Hypertension ARVD may be found in 2% of all cases of HTN and >90% of all patients with ARV D are hypertensive. Despite this frequent association it is often questionable whether a gi ven RAS lesion actually causes the HTN. In many patients the pattern is often that of sever e systolic HTN resistant to medical therapy. Epidemiology Post-mortem studies have found an increased prevalence of incidental ARVD with increasing age. P. A. KALRA AND J. E. SCOBLE 294 More than 35% of elderly patients with congestive cardiac failure (CCF) will have ARVD, and this association is now of growing interest because of the potential for revasculariza- ti on to improve cardiac function and patient survival. It is likely that in many patients essential HTN more often contributes to the development of ARVD, rather than the latter being important in the pathophysiology of the HTN. It is th is hypertensive renal damage which is also thought to be a major contributor to the CKD see n in many patients with ARVD. Non-renal atheromatous macrovascular disease Many patients have asymptomatic, clinically si lent ARVD that is detected incidentally during investigation for other extrarenal atheromat ous conditions. Atherosclerotic RAS can be detected in: \200 \200 \200 Acute kidney injury ARVD may present with AKI for a variety of reasons: \200 severe bilateral RAS or occlusion (an indication for revascularization therapy); accelerate d-phase HTN (an indication for revasculariza- tion therapy); cholesterol atheroembolization (seen in patients with severe aortic atheroma who undergo angiographic pro- cedures or ant icoagulation; Fig. 9.2.3); damage caused by radiocontrast agents during intra- arterial or CT angiography; acute tubular necrosis (ATN) due to a general fall in per- fusion pressure; in association with use of ACEIs or ARBs (see below). There should be a high clinical susp icion of underlying RAS if a signi \201 cant deterioration in renal function occurs after initiation of ACEI or ARB therapy (e.g. >30% increase in serum creatinine). AKI is not unco mmon in patients treated with these drugs and is most often associated with volume depletio n during intercurrent illness rather than the effects of a RAS lesion. Although ACEIs and A RBs can usually be reintroduced safely after stabilization of the patient \200\231s circula tion, renal artery imaging should be considered as a minority of patients will have signi \201 cant RAS that might require a revascularization procedure to allow uncomplicated use o f these bene \201 cial drugs. 30 \200\22350% of patients with peripheral vascular disease; 10 \200\22315% of patients wit h coronary artery disease; 30% of patients undergoing investigation of aortic aneu- rysm; 1 0% of patients with cerebrovascular disease. Physical signs and other suggestive features of ARVD The presence of audible vascular bruit s (epigastric, renal or ilio-femoral) in a patient with unexplained HTN and/or CKD is sugge stive of ARVD. Patients with unilateral signi \201 cant RAS or RAO may have an atrophic ki dney. An unexplained 1.5 cm disparity in bipolar renal length on USS is also an indication to investigate for ARVD. Investigation Random cholesterol need not be elevated. Urinary protein:creatinine ratio (PC R) or albumin creative ratio (ACR) should be assessed. Proteinuria is commonly present in A RVD and is usually re \202 ective of the degree of underlying renal parenchymal damage, as is the case in CKD from other causes. Two-dimensional USS may show renal asymmetry. There are a number of options for imaging of the renal arteries. Chronic kidney disease Many patients with newly identi \201 ed CKD referred to neph- rolog y clinics are found to have ARVD after further investi- gation, and this incidental present ation is by far the commonest. Hypertension is usually also present. A recent report of the US dialysis population showed that 11% had ARVD. In most cases HTN rather than ischemia is thought to be the most important factor in the pathogenesis of CKD and ESRD. ARVD is more often an association of, rather than the cause of, the majority of these cases of CKD and E SRD. The few histopathological studies in ARVD have shown a pattern of intrarenal injury th at is non-speci \201 c and hard to distinguish from hypertensive damage. This has implicat ions for treatment and it is also re \202 ected in the outcomes after renal revascularizat ion procedures. Magnetic resonance angiography (MRA) This is non-invasive. Sensitivity and speci \201 city for detection of RAS are >90% (Fig. 9.2.4). Cardiac failure Signi \201 cant RAS lesions can be detected in patients present- ing with cardiac failure. \200\230Flash pulmonary edema \200\231 refers to a life-threatening pres- entation of acute heart failure with no evidence of signi \201 - cant myocardial ischemia . There is usually severe HTN, and patients have signi \201 cant bilateral RAS. This is co nsidered a de \201 nite indication for revascularization. Fig. 9.2.3 Cholesterol embolization within renal arterioles. Atheromatous material is seen blocking the arteriolar lumen, containing several cholesterol clefts. CHAPTER 9.2 Renovascular disease 295 Fig. 9.2.6 Histopathological changes in ARVD. Non- speci \201 c tubular atrophy, interstit ial \201 brosis and glomer ulosclerosis; features are often indistinguishable from hypert ensive injury. Fig. 9.2.4 Magnetic resonance angiogram showing signi \201 cant right ostial RAS and left renal artery occlusion. The main limitation is the risk of contrast nephropathy in patients with advanced CKD. Duplex ultrasonography Although time-consuming and operator dependent, this technique is no n-invasive and can be very accurate for detection of signi \201 cant RAS. Key measurements are peak velocity of renal arterial blood \202 ow and intrarenal vascular resistive inde x (RI). Renal scintigraphy It is often important to assess the function of each kidney in ARVD. Thi s can be performed accurately by use of DMSA and isotopic GFR techniques in combination. Th e demonstration of a non-functioning/poorly function- ing RAS kidney with scintigraphy can also be useful. Captopril renography is now rarely used to detect func- tionally signi \201 cant RAS as its diagnostic usefulness is limited in CKD. Renal angiography Conventional angiography is now reserved to con \201 rm the presence of RAS at the time of a revascularization pro- cedure, or in diagnosis of more complicated/unc ertain cases. Selective renal angiography provides the best means of de \201 ning distal R AS lesions. Limitations of angiography include: \200 \200 \200 Fig. 9.2.5 CT angiography showing signi \201 cant left ostial RAS. Note the heavily calci \201 ed aorta and left renal artery. provides only 2-D images; no functional information; invasive with a risk of atheroembolism following instru- mentation of aorta and renal artery; associated risk of contrast nephrop athy. It is of limited usefulness for de \201 ning distal disease. Although the contrast agent w as previously thought to be non-toxic there are now concerns over use of gadolinium- enhanc ed MRA in patients with advanced CKD. Over 250 cases of nephrogenic fibrosing dermopathy ha ve accompanied use of certain preparations of gadolin- ium although the majority of cases h ave occurred in dialysis patients. Pathology Atherosclerotic RAS lesions occur most commonly (90%) at the renal ostia, at or w ithin 1 cm of the aortorenal junction. It is likely that sheer stress injury contributes to develop- ment of atheromatous plaques at these sites in predis- posed individuals. Computed tomography angiography or multislice CT This has a similar sensitivity and speci \201 city to MRA for detec- tion of RAS. CT will demonstrate calci \201 cation (Fig. 9.2.5 ) which, if present at the renal ostium, can make assessment of the degree of RAS dif \201 cult. P. A. KALRA AND J. E. SCOBLE 296 Calci \201 cation is commonly seen in association with the plaques. Bilateral ARVD is pres ent in 30% of individuals at presen- tation, and at this stage 25% already have at least o ne RAO. The intrarenal \200\230parenchymal \200\231 injury that occurs in associa- tion wi th CKD is non-speci \201 c (Fig. 9.2.6), with variable contributions from: \200 \200 \200 focal segmental or global sclerosing glomerulopathy. The latter are occasionally seen with nephrotic presentations. Treatment Historically, repeat angiographic studies indicated that medically managed RAS le sions were at increased risk of progressing to more severe stenoses or to RAO ( 10% of case s per year). This led to the increased use of revascularization proce- dures in an effort t o reduce the risk of loss of functioning renal mass. This view has been challenged during t he last decade and there are a number of ongoing RCTs which will hopefully address this que stion. ischemia; hypertensive damage; cholesterol atheroemboli. The natural history of RAS is usually one of slowly progres- sive stenosis of the renal art eries. In one study examining the epidemiology of renal atrophy in ARVD, 20% of kidneys su pplied by an artery with a high grade RAS were seen to atrophy (here de \201 ned as reduc- tion in length >1 cm) by 2 years, but atrophy was also seen in 5.5% of kidneys supplied by a normal vessel. Systolic hypertension was independently associated with a risk of renal a trophy. Medical treatment ARVD is part of a diffuse vascular disease process. Strategies aimed at s lowing progression will reduce ischemic complications and should include: \200 \200 \200 \200 lifestyle modi \201 cation; statins; antihypertensives; antiplatelet therapy. Pathogenesis of renal dysfunction in ischemic nephropathy Renal dysfunction is frequently s een in patients with ARVD. There is often an assumption that reduced renal blood \202 ow always accompanies severe RAS lesions and that this is responsible for the renal functional changes. This is not supported by data on outcome following renal revascularization. The m ajority of patients ( 75%) who undergo renal revascu- larization for severe RAS lesions sho w no improvement in renal function despite restoration of renal artery patency. There is a poor correlation between severity of RAS lesions and renal function either in groups of pat ients with different degrees of RAS, or in individual kidneys when GFR is measured isotopic ally. Although few would argue that RAS lesions >75% are likely to be functionally signi \201 cant, it does not necessarily follow that renal function will improve after revascular ization \200\223 this depends on the degree of irreversible damage that has occurred in th e kidney supplied by the narrowed vessel. For RAS lesions of 50 \200\22375% the situation i s even less clear; many of these will be functionally insigni \201 cant, although some kid neys do improve after angioplasty. Several pieces of evidence suggest that intrarenal \200 \230paren- chymal \200\231 injury is most likely due to longstanding hyperten- sion in the majority of ARVD patients who have CKD. The hypertension likely pre-dates RAS development i n most cases. Pre-existing hypertensive injury would explain why the majority of patients w ith RAS fail to show an improvement in renal function after revascularization. Proteinuria is a key marker of intrarenal injury, as it is in CKD from other causes, and it is strongly linked to renal function at diagnosis as well as long-term outcome in patients with ARVD. Histopathological studies have been limited in ARVD, but changes identi \201 ed in patient s with RAS have demonstrated a picture which can be indistinguishable from hypertensive dam age, the exception being those patients with choles- terol atheroembolism, or severe ischem ic lesions such as Lifestyle modi \201 cation: reduced dietary intake of salt and increased exercise; cessati on of smoking. Statins: can slow progression and may induce regression of atherosclerotic c oronary and renal artery lesions. They may also have beneficial effects independent of lipi d- lowering including: \200 \200 stabilization of atherosclerotic plaque; reduction of proteinuria. Antihypertensive therapy: combinations of several antihy- pertensive drugs may be required for effective BP control (target <130/80, or 125/75 in those with signi \201 cant pro- tei nuria). As many ARVD patients have coronary artery disease, left ventricular dysfunction, p roteinuria and a tendency to progressive renal parenchymal damage, both ACEIs and ARBs shou ld be the antihypertensive drugs of choice for these patients. Renal function needs to be c arefully monitored in case it deteriorates acutely with these drugs. Antiplatelet therapy: although no evidence exists for a bene \201 cial effect of aspirin in the treatment of ARV D, most clinicians would advocate its use. Renal revascularization Renal revascularization refers to a procedure that restores renal a rtery patency. During the course of the last 15 years percutaneous treat- ments have been f avored, and now >95% of revasculariza- tions are with angioplasty/stenting. The remainder a re direct surgical revascularization proce- dures such as renal endarterectomy, bypass with saphen- ous vein or arti \201 cial grafting, or autotransplantation. There are speci \201 c clinical situations where there is almost unanimous agreement for the value of revas cularization in ARVD: \200 \200 patients with AKI secondary to severe RAS; control of severe HTN, when resistant to several (e.g. >4) antihypertensive drugs in combination; serious comorbid cardiac disease (e.g. \200\230 \202 ash \200\231 pulmonary edema). CHAPTER 9.2 Renovascular disease 297 There is no indication for routine repeat renal artery imag- ing in these patients. There are several other clinical scenarios where there is uncertainty over the bene \201 t of revascularization: \200 preservation of renal mass (preventing RAO in patients with signi \201 cant RAS); slowing or halting progressive CKD; allowing the use of ACEIs/ARBs (performing revasculari- zation in those patients who need these therapies but in whom renal function deteriorated when the y were pre- viously prescribed); clinically stable patients with high grade RAS; Prognosis Patients with ARVD have a high mortality, and this is largely conferred by the in \202 uence of their macrovascular comorbidities. Progression to ESRD only occurs in a min ority of patients presenting with CKD. A recent retrospective study has shown that statin t herapy in conservatively managed ARVD patients was associated with a 72% reduction in likel ihood of progression of RAS lesions. Although statin therapy may reduce the risk of progres sion of atherosclerotic lesions, studies which might show a sur- vival bene \201 t have no t been performed In a large US epidemiological study the risk of death in patients with A RVD was almost six times that of develop- ing ESRD. Factors associated with reduced surviva l are: \200 \200 \200 Currently, there is no evidence to support the use of revas- cularization in this second gr oup of patients. Percutaneous procedures are not without risk: \200 arterial dissection, rupture or thrombosis; \200 cholesterol embolization; \200 contrast nephropathy. Arterial damage occurs in 1% of those treated with stent- ing while cholesterol embolizati on and contrast nephropa- thy is seen in a slightly greater proportion. High quality large randomized trial evidence is required to help guide the clinician with regard to optimal ap plication of interventional therapy. None of the four published clinical trials addressing this issue has shown a bene \201 cial improvement in renal function or mortality after ang ioplasty, but each of these trials was small. One trial has established that ostial RAS les ions should be treated with stent placement, as the rate of restenosis is high with angiopl asty alone. There have been many retrospective studies of revascu- larization reported from individual centers, and in most of these a de \201 nite improvement in renal function is reported in 25% of patients. Large scale RCTs are essential in order to determine the over all effects of revascularization, and to help identify which subgroups will bene \201 t fr om the procedure. The UK-based ASTRAL trial (completed recruitment of 806 patients in Octob er 2007) reported its initial \201 ndings in April 2008 (see below). A US-based study, CO RAL, will recruit a similar number of patients and should publish in several years \200\231 time. greater extrarenal macrovascular disease burden; poor renal function at the time of diagnos is of ARVD. Dialysis patients with ARVD have an annual mortality rate approaching 33%. Whil e renal artery revascularization will improve renal function in selected individuals, no tr ial has shown an over- all bene \201 t of intervention in terms of renal function or sur- vival in ARVD populations. The ASTRAL trial unequivocally demonstrates this (see below). Future prospects There is a major need to increase the evidence base relat- ing to the mana gement of ARVD, and two large multicentre international trials have either just completed o r are still recruiting. The ASTRAL trial ASTRAL has recently reported its initial results. In this trial 806 patien ts with ARVD, in whom the referring clinician was uncertain of whether or not to perform re vascularization, were randomized on a one-to-one basis to: \200 \200 medical therapy; or renal revascularization (angioplasty plus stenting). The primary outcome measure was to assess whether revascularization affected change in rena l function with time, and secondary outcomes were BP control, effects upon cardiovascular e vents and death. The initial results encompassed a mean follow-up period of 27 months. At 1 2 months after randomization, change in renal function, systolic and diastolic BP control, combined renal or cardiovascular end-points and survival were iden- tical in the two arms o f the study. Hence, conclusively, at 12 months after treatment there is no bene \201 t of perform- ing revascularization in ARVD patients with auotomically signi \201 cant but asym ptomatic lesions. Whether any longer term bene \201 ts might result from intervention will be deter- mined after further follow-up of study patients. The ASTRAL cardiac substudy is investigating whether renal revascularization bene \201 cially affects cardiac structure a nd function in a subgroup of 60 patients who have undergone baseline and 1 year cardiac MR I. The results should be available by the end of 2008. Follow-up All patients with ARVD should be followed up to assess clinical progress, especia lly as they are at high risk of vascu- lar events. Monitoring should occur on a 6-monthly b asis and will involve assessment of: \200 \200 \200 \200 \200 BP control; renal function; cholesterol; urinary PCR; new vascular events. Any signi \201 cant changes will necessitate review of medica- tions but may also indicate the need for repeat renal artery imaging. Development of significant proteinuria should tr igger consideration of ACEI or ARB therapy, if not already prescribed. Onset of new vascula r events (e.g. intermittent claudication) will necessitate referral to other specialist ser vices. P. A. KALRA AND J. E. SCOBLE 298 The CORAL study This US-based study seeks to recruit 1080 ARVD patients, and is designed to investigate: \200 Moss JG, Kalra PA, Cleveland T, Hamilton G. Renal and intestinal vascular disease. In: Bear d JD, Gaines PA (eds), Vascular and endovascular surgery. A companion to specialist surgica l practice. Elsevier, Edinburgh; 2005: pp. 265 \200\223283. whether renal artery angioplasty + stenting will improve survival; the occurrence of major cardiovascular events. Internet resources ASTRAL trial site: Recruitment is ongoing, and the trial should report in 2011. As well as providing guidance on the overall outcome of RAS patients treated with revascularization, it is hoped that sub group analyzes within these RCTs may help to identify those patients who are most likely to bene \201 t from revascularization, in terms of renal function as well as car- diac event s and survival. http://www.astral.bham.ac.uk CORAL trial site: http://www.coralclinicaltrial.org/ The Renovascular Forum: http://www.renovascularforum.org Journal of Renovascular Disease: http://www.journalrenovasculardisease.com Further reading Cheung CM, Hegarty J, Kalra PA. Dilemmas in the management of See also Clinical approach to hypertension, p. 286 Ischemic acute kidney injury, p. 356 Hyp ertension in CKD, p. 406 renal artery stenosis. Br Med Bull 2005; 73: 35 \200\22355. Greco RA, Breyer-Lewis J. Atheromatous renovascular disease. In: Johnson RJ, Feehally J (ed s), Comprehensive clinical nephrology. London: Harcourt; 2007: pp. 725 \200\223744. This page intentionally left blank A. STANLEY 300 Malignant hypertension Introduction The term \200\230malignant \200\231 hypertension (or malignant nephro- sclero sis) was appropriately coined 80 years ago. At that time the only available treatment was phenobarbital or other potent sedatives. Life expectancy was <25% at 12 months and <1% at 5 years with uremia as the common mode of death. Etiology The precipitating event is an increase in peripheral vascular arterial resistance. Such changes usually occur over years in patients with essential HTN, but in malignant HTN they occur over weeks to months and lead to severe HTN. The rise in peripheral vascular re sistance leads to an increased release of circulating vasoconstrictors and other neuro-humo ral factors including: \200 \200 \200 De \201 nition Malignant hypertension (HTN) is de \201 ned as: \200 renin; angiotensin II; noradrenaline (norepinephrine). acute severe elevation of BP (often >220/120 mmHg) with \200 evidence of grade 3 ( \202 ame-shaped hemorrhages and exudates) or grade 4 (papilloedema) hypertensive retin- opathy. This further fuels the rise in BP. Other key pathological changes include: Widespread endot helial damage in arterioles and small arteries with \201 brinoid necrosis (microangiopath y). This results in a loss of the normal endothelial control of BP regulation (e.g. nitric oxide synthesis). Endothelial damage is particularly marked in the kidney microcirculation with histological changes similar to those seen in other thrombotic microangiopathies such as scle- roderma and hemolytic uremic syndrome. Microangiopathic hemolytic anemia develops as a conse- quence of red blood cell fragmentation by \201 brin strands in the microcircu lation. Arteriolar dilation will occur when BP exceeds the normal autoregulatory range. Dil ation of cerebral arteries can result in cerebral edema and thus papilloedema. There may be other symptoms or signs re \202 ecting end- organ damage, but these are not n ecessary for the diagnosis. In those who were normotensive previously and who develop sever e HTN (e.g. eclampsia or acute glomeru- lonephritis), malignant HTN can develop at lower le vels of BP (diastolic BP of 100 mmHg). There are several other overlapping terms to descri be severe HTN. Accelerated HTN refers to those with severe HTN and a recent increase in BP, but hypertensive retinopathy is at worst grade 3. At presentation, patients with severe HT N can be classi- \201 ed as: \200 \200 hypertensive emergencies. hypertensive urgencies; or Clinical features A thorough assessment of the patient is important, as it will ultimately determine the appropriate method of treat- ment. The assessment should answer three key que stions: \200 Hypertensive emergencies present with acute complica- tions (e.g. AKI, pulmonary edema, str oke, Table 9.3.1). Hypertensive urgencies may be asymptomatic or present with headache, vis ual disturbances, nausea and vomiting. This classi \201 cation will determine treatment op tions. Does the patient have an acute complication as a result of severe HTN? Is there evidence of long-term end-organ damage? Is secondary HTN a possibility? \200 Epidemiology Before modern antihypertensive drugs became available, 7% of hypertensive sub jects were diagnosed with malig- nant HTN; nowadays this accounts for <1%. The average age of onset is 40 years. History Baseline features to assess: \200 \200 \200 duration of HTN and BP values; treatment history and concordance with treatment; any advers e drug reactions. Predisposing factors The risk of malignant HTN is increased in: \200 \200 \200 \200 \200 \200 Identifying complications/end-organ damage Symptoms suggesting an acute complication (Table 9.3.1): \200 \200 \200 \200 \200 blacks; males; tobacco smokers; nonconcordance with antihypertensive drugs; catecholamine c rises (pheochromocytoma/cocaine); monoamine-oxidase inhibitor interaction with tyramine- co ntaining food; combined oral contraceptive pill (OCP); eclampsia; secondary HTN (e.g. acute glomerulonephritis, renovas- cular disease, hyperaldosteronism); acute B-blocker withdrawa l. headache; chest pain; breathlessness; confusion; neurological de \201 cit. Symptoms related to long-term end-organ damage: \200 \200 \200 \200 \200 \200 ischemic heart disease; heart failure; cerebrovascular disease; peripheral vascular disease ; renal impairment. CHAPTER 9.3 Malignant hypertension 301 Investigations Investigations will both support the \201 ndings from clinical examination and highlight other complications, such as microangiopathic hemolytic anemia, which may no t be apparent clinically. The following are the essential investigations on admission: \200 \200 \200 \200 \200 Table 9.3.1 Acute complications of severe hypertension Acute pulmonary edema Acute kidney injury Aortic dissection Catecholamine crisis Cerebral i nfarction Eclampsia Encephalopathy Intracerebral hemorrhage Microangiopathic hemolytic anem ia Myocardial ischemia/infarction Subarachnoid hemorrhage full blood count and blood \201 lm; urea, creatinine and electrolytes; glucose; ECG; urin alysis. Other investigations necessary at the time of admission will depend on the patient \200\231 s clinical status but may include: \200 \200 \200 CXR; CT or MRI scan of the brain; ECG. Identifying causes of secondary hypertension History of any recent \200\230over-the-counte r \200\231 and/or prescribed drug therapy: \200 NSAIDS; \200 combined oral contraceptiv es; \200 corticosteroids; \200 sympathomimetics. Although the majority of patients presenting with malig- nant HTN will have essential HTN, there is a greater prev- alence of an underlying cause in these patients. Unless the cause is obvious, further specialist tests are advised as follows: \200 serum renin and aldosterone (hyperaldosteronism/ Conn \200\231s syndrome); renal USS (under lying renal disease); MR renal angiogram (renovascular disease); urinary catecholamines (ph eochromocytoma). History of recreational drug use (e.g. cocaine). History of renal or urological disease. Ph eochromocytoma might be suggested by: \200 \200 \200 \200 \200 \200 episodic palpitations; sweating; chest pain; paroxysmal HTN. The serum lipid pro \201 le is an important additional test as it will help to assess over all cardiovascular risk. Treatment When a patient presents with a sudden increase in BP resulting in severe HTN, it is the clinical status of the patient, not the level of BP per se, that dictates therapeuti c management. After assessing the patient, it will be clear if the patient has an acute com plication of severe HTN or evidence of end- organ damage. There may be some evidence sugges ting a secondary HTN cause. The next stage of the patient \200\231s management is determine d by the answer to the following two questions. Assessing overall cardiovascular risk As with any case of HTN the patient \200\231s overall cardiovascu- lar risk should be assessed: \200 \200 \200 \200 \200 \200 \200 obesity; high salt intake; excess alcohol; lack of exercise; diabetes mellitus; hyperlipide mia; smoking. Does the patient require hospital admission? Only those hypertensive patients without an ac ute compli- cation or grade 3 or 4 hypertensive retinopathy can be safely managed as outpat ients (this is also dependent on normal blood results). In these cases, oral treatment can be initiated with regular follow-up at intervals of 2 \200\2233 days by the patient \200 \231s primary care physician. A further assessment in a specialist HTN or nephrology clinic within a week is mandatory. Examination Blood pressure should be measured in both arms, lying and standing. Clinical si gns suggesting an underlying cause include: \200 \200 \200 \200 general appearance: Cushing \200\231s syndrome/acromegaly; reduced peripheral pulses: coarc tation of the aorta; abdominal bruit: renovascular disease; abdominal masses: polycystic ki dneys. Clinical signs suggesting end-organ damage: \200 \200 Does the patient require intravenous or oral antihypertensive treatment? Patients presentin g with an acute complication (Table 9.3.1) are, by de \201 nition, hypertensive emergencie s and require IV drug therapy. These patients should be managed in a monitored environ- men t with continuous ECG recording and regular BP mon- itoring. An intra-arterial line for BP monitoring may be useful but is not essential. cardiomegaly; retinopathy. Clinical signs suggesting an acute complication: \200 neurological de \201 cit: cerebral infarction, cerebral hemor- rhage or subarachnoid hemor rhage; pulmonary edema: heart failure; confusion or coma: hypertensive encephalopathy; uneq ual BP in right and left arms: aortic dissection. \200 \200 A. STANLEY 302 In contrast, those patients presenting as a hypertensive urgency can be admitted to a less intensively monitored environment and oral drug therapy will suf \201 ce. Table 9.3.2 Summary of IV antihypertensive drugs Drug Mode of action and indications Nitroprusside Causes relaxation of vascular smooth muscle. Treatment goals in patients with malignant hypertension The goal of antihypertensive therap y is to reduce the BP to a \200\230safe \200\231 level rather than to normalize it. More a ggressive BP lowering may exceed the ability of the brain to maintain cerebral blood \202 ow. Intravenous drug therapy for patients with a hypertensive emergency should ideally red uce the mean BP by 25% over the course of 2 \200\2234 h. Oral treatment can be introduced e arly to allow weaning of IV therapy after 24 \200\22348 h. For those patients presenting wi th a hypertensive urgency, oral treatment should aim to reduce mean BP by 25% over 24 h. Used in most hypertensive emergencies. Caution cyanide toxicity and severe metabolic acidosis in renal failure. Fenoldopam Agonist action via selective peripheral DA1-receptors, which produces: \200 vasodilatatio n \200 increased renal perfusion \200 enhanced natriuresis. Used in most hypertensive emergencies (no UK license) especially in renal insuf \201 cienc y. Blocks B1-adrenergic receptor sites, A1-adrenergic receptor sites, and B2-adrenergic rec eptor sites. Labetolol Choice of antihypertensive medication There is no de \201 nitive study that has highlighte d a drug of choice, either IV or oral, in the management of hyperten- sive emergencies or u rgencies. The only exception is a comparison of nitroprusside and fenoldopam in patients wi th renal impairment. Fenoldopam was shown to improve natriuresis, diuresis and renal func- tion. Fenoldopam is not licensed in the UK. Alternative to nitroprusside. Not used in heart failure or catecholamine crisis. Hydralazine Causes direct vasodilation of arterioles. Only indicated in pregnancy/eclampsia as it impro ves uterine blood \202 ow. Nitrogylcerine Preferred agent for patients with myocardial ischemia/infarction complicating hypertension. Blocks A1- and A2-adrenergic receptor sites. Intravenous treatment In general, nitroprusside is the IV drug of choice in patients withou t significant renal impairment or myocardial ischemia. In patients with these conditions la betolol or nitroglycerine are preferable. If one agent is not effective, sensible combinati ons would include nitroprusside and labetolol or nitroglycerine and labetolol. The availabl e IV antihypertensive drugs are summarized in Table 9.3.2. Phentolamine Used exclusively as \201 rst-line treatment for catecholamine crises. The BP does not need to be ideally controlled, but the patient will need regular review eve ry 2 weeks for BP measurement and adjustment of treatment if required. Further investigatio ns (see above) will need to be planned. Prior to discharge, a specialist with an interest i n HTN should ideally review the patient, or an early appointment made in a dedicated specia list clinic (within 2 weeks). In the longer term, cardiovascular risk assessment, to take i nto account primary or secondary prevention, should be undertaken. Oral treatment Oral treatment requires drug therapy of rapid onset (<12 h). Nifedipine and atenolol are the drugs of choice. ACEIs (or ARBs) are reserved for patients with sclero- de rma. These drugs are also effective in severe HTN, but their use in a nonscleroderma popula tion is cautioned especially if renovascular disease is suspected. The use of sublingual or oral liquid nifedipine is dangerous as the fast absorption of these formulations can resul t in sudden and large falls in BP. Prognosis With successful early management of malignant HTN life expectancy is similar to p atients with uncomplicated HTN. Further reading Anonymous. Treatment of hypertensive urgencies and emergen- cies. European Society of Hypertension Scienti \201 c Newsletter: Update on Hypertension Management 2006; 7(28): http://www.eshonline. org/education/newsletter/2006_28_agabiti_rosei.pdf Intravascular volume assessment After BP correction some patients may develop intravascu- l ar volume depletion and require IV \202 uid. Volume depletion can occur as a consequence of prior excessive vasoconstriction or pressure-related diuresis: high BP can lead to an in creased GFR and a reduction in renal tubular sodium reabsorption. This is particularly rele vant in the management of patients with acute pulmonary edema as a hypertensive emergency w here \201 rst-line treatment is often with a loop diuretic. Elliott WJ. Management of hypertension emergencies. Curr Hypertens Rep 2003; 5 486 \200\223492. Kaplan NM. Management of hypertensive emergencies. Lancet 1994; 344: 1335. Lip GY, Beevers M, Beevers DG. Does renal function improve after diagnosis of malignant pha se hypertension? J Hypertens 1997; 15: 1309. Murphy MB, Murray C, Shorten GD. Fenoldopam: a selective peripheral dopamine-receptor agoni st for treatment of severe hypertension. N Engl J Med 2001; 345 1548 \200\2231557. Follow-up Patients can be safely discharged once their clinical status has improved and the ir BP is stable. van den Born BJ, Honnebier UP, Koopmans RP, van Montfrans GA. Microangiopathic hemolysis an d renal failure in malignant hyper- tension. Hypertension 2005; 45: 246. CHAPTER 9.3 Malignant hypertension 303 Internet resources British Hypertension Society: London Hypertension Society (an excellent link to many of the national guidelines on manage ment of hypertension): http://www.lhs.sgul.ac.uk/links/guidelines.htm www.bhsoc.org/ NICE C G34 Hypertension guideline: See also Clinical approach to hypertension, p. 286 Renovascular disease, p. 292 Hypertensiv e children, p. 304 Hypertensive disorders in pregnancy, p. 310 www.nice.org.uk/nicemedia/pdf/Hypertension Guide.pdf Hypertension Education Foundation: http://www.hypertensionfoundation.org/ European Society of Hypertension: http://www.eshonline.org/ P. HOUTMAN 304 Hypertensive children Introduction Hypertension in childhood is an uncommon clinical prob- lem. When it occurs, i ts investigation and management is often quite protracted and requires a specialist approac h. Although it is increasingly recognized that \200\230adult \200\231 hyperten- sion often has its roots in adolescence, the assumption in children should be that it is likely to be secondary to a speci \201 c cause until shown otherwise. ated in terms of appropriate normal data obtained using comparable methods. Invasive BP monitoring In sick and premature neonates BP is often measured inva- sively usi ng umbilical or peripheral arterial catheters. This must be compared with appropriate norma l values for mean BP. Indications for measuring BP in children In older children it is appropriate to take BP rou tinely in any medical consultation. In children younger than 3 years this is less easily r ecom- mended but certainly it should be considered if there are any relevant concerns such as renal tract problems. De \201 nitions in children The de \201 nition of hypertension in children is not simple. BP is directly related to size (both height and weight) in growing individuals. Tables and charts are available with ranges of systolic and diastolic BPs according to gender, age, h eight and weight. These are expressed as BP percentiles. They are an important resource whe n evaluating BP in both population samples (for research), and individually in clinical pra ctice. Hypertension is de \201 ned as an average systolic and/or diastolic BP above the 95 th percentile for these parame- ters of growth, with measurements on three or more sepa- ra te occasions. BP between the 90th and 95th percentiles is now known as \200\230prehyperten sion \200\231. Within the hypertensive range, severity can be categorized into two stages: signi \201 cant and severe hypertension. BP >5 mmHg above the 99th percentile requires urg ent evaluation. Table 9.4.1 gives approximate values for \200\230signi \201 cant \200\231 and \200\230severe \200\231 hypertension and may be used as a very rough guide to BP leve ls that should be investigated and managed effectively. Screening the pediatric population for hypertension cannot yet be advised, but this may be a future proposal, particularly in adolescence. Causes of hypertension Renal diseases predominate as secondary causes of hyper- tension in children. Transient hypertension Blood pressure can be transiently raised in acute neph- ropathies. C onditions relatively commonly encountered in childhood include: \200 \200 \200 postinfectious glomerulonephritis; Henoch \200\223Sch nlein purpura; hemolytic \200\223ure mic syndrome. Paradoxically BP can also be raised in hypovolemic states, such as seen in nephrotic relaps e, associated with vasocon- striction. Sustained hypertension In sustained hypertension, it is helpful to distinguish neonates fro m older age groups. Coarctation of the aorta and other vascular problems including renal ar tery stenosis and thromboses relating to umbilical arterial catheterization are important c auses in the very young. The range of conditions associated with sustained child- hood hype rtension is very broad (Table 9.4.2). These prob- lems can present at any age, but it shoul d be noted that many of the processes are developmental in origin. The most important are d iscussed below.