Current concepts in treatment of hypertensive emergencies

Current concepts emergencies

in treatment

of hypertensive

Donald G. Vidt, M.D. CZeueZurz& Ohio

In defining hypertensive crisis, it is important to delineate a true emergency from an urgency. A hypertensive emergency is present if there is immediate risk to the cardiovascular system, and blood pressure must be reduced to a safer level in a matter of minutes to 1 hour. A hypertensive urgency is less acute; a patient may have accelerated or even malignant hypertension but no immediate risk to the cardiovascular system. Therefore, blood pressure reduction to a safer level may take place more slowly, from 1 to 24 hours. Whereas an oral loading regimen may be appropriate for management of hypertensive urgencies, parenteral antihypertensive agents are most appropriate for the initial management of a hypertensive emergency. A hypertensive emergency should never be determined solely on the basis of the level of systolic or diastolic blood pressure. For example, a patient who presents to the emergency room with a blood pressure of 240/140 mm Hg may have accelerated hypertension but is not considered an emergency if there is no evidence of severe headache or encephalopathy, cardiac decompensation, rapid changes in renal function, and therefore no evidence of rapid deterioration of target organ function. On the other hand, a patient with modest elevation of blood pressure complicated by acute medial dissection of the aorta or associated with acute pulmonary edema is a true hypertensive emergency and must be treated accordingly. INITIAL

MANAGEMENT

Hospitalization is indicated in the initial management of the patient with a hypertensive emergency. A history and physical examination should be performed expeditiously upon presentation to determine and assess the degree of target organ involvement, evidence of other major system diseases that From the Department Nephrology, Cleveland

of Nephrology, Clinic.

Department

of Hypertension

and

Reprint requests: Donald G. Vidt, M.D., Department of Hypertension and Nephrology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44lOti.

220

may affect choice of antihypertensive therapy: the examination should also be designed to assess or identify any underlying secondary causes of hypertension that might be responsible for the hypertensive emergency, i.e., pheochromocytoma or a hypertensive crisis associated with high circulating catecholamine levels. Patients in this latter group tend to be resistant to many of the parenteraI agents available. Urinalysis and renal function studies tc determine the presence and degree of renal impairment, and chest x-ray examination and electrocardiogram to assess the degree of cardiac involvement and the presence or absence of congestive heart failure, should be performed. In addition, a complete blood count should be performed at the initial evaluation, because acute angiopathic hemolytic anemia is commonly associated with accelerated or malignant hypertension. Drug therapy should commence immediately upon the completion of the initial evaluation and the obtaining of laboratory studies. Initiation of drug therapy to lower blood pressures to a safer level should not wait for the processing of laboratory results. Once safer levels of diastolic and systolic blood pressures have been obtained, additional diagnostic studies can be undertaken if the etiology of the hypertension remains unknown. The initial goal of therapy is not to achieve a normal blood pressure but, more appropriately, a diastolic blood pressure of 100 to 110 mm Hg to minimize the risk of a too low level of cerebral or cardiac perfusion. After blood pressure is reduced to this level, then over several days a normal goal blood pressure, as tolerated by the individual patient, can be achieved. Therefore, initiaI therapy of a hypertensive emergency will often be based on a presumptive diagnosis. The etiology of the hypertension may not be fully understood but, with the exception of pheochromocytoma, should not affect the initial selection of antihypertensive therapy. Parenteral agents available for use in hyperten-

"o,"rne

111

Treatment

Number 1

Table

hypertensive

emergencies

22 1

I. Direct vasodilating drugs for the treatment of hypertensive emergencies of administration

Method Preparation*

Intermittent

IM

Sodium nitroprusside Nitroglycerin Diazoxide

Hydralazme

hydrochloride

IM = intravascutar; IV = intravenous. *In most cases, a rapidly acting diuretic

tStart

of

with smallest

lo-50 should

rngt

be given intravenously

Continuous 0.510 gg/kg/min 5-100 gg/min 15-30 mg/min unti1 effect is achieved

50-100 mg bohrs injection (within 30 seconds) every IO-15 minutes lo-20 mg/20 ml$ at the beginning

IV

the desired

200 mg/L

and at appropriate

intervals

throughout

treatment.

dose listed.

Unject from syringe at rate of 1 m&in until the desired effect is obtained. (From Vidt DC, Gifford RW Jr: Cleve Clin Q 61:421, 1984. Adapted with permission.)

Table

Il. Sympathetic inhibiting drugs for the treatment of hypertensive emergencies of administration

Method Preparation*

IM

Intermittent

Lahetalolt Trimethaphan Phentolamine Reserpine

20-80 mg by intermittent every IO-15 minutes

IV

Continuous injection

0.5-2.0

IV

mg/kg/min

1000 mg/L

camsylate

5-10 mg$ l-5

rngl

Methyldopa

Abbreviations as in Table I. *In most cases, a rapidly acting diuretic should be given intravenously tNot yet approved by FDA. $Start with smallest dose listed. (From Vidt DG, Gifford RW Jr: Cleve Clin Q 51:421, 1984. Adapted

200 mg/L

5-10 mg boius injection l-5 mg from syringe over 3-5 minutes 250-500 mg in 100 ml over 30.60 minutes

at the beginning

and at appropriate

intervals

throughout

treatment,

with permission,)

sive emergencies fall into two general categories: the agents that are direct vasodilating drugs (Table I) and agents that act by a variety of mechanisms to

inhibit the sympathetic or adrenergic nervous system (Table II). Ideally, the agent and method of administration should allow a controlled reduction as opposed to a precipitous reduction in systolic and diastolic blood pressure. DIRECT VASODILATORS

Direct vasodilating drugs include sodium nitroprusside, nitroglycerin, diazoxide, and hydralazine (Table I). Although verapamil and nifedipine are not approved in the United States for the treatment of hypertension, experimental studies have proved them effective and potent agents in the treatment of hypertensive urgencies or emergencies.l*z Hydralazine. Hydralazine is the oldest agent of the direct vasodilators, marketed in the 1960s. It is the least consistent in its effects and has fallen into disuse by most clinicians for an array of hyperten-

sive emergencies, because of the development of more potent and predictable vasodilating agents. It is still widely used by obstetricians as the drug of choice in the treatment of severe preeclampsia or eclampsia. It has the advantages of convenience of administration in that it can be administered intramuscularly, by intermittent intravenous injection, or by continuous infusion. A rapid blood pressure response occurs with any one of these modes of administration.3 When used in appropriate doses, hydralazine is not associated with hypotension. It does not cross the blood-brain barrier, so there are no associated mental function changes like those seen with some of the sympathetic inhibitors. However, hydralazine may cause significant reflex tachycardia, which may pose a risk in patients with unrecognized, underlying coronary artery disease. Nitroglycerin. Nitroglycerin, recently made available as an intravenous preparation, must be administered by continuous intravenous infusion. Both its

January,

~22

Vidt

American

I

,

,

1

1

1

1

30

60

90

120

150

180

d0 lnderal(40 Apresoline tiygroton

mg) (25 mg) (50 mg)

1~386

Heart Journal

r

210

Time (min)

Time (rni~~~~o Diazoxide(mg) 50

Fig.

1.

50

io

50

;O :O ;O Lasix (40 mg)

Response to a large bolus (upper

punel)

50

and small bolus (lower

panel)

administration

of

d&oxide.

onset and offset are quite rapid, so that the antihypertensive effects of the intravenous infusion last only slightly longer than the duration of infusion. Use of nitroglycerin may be appropriate in some situations in which sodium nitroprusside is contraindicated, such as prolonged use in patients with advanced renal failure, but its relative potency should not be misinterpreted. Nitroglycerin does not

have the potency as an antipressor agent that is seen with sodium nitxoprusside. In fact, intravenous nitroglycerin-like all of the oral and transdermal nitroglycerin preparationshas its primary effects on preload in lower dosages; as the infusion rate is increased, there is some afterload reduction. Xntravenous nitroglycerin may be the drug of choice in treatment of the patient

Volume 111 Number 1

with moderate hypertension associated with coronary ischemia because it provides collateral coronary vasodilatation, a property not seen with the administration of sodium nitroprusside or diazoxide. Diazoxide. Diazoxide and sodium nitroprusside are the two most commonly used direct vasodilating agents. Diazoxide is administered as a 50 to 100 mg bolus injection within a 30-second period every 10 to 15 minutes. In addition, recent data indicate that diazoxide can also be administered by continuous intravenous infusion (15 to 30 mg/min), and one can achieve the same controlled reduction in blood pressure that occurs with a small bolus administration.* There is no questioning of d&oxide’s potency as a hypotensive agent in 90% of administered dosages, but when large boluses of the drug are administered, a precipitous uncontrolled reduction in blood pressure occurs within 3 to 5 minutes; the nadir is reached usually within 5 minutes and blood pressure then stabilizes at that lower level for periods of several hours or, in certain cases, for as long as 24 hours. Precipitous uncontrolled reduction of pressure with diazoxide has led to numerous reported cases of myocardial infarction or completed strokes in patients administered this agent in large boluses5v6 Therefore, small bolus or pulse administration of this agent has been the popular treatment for the past 10 years6 Fig. 1 shows the striking difference in response to a large bolus compared with the small bolus administration of d&oxide: with the latter it is possible to achieve a controlled reduction of blood pressure to a more desired initial goal of pressure. The major disadvantage of diazoxide administration is similar to that seen with hydralazine and other direct vasodilators-i.e., association with reflex tachycardia that can precipitate or worsen angina1 symptoms in patients with coronary disease. Often it is necessary to administer intravenous small doses of a beta blocker such as propranolol, to control reflex increases in heart rate when using d&oxide. Sodium nitroprusside. The hallmark agent by which all new pare&era1 antihypertensive agents have been judged in the last decade is sodium nitroprusside, Clearly, this agent is the most potent and most predictably effective agent available for the treatment of hypertensive crises.7*s Its onset of action is virtually instantaneous. It allows a controlled titration of blood pressure, which is the most desirable response in the treatment of any hypertensive crisis. Its effect on preload as well as afterload has made it a popular agent in the initial manage-

Treatment

of hypertensive

emergencies

223

ment of patients with intractable congestive heart failure, whether or not associated with significant hypertension. Sodium nitroprusside does not cross the blood-brain barrier, so it is not associated with sedation or somnolence. A disadvantage of sodium nitroprusside is that it requires careful and constant bedside nursing supervision, because of its administration with a variable-rate infusion pump. Therefore, it is best administered in an intensive care environment where appropriate bedside care is available. The agent is rapidly degraded by light, so that intravenous administration equipment must be covered appropriately. In addition, sodium nitroprusside is metabolized to an intermediate cyanide, which is then rapidly converted to thiocyanate that is excreted subsequently by the kidneys. Recent case reports have suggested that patients with severe hepatic disease or patients with extremely poor tissue perfusion, usually in association with severe congestive heart failure, may build up cyanide to toxic concentrations due to impaired metabolism of nitroprusside.g It is well known that thiocyanate can build to toxic concentrations in patients receiving sodium nitroprusside for prolonged periods, when the course of these patients is complicated by significant renal insufficiency. ADRENERGIC

AGENTS

Reserpine. Reserpine is rarely used today because of the availability of other adrenergic inhibitors and vasodilators that have lower adverse effect profiles. Reserpine is a slow-acting agent; whether given intramuscularly or intravenously, there is a 2- to 3-hour delay between administration and onset of effective antihypertensive results. It induces rather profound sedation and somnolence, so that by the time effective therapeutic doses are administered, the patient is lethargic if not semiconscious, which makes the following of vital signs and mental status rather difficult in some hypertensive crises that may be associated with acute intracerebral events. Methyldopa. Methyldopa is available as an intravenous preparation. It is less consistently effective than any of the other adrenergic blockers. It is no longer used for the management of hypertensive emergencies, but is still employed in hypertensive patients undergoing surgical procedures who are unable to take their usual antihypertensive agents for a period of several days in the early postoperative period. Phentolamine. Use of phentolamine, a nonselective alpha-blocking agent, is restricted today for treatment of hypertensive emergencies associated with

224

Vidt

Labetalol

IV infusion 0.5 @mm

BP HR 2601

Labetabl

IV inhdon

2 mghnin

BP HR a 2601

llne

(hr)

Fig. 2. Dose-response curves of two patients who received labetalol at an infusion rate of 0.5 mg/min 2.0 mg/min. (From Dal Palu C, et ak Br J Clin Pharmacol 13(suppl 1):975, 1982. Reproduced permission.)

high circulating levels of catecholamines-e.g., in the patient with pheochromocytoma. In rare cases, sudden release of catecholamines and marked hypertension occur in association with patients on monoamine oxidase inhibitors who have ingested foods or beverages containing tyramine or other catecholamine precursors. Also, rebound high blood pressure occurs in patients treated with central alpha agonists such as clonidine or guanabenz, where medications being taken in moderate doses have been suddenly interrupted or discontinued. Trimethaphan. Trimethaphan is aIso one of the earliest available adrenergic inhibitors. A ganglion blocker, trimethaphan is rarely used today in the treatment of a hypertensive crisis, except in the management of hypertension in association with acute medial dissection of the aorta, where it is usually administered in combination with reserpine, occasionally guanethidine, and possibly with a beta blocker, because of its abilities to reduce preload, cardiac output, and subsequent shearing forces or the velocity of left ventricular ejection. Labetaloi. Labetalol, the newest addition to the group of adrenergic agents, is a combined alpha and beta blocker. It is available both as an intravenous agent and as an oral agent. It has proved useful in the treatment of hypertensive urgencies and emergencies of various etiologies.“* I1 Like sodium nitroprusside, labetalol, 20 to 80 mg, can be administered as small bolus injections every 10 minutes, or 0.5 to 2.0 mg/kg/min by continuous infusion. The goal should always be early conversion from parenteral to oral therapy; in this case that

to by

conversion may be eased by the availability of a drug with both oral and intravenous preparations. Fig. 2 shows dose-response curves from two patients who received labetalol at an infusion rate of 0.5 mg/min to an infusion rate of 2.0 mg/min. The controlled reduction in blood pressue achieved with labetalol is dose-dependent, i.e., the rate of blood pressure reduction is accelerated with an increase in the infusion rate of labetalol.lz Our experience with labetalol indicates that 20 to 40 mg bolus injections are associated not with reflexive tachycardia but instead with a modest bradycardia. Therefore labetalol, with its acute effects on peripheral resistance (afterload) and its ability to forestall reflex tachycardia, is an agent that has proved suitable in patients with underlying coronary disease and in situations of severe hypertension in association with acute myocardial infarction or following acute vascular surgical procedures. Labetalol is effective by continuous infusion or by pulse administration. Its effects may persist for periods of several hours to as long as 24 hours following the last dose of labetalol; thus another advantage of this agent is in providing time to begin conversion from parenteral to oral therapy. Labetalol’s disadvantages lie primarily in its betablocking effects, which predominate over the alpha effects. With the intravenous preparation, these beta effects may predominate by as much as seven times over the alpha-blocking effects. Also, while the drug has been effective in the treatment of hypertensive crises associated with pheochromocytoma

Volume 111

Treatment

Number 1

of hypertensive emergencies 225

and high circulating levels of catecholamines, there have been several reports of paradoxic hypertension. Until this issue is resolved, labetalol should not be used in the treatment of patienti with a hypertensive crisis that is clearly associated with pheochromocytoma. Combination therapy. The acute reduction in blood pressure associated with parenteral administration of the antihypertensive agents mentioned above is often associated with sodium and water retention. If a parenteral agent is used for periods exceeding 24 hours, pseudotolerance to the agent may develop as a result of the expansion of intravascular volume. Concomitant intravenous administration of a loop diuretic such as furosemide, 20 to 40 mg, bumetanide, 0.5 to 1.0 mg, or ethacrynic acid, 25 to 50 mg, in repeated dosages (every 2 to 3 hours initially, then 4 to 6 hours if needed to maintain adequate urine volume) is warranted.

a true hypertensive emergency or a hypertensive urgency, because all patients with malignant hypertension do not necessarily require the immediate administration of antihypertensive parenteral agents unless that malignant hypertension is complicated by rapidly progressive target organ dysfunction. On the other hand, without encephalopathy and with stable cardiac and renal function, it may again be quite appropriate totreat that patient with a variety of loading regimens of oral agents (such as clonidine) that provide the ability to reduce blood pressure over periods of 1 to several hours or up to 24 hours. In summary, the patient with a hypertensive emergency always requires hospitalization and continuous monitoring. Rapid initial assessment should be followed by the choice of an initial agent that allows a controlled reduction of blood pressure and an initial goal of blood pressure reduction.

DISCUSSION

REFERENCES

Several examples of hypertensive emergencies and a choice of agents in each situation follow. In hypertensive encephalopathy, the classical presentation of a hypertensive emergency, blood pressure should be rapidly controlled and brought to a safer but not normal level (diastolic blood pressure 100 to 110 mm Hg). Sodium nitroprusside, small bolus injections of diaxoxide, labetalol, or possibly trimethaphan, can be administered in this setting. Use of reserpine or methyldopa should be avoided because of their depressant effects on the central nervous syskm; these effects make it difficult to accurately assess vital signs. The agent of choice for the patient with a hypertensive emergency or severe hypertension associated with acute coronary insufficiency is nitroglycerin if blood pressure is not severely elevated, and sodium nitroprusside if blood pressure is severely elevated. Secondary choices are labetalol or trimethaphan, agents that enable a controlled reduction in blood pressure in these individuals. Direct vasodilating agents that are associated with reflex tachycardia and subsequent increases in myocardial oxygen utilization and heart work, should be avoided. In the patient with malignant hypertension, it is critical to determine whether the patient represents

1. Wasir HS, Kasliwal RR, Bhatia ML: Immediate effect of intravenous verapamil in hypertension. Indian Heart J 31:326, 1979. 2. Bertel 0, Conen D, Radu EW, et al: Nifedipine in hypertensive emergencies. Br Med J 286:19, 1983. 3. Koch-Weser J: Hydralazine. N Engl J Med 295:320, 1976. 4. Garrett BN, Kaplan NM: Efficacy of slow infusion of diazoxide in the treatment of severe hypertension without organ hypoperfusion. AM HEART J 103:390, 1982. 5. Kumar GK, Dastoor FC, Robayo JR, et ab Side effects of diazoxide. JAMA 235:275, 1976. 6. Wilson DJ, Lewis RC, Vidt DG: Control of severe hypertension with pulse diazoxide. Zrz Vidt DG, editor: Cardiovascular Therapy, Philadelphia, 1982, F.A. Davis Company, p 79. 7. Palmer RF, Lasseter KD: Sodium nitroprusside, N Engl J Med 292: 294, 1975. 8. Vidt DG, Gifford RW Jr: A compendium for the treatment of hypertensive emergencies. Cleve Clin Q 51:421, 1984. 9. Vesey CJ, Cole PV, Simpson PJ: Cyanide and thiocyanate concentrations following sodium nitroprusside infusion in man. Br J Anaesth 48:651, 1976. 10. Cressman MD, Vidt DG, Gifford RW Jr, Moore WS, Wilson DJ: Intravenous labetalol in the management of severe hypertension and hypertensive emergencies. AM HEART J 107:980, 1984. Il. Cumming AMM, Brown JJ, Lever AF, et al: Intravenous labetalol in the treatment of severe hypertension. Br J Clin Pharmacol 13(suppl):935, 1982. 12. Dal Palu C, Pessina AC, Semplicini A, et al: Intravenous labetalol in severe hypertension. Br J Clin Pharmacol 13tsuppl 1>:97S, 1982. 13. Briggs RS