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Malignant hypertension and the hypertensive crisis: handling all hazards

Malignant hypertension and the hypertensive crisis: handling all hazards DONALD G VIDT, MD Malignant hypertension, although a rather uncommon clinical syndrome, can be very dramatic in presentation and
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Malignant hypertension and the hypertensive crisis: handling all hazards DONALD G VIDT, MD Malignant hypertension, although a rather uncommon clinical syndrome, can be very dramatic in presentation and requires immediate diagnosis and rapid treatment. This chapter is designed to cover the clinical approach to the patient with malignant hypertension, and describe a rational approach to the patient with a hypertensive crisis. It is important to recognize that these two entities are not necessarily synonymous (Table i). In fact, the initial approaches to the therapy of malignant hypertension and to a true hypertensive emergency such as hypertensive encephalopathy may be quite different. Signs and clinical findings of malignant hypertension There are some characteristic clinical findings in a patient with malignant hypertension, relating primarily to the target organs that are typically involved in the course of aggressive hypertensive disease. All patients with this degree of hypertension will, of course, have marked elevation in diastolic pressure, which often exceeds 140 mm Hg. One will almost always see left ventricular hypertrophy by clinical examination, electrocardiogram (ECG), or X-ray, and often congestive heart failure and/or pulmonary oedema. Histopathologically, severe arteriolar sclerosis and fibrinoid necrosis in various vascular beds are typical. This is probably best seen in the vascular bed of the kidney and undoubtedly contributes to the azotaemia and progressive renal failure. However, the patient with a hypertensive crisis, because of the abrupt onset of the syndrome (as opposed to long-standing malignant hypertension) may or may not have renal failure. Thus, the absence of azotaemia does not necessarily rule out a hypertensive crisis. The central nervous system manifestations of accelerated or malignant hypertension will usually include headache, dizziness, blurring of vision, or retinopathy, and may at times progress to the typical syndrome of hypertensive encephalopathy. The hallmark of hypertensive encephalopathy is the change in mental status. Altered consciousness from irritation to obtundancy, from agitation to coma transient ischaemic attacks with occasional blindness, and changing focal neurological signs may all occur. velops hypertensive encephalopathy or another type of hypertensive crisis may or may not have advanced funduscopic changes, simply because the hypertensive crisis has progressed so rapidly that he may not have had time to develop the hallmark funduscopic changes. However, you will always see at least marked arterial spasm and/or retinal sheening in these individuals. Initial evaluation My approach to the patient with malignant hypertension depends, in large part, upon the degree of target organ involvment. Does the patient have an encephalopathic picture? Is the patient in pulmonary oedema or intractable heart failure? Does the patient have rapidly progressive renal failure in association with his hypertension? These are some of the questions Careful ophthalmoscopy is of critical importance in the accurate diag- that you must ask and answer as you examine the patient. There are some nosis of malignant hypertension. The clinical characteristics that help us to fundus may show marked arterial constriction or spasm in addition to the initially distinguish the patient with malignant hypertension from the one cotton-wool type of exudates and the who has progressed to a syndrome that flame-shaped haemorrhages, which we might define as a true hypertensive are characteristic of accelerated hypertension, as well as the oedema of the crisis. Typically, the onset of malignant hypertension is rather insidious. optic disc, or papilledema, that has It usually occurs in the context of established hypertension, either of the been considered classical of group 4 funduscopic changes of malignant essential variety, or secondary to some hypertension. The patient who deother problems such as renal parenchymal disease. The hypertension and Dr Vidt is head of the clinical section in the department of hypertension and nephrology target at organ involvment progress The Cleveland Clink Foundation, in the gradually, usually over a period of USA. weeks and often months. On the other This article has been adapted from a CME text published by Academic Press, specially hand, the onset of a typical hypertensive crisis (eg hypertensive en- for Modern Medicine. cephalopathy) is rather abrupt, usually File under 7/12 in the Index Modem Medic ine /September dbumsajl irewew TABLE 1 Malignant hypertension or hypertensive crisis?: spotting the clues Malignant hypertension Insidious onset; hypertension and target organ involvement progress gradually, over a period of weeks or months Azotaemia and progressive renal failure common Funduscopic changes common; arterial constriction or spasm, cotton-wool type exudates, flame-shaped haemorrhages, oedema of optic disc Blood pressure usually can be lowered within 24 to 72 hours, often with oral therapy Hypertensive crisis Abrupt onset, usually in matter of hours, rarely more than 24 hours May or may not have azotaemia and renal failure May or may not have funduscopic changes; marked arterial spasms and/or retinal sheening, at least Requires immediate reduction of blood pressure, often with intramuscular or intravenous drugs It untreated, 50% mortality within six months, 100% within one to two years in a matter of hours rarely more than 24. This may be the most important clinical distinction between the two. Blood pressure is markedly elevated in both cases, usually 130 to 140 mm Hg diastolic or higher. It is extremely important to differentiate clinically between malignant hypertension and hypertensive crisis, since the prognosis of these conditions differs significantly. A true hypertensive emergency is often fatal within a matter of hours or several days, whereas most patients with malignant hypertension, if untreated, will die within six months (50% mortality in six months and 100% mortality within one to two years). Obviously, the risk of sudden death in a patient with a hypertensive crisis will alter our choice of therapy. Whereas the pauent with a hypertensive crisis will require immediate reduction of blood pressure, often via the administration of intramuscular or intravenous drugs, the pauent with malignant hypertension who has not reached a crisis can often be treated with oral therapy. Usually, lowering blood pressure to a safer level within 24 to 72 hours will be sufficient in this pauent. Treatment Regardless of whether a patient has malignant hypertension or a hypertensive crisis, some of the initial management should be the same. The doctor must realize that the patient with malignant hypertension may rapidly progress to frank hypertensive crisis. The patient must be treated in the hospital and probably best managed in an intensive care-type environment, if available. Your initial evaluation should be brief, rather than extensive. Our initial evaluation includes a brief history, and a physical examination, aimed primarily at the target organs classically involved in hypertension to determine the degree of involvement. 1-2 In addition, we like to see a plasma catecholamine and/or spot urine for metanephrine because of all Often fatal within matter of hours or days the secondary types of hypertension, pheochromocytoma responds poorly to the usually administered antihypertensive agents. Since specific alphablockers for high-catecholamine hypertension are available, I would like to identify that patient early. After a brief evaluation, the doctor should proceed to initiate therapy to lower blood pressure, without waiting for results of all his studies. After early treatment and reduction of blood pressure to safer levels, further diagnostic evaluation may be undertaken, in an attempt to delineate the underlying cause of that patient's hypertensive disease. Oral therapy of malignant hypertension If the patient has malignant hypertension, and it is determined that the situation is not critical, then oral antihypertensive therapy can be initiated in several ways. This essentially consists of the step-care approach to Modem Medic ine /September elweal irwifcw hypertension similar to that recommended for the treatment of the pauent with asymptomatic essential hypertension, the difference being that in the asymptomatic mild or moderate hypertensive, one would begin with single-drug therapy. This would be followed by the addition of a second or third drug over a period of weeks or several months. Obviously, the pauent with malignant hypertension and a diastolic pressure in excess of 120 to 130 mm Hg or more is most unlikely to respond to single-drug therapy. Our approach to that pauent is still simple, except that instead of initiating therapy with a diuretic alone, we would start with at least two-drug therapy (Table 2). We may elect to initiate therapy with an optimal dose of a diuretic plus a sympathetic inhibitor. It might be methyldopa (Aldomet) or clonidine (Catapres), or perhaps one of the beta-blocking drugs such as propranolol HC1 (Inderal), metaprolol tartrate (Lopresor), nadolol (Corgard), atenolol (Tenormin), or timolol (Blocadren). I would start these agents not necessarily in optimal dosage, but certainly in significant dosage. Instead of waiting a week or a month between increments, we may wait only 24 to 48 hours between them and rapidly advance the dosage to achieve control. If the hypertension is severe enough, you might initiate treatment with triple-drug therapy (in this case, however, it might be wise to start with an intravenous hypotensive agent). You might first introduce an effective diuretic coupled with a sympathetic inhibitor accompanied by a direct vasodilating drug such as hydralazine HC1 (Apresoline), or you might prefer to use, as a third-step agent, prazosin HC1 (Minipress), a drug with postsynaptic alpha-blocking properties. Both of these regimens have proved to be very efficient in the patient with malignant hypertension. The use of an optimal dose of a thiazide diuretic combined with methyldopa or clonidine and with hydralazine, particularly in patients with minimal impairment of renal function, will often bring pressures down within 24 to 48 hours. If, on the other hand, that patient has significant impairment in renal function, we would opt for a loop diuretic such as furosemide (Lasix) because of its greater diuretic and natriuretic potency when combined with a sympathetic inhibitor and possibly a vasodilator. For the patient resistant to this regimen, the potent vasodilator minoxidil may be substituted for hydralazine. Minoxidil may be considered a super hydralazine because it is an extremely potent vasodilator, and, as Stepl TABLE 2 is true for hydralazine, should always be used in combination with a diuretic to prevent sodium and water retention, and preferably with a betablocker to prevent the reflex tachycardia that is typical of direct vasodilating agents. This triple combination comprises an effective regimen in patients with otherwise resistant malignant hypertension. Guanethidine (Ismelin) is a potent adrenergic-inhibiting agent and may be added or substituted for the step II drug if the initial steps in therapy are Drugs for the treatment of malignant hypertension Chlorthalidone (Hygroton) Metolazone (Zaroxolyn) or Hydrochlorothiazide* (Dichlotride, et al) Furosemide (Lasix)t ADD mg/day Step 2 Clonidine (Catapres) 0,2-2,4 Methyldopa (Aldomet) Atenolol (Tenormin) ; Metoprolol tartrate (Looresor) $ Nadolol (Corgard) $ Propranolol HCI (Inderal) $ Timolol (Blocadren) 20-60$ Prazosin HCI (Minipress) 1-20$ Step 3 Step 4 ADD Hydralazine (Apresoline) Minoxidil ADD Guanethidine sulphate (Ismelin) SUBSTITUTE II ,5-300 Step 5 Captopril (Capoten) * Numerous preparations available in class of thiazide diuretics. t If creatinine 3,0 mg/dl, substitute furosemide mg/ day; may be given in two to four divided doses. t Exact dosage range not yet determined. May be used as a step 3 drug if not added in step 2. May substitute minoxidil in resistant cases. ICaptopril may be substituted for other therapy, usually administered three times daily. Source: Dr Vidt Modem Medicine /September ineffective. In patients with impaired renal function, guanethidine is best avoided as adverse effects, particularly orthostatic hypertension, may be exaggerated. Captopril (Capoten) 6 is the first of a new generation of oral angiotensinconverting enzyme inhibitors. This agent effectively blocks the conversion of angiotensin I to the potent vasopressor peptide angiotensin II and also blocks the degradation of vasodilator bradykinins. Captopril has been approved for use in hypertensive patients who are resistant to or do not tolerate traditional antihypertensive therapy. The final place of captopril in the treatment of hypertension may ultimately depend on further clarification of its adverse effects profile. It is desirable to discontinue other therapy for one week prior to initiating captopril to avoid severe hypotensive reactions with initiation of this agent. In severe or resistant hypertensives, addition of a diuretic and at times an adrenergicblocking agent as well will be required. The dosage of captopril must be carefully individualized according to each patient's clinical response and careful adjustment of dosage intervals will be required in patients with impaired renal function. Emergency management of hypertensive crisis But what happens if you determine that your patient has a hypertensive crisis, or if you feel that the patient's blood pressure should be controlled not within 48 to 72 hours, but within a TABLE 3 Drugs for the treatment of hypertensive crises Preparation Direct vasodilators Hydralazine (Apresoline) /20 mlf Diazoxide (Hyperstat) 300 (bolus) or (minlbolus); repeat q5-15min Sodium nitroprusside Sympathetic inhibitors Reserpine (Serpasil) /1-5 Ganglion-blocking agent Trimethaphan camsylate (Arfonad) Methyldopa (Aldomet) /100 ml* Phentolamine (Regitine) (rapidly) Modem Medic ine /September * Start with smallest dose listed. t Inject from syringe at rate of 1 ml/min until desired effect is obtained, t Infuse over period of 30 to 60 minutes. For pheochromocytoma; also for monoamine oxidase crises and clonidine (Catapres) withdrawal. Source: DG Vidt, RW Gifford. Cleve Clin Q 1978;45: cikmcajl rewfew. matter of minutes to several hours? Then you have committed yourself to the use of parenteral drugs. 3 4 This may include the patient with hypertensive encephalopathy complicating underlying chronic hypertensive disease, or the occasional crisis associated with intractable heart failure or pulmonary oedema. It may also include the patient with a pheochromocytoma, or the severe hypertensive crisis that occurs with glomerular nephritis or convulsive eclampsia of pregnancy. We will also occasionally see this in association with severe head injuries and rarely as a complication of severe, usually 60 to 70%, body burns. There are several drugs to choose from for the treatment of hypertensive crisis (Table 3). One may opt for a catecholamine depletor such as reserpine (Serpasil), which can be given intramuscularly, or ganglionic blocking agents such as trimethaphan camsylate (Arfonad). These drugs are rarely used today for treatment of chronic essential hypertension, but they still have limited use in the treatment of hypertensive crises. Or you may choose methyldopa, which is available for intravenous administration, or the alpha-blocker phentolamine (Regitine), which is reserved for the treatment of hypertension associated with high circulating catecholamines of a pheochromocytoma or in patients on monoamine oxidase inhibitors, and rarely in patients following the abrupt discontinuation of the central-acting drug clonidine. The other major category of parenteral agents available is the direct vasodilating drugs: hydralazine, which may be administered intramuscularly or intravenously, or two very potent vasodilators, diazoxide (Hyperstat), which is given by intermittent, rapid bolus injections or possibly sodium nitroprusside, administered by continous intravenous infusion. Once committed to parenteral therapy, you must still determine how rapidly to lower the blood pressure, which may dictate the drug to be used. For instance, sodium nitroprusside given by intravenous infusion is capable of lowering blood pressure within a matter of seconds to several minutes. Diazoxide has its maximal hypotensive effect within three to five minutes following a rapid bolus administration. On the other hand, reserpine given intramuscularly will exert its antihypertensive effect two to three hours following its administration. Similarly, methyldopa given intravenously has a lag time of two to three hours between administration and effective hypotensive action. Between these extremes, an intramuscular dose of a ganglionic blocker or of hydralazine If the patient is in the ICU where close monitoring is possible, you can use rapidly acting agents but if he's on the ward without constant supervision, you might choose a slower-acting agent. will probably begin to lower pressure within 20 to 30 minutes, or within 10 to 15 minutes if given intravenously. The second decision to be made, related to the first, is the route of administration. Some of these drugs, such as sodium nitroprusside and diazoxide, can only be given intravenously, whereas the other agents discussed present several choices for route of administration: intramuscularly with reserpine, intramuscularly or intravenously for a ganglionic blocker such as trimethaphan or a vasodilator like hydralazine. Another factor that may contribute to the decision is the available facilities. If close monitoring is available (eg in the ICU), you can utilize the rapidly acting agents, but if the patient is on the ward, where you cannot be assured of constant bedside supervision, you may elect to utilize an agent that is effective more slowly, and may be given by the intramuscular or intermittent IV route. Diazoxide I must admit that my own preferences in patients with a hypertensive crisis lie primarily with two direct vasodilators, diazoxide and sodium nitroprusside, because these two agents have proved themselves effective in a much higher percentage of hypertensive crises, regardless of the aetiology or severity of the hypertension, or the patient's level of renal function. Diazoxide can yield a precipitous reduction in blood pressure within three to five minutes following the intravenous administration of a 300-mg bolus. The maximum hypotensive response usually occurs within five minutes, and the blood pressure will not usually go any lower. 5 Side effects The precipitous reduction in blood pressure following an IV bolus of diazoxide can create some serious problems, and probably constitutes the major drawback of this drug, especially in patients with cerebral or coronary insufficiency. Indeed, there have been a number of case reports of completed strokes or myocardial infarctions following large bolus treatment with diazoxide. In these patients, it is advisable to titrate the blood pressure with small (50- or 75-mg) boluses. I have used this mode of administration in approximately 50 high-risk hypertensive patients with cerebral and/or coronary disease, with effective hypotensive management in 85% to 90% without complications. Thus, in the high-risk patient, this minibolus administration is the method of choice. Sodium nitroprusside Sodium nitroprusside is the most predictably effective hypotensive agent available. No type of hypertension is known to be refractory to sodium nitroprusside. Instantaneous onset of action can be a definite advantage, and careful adjustment of the infusion rate allows you to titrate the blood pressure to any level. This is particularly advantageous in the patient with an intracrania
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