Epidemiology

Malignant hypertension may be becoming rarer in some countries, particularly amongst white populations, but it still remains a common problem in developing countries and in other populations with health and social deprivation, where it is an important cause of endstage renal failure. In west Birmingham in the United Kingdom, the incidence of malignant hypertension is around 1 to 2 per 100 000 population per year, with no clear reduction between 1970 and 2006 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 population, where the incidence rate was approximately 2.6 per 100 000 per year, and was higher among blacks.

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 association between cigarette smoking and malignant 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 uncertain whether oral contraceptives cause hypertension directly, or whether they simply exaggerate a tendency in women who already have a propensity to raised blood pressure.

Malignant hypertension can occur in older people, and is more common in Afro-Caribbean than in white and Indo-Asian populations. 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 systolic 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 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. Nevertheless, it is possible that there has been no real decline in malignant hypertension, but merely a failure to recognize this life-threatening condition.

Clinical features

The predominant presenting symptom is visual disturbance with or without headaches, but 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 30 years surveyed (average blood pressure 229/142 mmHg), despite improvements in antihypertensive therapy. Heart failure, angina, or myocardial infarction are complicating features in approximately 20% of patients, and the ECG shows that many patients to have cardiomegaly and left ventricular hypertrophy. Nevertheless, some patients do have normal chest radiographs, ECGs, or echocardiograms despite very high blood pressure, suggesting that hypertension may have been of recent onset.

Investigation

All patients with malignant hypertension need a detailed clinical 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 absence of primary renal disease, but the presence of proteinuria is a poor prognostic sign. The kidneys should be imaged by abdominal 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. A 24-h urinary collection is necessary for catecholamines (see Chapter 16.17.3) and so is protein excretion assessment in all patients (or the latter can be estimated by albumin/creatinine 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 microangiopathic haemolytic anaemia—with red cell fragmentation and intravascular haemolysis—possibly related to the degree of arteriolar fibrinoid necrosis. 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 hypertension. Only very rarely does hypokalaemia indicate primary hyperaldosteronism (Conn’s syndrome), but if it is extreme or persists despite good blood pressure control, then the characteristic findings of low renin levels, but high aldosterone concentrations, may be present. More commonly, both plasma renin and aldosterone levels are high in malignant hypertension, usually attributed to juxtaglomerular ischaemia. Inflammatory markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) 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 biopsy 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, cardiac hypertrophy was common and associated with systolic dysfunction and a dilated left atrium, irrespective of the duration of known hypertension. These structural/functional abnormalities may predispose patients to cardiovascular complications including heart failure and cardiac arrhythmias, such as atrial fibrillation.

Complications

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 independent predictors of survival.

When antihypertensive therapy is initiated and blood pressure control achieved, the effect on renal function is variable. In the short term, renal function stabilizes in 10% of cases, deteriorates 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. 16.17.5.3), but mainly because of higher serum creatinine levels at presentation.

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Fig. 16.17.5.3

Proportion with renal failure after presentation with malignant hypertension, stratified for ethnicity.

From van den Born et al 2006 - Van den Born BJ et al (2006). Ethnic disparities in the incidence, presentation and complications of malignant hypertension. J Hypertens 24, 2299-304 (http://journals.lww.com/jhypertension/Abstract/2006/11000/Ethnic_disparities_in_the_incidence,_presentation.27.aspx).

Isles and co-workers 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 maintain or recover renal function, except possibly in the short term, and commonly progress to endstage renal failure; and (3) a small group with acute renal failure. It is possible that some of these patients may have poststreptococcal acute nephritic syndrome, characterized 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 function 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 presentation 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 presentation. The severity of malignant hypertension at presentation did not predict outcome, but the quality of control of systolic blood pressure at follow-up and the height of the serum creatinine at presentation did, suggesting that careful monitoring of renal function and aggressive treatment of blood pressure is mandatory in patients with this condition.

High serum urate levels are associated with greater renal impairment 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 hypertension and chronic hyperlipidaemia, as well as cigarette smoking. In younger patients, and particularly in women, renal artery stenosis may be due to fibromuscular dysplasia of the renal arteries, with the characteristic ‘string of beads’ appearance on renal angiography. The value of surgical or angioplastic correction of atheromatous disease is debatable, possibly producing no better results than effective blood pressure control with antihypertensive drugs. In patients with fibromuscular dysplasia, however, renal angioplasty with stenting is worthwhile and will often lead to a normal blood pressure level.

Management

All patients with malignant hypertension require assessment, investigation, 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 to 105 mmHg 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 ischaemia. More aggressive antihypertensive therapy is both unnecessary 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 to 20 mg of the tablet formulation, which can be repeated or increased, as necessary, 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 infarction, and myocardial infarction with nifedipine therapy using the short-acting sublingual capsules, which produce unpredictable 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 phaeochromocytoma. It is sensible to start with small doses, such as 25 mg of atenolol, increasing dose as necessary. The combination 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 secondary 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 secondary 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 mmHg. Triple or quadruple drug regimens are invariably necessary in the long term.

Drugs for the treatment of hypertensive emergencies and urgencies anre summarized in Tables 16.17.5.2 and 16.17.5.3.

Prognosis

If malignant hypertension is left untreated, around 80% of patients die 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 survival rates improved from 31.4% prior to 1967 to 91.9% for the years 1997 to 2006. (Fig. 16.17.5.4). The series by Scarpelli and coworkers reported a 12-year survival rate of about 69%, although patients with malignant hypertension diagnosed after 1980 had a 100% survival rate. More contemporaneous data from the Amsterdam series, describing patients incident 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.

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Fig. 16.17.5.4

Five-year survival by decade of diagnosis. MHT, malignant phase hypertension.

Reprinted by permission from Macmillan Publishers Ltd: American Journal of Hypertension, Lane DA, Lip GYH, Beevers DG, Improving survival of malignant hypertension patients over 40 years. 22: 1199–204, copyright (2009).

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 left ventricular failure

Hypertension causes heart failure by a number of mechanisms: 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 coronary artery disease and the precipitation of cardiac arrhythmias (such as atrial fibrillation). Severe hypertension results in a significant 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 preload 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 thiosulphate can be used in affected patients to provide a sulphur 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 inhibitors 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 regression 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 following severe and sudden rises in blood pressure. There is failure of autoregulatory vasoconstriction with focal or generalized dilatation of small arteries and arterioles. 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 condition is now very rare, and it is essential to perform a CT or an MRI scan to ensure that this hypertensive emergency is distinguished from other neurological syndromes associated with high blood pressure, including intracerebral or subarachnoid haemorrhage, ischaemic stroke, or lacunar infarction.

Hypertensive encephalopathy is usually associated with a history of hypertension that has been inadequately treated, or where previous treatment has been discontinued. It is characterized by the insidious onset of headache, nausea, and vomiting, followed by visual disturbances and fluctuating, nonlocalizing 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, and 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 indicated in the management of patients with malignant hypertension; but if obtained (perhaps in ignorance of the diagnosis) the cerebrospinal 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 hypertensive 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 administration to minimize reflex sympathetic stimulation. Sublingual nifedipine capsules should never be used (see above). Phentolamine is used only in patients with severe hypertension due to increased catecholamine activity, such as that seen in phaeochromocytoma, 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 elsewhere (see Chapter 14.4). They may present with clinical features similar to hypertensive encephalopathy, and treatment is broadly similar, with labetolol infusions, magnesium sulphate, and early delivery 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 glycoprotein IIb/IIIa inhibitors), or thrombolytic therapy is administered.

The appropriate initial treatment of patients with severe hypertension (>180/110 mmHg) 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 malignant hypertension, a gradual reduction is recommended in an endeavour 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 absorption 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 mmHg), or revascularization with primary percutaneous coronary angioplasty can be considered as an alternative 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 admitted to hospital following an acute stroke. Cerebral autoregulation is commonly impaired in this context, with flow becoming pressure dependent. Thus, 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 management of this common problem. Current consensus only recommends acute blood pressure lowering where there is associated acute end-organ damage—e.g. cardiac (acute myocardial infarction, severe left ventricular failure) or vascular urgencies (aortic dissection), hypertensive encephalopathy, acute renal failure, concurrent coagulant therapy (thrombolysis, intravenous heparin, etc.), or persistent blood pressure elevation with a threshold of greater than 200/120 mmHg for ischaemic stroke and greater than 180/105 mmHg 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 contraindicated. 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:

1. 1 Before a stroke, it is of benefit to have blood pressure reduced to below 140/85 mmHg, as stroke prevention can be achieved.

2. 2 During a stroke, it is detrimental to have hypertension treated aggressively, in view of the disordered cerebral autoregulation.

3. 3 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.

In the last decade, many studies have reported on the effects of antihypertensive drugs—predominantly ACE inhibitors or angiotensin receptor blockers—in the poststroke setting. The Heart Outcomes Prevention Evaluation (HOPE) study reported a subset of 1013 subjects with a previous history of stroke or transient ischaemic attack (TIA), where there was a nonsignificant 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 recurrent 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.

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 pressure to around 110 mmHg and the heart rate to 60 to 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 conjunction 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 confirm the dissection, identifying whether the ascending aorta is involved, and defining any vascular abnormalities resulting from the dissection.