Maligant hypertension: The Brazilian experience

Kidney International, Vol. 25 (1984), pp. 209—217

NEPHROLOGY FORUM

Malignant hypertension: The Brazilian experience Principal discussant: OSWALDO RAMOS Escola Paulisia de Medicina, São Paulo, Brazil

Following admission the blood pressure was reduced to 160/100 mm Hg by the intravenous administration of diuretics and sodium nitroprus-

Editors

side. The pulse rate diminished to 100 beats/mm. and dyspnea

JORDAN J. COHEN JOHN T. HARRINGTON JEROME P. KASSIRER NIcOIAos E. MADIAS

disappeared. On the following day, the nitroprusside infusion was discontinued for

4 hours, but the blood pressure again rose to 250/170 mm Hg. The patient was given 150mg of captopril orally, and hemodynamic changes

were measured via a Swan-Ganz catheter. Two hours after captopril was given, mean arterial pressure decreased from 175 to 140 mm Hg. and the pulmonary wedge pressure decreased from 5.5 to 3.0 mm Hg. The cardiac index increased from 3.6 to 4.! liter/m2; no change was observed in the heart rate.

Managing Editor CHERYL J. ZUSMAN

In spite of continued oral administration of 50 mg of captopril every 6 hours and 40 mg of furosemide every 12 hours, the blood pressure again soared to the level present on admission. Two days after the first dose of captopril. another single oral dose of captopril, 50 mg, was administered when the blood pressure was 250/140 mm Hg. Neither the arterial pressure nor any other hemodynamic parameters changed significantly

Michael Reese Hospital and Medical Center University of Chicago Pritzker School of Medicine

and

New England Medical Center Tufts University School of Medicine

following this dose. By this time the BUN and plasma creatinine had

risen to 104 mg/dl and 9.7 mg/dl, respectively. After the lack of response

Case presentation A 41-year-old white woman was evaluated at Hospital Säo Paulo, Brazil, for hypertension that had been treated inadequately for 6 years. She reported pallor, weakness, scotomata, progressive weight loss, and morning occipital headaches. Three days before admission, she experi-

to captopril, 1700 ml of fluid was withdrawn by ultrafiltration over 4 hours. Striking decreases in blood pressure, central venous pressure, and cardiac index were observed, and administration of normal saline and packed red cells was necessary to restore intravascular volume. intravenous nitroprusside therapy again controlled blood pressure. The following day administration of only alpha-methyldopa (1 g/day) and furosemide (80 mg/day) kept the blood pressure under control, and the nitroprusside infusion was discontinued. Two days after this oral regimen was instituted (3 days after admis-

sion), the blood pressure again rose, and hemodialysis was begun because of further deterioration of renal function. Several therapeutic maneuvers, including the use of minoxidil and beta blockers, were tried without achieving successful control of the hyperten ', and the hemodialpatient died from sepsis 9 months later while still in a chro ysis program.

enced dizziness, blurred vision, intermittent hematuria, shortness of breath, and orthopnea. The day before admission, she had hemoptysis and increased shortness of breath. On physical examination, the patient appeared severely ill; she was pale and dyspneic, and she had jugular venous engorgement. The blood pressure was 250/170 mm Hg; pulse rate, 146 beats/mm; and respira-

tions, 36/mm. Funduscopy revealed increased central light reflex of arteries, arteriovenous nicking, arterial vasospasm, cotton-wool and

Discussion

hemorrhagic patches, and bilateral papilledema. Rales were detected in

DR. OSWALDO RAMOS (Full Profrssor of the Department of Medicine and Chief of Nephrology Division of Escola Paulista de Medicina, São Paulo, B"azil): The prevalence of hypertenpulses were present and symmetrical, and there were no bruits. No sion in Brazil is similar to that in developed countries. One of edema was present, but muscular wasting of the extremities was the lower two-thirds of both lung fields. Tachycardia and a gallop rhythm without cardiac murmurs also were present. There was epigastric tenderness and the liver was enlarged and tender. All peripheral apparent. The electrocardiogram revealed left ventricular hypertrophy and sinus tachycardia. A plain chest x-ray film revealed an increased

our recent studies, which investigated blood pressure in the labor force in São Paulo, a major Brazilian industrial center,

cardiac silhouette and left ventricular enlargement; the pulmonary

revealed that 18.1% of males and 6.6% of females had diastolic blood pressures higher than 90 mm Hg [11. Another inquiry,

circulation was congested. Laboratory tests revealed the following: blood pH, 7.41; P02, 53 mm Hg; PCO2, 31 mm Hg; BUN, 83 mg/dI; creatinine, 6.5 mg/dl: serum

sodium, 130 mEq/liter; serum potassium, 4.7 mEq/liter. Urinalysis revealed 1.5 g/liter of protein with many white blood cells and red blood

cells; hemoglobin, Il g/dl; hematocrit, 33%; white blood cell count, 11,900/mm3 with 82% total neutrophils; platelets, 250,000/mm3; sedimentation rate, 45 mm/hr. The serum CPK was normal; the serum LDH

was elevated (595 U), as was the amylase (565 U). The peripheral plasma renin activity was 10 ng/ml/hr.

studying a general population in another Brazilian state, showed that the prevalence of individuals with a diastolic blood pressure over 95 mm Hg was 11% [21. In our study, 1% of males

were classified as having severe or malignant hypertension. I

might add that unfortunately only 5% of all hypertensive patients in our study were receiving antihypertensive therapy, primarily because of economic reasons [Iii. Malignant hyperten-

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Nephrology Forum

sion therefore is an important health problem in Brazil and in other countries at similar stages of development. Malignant hypertension classically is characterized by the presence of elevated blood pressure accompanied by exudates, hemorrhages, and papilledema in the eye grounds, rapid deteri-

phenomenon well documented in the early phase of malignant hypertension [12—141.

Arterial hypertension causes a substantial pressure load on the left ventricle; as a consequence, left ventricular hypertro-

phy is frequently observed on the electrocardiogram. Left oration of renal function, and the appearance of multiple ventricular hypertrophy occurred in one-third and was associatarteriolar lesions, with fibrinoid necrosis in the arteriolar wall. ed with alterations in the T waves in another one-half; isolated In this presentation, and in the cases studied in our division, we T-wave alterations were observed in another 10% [7]. Cardiac diagnosed malignant hypertension when high diastolic blood arrhythmias were seen in 37% of our 50 patients [7], and the pressure was accompanied by the presence of bilateral electrocardiogram was normal in only 10%. papilledema. Proteinuria is a frequent finding in malignant hypertension

Clinical aspects Malignant hypertension, generally a complication of essential hypertension, rarely occurs in previously normotensive individuals. When it is manifest in a patient with no history of high blood pressure, renovascular hypertension should be suspected. Even though malignant hypertension usually follows essential hypertension, other hypertensive states also can cause it

[31. In the absence of adequate treatment, the prognosis of malignant hypertension remains dismal: without treatment, only 25% of patients survive more than one year [4—61.

and can reach nephrotic range. In 15% of the patients we studied, however, no proteinuria was detected at first examina-

lion [71. In the absence of treatment, renal function rapidly deteriorates in all cases even though it may be near normal initially. Although hypertension can result from chronic renal

disease, as a rule renal failure in patients with malignant hypertension is the consequence rather than the cause of the severe hypertension. Vascular lesions in malignant hypertension The arteriolar lesions of malignant hypertension are found in

Blood pressure levels in malignant hypertension, although many organs, including brain, pancreas, heart, intestine, elevated, need not be extremely high. Thus, of 50 patients we spleen, and kidney [3, 15, 161. Two different renal lesions have studied several years ago, 12% had systolic pressures below 180 been described in malignant hypertension: fibrinoid necrosis mm Hg and diastolic pressures below 120 mm Hg, whereas 24% and proliferative arteritis. This combination of lesions is also had systolic pressures above 260 mm Hg and 25% had diastolic called hyperplastic arteritis, fibrinoid intimal hyperplasia, and pressures higher than 180 mm Hg [7]. Patients with malignant musculo-mucoid intimal hyperplasia. Fibrinoid necrosis is the hypertension have evidence of generalized arteriolar damage most characteristic lesion [4, 17, 18] and presumably results causing functional deterioration in many organ systems. The from the leakage of fibrin and other plasma elements into the brain, heart, and kidneys are most noticeably involved. The arteriolar wall. This lesion is recognized by a fibrillar, homogeusual prevalence of the major signs and symptoms is illustrated nous, eosinophilic material composed of fibrin, connective in the 50 patients we studied: headache, 86%; proteinuria, 85%; tissue matrix, and necrotic muscle cell debris in the wall of the visual blurring, 80%; dizziness and vertigo, 72%; other urinary blood vessel. The second lesion, proliferative arteritis, is charalterations, 63%; abdominal pain, 59%; weakness, 49%; heart acterized by marked thickening of the intima due mainly to the failure, 37%; and neurologic alterations, 31% [7]. These figures presence of smooth muscle cells, basement membrane material, do not differ from those reported in the literature in the 1950s [3, and acid mucopolysaccharide; as a result the vascular lumen 8]. progressively narrows. Proliferative endarteritis seems to occur Headache is doubtlessly the most common symptom of the more frequently in some American blacks than in other subsets disease and also the earliest, since it seems to precede the full of patients with malignant hypertension [191. This same lesion clinical picture by about 6 months. In our survey [7], the can arise in settings other than malignant hypertension, for headache was typically occipital in location and more intense example, in scleroderma and after prolonged dialysis [19]. when the patient awakened in the morning. Hypertensive Many studies dating as far back as the l950s have demonstrated encephalopathy, the most frequent neurologic manifestation of that prompt and total correction of the hypertension, regardless malignant hypertension, was characterized by the sudden onset of the therapeutic agents used, halts or reverses the arteriolar of headache, nausea, vomiting, and at times confusion. The damage [20, 21]. encephalopathy might be due to mild cerebral edema resulting The precise sequence of events that links high blood pressure from a breakdown of cerebral autoregulation of blood flow. to the arteriolar lesions is still being worked out. One hypotheBlood flow to the brain is usually kept constant despite wide sis is that the permeability of the arterial wall increases because variation in perfusion pressure [9, 10]. When the increase in of alternating contraction and dilation of the arterial vessels. perfusion pressure is excessive, however, autoregulation This hypothesis is based on the studies by Byron [22] and Giese breaks down and segmental arteriolar dilations and cerebral [23]. Giese, utilizing radioactive colloidal carbon, demonstrated edema can occur [10, II]. increased permeability of the vascular wall only in the dilated A frequent but poorly explained finding in most series of segments [23]. These findings were confirmed in electron malignant hypertension is weight loss, which affected 56% of microscopic studies of rat mesenteric arterioles [241. In this our patients [71 and 75% of Kincaid-Smith's [31. Weight loss is investigation, Goldby and Beilin showed that severe hypertenaccompanied by muscle wasting, and perhaps is caused by the sion caused an increase in the number of dilated segments, reduced blood supply to the muscles, which in turn is due to whereas correction of the hypertension eliminated both the generalized arteriolar damage. Some weight loss also might be constriction and dilation. The increased permeability of the

explained by excess salt and water lost by the kidneys, a arteriolar wall also returned to normal. According to the

Malignant hypertension: The Brazilian experience

Laplace law, for a given level of blood pressure, the larger the

dilation of the vessel, the greater will be the stress on the vascular wall. Thus dilation of a vessel wall, such as that demonstrated by these studies, intensifies the effects of hypertension on the vascular wall and favors the infiltration of plasma into the vascular wall. As a consequence of progressive dilation, the endothelium becomes damaged, permitting plasma to infiltrate the vascular wall, thus compressing and destroying smooth muscle cells. The plasma accumulated in the subintima causes further narrowing and, at times, occlusion of the lumen of small vessels as well as edema of the neighboring tissues. This accumulation of plasma in the vessel wall was referred to as "plasmatic vasculosis" in some of the earlier literature [25—27]. The fibrinogen in plasma is converted into fibrin when it contacts cell components. This fibrin plus the concomitant

211

hypertension per Se. In essence, a vicious cycle is created in which hypertension causes greater vascular permeability, which ultimately induces narrowing of the arteriolar lumen and consequent stimulation of the renin-angiotensin system, which in turn can cause a further increase in the permeability of the vascular endothelium as I noted earlier [371. These findings favor our hypothesis that both angiotensinmediated vasoconstrictor and increased permeability effects are important in producing the vascular damage of malignant hyper-

tension. However, malignant hypertension can occur even

when the angiotensin levels are very low; as examples, malignant hypertension can be induced in rats by deoxycorticosterone administration [12, 381, and occurs, albeit rarely, in primary hyperaldosteronism in humans [391.

Vasopressin has been suggested as the mediator of the necrosis of smooth muscle cells comprise the lesion called vascular damage in the DOCA-salt model of hypertension in fibrinoid necrosis. The damaged endothelium in turn attracts rats and I will now review the experimental data regarding this platelet microthrombi and provokes localized intravascular hypothesis. coagulation with local platelet consumption, and even thrombo-

cytopenia. The fibrin deposits also can induce red blood cell aggregation followed by red cell fragmentation and hemolysis, that is, the microangiopathic hemolytic anemia of malignant hypertension [281.

The available data clearly demonstrate that high blood pressure per se is the fundamental cause of the vascular lesions [29, 30]. Evidence also indicates that the degree of arterial damage in experimental animals and in humans with hypertension tends

to parallel the level of blood pressure [20, 21, 31, 32]. This finding, however, does not preclude the possibility that vasoconstricting substances in general, and angiotensin in particular, might be important in the genesis of the vascular lesions of malignant hypertension. These vasoactive substances may act not only by increasing blood pressure but also by increasing vessel wall permeability. We believe that, in fact, there are two major mechanisms that cause the vascular lesions of malignant hypertension. One is the high blood pressure per Se; the second is the effect of hormones, particularly angiotensin, on vascular permeability. In our own

experience, approximately 75% of patients with malignant hypertension have an increase in plasma renin activity and, consequently, have elevated plasma angiotensin and aldosterone levels. Angiotensin acts directly on the smooth muscular cell of the vascular wall [33, 34]. Specific angiotensin receptors have been demonstrated in a microsomal fraction of vascular

cell muscle, and displacement of calcium ions from these microsomal particles follows angiotensin-receptor interaction [35, 36]. In addition to its well-known arteriolar constrictor action, angiotensin II (as well as other vasopressor agents)

increases the permeability of the vascular wall by causing contraction of the endothelial cells and altering the endothelial junctions [36]. This increased permeability facilitates aggregation of circulating platelets. The platelets immediately contract and degranulate, thereby releasing serotonin and histamine, among other substances. These substances also increase endo-

In the DOCA-salt, low-angiotensin model of malignant hypertension in rats, Mohring and coworkers noticed that immediate-

ly following the well-known sodium and water diuresis, the plasma concentration of arginine vasopressin increased manyfold [40]. A significant increase in plasma vasopressin concentration also has been found during the course of the high-renin malignant hypertension in rats [411. In these two types of malignant hypertension in rats, a specific serum antibody against arginine vasopressin decreases the blood pressure [40, 41]. Additionally, a direct and reciprocal interaction between arginine vasopressin and angiotensin II has been suggested in physiologic [42—44] and hypertensive [40, 41] states. Evidence countering the argument that vasopressin is a cause of vascular

damage in malignant hypertension also has been adduced. Rabito, Carretero, and Scicli showed that administration of an

arginine vasopressin antagonist did not induce significant changes in the mean blood pressure either in DOCA-salt, malignant hypertension or in two-kidney, one-clip Goldblatt malignant hypertension [45]. Woods and colleagues, using a high-renin model of malignant hypertension in vasopressin-deficient rats, concluded that arginine vasopressin does not play a primary role in the pathogenesis of this model of malignant hypertension [46]. Their conclusion is based on the fact that the development and severity of

hypertension either functionally or histologically were about the same in rats with and without arginine vasopressin deficiency. Moreover, similar elevations of plasma angiotensin II levels in both groups of rats indicate that the renin-angiotensin system

does not "compensate" in any way for the lack of arginine vasopressin [46]. Finally, to offer a provisional conclusion about the pathogenesis of vascular lesions in malignant hypertension, I will quote Gavras et al: ". . . in addition to the mechanical effect of high blood pressure, a number of other factors determine the occurrence and severity of hypertensive vascular injury: vasoactive

hormones, sodium kinetics and changes in blood rheology

thelial contraction and vascular permeability, thus favoring further the movement of plasma into the vascular wall.

[471."

In malignant hypertension, the increase in angiotensin levels can be primary, as in patients with stenosis of a major renal

Converting enzyme inhibition in malignant hypertension Plasma renin activity is elevated in most patients with malignant hypertension [481 but the significance of this increase has not yet been completely clarified. We do not know whether the

artery. In most patients, however, the increase in angiotensin is secondary to renal arteriolar constriction due to the increased

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Nephrology Forum

MAP

MAP

200

190

Furosemide Captopril Captopril

mm Hg + diazepam 50 mg 100 mg

mm Hg

190

Captopril 150 mg

—I

C

150 mg

+

175

180 170 160

C 150 mg

Furosemide

160

80 mg

n = 20

150

145 -

140

CAP 150

130 120

.1

130

n =8

CAP 50

I

110

100J

0 1530 60 90 120135150 180 210 240

300

360

Time, minutes

115-______

n=9

tn=36 L

0 30 60 90 120 150 180 210 240270 300 330 360

Time, minutes 1. Mean arterial pressure (MAP) values in 12 patients with malignant hypertension receiving taptopril or caplopril plus firose- Fig. 2. Mean arterial pressure responses to the combination oflfurose-

Fig.

mide. See text for details. (Data from Ref. 49).

mide and diazepam plus one or more doses of captopril (CAP) in 89 patients during hypertensive crisis. (Reproduced from Ref. 52).

increase in renin causes malignant hypertension, or whether the renin increase merely represents a nonspecific response to renal

captopril in a separate group of 89 patients in hypertensive crisis that did not respond to furosemide, whether or not the made possible testing of the hypothesis that the renin-angioten- patients were in the malignant phase [521. Hypertension was isehemia. The availability of a converting enzyme inhibitor

sin system is involved in the pathogenesis of the hypertension, and allowed evaluation of whether blockade of this system is valuable therapeutically. We treated 12 patients with malignant hypertension according to the following protocol [49]. Captopril was given orally in an initial dose of 150 mg shortly after each patient was admitted to the hospital. The blood pressure was measured every 15 minutes, and a second oral dose of 150mg of captopril was given if the diastolic pressure had not fallen below 130mm Hg. If the diastolic pressure still exceeded 130mm Hg after the second dose, oral ftirosemide, 40 mg, was added to the therapeutic regimen.

controlled acutely in 69 of these 89 patients when variable oral doses of captopril were used (Fig. 2); 36 patients responded to 50 mg, 24 to 100 mg, and 9 required 150 mg. Although oral eaptopril alone is a useful agent in acute hypertensive emergen-

cies, it does not by itself provide sustained control of blood pressure in most patients with malignant hypertension. All the patients we studied required a diuretic plus beta or alpha-i blocking agents for sustained control [49]. In all patients,

addition of a diuretic was necessary within 24 to 36 hours after the initial dose of captopril was given. The reasons for the lack of sustained response are not known. To explore further the blood pressure response to captopril, Figure 1 illustrates that a single oral dose of 150 mg of captopril lowered blood pressure to normal in 8 of 12 patients we performed hemodynamic studies in a separate group of 11 with malignant hypertension [49]. The response occurred within patients with malignant hypertension [53]. These 11 patients 15 minutes after the drug was administered; the maximal effect received 150 mg of captopril orally; blood pressure, cardiac was observed between 60 and 90 minutes. In 4 patients the output, and pulmonary pressure were monitored for 4 hours. initial depressor response was not adequate, and a second dose Eight of the II patients responded to captopril, with mean of captopril was necessary. In one of these 4 patients, captopril arterial pressure falling by 20 mm Hg or more. The fall in total alone did not decrease the blood pressure significantly, hut the peripheral resistance correlated highly with the prevailing levels addition of furosemide brought the blood pressure virtually to of plasma renin activity (r = 0.72, P <0.01). Previous studies of the response to captopril in patients with normal (Fig. 1). We found a statistically significant correlation between the basal plasma renin activity and the decrease in nonmalignant hypertension indicated that cardiac index did not blood pressure in these 12 patients (r = 0.91). These data increase [50, 541. In contrast, our studies in these 11 patients indicated that oral captopril could promptly decrease blood showed that the cardiac index increased significantly from 3.29 0.13 to 3.68 0.15 liter/mm2 (range, -2 to 24%) (P < 0.001) pressure for at least short periods in the majority of patients with malignant hypertension. Furthermore, the increase in within 2 hours after captopril administration [53]. This phenomblood pressure seemed to be related to an increased activation enon was not associated with changes in blood volume or distribution. The degree of anemia did not seem to explain the of the renin-angiotensin system [48, 50]. Similar therapeutic value for converting enzyme blockade increase in cardiac output, nor did the presence of heart failure

during hypertensive crisis also was shown by Tuft and col- account for the unexpected results. We hypothesize that in leagues [511. Because of these preliminary findings, we have malignant hypertension the high levels of peripheral resistance conducted a cooperative study to evaluate the effectiveness of prevent cardiac output from increasing to higher than normal

213

Malignant hypertension: The Brazilian experience

levels. Thus, the vasodilation induced by angiotensin blockade

merely unmasks the underlying hyperkinetic status of the circulation [53].

Prostaglandins and the kallikrein-kinin system In addition to the renin-angiotensin system, other hormonal

systems might participate in the pathogenesis of malignant hypertension. For example, a deficiency of prostaglandin production has been described in human essential hypertension [55], and prostaglandin excretion diminished in hypertensive subjects following furosemide administration [56]. Neverthe-

10

9

8

7 6. 4

less, as pointed out in a recent review [57], more clear-cut evidence of the role of prostaglandins in human hypertension is needed. Kinins, known to be potent vasodilators, do exert a marked influence on renal water and electrolyte excretion [58—60]. The role of the kallikrein-kinin system in human hypertension has been the subject of investigation for some time. Most studies

support the hypothesis that urinary excretion of kallikrein is

L1 Kgn-Try

r'i Kgn-HuUK

ii _______ KPF

gBK/mI decreased in human essential hypertension; however, this is not a universal finding [60, 61]. Urinary kallikrein excretion is Fig. 3. Values of kininogen (Kgn), as determined by trypsin (Try) or human urinary kallikrein (I-lu Uk) and of kinin potenhiating factor increased in a large majority of patients with hyperaldosteron- (KPF). BK refers to bradykinin; LBK refers to lysyl-bradykinin. Open ism, but Lawton et al could find no significant correlation bar denotes normal controls (n = 10), striped bar denotes patients with between urinary kallikrein excretion and aldosterone or plasma mild to moderate essential hypertension (n = 16), and solid bar denotes renin activity [621. Lee et al documented the presence of a patients with malignant hypertension (n = 12). (Reproduced from [64] defect in the kallikrein-kinin system in rats with malignant by permission of the American Heart Association, Inc.) sg8K/mI

hypertension [63]. We evaluated the kallikrein-kinin system in human malignant hypertension through measurement of plasma levels of kininogen (Kgn) [64]. As illustrated in Figure 3, plasma results [65]. The drug's immediate but transitory action requires

levels of Kgn diminished dramatically in 12 patients with

malignant hypertension as compared to 10 normotensive controls and 16 patients with mild to moderate essential hypertension. The reason for the fall in Kgn is not clear but might reflect increased consumption, diminished synthesis of the kinin precursors, or both. This fall affects both forms of Kgn in plasma, that is, low- and high-molecular-weight kininogen, and persists for at least 3 months after blood pressure has been controlled. Further studies are needed to determine why Kgn levels are

that it be administered by continuous infusion under close medical supervision. We routinely use sodium nitroprusside infusion (0.2 mg/mI) as the initial treatment of malignant arterial

hypertension. In one series of 64 patients with malignant

hypertension who were admitted to our hospital (but who did not receive captopril), the average infusion of sodium nitroprusside was 6.8 mg/br, with minimum and maximum values of 1.4 mg/hr and 14.0 mg/hr respectively (unpublished data). In most patients, the arterial pressure was controlled within minutes low, but these observations permit the speculation that a after the infusion began. We were able to discontinue giving the decreased activity of the kallikrein-kinin system might be drug between 6 and 300 hours later. The use of nitroprusside not involved in the pathogenesis of malignant hypertension in some only provided rapid control of arterial pressure, but permitted patients. most patients to respond to previously ineffective antihypertensive regimens. The exact explanation for this finding is not Treatment known. Another potent vasodilator useful in malignant hypertension A detailed discussion of the therapy of malignant hypertension is beyond the scope of this presentation; because this is diazoxide administered as a bolus or as a slow infusion [66]. subject has been reviewed extensively, I will limit my com- Its hypotensive effect is immediate, and the blood pressure usually stabilizes during the first few hours. The duration of the ments to general guidelines for treatment. Malignant hypertension remains a clinical emergency, and response is 2 to 12 hours, with a usual mean of 6 to 8 hours. As the patient should be hospitalized immediately for intensive mentioned earlier, in our hands the use of a converting enzyme treatment. The goal of therapy is to lower arterial pressure to inhibitor is a reasonable therapeutic alternative for malignant normal as rapidly as possible without further impairing blood hypertension [49, 52, 53]. Favorable results also have been perfusion to vital organs. To achieve this goal, initially one must reported with minoxidil, a potent direct vasodilator [67, 68]. use drugs with a powerful and immediate vasodilating action. Calcium channel blocking agents, particularly nifedipine, also

Diuretics should be employed in parallel to potentiate the response to the vasodilators and to counteract the salt retention induced by the vasodilators. The most powerful parenteral vasodilating agent available is sodium nitroprusside. All reported applications of the drug in humans and animals with hypertension have yielded excellent

have been used for acute control of hypertension but their specific place in the therapy of malignant hypertension is

unsettled. After we control the arterial pressure, we continue therapy

using thiazide diuretics when renal function is reasonably preserved, or using loop diuretics when an appreciable degree

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Nephrology Forum

of renal impairment is present. Because of the increasing

some degree of renal function? Drs. Blythe and Woods at

evidence that a hyperkinetic circulation is present in malignant hypertension [53, 691, we routinely use beta blockers (such as propranolol, daily doses of 320 mg or more), alpha-blockers (for example, prazosin, in doses varying between 3 and 12 mg/day),

Chapel Hill many years ago showed that once the BUN rose to over 90 mg/dl, the likelihood of reversing renal insufficiency was quite low [72]. Does their conclusion fit with your own experience? DR. RAMOS: In general, I certainly agree with the finding of or centrally acting alpha agonists (aipha-methyldopa or Blythe and Woods 72]. Recently Lawton claimed that vigorous clonidine). In our experience the control of arterial pressure in malignant antihypertensive treatment of patients with malignant hypertenhypertension, especially during the initial phase of treatment, sion resulted in stabilization of renal function in 10% of the can worsen renal function. This decline in renal function is patients, progressive deterioration in about 30%, and transient frequently transitory and is not a contraindication to aggressive deterioration with subsequent improvement in a few weeks in antihypertensive therapy. Patients with considerably impaired about 60% [73]. We have not carried out a formal, long-term renal function prior to antihypertensive therapy may develop followup study on antihypertensive treatment in patients with uremia. In this situation, it is better in the short run to employ malignant hypertension; however, in the 12 patients with maligdialysis because in the long run, control of blood pressure may nant hypertension whom we treated initially with captopril [42], improve perfusion of the kidney and ultimately renal function. 9 were followed for at least 6 months and the outcomes were as Rarely, the arterial damage is so extensive that both renal follows: in 7 in whom the initial plasma creatinine levels were deterioration and blood pressure become uncontrollable even 1.4, 2.4, 2.5, 2.6, 3.9, 4.9, and 5.1 mg!dl, respectively, renal with the most aggressive therapeutic programs. As a general function remained stable or improved slightly. In the remaining rule, the therapeutic approaches I have outlined have practical- 2 patients in whom the initial plasma creatinine levels were 9.0 ly eliminated the need for renal embolization or bilateral and 14.5 mg/dl, renal function further deteriorated with treatnephrectomy in patients with severe, refractory hypertension ment, and dialysis was required. It is my hypothesis that improvement of renal function with [70, 711. Let us return to our discussion of the patient presented today, treatment depends on whether the intrarenal arterioles are able who had been inappropriately treated for hypertension for to dilate sufficiently in response to the systemic vasodilation

many years. The diagnosis of malignant hypertension was induced by antihypertensive treatment. In patients in whom based on the presence of encephalopathy, episodes of bloody vasodilation of systemic arterioles is greater than that in the urine, high diastolic blood pressure and, most important, bilateral papilledema. Funduscopy disclosed arteriovenous nicking and arterial tortuosity as well as cotton-wool and hemorrhagic exudates. Weight loss, impaired renal function, increased levels

of plasma renin activity, and overt heart failure all were present. The role of angiotensin in maintaining elevated blood pressure was well demonstrated because oral administration of 150 mg of captopril produced a substantial fall in the mean arterial pressure. This decrease was due to a dramatic reduction of the

total peripheral resistance, which was accompanied by an increase in the cardiac index. The acute response to captopril was impressive but ceased after a few hours. This secondary failure of captopril apparently was not due to fluid retention, because the withdrawal of 1.7 liters of fluid after 4 hours of ultrafiltration suddenly decreased blood pressure and central venous pressure to very low levels.

When intravascular volume was restored to normal, blood pressure returned to the previous high levels. These findings, coupled with the observation that the blood pressure was controlled when alpha-methyldopa was administered, suggested that the elevated blood pressure in this patient might have

been maintained by hyperactivity of the adrenergic system. Blood pressure subsequently rose again and renal function deteriorated further, requiring that hemodialysis be instituted. Despite several different therapeutic regimens, the blood pressure could not be controlled adequately, and the patient died 9 months after the first admission. Questions and answers DR. JOHN T. HARRINGTON: Dr. Ramos, can you expand on your comment that effective treatment of hypertension, even in

patients with severe renal failure, often leads to restoration of

renal arterioles, renal function may deteriorate as the systemic blood pressure is reduced. In patients treated with captopril,

what happens to renal function is not predictable because angiotensin II is an important factor in the maintenance of GFR during states of reduced renal blood flow [74, 75]. DR. NESTOR SCHOR (Nephrology Division, Escola Paulista de Medicina): How do you explain the fact that whereas most of your patients with malignant hypertension have an initial salutary response to captopril alone, blood pressure control is not maintained with the drug chronically? DR. RAM05: We believe that angiotensin II is a very important cause of the high blood pressure in malignant hypertension, but it is not the only factor. When angiotensin II production is

blocked and blood pressure drops, salt retention becomes an important factor in maintaining an elevation of blood pressure. We also observed that the patients with malignant hypertension

who became unresponsive to captopril also became more responsive to oral sympatholytic agents. This observation suggests that captopril stimulates the sympathetic nervous system in some way. DR. HARRINGTON: If captopril does stimulate the sympathet-

ic nervous system, one might speculate that catecholamine levels in blood or urine would be elevated in patients treated with captopril, Have you or others measured catecholamine levels in patients with malignant hypertension before and after captopril treatment? DR. RAMOS: No, we did not. My speculation is based on the observation that adrenergic blockade becomes more effective in lowering blood pressure following captopril treatment. Moreover, in a study in our laboratory of rats with methyl-prednisolone-induced hypertension, prolonged captopril administration

led to increased activity of the sympathetic nervous system [76].

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Malignant hypertension: The Brazilian experience

DR. R0GERI0 A. MULINARI (Nephrology Division, Escola Paulista de Medicina): What do you think is the role of ADH in the pathogenesis of malignant hypertension'? DR. RAMOS: I believe that ADH might play a role in some forms of malignant hypertension, but this subject only will be clarified when a specific ADH antagonist becomes available for clinical use. DR. HARRINGTON: Dr. Gary Robertson has measured ADH levels in a number of different clinical situations [77]. I don't know the answer to Dr. Mulinari's question, but patients with the syndrome of inappropriate antidiuretic hormone secretion

patients with malignant hypertension did not have prOteinuria when first examined. In our experience with malignant hypertension, practically all patients have some degree of proteinuria. Could you comment on this apparent discrepancy? DR. RAMOS: The diagnosis of malignant hypertension in some

of our patients was made very early, when renal function was still well preserved. All patients with malignant hypertension have some degree of proteinuria if the disease is allowed to

progress. In our study, in which we used routine clinical methods for detection, we observed proteinuria in 85% of the patients, and levels varied from 0.18 to 15.5 g/liter [7].

due to bronchogenic carcinoma, despite high blood levels of ADH and volume expansion, usually are not hypertensive [78]. DR. RAMOS: Dr. Saragoça, the presence of congestive heart

Reprint requests to Dr. 0. Ramos, Disciplina de Nefrologia, Escola Paulista de Medicina, Rua Botucatu, 720-São Paulo-Brazil

failure prior to captopril treatment also could explain the increase in cardiac output following captopril in the 11 malignant hypertensive patients you studied [40]. Do you have any comments? DR. MANOEL A.S. SARAGOcA (Nephrology Division, Escola

Paulista de Medicina): Increases in cardiac output are commonly observed in patients with congestive heart failure treated with vasodilators. Therefore, the increased cardiac output we observed could be due simply to varying degrees of congestive

heart failure. I don't think this is the case, however, because only 4 of the 11 patients had low stroke-volume indices, and in

these patients, the reductions were modest when compared with those usually observed in patients with congestive heart failure. Furthermore, only 3 of these 4 patients had high

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These data corroborate our view of a hyperkinetic circulation in

malignant hypertension that was unmasked by vasodilation secondary to angiotensin converting enzyme blockade. DR. HARRINGTON: You mentioned vasospasm of the renal arteries as one of the functional changes that might influence

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