Symposium on

THE PRACTICAL MANAGEMEbiT OF PATIENTS WITH SEVERE HYPERTENSION AND HYPERTENSIVE EMERGENCIES

Sponsored by an educational grant from Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT.

INTRODUCTION

Morbidity and mortality due to malignant hypertension and hypertensive emergencies have declined significantly in the past 25 years, in part because of the development of many effective and safe antihypertensive agents.

Credit must also be given to more aggressive therapy of patients, not only patients with accelerated or malignant hypertension, but also patients with mild to moderate hypertension.

Clinical trials over the last 20 years clearly have shown the ability to prevent progression of blood pressure to a more accelerated form of hypertension by aggressive therapy of mild and generally uncomplicated hypertension.

Today, a hypertensive urgency or emergency in most cases represents a failure of medical management of lesser degrees of hypertension. Yet, certainly when the hypertensive urgency or emergency does present, it represents a challenge to the primary care physician or to the emergency room physician, and recognition and prompt institution of antihypertensive therapy is capable of preventing the severe morbidity and mortality formerly associated with these crisis forms of hypertension.

This symposium addresses several areas of severe hypertension and hypertensive emergencies, including pathophysiology, management, and effects of rapid blood pressure reduction on cerebral blood flow.

Donald G. Vidf, M.D. Department of Hypertension and Nephrology

Cle veiand Clinic

Hypertensive emergencies and urgencies: Pathophysiology and clinical aspects

Mark Houston, M.D. Nushville, Term.

Approximately 25% to 30% of the United States population has hypertension, (blood pressure greater than 160/95 mm Hg).’ Approximately 70% have mild hypertension (diastolic blood pressure 90 to 104 mm Hg) and 90% have mild to moderate hypertension (diastolic blood pressure 90 to 114 mm Hg).l Severe hypertension, diastolic blood pressure greater than 115 mm Hg, occurs in about 10% of these peop1e.l A hypertensive crisis-emergency or urgency-evolves when structural changes in the

From the Medical Intensive Care Unit and Cooperative Care Center, Vanderbilt University Medical Center.

Reprint requests: Mark Houston, M.D., Assistant Professor of Medicine, S-1125 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232.

vasculature occur as a consequence of chronic hyper- tension and/or because of functional vasoconstrict- ing forces.z This state has also been called malignant or accelerated hypertension.

Our knowledge of the pathophysiology of hyper- tensive crisis and approaches to treatment have changed over the past 10 years. Some reasons for this improved understanding include the recogni- tion that the basic pathologic lesion in the arterioles is a fibrinoid necrosis and proliferative endarteritis, the ability to measure vasoconstricting substances, the assessment of volume status, the importance of a less zealous approach to reducing blood pressure, and the development of new antihypertensive agents. Generally, a hypertensive emergency occurs when the diastolic blood pressure is 120 to 130 mm

206 Houston

Blood pressure = cardiac output T systemic vascular reststance A

,/’ ” \,,

Peripheral vascular Renal vascular resistance reslstance

Fig. 1. Hemodynamics of hypertensive crisis and essen- tial hypertension. In established hypertension there is decreased cardiac output (up to 25%) and a marked increase in systemic vascular resistance. Age, race, and duration of hypertension all relate to hemodynamic differ- ences. In malignant hypertension there is a marked increase in systemic vascuIar resistance because of the structural sequelae of chronic hypertension and functional vasoconstricting forces.

OL 12345678 9 10

Years

Fig. 2. survival rate percentages of hypertensive patients with different grades of retinopathy. (From Bar- nett AJ, Silberberg FG: Med J Aust 2:960, 1973. Repro- duced by permission.)

Hg in association with end-organ damage that is either progressive or present at the time of the initial evaluation (Table I). Most patients with a hyperten- sive emergency should be treated expeditiously, within minutes to an hour, but controversy exists regarding the rapidity of the fall and the level to which blood pressure should be lowered.3-s

On the other hand, a hypertensive urgency gener- ally does not involve severe target organ damage, although diastolic blood pressure is 120 mm Hg or greater-similar to that of a hypertensive emergen- cy (Table II). Most patients with a hypertensive urgency can probably be treated less expeditiously (within 24 hours) than those with emergency. The prognosis tends to be better, and patients do not necessarily require hospitalization.

The primary hemodynamic abnormality in essen- tial hypertension is an elevation of systemic vascular resistance, a combination of both peripheral and renal vascular resistance (Fig. l).6 Hemodynamic differences among patients are related to age, race,

January, 1966 American Heart Jownd

Table I. Hypertensive emergencies

Diastolic blood pressure greater than 120 mm Hg with:

Intracranial hemorrhage or thrombotic cerebrovascular acci-

dent Subarachnoid bleeding Hypertensive encephalopathy Acute aortic dissection Acute pulmonary edema, acute congestive heart failure, and

acute left ventricular failure Eclampsia (toxemia of pregnancy) Pheochromocytoma hypertensive crisis Grade 3 or 4 Keith-Wagener funduscopic changes Acute renal insufficiency or failure Myocardial insutficiency syndromes (unstable angina Peck-

ris, acute myocardial infarction)

Table ii. Hypertensive urgencies

Accelerated hypertension with severe blood pressure eleva- tion (diastolic blood pressure usually 2120 mm Hg) with minimal end-organ damage in which there is no evidence of those conditions in hypertensive emergency and no impending complications

Grade 1 or 2 Keith-Wagener funduscopic changes Postoperative hypertension Preoperative uncontrolled or untreated hypertension

sex, and duration of hypertension.‘jr7 In established hypertension, the cardiac output decreases by as much as 25%, and there is a marked increase in systemic vascular resistanue.6 In a hypertensive cri- sis, there is a marked increase in systemic vascular resistance because of structural sequelae of chronic hypertension and functional vasoconstricting forces.2 Therapy, therefore, should be aimed at correcting this hemodynamic derangement.

SEVERE HYPERTENSION

Morbidity and mortality. The morbidity and mortal- ity associated with severe hypertension are drarnat- ic. Barnett and Silberber? found that patients with grade 4 Keith-Wagener hypertensive diabetic reti- nopathy (hemorrhages, exudates, papilledema) had a 50% &year survival rate (Fig. 2). Breckenridge et al9 compared the 5-year survival rates with the degree of retinopathy and that of renal insufhciency (Table III). They found that hypertensive patients with grades 1 and 2 retinopathy and normal renal function (blood urea nitrogen level <18 mg/lOO mg) had a 90% &year survival rate. However, when abnormal renal function (blood urea nitrogen level >18 mg/lOO mg) was considered, the 5-year survival rate dropped to 81% . This rate fell to 64 % among patients with malignant hypertension with papilled- ema but normal renal function and to 23% among

Hypertensive urgencies and emergencies 207

Table Ill. Prognosis for treated hypertensive patients with normal or elevated levels of blood urea nitrogen and with different grades of funduscopic changes from 1960 to 1967

5-year suruiual rate (76)

Accelerated Nonexudative hypertension:

retinopathy Hemorrhage and exudate Renal function (Grade 1-Z) (Grade 3)

BUN <18 mg/lOO mg 90 84 BUN >18 mg/lOO mg 81 57

BUN = blood urea nitrogen. From Breckenridge A, Dojlery CT, Parry EHO: (QJ Med 39:411, 1970. Reproduced by permission.)

Malignant hypertension: Papilledema

(Grade 4)

64 28

those severely hypertensive patients with renal insufficiency.

clinical presentation. Although a diastolic blood pressure exceeding 120 mm Hg indicates a hyperten- sive crisis, the level of blood pressure elevation must be considered in conjunction with both clinical and laboratory assessment of end-organ damage to define an emergency or an urgency. Not all precipi- tating events of a hypertensive crisis are known (Table IV). The most common event is a sudden elevation of blood pressure in a patient with preex- isting chronic hypertension7 Other causes include renovascular hypertension, acute glomerulonephri- tis, eclampsia, pheochromocytoma, antihypertensive therapy withdrawal syndromes, head injuries, renin-secreting tumors, or ingestion of catechol- amine precursors in patients taking monoamine oxidase inhibitors.lO

The main clinical findings of malignant hyperten- sion are numerous and include changes in the fun- dus of the eye, necrotizing arteriolitis (hemorrhages, exudates), and disc edema or papilledema; also included are neurologic signs, visual changes, nau- sea, vomiting, headache, confusion, somnolence, stu- por, neurologic deficits, seizure, or coma caused by increased intracranial pressure.7*‘1-14 Often during a hypertensive crisis there is a decline in renal func- tion with oliguria and azotemia, and the urinalysis shows proteinuria, hematuria, and casts. Microan- giopathic hemolytic anemia may be found on the blood smear. Most patients have some degree of left ventricular failure due to the increased afterload, particularly if there is underlying cardiovascular disease: 11-14

Malignant hypertension may occur by itself or it may be associated with other major organ involve- ment that seems to predominate over the hyperten- sion in the clinical presentation.3* 7* lo, l5 Patients with hypertensive emergencies may present with acute left ventricular failure (pulmonary edema), coronary insufficiency (angina, myocardial infarction), aortic

Table IV. Precipitating factors in hypertensive crisis

Accelerated sudden rise in blood pressure in a patient with preexisting essential hypertension

Renovascular hypertension Glomeruionephritis-acute Eclampsia Pheochromocytoma Antihypertensive withdrawal syndromes Head injuries Renin-secreting tumors Ingestion of catecholamine precursors in patients taking

monoamine oxidase inhibitors

dissection or leaking aneurysm, intracranial hemor: rhage, cerebrovascular accident, and subarachnoid hemorrhage or postoperative bleeding.3* 7* lo, I5

Furthermore, malignant hypertension may be associated with catecholamine-excess-related syn- dromes (monoamine oxidase inhibitors, pheochro- mocytoma, abrupt withdrawal of antihypertensive medication) and toxemia of pregnancy. A different approach to therapy is required in each of these instances.3~ 7s lo, l5

Therefore, factors that constitute malignant hypertension include the absolute level of blood pressure, its rate of rise, and the development of end-organ damage. For example, the blood pressure level does not always correlate with whether the patient has hypertensive emergency or urgency. A tremendous overlap can occur in the actual level of both systolic and diastolic blood pressure in benign or malignant hypertension (Fig. 3).z It is also impor- tant to consider the type of vasoconstrictive sub- stances that are present, whether they have any direct vasculotoxic effects, and to determine the extent of end-organ damage, if any.

PATHOPHYSIOLOGY

Malignant hypertension, if untreated, quickly results in death, usually related to central nervous system events (cerebrovascular accident), cardiovas-

208 Houston

Systolic

January, 1986

Ainerican Heart .JoumaL

Diastolic

MalIgnant Benign

230 .

270 .

260 a

250

Malignant Benign

. .

.

: &. . a

~ 230

g 220

E 210 r

150-

140-

SF 130-

g 120-

llO-

loo-

go-

. . .

Fig. 3. Systolic and diastolic blood pressure levels in age- and sex- matched patients with severe benign and malig- nant hypertension. (From Kincaid-Smith P: Aust NZ J Med 11 (Suppl 1):64, 1981. Reproduced by permission.)

cular events (acute myocardial infarction, congestive heart failure), or renal failure?*7 The underlying pathology of hypertensive crisis is apparently re- lated to myointimal proliferation (Fig. 4).zv wx There is ample evidence that the actual blood pressure level is only one factor in this process and may have little to do with the conversion of the benign stable or asymptomatic form of hypertension to the malig- nant phase. Rather, vascular lesions develop in the kidneys and cause rapid progression of renal failure and hypertension.2s11-16 This “onion skin” lesion of the ‘interlobular arteries caused by myointimal pro- liferation has a common pathogenesis secondary to organization of thrombi, which form on damaged endothelium. This lesion is similar to that seen in scleroderma, thrombotic microangiopathy, and allo- graft rejection.5

Fig. 5 summarizes the general events that occur in the pathogenesis of a hypertensive crisis.2 A high blood pressure level is associated with structural changes that are related to increased vascular reac- tivity. Circulating vasoconstrictors (renin, angioten- sin II, norepinephrine, and vasopressin) lead to a relative vasodilation or constriction of the efFerent- afferent arteries of the kidney.2 Continued occur- rence of these events causes a pressure diuresis that can result in hypovolemia.

These events, in turn, set up a vicious cycle? Initial vasoconstrictive changes occur with sausage stringing (alternating areas of constriction and dila- tion) in the renal arteries; endothelial damage and platelet aggregation lead to further release of toxic substances, particularly thromboxane, which then causes platelet plugging, ischemia, and further

Fig. 4. Cellular myointimal hyperplasia in an interlobu- lar artery, the hallmark of malignant hypertension. Single arrow = internal elastic lamina; double arrow = deposit of fibrin between proliferating cells. (Weigert’s elastic and van Gieson stain. ~500.) (From Kincaid-Smith, P: Aust NZ J Med ll(Supp1 1):64, 1981. Reproduced by permis- sion.)

myointimal proliferation. Replacement of sodium and fluids may interrupt this vicious cycle, reduce blood pressure, and improve renal function.2*17-*g

Volume depletion occurs in most patients with hypertensive emergency.z* 17-lg If there is no clinical evidence of volume overload and the hypertensive levels have been sustained for several days, there is a much greater chance that the patient is volume deplete% diuretic therapy as an initial treatment in the absence of a good clinical indication may further exacerbate this cycle.

Therefore, hypertension that occurs with malig- nant arteriolopathy with inflammation and necrosis of arterioles leads to platelet plugging, fibrin deposi- tion, and hemolytic anemia and causes cerebral ischemia. It may cause cerebral edema and eventu- ally a breakdown of autoregulation. It also results in myocardial and renal ischemia. Malignant hyperten- sion results from the combination of chronic increased vascular reactivity with the increased lev- els of vasoactive constricting substances.

The concept of pressure diuresis is still controver- sial, Click et aL20 and Kin&d-Smith2 showed that pressure diuresis is caused by the vasoconstricting effects on renal arterioles of angiotensin II, norepi- nephrine, and vasopressin and results in intravascu- lar vohrme depletion in patients with malignant hypertension. There is an increase in the afIerent arteriolar but not in the efferent arteriolar lumen size in hypertensive animals. There is an increased

Volume 111

Number I Hypertensive urgencies and emergencies 209

vasoconstrictor response in the efferent arteriole to both norepinephrine and angiotensin II. These com- bined changes could cause an increase in glomerular capillary pressure and pressure natriuresis in hyper- tensive animals.2o This volume depletion leads to a net loss of sodium and water and necessitates a change in management. There are some reported cases of a reduction of blood pressure in patients who were volume depleted and hypertensive and who received normal saline solution. This favorable response was presumably the result of a negative feedback on the production of angiotensin II and other vasoconstricting agents. Sodium restriction and overzealous use of diuretics during the first 24 to 48 hours may be contraindicated in most patients?, 17-ls

GENERAL PRINCIPLES OF THERAPY

Specific treatment principles for both hyperten- sive urgency and emergency are discussed elsewhere in this symposium. Generally, it is important to balance the treatment-lowering the blood pressure and maintaining perfusion both to and within the organs.z~4*z1-z7 If blood pressure is lowered too quickly or excessively, the respective organ may be unable to autoregulate blood flow. Acute lowering of the blood pressure can result in damage to the brain, heart, or kidney. Thus, normotension, at least in most cir- cumstances, probably should be avoided during the first few days of therapy.314v21-27 The mean arterial blood pressure should remain about 160/100 mm Hg for the first few days until the body can adjust to the lower blood pressure levels?~4~z7

SUMMARY

A hypertensive urgency should be distinguished from a hypertensive emergency. Although the dis- tinction may not always be obvious, certain guide- lines may help the clinician determine which thera- peutic approaches are most appropriate for each patient. Hypertensive emergencies include those conditions in which new or progressive severe end- organ damage is present and a delay in appropriate therapy might result in permanent damage, progres- sion of complications, and a poor prognosis. Hyper- tensive urgencies include those conditions with min- imal to no obvious end-organ damage in which blood pressure should be lowered expeditiously. The risk of immediate complications or organ damage is less likely to occur, and thus the immediate prognosis is better, ahhough the ultimate prognosis, if untreated, is poor. There is a marked individual, racial, sexual, and age difference in the ability to tolerate high intraarterial pressure, as evidenced by

Increased vascular reactk’lty

t Sodurn”pressure’ duress (differential effect 0”

aflerent and elferent renal arteriole) t Hypovolem~a t

Increased angloterlsln II

- norepmephrlne “asopresl”

endot?elial damage and platelet aggregauon

* release Lf platelet

factors and thromboxane

h platelet and fibrin

mgratlon and mjtogenic factors 4

platelet and fibrin deposItIon m~croangtopath~c hemotyW anern~~ and

mtravascLllar coagulalIoll /

Fig. 5. Pathogenesis of a hypertensive crisis.

patients’ symptoms and signs of end-organ dam- age.

Patients may have no symptoms of elevated blood pressure until significant intraarterial levels are reached. If symptoms are present, they may include headache, dizziness, blurred vision, shortness of breath (especially with exertion), chest pain, rapid pulse, palpitations, malaise and fatigue, nocturia, or pedal edema.7s “-” Signs of hypertensive disease vary and depend not only on the level of blood pressure but also include funduscopic changes with arteriolar narrowing, atrioventricular nicking, hemorrhages, exudates or papilledema, central nervous system changes and neurologic abnormalities, cardiac changes with gallop rhythm, cardiomegaly, tachy- cardia, ectopic ventricular beats, left ventricular hypertrophy or signs of congestive heart failure, pulmonary edema, and signs of renal insufficien- CY- I, 11-14

Although there is a definite correlation between the level of blood pressure and end-organ damage, there is no definite systolic or diastolic level of blood pressure that induces end-organ damage. Some patients may tolerate very high blood pressures with few symptoms or signs, whereas others may manifest end-organ damage at lower blood pressures. Thus, the definition of hypertensive emergency and urgen- cy depends on the clinical assessment of the blood pressure level and clinical and laboratory assess-

January, 1966

210 Houston American Heart Journal

merits of end-organ damage. The absolute blood pressure in itself does not determine the seriousness of the clinical situation, the expediency of treat- ment, or the need for in-hospital monitoring in a critical care unit.

It is important not to lower the blood pressure

6. Kaplan NM: Clinical hypertension, ed 3. Baltimore, 1982, The Williams & Wilkins Company.

7. Alpert MA, Bauer ,JH: Hypertensive emergencies: Recogni- tion and pathogenesis. Cardiovasc Rev Rep 6:407, 1985.

8. Barnett AJ, Silberberg FG: Long-term results of treatment of severe hypertension. Med J Aust 2:960, 1973.

9. Breckenridge A, Dollery CT, Parry EHO: Prognosis of treated hypertension: Changes in life expectancy and causes of death between 1952 and 1967. Q J Med 39:411, 1970.

10. Ram CVS: Hypertensive crisis. Part 2: Causes. J Cardiovasc Med 8:781, 1983.

11. Keith NM, Wagener HP, Kernchan JW: The syndrome of malignant hypertension. Arch Intern Med 41:141, 1928.

12. Derow HA, Altschule MD Malignant hypertension. N Engl J Med 213:951, 1935.

13. Mizoczek W: Malignant hypertension. Angiology 28:444,

ilished within -1 hour, whereas with hypertensive

precipitously or to a subnormal level particularly in patients with end-organ damage. Such treatment

urgencies control should be within 24 hours.

may critically reduce blood flow and perfusion to vital organs and induce a cerebrovascular accident, myocardial ischemia, or renal failure. A smooth,

Those patients who have hypertensive emergen-

gradual reduction in blood pressure is crucial to patient management with oral or parenteral antihy-

ties with malignant hypertension and end-organ

pertensive drugs. However, in hypertensive emer- aencies blood uressure control should be accom-

damage should be admitted to a hospital intensive care unit for evaluation and treatment. These

JAMA 237:l”i70, 1977.

1977. 14. Rabin E: Malignant hypertension. Can Med Assoc J 118:941.

16. Byrom FB: The evolution of acute hypertensive arterial

,O,Q

disease. Prog Cardiovasc Dis l7:31, 1974.

l.J,“.

17. Mohring J, Petri M, Szokol M, Haack D, Mohring B: Effects

15. Keith TA: Hvnertension crisis recotmition and manaeement.

of saline drinking on malignant course of renal hypertension in rats. Am J Physiol 230:849, 1976.

18. Mohring J, Mohring B, Petri M, Haack D: Vasopressor role of ADH in the pathogenesis of malignant DOC hypertension.

patients have a diffuse arteritis, as of a result of their hypertension, that may take 4 to 6 weeks to heal. Many patients who present with diastolic blood pressure 120 mm Hg or greater will be found to have a secondary cause of hypertension (such as renovas- cular hypertension) after careful evaluation. On the other hand, those patients with hypertensive urgen- cies as defined previously can be treated in the emergency room or outpatient department and can avoid hospital admission. Careful, immediate, and routine follow-up is important in these patients.

Am J PhysioI 232:F260, 1977. 19. Barraclough MA: Sodium and water depletion with acute

malignant hypertension. Am J Med 40:265, 1966. 20. Click RL, Joyner WL, Gilmore JP: Reactivity of glomerular

afferent and efferent arterioles in renal hypertension. Kidney Int 15109, 1979.

21. Ledingham JGG, Rajagopalan B: Cerebral complications in the treatment of accelerated hypertension. Q J Med 48:25, 1979.

22. Kumar GK, Dastoor FC, Robayo JR, Razzaque MA: Side effects of diazoxide. JAMA 235:275, 1976.

23. Montoliu J, Botey A, Pans JM, Revert L: Fatal hypotension in normal dose nitroprusside therapy. AM HEART J 97:541, 1979.

24. Graham DI: Ischaemic brain damage of cerebral perfusion failure type after treatment of severe hypertension. Br Med ,J 4:739, 1975. REFERENCES

I. United States Health Survey, Department of Health, Educa- tion, and Welfare Publication No. (HRA)-77-1310, Vital Health Studies.

2. Kincaid-Smith P: Understanding malignant hypertension. Aust NZ J Med 1 l(Supp1 11:64, 1981.

3. Alpert MA, Bauer ,JH: Hypertensive emergencies: Manage- ment. Cardiovasc Rev Rep 6:602, 1985.

4. Bertel 0, Conen D, Radu W: The management of hyperten- sive emergencies. Cardiovasc Rev Rep 5:601, 1984.

5. Ram CVS: Hypertensive crisis. Part 3: Drug treatment. -J Cardiovasc Med 8:917, 1983.

25. Hulse JA, Taylor DSI, Dillon MJ: Blindness and paraplegia in severe childhood hypertension. Lancet 2:553, 1979.

26. Cove DH. Seddon M. Fletcher RF. Dukes DC: Blindness after treatment for malignant hypertension. Br Med J 2:245, 1979.

27. Strandgaard S: Autoregulation of cerebral blood flow in hypertensive patients. The modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug- induced hypotension. Circulation 53:720, 1976.