Presentation is typically with visual disturbance, with or without headaches. Urinalysis may demonstrate proteinuria and haematuria, even in the absence of primary renal disease. Some patients with mild renal impairment at first presentation may improve, or even re- gain normal renal function, but this is unlikely to occur in those with more severe renal impairment at presentation. Patients with severe hypertension who are asymptomatic require controlled reduction in blood pressure with oral antihypertensive agents. Over-​rapid blood pressure reduction may be hazardous, leading on occasion to ischaemic complications such as stroke, myocardial infarction, or blindness. The maximum initial fall in blood pressure should not exceed 25% of the presenting value, with the initial aim of treatment being to lower the diastolic pressure to about 100 to 105 mm Hg over a period of 2 to 3 days. The first-​line oral antihypertensive agent is either a short-​acting calcium antagonist (such as nifedipine, 10–​20 mg of the tablet formulation: sublingual or capsular preparations should never be used) or a β-​blocker (such as atenolol, 25 mg initial dose). Hypertensive emergencies Patients who are symptomatic with acute life-​threatening com- plications of severe hypertension, such as hypertensive enceph- alopathy, hypertensive left ventricular failure, or aortic dissection, require parenteral antihypertensive therapy to promptly reduce the blood pressure in a carefully controlled manner. Blood pres- sure should be reduced by 25% over several hours, depending on the clinical situation, usually with a target diastolic blood pres- sure of less than 100 to 110 mm Hg. The first-​line treatment for most hypertensive emergencies is either intravenous sodium nitroprusside or intravenous labetalol, with β-​blockade essential in patients with aortic dissection. Hypertensive emergencies and urgencies carry a poor short-​and long-​term prognosis unless adequately managed. Initial over-​rapid reduction of blood pressure to a normal value is dangerous, but—​in the long term—​blood pressure should eventually be reduced to ac- cepted blood pressure targets. Introduction Hypertensive emergencies occur when severe hypertension is associated with acute end-​organ damage. These can take a variety of forms and can occur at any age. They may be acute

16.17.5  Hypertensive urgencies and emergencies 3801 life-​threatening medical conditions, and are associated with ei- ther severe hypertension or sudden marked increases in blood pressure (Box 16.17.5.1). Symptomatic patients with complica- tions such as aortic dissection and hypertensive encephalopathy require parenteral antihyperten­sive therapy to reduce the blood pressure promptly, but in a controlled manner and with careful monitoring because over-​rapid treatment may in itself be haz- ardous, leading, on occasions, to ischaemic complications such as stroke, myocardial infarction, or blindness. Thus, in patients who have severe hypertension but are asymptomatic, slower, con- trolled, reduction in blood pressure should be achieved with oral antihypertensive agents, making such situations hypertensive ‘urgencies’ rather than ‘emergencies’. In general, there has been a decline in the incidence of hyper- tensive emergencies over the past 20 years in the Western world, which may possibly be the result of the more effective detection, diagnosis, and treatment of mild to moderate hypertension. If patients with hypertensive emergencies are not recognized or treated appropriately, the mortality and morbidity can be very high, with the 1-​year mortality being 70–​90%, and the 5-​year mortality 100%. With adequate blood pressure control, the 1-​year and 5-​year mortality rates decrease to 25 and 50%, respectively. Hypertensive emergencies occur most commonly in patients with previous hypertension, especially if inadequately managed. Nevertheless, some patients can present with hypertensive emergen- cies de novo, without any previous history of hypertension. Very severe and malignant hypertension are more likely to be as- sociated with underlying causes such as renovascular disease, pri- mary renal diseases, phaeochromocytoma, and connective tissue disorders, but malignant hypertension complicating primary hyperaldosteronism (Conn’s syndrome) is very rare. About 40% of patients with malignant hypertension have an underlying cause. Pathophysiology The common denominator in hypertensive emergencies is in- tense peripheral vasoconstriction, resulting in a rapid rise in blood Box 16.17.5.1  Hypertensive emergencies and urgencies Hypertensive emergencies • Hypertensive encephalopathy • Hypertensive left ventricular failure • Hypertension with myocardial infarction or unstable angina • Hypertension with aortic dissection • Severe hypertension with subarachnoid haemorrhage or stroke • Phaeochromocytoma crisis • Recreational drugs—​amphetamines, LSD, cocaine, MDMA (ecstasy), and so on • Perioperative hypertension • Severe pre-​eclampsia or eclampsia Hypertensive urgencies • Malignant hypertension • Chronic renal failure • Pre-​eclampsia • Severe non​malignant hypertension LSD, lysergic acid diethylamide; MDMA, 3,4-​methylenedioxymethamphetamine. Endothelial dysfunction Marked activation of renin-angiotensin system Malignant hypertension Juxtaglomerular ischaemia Thrombotic microangiopathies Platelet activation, fibrinogen elevation Lipid abnormalities • Thrombocytopenia • Neurological symptoms • Linear flame-shaped haemorrhages • Exudates • Cotton wool spots with or without papilledema • LVH • Fibrinoid necrosis of arterioles • Proliferative endarteritis of arteries • Deterioration of renal function (↑serum urea and creatinine, proteinuria) • Diastolic dysfuncction • White matter oedema • Haemolytic anaemia Microangiopathy: Brain: Hypertensive retinopathy: Heart: Kidney: Fig. 16.17.5.1  Main potential mechanisms and target organ involvement in the diagnosis of malignant hypertension. LVH, left ventricular hypertrophy. Modified from Shantsila A, Lip GYH (2017). Malignant Hypertension Revisited—​ Does This Still Exist? Am J Hypertens, 30, 543–​9.

section 16  Cardiovascular disorders 3802 pressure and a vicious circle of events, including ischaemia of the brain and peripheral organs. This ischaemia stimulates neurohor- mone and cytokine release, exacerbating vasoconstriction and is- chaemia, further increasing blood pressure, and resulting in target organ damage. Renal ischaemia also leads to activation of the renin–​ angiotensin system (Fig. 16.17.5.1), causing further rise in blood pressure and microvascular damage with excessive endothelial in- jury. Myointimal proliferation in the vasculature may further ex- acerbate the situation, resulting in an intravascular prothrombotic state disbalance (agglutination/​ coagulation) and the development of thrombotic microangiopathies characterized by thrombocyto- penia and microangiopathic haemolytic anaemia (anaemia accom- panied by elevated serum lactate dehydrogenase and the presence of schistocytes in the peripheral blood smear), causing further micro- vascular dysfunction and organ ischaemia. With mild to moderate elevation of blood pressure, the initial re- sponse of the vasculature is arterial and arteriolar vasoconstriction— ​such autoregulation maintaining tissue perfusion at a relatively con- stant level and preventing the raised blood pressure from damaging smaller, more distal blood vessels. Later, arteriolar hypertrophy also minimizes the transmission of pressure to the capillary cir- culation. In normotensive subjects, the upper limit of autoregula­ tion can be a mean arterial pressure of 120 mm Hg (equivalent to 160/​100 mm Hg), but in chronic hypertension, where the vessels are hypertrophied by long-​standing hypertension, the lower limit of autoregulation of cerebral blood flow is shifted towards higher blood pressures (Fig. 16.17.5.2), with impairment of the tolerance to acute hypotension. However, the process of autoregulation fails with rapid and severe rises in blood pressure, leading to a rise in pressure in the arterioles and capillaries, causing vascular damage. Disruption of the endothelium allows plasma constituents (including fibrinoid material) to enter the vessel wall, narrowing or obliterating the lumen in many tissue beds, the level at which fibrinoid necrosis oc- curs depending upon the baseline blood pressure. In the cerebral circulation, this can lead to the development of cerebral oedema and the clinical picture of hypertensive encephalopathy. In addition to protecting the tissues against the effects of hyper- tension, autoregulation maintains perfusion during the treatment of hypertension via arterial and arteriolar vasodilatation. However, falls in blood pressure below the autoregulatory range can lead to organ ischaemia, and the arteriolar hypertrophy induced by chronic hypertension means that target organ ischaemia will occur at a higher pressure than in previously normotensive subjects. Malignant hypertension, a hypertensive ‘urgency’ The malignant phase of hypertension is a rare condition charac- terized by very high blood pressure, with bilateral retinal haem- orrhages and/​or exudates or cotton wool spots, with or without papilloedema (Fig. 16.17.5.3). Its pathophysiological definition is based on the histological hallmark of fibrinoid necrosis of arteri- oles in many tissues, particularly the kidney—​changes which are broadly similar to those seen in the haemolytic–​uraemic syndrome or scleroderma. Mucoid intimal proliferation in renal interlobular arteries and ischaemic collapse of the glomerular tufts may also be seen. Myointimal hyperplasia is a common finding in black pa- tients, with the consequent intrarenal vascular disease leading to ischaemia of the juxtaglomerular apparatus and activation of the renin–​angiotensin system with further vasoconstriction and wall damage, as well as exacerbation of hypertension. Epidemiology Malignant hypertension may be becoming rarer in some coun- tries, particularly among white populations, but it still remains a common problem in developing countries and in other popula- tions with health and social deprivation, where it is an important cause of end-​stage renal failure. In west Birmingham in the United Subepicardium Subendocardium Hypertensive subendocardium? 100 50 50 100 150 200 50 100 150 200 Mean arterial blood pressure (mm Hg) Myocardial blood flow (Percentage of control) Normotensive patients Treated hypertensive patients Hypertensive patients 100 50 Cerebral blood flow (Percentage of control) Fig. 16.17.5.2  Autoregulation of myocardial and cerebral blood flow in normotensive and hypertensive patients. Reprinted from The Lancet, Vol. 330, Strandgaard S and Haunsø S, Why does antihypertensive treatment prevent stroke but not myocardial infarction?,
pp. 658–​60. Copyright (1987), with permission from Elsevier. Fig. 16.17.5.3  Ocular fundus in hypertension, showing papilloedema, exudates, and a few haemorrhages.

16.17.5  Hypertensive urgencies and emergencies 3803 Kingdom, the incidence of malignant hypertension is around 1 to 2 per 100 000 population per year, with no clear reduction between 1970 and 2011 in the number of new cases seen, the mean duration of known hypertension before presentation, presenting blood pressures, or the number of antihypertensive drugs that were being used. These data are reinforced by an analysis from Amsterdam of 122 patients with malignant hypertension in a multiethnic popu- lation, where the incidence rate was approximately 2.6 per 100 000 per year, and higher among blacks, approximately 7.3 per 100 000 of population per year. Increasing hospital admissions of pa- tients with either malignant hypertension or hypertensive enceph- alopathy has been observed in retrospective analysis of US data since 2007. These observations may reflect increasing diagnosis of malignant hypertension with encephalopathy, but at the very least there is no evidence of decline in the incidence of malignant hypertension. Although essential hypertension is usually the most common underlying cause of malignant hypertension in adults, secondary causes (especially renal disease) are more prevalent among younger patients, being identified in up to 40% of white and 10% of black subjects. In children (aged <16 years) with malignant hypertension, parenchymal renal disease is the commonest cause (63%), with 33% having renovascular hypertension (aortoarteritis and fibromuscular dysplasia), and only 5% with essential hypertension. There is an unexplained association between cigarette smoking and the use of oral contraceptive pill and the development of ma- lignant hypertension, that remains unexplained. Very rarely, the oral contraceptive pill may be implicated, consistent with the well-​ recognized increase in blood pressure in some women taking the combined oestrogen/​progesterone oral contraceptive pill. It is un- certain whether oral contraceptives cause malignant hypertension directly, or whether they simply exaggerate a pre-​existing tendency to raised blood pressure. Malignant hypertension can occur in older people, and is more common in Afro-​Caribbean than in white and Indo-​Asian popula- tions. Possible reasons for this include the relative resistance of black patients to some antihypertensive therapies and, perhaps, poorer drug compliance. In many series, black individuals had higher sys- tolic blood pressures and more renal dysfunction than whites. One reason for the failure of malignant hypertension to decline in some centres may be inadequate medical screening facilities among poorly educated people with a limited understanding of the nature of the disease and the need to comply with antihypertensive therapy. Any reported tendency towards reduction in the incidence of malignant hypertension may be because increasing use of drug therapy in milder grades of hypertension prevents progression to the malignant phase. Diagnosis The diagnosis of malignant hypertension is usually based on the asso- ciation of severely elevated blood pressure with a Keith and Wagener stage III or IV retinopathy. More recently, it has been suggested to consider that malignant hypertension with retinopathy is only one of several possible presentation(s) of acute hypertension with multiorgan damage (MOD). The presence of disturbance of at least three different target organs (kidney, heart, brain or microangiopathy) in association with acute blood pressure elevation is described as ‘hypertension MOD’, which would need to be managed as a hyper- tensive emergency, even though retinopathy is lacking. Clinical features The predominant presenting symptom is visual disturbances, ac- companied in some cases by headaches. Unfortunately, some patients with malignant hypertension remain asymptomatic, and others present at a late stage of their disease, this proportion ranging from 10% to 75% in one series from Nigeria. In the west Birmingham series, the presenting mean systolic and diastolic blood pressures have remained surprisingly similar over the 50 years surveyed (average blood pressure 229/​142 mm Hg), despite improvements in antihypertensive therapy. Heart failure, angina, or myocardial infarction are complicating features in approximately 20% of patients. The ECG shows that many patients have left ven- tricular hypertrophy, and many have cardiomegaly on chest radiog- raphy. However, some patients do have normal chest radiographs, ECGs, or echocardiograms despite very high blood pressure, sug- gesting that hypertension may have been of recent onset. The pro- portion of de novo diagnoses of malignant hypertension ranges from 55% to 60% in different registries. Investigation All patients with malignant hypertension need a detailed clin- ical history and examination, and investigation with blood tests (full blood count, serum biochemistry including electrolytes and renal function), 12-​lead ECG, chest radiography, and urinalysis. Fundoscopy and retinal photography are mandatory. Urinalysis may demonstrate proteinuria and haematuria, even in the ab- sence of primary renal disease, but the presence of proteinuria is a poor prognostic sign. The kidneys should be imaged by ab- dominal ultrasonography to assess renal size and appearance, with a low threshold for proceeding to renal angiography to look for renal artery stenosis if the kidneys are asymmetric. In all pa- tients a 24-​h urine collection is necessary for catecholamines (see Chapter  16.17.3), and urinary protein excretion should be esti- mated (most readily by measurement of urinary albumin/​cre- atinine ratio, ACR). These initial screening tests serve to identify patients in whom additional investigations may be appropriate to detect an underlying cause of hypertension. The full blood count and film may reveal the anaemia of chronic renal failure or occasionally a thrombotic microangiopathy, with thrombocytopenia and microangiopathic haemolytic anaemia—​ with red cell fragmentation and intravascular haemolysis—​possibly related to the degree of arteriolar fibrinoid necrosis, excessive endothelial injury, along with activation of the renin-​angiotensin-​ aldosterone system and an intravascular prothrombotic state. The presence of thrombotic microangiopathy is associated with worse recovery of renal function in the long term. Serum urea and creatinine should initially be measured daily: renal impairment may have significant prognostic implications. Mild hypokalaemia due to secondary hyperaldosteronism may be present, which usually resolves after control of the hyper- tension. Only very rarely does hypokalaemia indicate primary hyperaldosteronism (Conn’s syndrome), but if it is extreme or per- sists despite good blood pressure control, then the characteristic findings of low renin levels, but high aldosterone concentrations,

section 16  Cardiovascular disorders 3804 may be present. More commonly, both plasma renin and aldosterone levels are high in malignant hypertension, usually attributed to juxta- glomerular ischaemia. The inflammatory markers erythrocyte sedi- mentation rate and C-​reactive protein are often modestly elevated in malignant hypertension, but measurement of autoantibodies (antinuclear antibodies and antineutrophil cytoplasmic antibodies) can be used to discern uncommon cases due to vasculitis. Renal bi- opsy is required to make a specific diagnosis in some instances, but should not be performed until blood pressure is controlled. The chest radiograph may show cardiomegaly and the presence of pulmonary oedema. In a recent series of patients with malignant hypertension undergoing echocardiography, features included left ventricular hypertrophy, impaired systolic and diastolic function, and a dilated left atrium, were evident. Systolic impairment, meas- ured by global longitudinal strain, improved significantly as early as 2 months after initiation of treatment and was usually restored completely at 1-​year follow-​up. Long-​term treatment with good blood pressure control results in regression of the left ventricular hypertrophy and improvement of diastolic dysfunction on tissue Doppler, although typically incomplete. These structural/​functional abnormalities may predispose patients to cardiovascular complica- tions including heart failure and cardiac arrhythmias, such as atrial fibrillation. Hypertension and atrial fibrillation commonly coexist, and both are additive to the risk of stroke. In particular, the presence of uncontrolled hypertension increases the risk of stroke and thromboembolism associated with this common arrhythmia. Atrial fibrillation can be regarded as another manifestation of hypertensive target organ damage. Complications Retinopathy As described earlier and in Chapter 16.17.2, the most widely used classification of hypertensive changes in the fundus is that of Keith, Wagener, and Barker—​the strength of this being the correlation in the original description between clinical findings and prog- nosis (Table 16.17.5.1). However, this classification has now been made obsolete by advances in the understanding of the patho- physiology of arterial hypertension and the availability of effective antihypertensive therapy. Ophthalmoscopic grading of the retinal changes in hypertension has been simplified into mild, moderate, and severe levels (see Chapter 16.17.2), and can be further reduced into two groups:  grade A  (non​malignant)—​arteriolar narrowing and focal constriction, which also correlate with age and general cardiovascular status as well as blood pressure; and grade B (malig- nant)—​linear flame-​shaped haemorrhages, and/​or exudates, and/​or cotton wool spots, with or without disc swelling. Papilloedema is an unreliable physical sign, and its presence or absence in the context of other grade B changes does not indicate a worse prognosis. Grades 1 and 2 are broadly similar and are related to age and gen- eral cardiovascular status as well as blood pressure. Grades 3 and 4 are much more alike and both are now considered to be ‘malignant’. See Chapter 16.17.2 for further discussion. Similar retinal appearances with haemorrhages and papilloedema can occur in severe anaemia, connective tissue disease, and in- fective endocarditis. Idiopathic intracranial hypertension with bilateral papilloedema is itself associated with hypertension and obesity but this is not indicative of hypertension entering its ma- lignant phase. Nevertheless, severe hypertension and lone bilat- eral papilloedema may be a variant of malignant hypertension, with similar clinical features and prognosis. The retinal features of malignant hypertension regress over a period of 2 to 3 months if good blood pressure control is achieved. There is an association between the degrees and dynamic of the retinal and renal function changes, thus emphasizing the fact that patients with malignant hypertension develop systemic microvascular damage/​dysfunc- tion involving several organs. Renal involvement Renal involvement in malignant hypertension has been referred to as malignant nephrosclerosis, manifest as haematuria, proteinuria, and (sometimes) acute renal failure. Renal failure is the commonest cause of death, with presenting urea and creatinine levels inde- pendent predictors of survival. When antihypertensive therapy is initiated and blood pres- sure control achieved, the effect on renal function is variable. In the short term, renal function stabilizes in 10% of cases, deteri- orates progressively in 30%, and deteriorates transiently before improving over a matter of weeks in the remainder. Renal failure is more frequent (two-​to threefold) in black, than in white, individuals (Fig. 16.17.5.4), but mainly because of higher serum creatinine levels at presentation. Table 16.17.5.1  The Keith, Wagener, and Barker classification of hypertensive retinopathy Grade 1 Grade 2 Grade 3 Grade 4 Retinal findings Mild narrowing or sclerosis
of the retinal arterioles Moderate to marked sclerosis of
the retinal arterioles Retinal oedema, cotton wool
spots, and haemorrhages All the above and optic disc oedema Exaggerated arterial light reflex Sclerosis and spastic lesions of retinal arterioles Venous compression at arteriovenous crossings (‘nipping’) Macular star Percentage surviving in original series 1 year 90 88 65 21 3 years 70 62 22   6 5 years 70 54 20   1

16.17.5  Hypertensive urgencies and emergencies 3805 Isles and coworkers have suggested that the renal outcome of patients with malignant hypertension can be considered in three groups, each with a different renal prognosis: (1) patients whose serum creatinine is less than 300 µmol/​litre at presentation, who do well with effective antihypertensive therapy; (2) patients with chronic renal failure (serum creatinine >300 µmol/​litre) who do not require renal dialysis immediately, but are unlikely to main- tain or recover renal function, except possibly in the short term, and commonly progress to end-​stage renal failure; and (3) a small group with acute renal failure. It is possible that some of these pa- tients may have poststreptococcal acute nephritic syndrome, char- acterized by retinopathy, fluid retention, and usually complete renal recovery. In the west Birmingham series, Lip et al. did not find such a clear distinction based on serum creatinine and found that renal func- tion continued to deteriorate among many patients with malignant hypertension, despite good blood pressure control at follow-​up. About half of the patients with severe renal impairment at pres- entation demonstrated either static or improved renal function, and there was no evidence that those cases where renal function remained static were those with less renal impairment at presenta- tion. The severity of malignant hypertension at presentation did not predict outcome, but the quality of control of systolic blood pres- sure at follow-​up and the height of the serum creatinine at pres- entation did, suggesting that careful monitoring of renal function and aggressive treatment of blood pressure is mandatory in patients with this condition. End-​stage renal disease remains a significant cause of death in patients with malignant hypertension. High serum urate levels are associated with greater renal impair- ment at baseline, as well as higher diastolic blood pressures, but are not predictive of deterioration in renal function or overall survival in patients with malignant hypertension. There are varying reports of the frequency of renovascular disease in malignant hypertension, which may be due to the frequency with which renal angiography is performed. In older patients, renal artery stenosis is likely to be due to atheromatous disease, which itself may be a consequence of chronic hyperten- sion and chronic hyperlipidaemia, as well as cigarette smoking. In younger patients, and particularly in women, renal artery sten- osis may be due to fibromuscular dysplasia of the renal arteries, with the characteristic ‘string of beads’ appearance on renal angi- ography. The value of surgical or angioplastic correction of ather- omatous disease is debatable, possibly producing no better results than effective blood pressure control with antihypertensive drugs. In patients with fibromuscular dysplasia, however, renal angio- plasty with stenting is worthwhile and will often lead to a normal blood pressure level. Management All patients with malignant hypertension require assessment, in- vestigation, and commencement of therapy under supervision, preferably as an in-​patient. Blood pressure should be measured 4-​ hourly, with the initial aim of treatment being to lower the diastolic pressure near about 100–​105 mm Hg over a period of 2 to 3 days, with oral therapy and dose escalation at daily intervals, if necessary. The maximum initial fall in blood pressure should not exceed 25% of the presenting value, gradual reduction allowing adaptation of disordered tissue autoregulation and avoidance of target organ is- chaemia. More aggressive antihypertensive therapy is both unneces- sary and dangerous, as it may reduce the blood pressure to below the autoregulatory range, leading to ischaemic events such as strokes, heart attack, or renal failure. The first-​line oral antihypertensive agent is either a short-​acting calcium antagonist (such as nifedipine) or a β-​blocker (such as atenolol). An appropriate dose of nifedipine is 10–​20 mg of the tablet formulation, which can be repeated or increased, as ne- cessary, to bring about gradual reduction in blood pressure. Nifedipine is not absorbed from the oral mucosa, and there have been reports of complications including visual loss, cerebral in- farction, and myocardial infarction with nifedipine therapy using the short-​acting sublingual capsules, which produce unpredict- able falls in blood pressure and should never be used. β-​Blockers are useful alternatives, but should be avoided in patients with asthma or where there is a high suspicion of an underlying phaeo- chromocytoma. It is sensible to start with small doses, such as 25 mg of atenolol, increasing the dose as necessary. The combin- ation of oral atenolol and nifedipine is often a well-​tolerated and effective regime. Diuretics should be restricted to those with evidence of fluid overload. Some patients are volume depleted, presumably sec- ondary to a pressure-​related diuresis and activation of the renin–​ angiotensin system. Captopril and the other angiotensin converting enzyme (ACE) inhibitors can produce rapid and dangerous falls in blood pressure, particularly in patients with hypokalaemic sec- ondary hyperaldosteronism and hyponatraemia secondary to juxtaglomerular ischaemia or renovascular disease, which may be unrecognized in the acute situation. Over a period of about 1 to 2 weeks, further antihypertensive drugs should be added in to achieve a gradual reduction of blood pressure to less than 140/​85 mm Hg. Triple or quadruple drug regi- mens are invariably necessary in the long term. 1.0 0.8 0.6 Proportion with renal failure 0.4 0.2 White patients Black patients 0 1 2 3 4 5 6 Years from admission Fig. 16.17.5.4  Proportion with renal failure after presentation with malignant hypertension, stratified for ethnicity. From Van den Born BJ, et al. (2006). Ethnic disparities in the incidence, presentation and complications of malignant hypertension. J Hypertens, 24, 2299–​304.

section 16  Cardiovascular disorders 3806 Drugs for the treatment of hypertensive emergencies and urgen- cies are summarized in Tables 16.17.5.2 and 16.17.5.3. Prognosis Historically, when malignant hypertension was left untreated, around 80% of patients died within 2  years, hence the name. In west Birmingham, between 1965 and 2006, after a median follow-​up of 103 months (range 1–​539 months), 40% were alive and not requiring renal replacement therapy, 3.2% were on long-​ term haemodialysis, and 40% were dead, with the remainder lost to follow-​up. The commonest causes of death were renal failure (39.7%), stroke (23.8%), myocardial infarction (11.1%), and heart failure (10.3%). The advent of effective and tolerable antihypertensive drug therapy has improved prognosis. For example, in the west Birmingham series, 5-​year mortality rates reduced from 76% prior to 1967 to 7% Table 16.17.5.2  Oral drugs for hypertensive emergencies and urgencies Category Example Comment β-​Blockers Atenolol (25–​50 mg) Safe unless contraindicated Calcium channel blockers Nifedipine capsules Dangerous Nifedipine tablets (10–​20 mg) Safe Amlodipine Onset of action is slow (c.5 days) Verapamil Useful if tachycardia or associated supraventricular arrhythmia Nicardipine Not better than nifedipine by mouth α-​Blockers Prazosin Little experience Doxazosin Little experience Phenoxybenzamine Phaeochromocytoma Diuretics Thiazides Slow onset Loop diuretics Only if heart failure ACE inhibitors Captopril (6.25–​50 mg, three times a day) If patient on diuretic, or if renal artery stenosis is undiagnosed, may cause rapid falls in blood pressure and acute renal failure Table 16.17.5.3  Parenteral drugs for the treatment of hypertensive emergencies Action Administration Use and adverse effects Comment Sodium nitroprusside Dilates both arterioles and veins via generation of cGMP which then activates calcium-​sensitive potassium channels in the cell membrane IV infusion; rapid onset and offset of action, minimizing the risk of hypotension Recommended starting dose is 0.25–​0.5 μg/​kg per min, increased as necessary to a maximum dose of 8–​10 μg/​kg per min, for up to 10 min Nitroprusside should not be given to pregnant women Can cause intrapulmonary shunting and coronary ‘steal’ Thiocyanate and cyanide toxicity manifest by clinical deterioration, muscle twitching, altered mental status, and lactic acidosis, and can be fatal The most effective parenteral drug for most hypertensive emergencies Easy to control on a minute-​to-​ minute basis Glyceryl trinitrate (nitroglycerin) Similar action to nitroprusside, but greater venodilatation IV infusion, 5–​100 μg/​min Onset of action is 2–​5 min, duration of action 5–​10 min Headache (due to direct vasodilatation) and tachycardia (reflex sympathetic activation) Vomiting Methaemoglobinaemia Most useful in patients with symptomatic coronary disease and in those with hypertension following surgery Labetalol Combined β-​and α-​blocker Rapid onset of action (5 min or less) Bolus of 20 mg initially, followed by 20–​80 mg every 10 min to a total dose of 300 mg The infusion rate is 0.5–​2 mg/​min Avoid in patients with contraindications to β-​blockers Safe in patients with active coronary disease since it does not increase the heart rate Also useful in the perioperative care of patients with severe hypertension Esmolol β-​Blocker Rapid onset and offset of action IV infusion, titrated to heart rate and blood pressure response Reduces myocardial ischaemia Avoid in patients with contraindications to β-​blockers Useful in tachycardias, hyperdynamic heart, arrhythmias (e.g. atrial fibrillation), perioperative hypertension, aortic dissection Nicardipine Dihydropyridine calcium channel blocker IV infusion at 5–​15 mg/​h Headache and flushing Tachycardia Becoming more popular Useful for most hypertensive emergencies, except acute heart failure

16.17.5  Hypertensive urgencies and emergencies 3807 for the years 1997 to 2011 (Fig. 16.17.5.5). The series by Scarpelli and coworkers reported a 12-​year survival rate of about 69%, al- though patients with malignant hypertension diagnosed after 1980 had a 100% survival rate. More contemporaneous data from the Amsterdam series, describing patient incidents between 1993 and 2005, showed that 10% had died and 19% needed renal replacement therapy after a mean follow-​up of 4 years. Hence, whatever the cause of malignant hypertension, progressive renal impairment is still a common complicating factor, with many patients needing dialysis in the long term. The importance of early diagnosis is emphasized as patients tend to develop clinical symptoms only at a late stage of their disease. Black men with malignant hypertension have a poor prognosis when compared with other ethnic groups or women; they also present with more severe hypertension and greater renal damage, which are independent predictors of outcome and explain the poorer prognosis. Hypertensive emergencies Hypertensive left ventricular failure Hypertension causes heart failure by a number of mechan- isms: these include pressure overload on the heart due to the raised peripheral vascular resistance, reduced left ventricular compliance (e.g. in left ventricular hypertrophy), an increased risk for cor- onary artery disease and the precipitation of cardiac arrhythmias (such as atrial fibrillation). Severe hypertension results in a signifi- cant increase in afterload and may result in decompensation of the failing heart. In very severe hypertension with marked pulmonary oedema, intravenous sodium nitroprusside may be necessary to reduce pre- load and afterload in addition to conventional management with opioids and loop diuretics. However, metabolism of nitroprusside to cyanide, possibly leading to the development of cyanide or (rarely) thiocyanate toxicity, may be a limitation. This manifests with altered mental status and lactic acidosis, and can be fatal. The risk of toxicity is increased in children, also with prolonged treatment (>24–​48 h), underlying renal insufficiency, and requirement for high doses (>2 µg/​kg per min). An infusion of sodium thiosulfate can be used in affected patients to provide a sulfur donor to detoxify cyanide into thiocyanate. Nitrates may also be used to treat hypertensive left ventricular failure, but they are less potent than sodium nitroprusside. ACE in- hibitors should be considered only after the patient’s condition is stabilized, when they are well established to be life-​saving in those with left ventricular systolic impairment, lead to long-​term regres- sion of left ventricular hypertrophy, and may also improve heart failure secondary to diastolic dysfunction. Hypertensive encephalopathy Hypertensive encephalopathy refers to the presence of signs of cerebral oedema caused by breakthrough hyperperfusion fol- lowing severe and sudden rises in blood pressure. There is failure of autoregulatory vasoconstriction with focal or generalized dila- tation of small arteries and arterioles and impaired macro-​and Action Administration Use and adverse effects Comment Diazoxide Arteriolar vasodilator that has little effect on the venous circulation IV bolus 50–​150 mg or infusion 2–​10 mg/​h Peak effect seen within 15 min, lasts for 4–​24 h Do not use in patients with angina pectoris, myocardial infarction, pulmonary oedema, or a dissecting aortic aneurysm Can cause marked fluid retention and a diuretic may be needed Give β-​blocker to block reflex activation of the sympathetic nervous system Rarely used nowadays as may cause excessive blood pressure reduction which is difficult to reverse Hydralazine Direct arteriolar vasodilator IV bolus Initial dose is 10–​20 mg Fall in blood pressure begins within 10–​30 min and lasts 2–​4 h Tachycardia, flushing, headache, vomiting Aggravation of angina Hypotensive response to hydralazine is less predictable Used in pregnant women Phentolamine α-​Adrenergic blocker IV bolus, 5–​10 mg every 5–​15 min as necessary Severe hypertension due to phaeochromocytoma and other syndromes of increased catecholamine activity, such as drug abuse, MAO-​ induced hypertension, and so on Tachyphylaxis means that doses need to be escalated IV, intravenous; MAO, monoamine oxidase. Table 16.17.5.3  Continued 80 76% 74% 26% 20% 7% 60 40 5-year mortality, % 20 0 1958–1966 1967–1976 1977–1986 Years of diagnosis 1987–1996 1997–2011 Fig. 16.17.5.5  Rates of 5-​year mortality in patients with malignant hypertension diagnosed in different time periods. From Shantsila A, Shantsila E, Beevers DG, Lip GYH (2017). Predictors of 5-​year outcomes in malignant phase hypertension: the West Birmingham Malignant Hypertension Registry. J Hypertens, 35, 2310–​14.

section 16  Cardiovascular disorders 3808 microvascular function. This leads to high cerebral blood flow, dysfunction of the blood–​brain barrier, and the formation of brain oedema, which is thought to cause the clinical symptoms. The con- dition is now very rare, although recent retrospective analysis of the US data showed an increasing trend for the hospital admission of patients with either hypertensive encephalopathy or malignant hypertension after 2007. These observations could reflect improved recognition and diagnosis of malignant hypertension with enceph- alopathy, as admissions for essential hypertension fall. It is essential to perform a CT or an MRI scan to ensure that this hypertensive emergency is distinguished from other neurological syndromes as- sociated with high blood pressure, including intracerebral or sub- arachnoid haemorrhage, ischaemic stroke, or lacunar infarction. Hypertensive encephalopathy is usually associated with a history of hypertension that has been inadequately treated, or where pre- vious treatment has been discontinued. It is characterized by the in- sidious onset of headache, nausea, and vomiting, followed by visual disturbances, field loss, and fluctuating, non​localizing neurological symptoms such as restlessness, confusion, and—​if the hypertension is not treated—​seizures and coma. Severe retinopathy is frequently, but not always, present. CT or MRI may demonstrate white matter oedema, with the reso- lution of changes after patient stabilization. One of these tests is mandatory to exclude cerebral haemorrhage or infarction. Indeed, the increased use of CT scanning has demonstrated that almost all patients who appear to have hypertensive encephalopathy have cerebral infarction or haemorrhage with surrounding oedema and space-​occupying cerebral symptoms. Lumbar puncture is not indi- cated in the management of patients with malignant hypertension; but if obtained (perhaps in ignorance of the diagnosis) the cerebro- spinal fluid is usually normal, although at an increased pressure. The ECG may show variable transient, focal, or bilateral abnormalities. Sodium nitroprusside is the drug of choice for genuine hyperten- sive encephalopathy, but is not usually given if there is a cerebral infarct or haemorrhage. Parenteral labetalol and nitrates have also been used successfully. Rarely, diazoxide and hydralazine have been given, but they can cause precipitate and life-​threatening acute falls in blood pressure, and they require concurrent β-​blocker adminis- tration to minimize reflex sympathetic stimulation. Sublingual ni- fedipine capsules should never be used (see ‘Management’, earlier). Phentolamine is used only in patients with severe hypertension due to increased catecholamine activity, such as that seen in phaeo- chromocytoma, or after tyramine ingestion in a patient being treated with a monoamine oxidase inhibitor. ACE inhibitors are best avoided in the early stage as they may, even in a very low dose, cause precipitate falls in blood pressure and life-​threatening reduction in cerebral perfusion, particularly when patients are fluid depleted due to diuretic therapy or in the presence of renal artery stenosis. Severe pre-​eclampsia and eclampsia are discussed in detail else- where (see Chapter 14.4). They may present with clinical features similar to hypertensive encephalopathy, and treatment is broadly similar, with labetalol infusions, magnesium sulphate, and early de- livery of the fetus. Hypertension with unstable angina or acute
myocardial infarction In a patient presenting with an acute coronary syndrome (unstable angina or acute myocardial infarction) and severe hypertension, a ‘true’ hypertensive emergency, such as aortic dissection, must first be ruled out. The risk of bleeding and stroke is significantly increased if anticoagulation with heparin, antiplatelet therapies (such as glyco- protein IIb/​IIIa inhibitors), or thrombolytic therapy is administered. The appropriate initial treatment of patients with severe hyper- tension (>180/​110 mm Hg) and an acute coronary syndrome should include the initiation of intravenous nitrates, with intravenous labetalol, sodium nitroprusside, or nicardipine as alternatives. The reduction of blood pressure should not be too abrupt: as with ma- lignant hypertension, a gradual reduction is recommended in an en- deavour to avoid further myocardial or brain ischaemia. As stated previously, sublingual nifedipine—​once considered as a first-​line drug—​should not be used in view of its negligible oral absorp- tion and the unpredictable hypotensive effects from later gastric absorption. Anticoagulation or thrombolytic therapy can be administered when the blood pressure is adequately controlled (<180/​110 mm Hg). In many centres, revascularization with primary percutaneous coronary angioplasty is increasingly the initial management option for acute ST-​segment elevation myocardial infarction (STEMI). Hypertension with acute stroke and after a stroke It is common to find modestly elevated blood pressure in patients ad- mitted to hospital following an acute stroke. Cerebral autoregulation is commonly impaired in this context, with flow becoming pressure dependent, hence excessive antihypertensive treatment may serve to worsen the cerebral damage resulting from intracerebral infarction or haemorrhage, and stroke physicians are very wary about lowering the blood pressure. There are few randomized controlled trials to inform the man- agement of this common problem. Current consensus only recom- mends acute blood pressure lowering where there is associated acute end-​organ damage—​for example, cardiac (acute myocardial infarc- tion, severe left ventricular failure) or vascular urgencies (aortic dissection), hypertensive encephalopathy, acute renal failure, con- current anticoagulant therapy (thrombolysis, intravenous heparin, and so on), or persistent blood pressure elevation with a threshold greater than 200/​120  mm Hg for ischaemic stroke and greater than 180/​105 mm Hg for haemorrhagic stroke. In these cases, oral therapy with small doses of nifedipine or atenolol may be required. Parenteral treatment or sublingual nifedipine is always contraindi- cated. The calcium antagonist nimodipine has beneficial effects on cerebral vasospasm following subarachnoid haemorrhage, but these effects are not related to the small fall in blood pressure with this drug. Severe hypertension after a stroke is a risk factor for further stokes, and long-​term treatment is worthwhile. It is unclear whether the immediate treatment of mild hypertension is of benefit. The role of antihypertensive medication before, during, and after a stroke can, therefore, be summarized as follows: • Before a stroke, it is of benefit to have blood pressure reduced to below 140/​85 mm Hg, as stroke prevention can be achieved. • During a stroke, it is detrimental to have hypertension treated ag- gressively, in view of the disordered cerebral autoregulation. • After a stroke, the epidemiological associations of hypertension with recurrent stroke have not been entirely consistent, with some studies showing no association or a J-​shaped relationship.

16.17.5  Hypertensive urgencies and emergencies 3809 In recent years, many studies have reported on the effects of antihypertensive drugs—​predominantly ACE inhibitors or angio- tensin receptor blockers—​in the early post-​stroke setting. The Heart Outcomes Prevention Evaluation (HOPE) study reported a subset of 1013 subjects with a previous history of stroke or tran- sient ischaemic attack (TIA), where there was a non​significant 15% reduction in total stroke recurrence with ramipril. In the PROGRESS trial, 6105 normotensive and hypertensive patients with a history of ischaemic or haemorrhagic stroke or TIA were randomized to perindopril (± indapamide), which reduced re- current stroke by 28% and major vascular events by 26% during 4 years of follow-​up. The Morbidity and Mortality after Stroke Eprosartan Study (MOSES) compared eprosartan (an angiotensin receptor blocker) to nitrendipine (a dihydropyridine calcium channel blocker) in hypertensive-​stroke survivors and found a 21% risk reduction in the primary endpoint of all cardiovascular and cerebrovascular events and a 25% reduction in recurrent cerebrovascular events in the eprosartan-​treated patients. In the CATIS Randomized Clinical Trial, patients with acute ischaemic stroke (n  =  2038) were randomly assigned to receive antihypertensive treatment (aimed at lowering systolic blood pressure by 10% to 25% within the first 24 h after randomization, achieving blood pressure less than 140/​90 mm Hg within 7 days, and maintaining this level during hospitalization) or to discon- tinue all antihypertensive medications (control) during hospi- talization (n = 2033). In this trial, blood pressure reduction with antihypertensive medications, compared with the absence of hyper- tensive medication, did not reduce the likelihood of death and major disability at 14 days or hospital discharge. Data from the large Safe Implementation of Thrombolysis in Stroke–​ International Stroke Thrombolysis Register (SITS-​ISTR) of 11 080 patients showed a U-​shaped relation of death and physical independency with post-​thrombolysis systolic blood pressure, with blood pressure of 141–​150 mm Hg associated with the most favour- able outcomes. The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial pilot (INTERACT1) (n  =  404) and main INTERACT2 (n  =  2839) studies compared intensive (target <140 mm Hg) or guideline-​recommended (target <180 mm Hg) systolic blood pressure lowering treatment in patients with spon- taneous intracranial haemorrhage (<6 h). These showed favourable outcome on physical independency for intensive BP control (odds ratio 1.13, 95% confidence interval 1.00–​1.26; p = 0.042) over the early and later recovery periods. Management of blood pressure in a patient
with aortic dissection The detailed presentation, diagnosis, and treatment of aortic dissection is discussed in Chapter 16.14.1. On suspicion of the diagnosis, whether or not surgery is indicated, all patients should be treated pharmacologically to reduce the systolic blood pres- sure to around 110 mm Hg and the heart rate to 60–​70 beats/​ min, thus reducing the force of systolic ejection to reduce aortic shear stress and limit the size of the dissection. Labetalol is an effective agent, or alternatively, sodium nitroprusside in con- junction with a β-​blocker may be used. Patients should ideally have haemodynamic monitoring with an arterial line in position. Diagnostic tests are then performed on an urgent basis to con- firm the dissection, identifying whether the ascending aorta is involved, and defining any vascular abnormalities resulting from the dissection. Acknowledgement We acknowledge the contribution of D. Gareth Beevers to previous editions of this chapter. FURTHER READING Bloxham CA, Beevers DG, Walker JM (1979). Malignant hyperten- sion and cigarette smoking. Br Med J, i, 581–​3. Cremer A, et al. (2015). From malignant hypertension to hypertension-​ MOD: a modern definition for an old but still dangerous emergency. J Hum Hypertens, 30, 463–​6. Gudbrandsson T, et  al. (1979). Malignant hypertension. Improving prognosis in a rare disease. Acta Med Scand, 206, 495–​9. Harvey JM, et al. (1992). Renal biopsy findings in hypertensive patients with proteinuria. Lancet, 340, 1435–​6. He J, et al. (2014). Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. JAMA, 311, 479–​89. Isles CG, McLay A, Boulton Jones JM (1984). Recovery in malignant hypertension presenting as acute renal failure. Q J Med, 212, 439–​52. Jhetam D, et al. (1982). The malignant phase of essential hypertension in Johannesburg blacks. S Afr Med J, 61, 899–​902. Kadiri S, Olutade BO (1991). The clinical presentation of malignant hypertension in Nigerians. J Hum Hypertens, 5, 339–​43. Keith NM, Wagener HP, Barker NW (1939). Some different types of essential hypertension: their course and prognosis. Am J Med Sci, 196, 332–​43. Kumar P, et al. (1996). Malignant hypertension in children in India. Nephrol Dial Trans, 11, 1261–​6. Lane DA, Lip GYH, Beevas DG (2009). Improving survival of malignant hypertension patients over 40 years. Am J Hypertens, 22, 1199–​204. Leishman AWD (1959). Hypertension—​treated and untreated: a study of 400 cases. Br Med J, i, 1361–​3. Lim KG, et al. (1987). Malignant hypertension in women of childbearing age and its relation to the contraceptive pill. BMJ, 294, 1057–​9. Lip GYH, et  al. (1995). Severe hypertension and lone bilateral papilloedema: a variant of malignant phase hypertension. Blood Press, 4, 339–​42. Lip GYH, et al. (1995). Malignant hypertension in the elderly. Q J Med, 88, 641–​7. Lip GYH, Beevers M, Beevers DG (1997). Does renal function improve following diagnosis of malignant phase hypertension? J Hypertens, 15, 1309–​15. Lip GYH, Beevers M, Beevers DG (2000). Serum urate is associated with baseline renal dysfunction but not survival or deterioration in renal function in malignant phase hypertension. J Hypertens, 18, 97–​101. Lip GY, et al. (2010). Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-​based approach: the Euro Heart survey on atrial fibrillation. Chest, 137, 263–​72. Mamdani BH, et al. (1974). Recovery from prolonged renal failure in patients with accelerated hypertension. N Engl J Med, 291, 1343–​4.

section 16  Cardiovascular disorders 3810 Pitcock JA, et al. (1976). Malignant hypertension in blacks. Malignant intrarenal arterial disease as observed by light and electron micros- copy. Hum Pathol, 7, 333–​46. Scarpelli PT, et al. (1997). Accelerated (malignant) hypertension: a study of 121 cases between 1974 and 1996. Nephrology, 10, 207–​15. Schrader J, et al. (2005). Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke, 36, 1218–​26. Shantsila A, Lip GYH (2017). Malignant hypertension revisited—​does this still exist? Am J Hypertens, 30, 543–​9. Strandgaard S, Paulson OB (1996). Antihypertensive drugs and cere- bral circulation. Eur J Clin Invest, 26, 625–​30. Van den Born BH, et al. (2019). ESC Council on hypertension pos- ition document on the management of hypertensive emergencies. Eur Heart J Cardiovasc Pharmacother, 5, 37–46. Van den Born BJ, et al. (2006). Ethnic disparities in the incidence, pres- entation and complications of malignant hypertension. J Hypertens, 24, 2299–​304. Veriava Y, et al. (1990). Hypertension as a cause of end-​stage renal failure in South Africa. J Hum Hypertens, 4, 379–​83. Webster J, et al. (1993). Accelerated hypertension—​patterns of mor- tality and clinical factors affecting outcome in treated patients.
Q J Med, 86, 485–​93. Zampaglione P, et al. (1996). Hypertensive urgencies and emer- gencies. Prevalence and clinical presentation. Hypertension, 27, 144–​7.