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Treatment of “hypertensive encephalopathy” (accelerated hypertension). Part II
Appraisal therapy
Treatment
and reappraisal Edited
of
(accelerated
by Arthur
“hypertensive hypertension).
A
non-diuretic benzothiadiazine drug, diazoxide (Hyperstat) , has been evaluated over the past 4 to 5 years for the treatment of “hypertensive crises.” It is not as yet commercially available. When given intravenously (250 to 350 mg. in 1.5 to 30 sec.) dramatic lowering of blood pressure usually occurs within 1 to 2 minutes. The duration of the effect is variable (from 1 to 18 hr.). Repeated injections frequently do not produce the same degree or duration of blood pressure lowering. Diazoxide presumably produces its effect by a direct action on arteriolar smooth muscle since peripheral resistance is lowered and cardiac output does not decrease despite a marked fall in blood pressure. This drug appears to be of great value in treatment where a rapid reduction in blood pressure is indicated (acute pulmonary edema or severe cerebrovascular symptoms). Diazoxide administration results in the lowering of blood pressure when the patient is in the recumbent position and usually does not produce pronounced postural blood pressure changes. Side effects include transient hyperglycemia and occasional electrocardiographic abnormalities (S-T and T wave changes) suggestive of coronary insufficiency. After several injections, the patient is usually able to begin oral therapy with other agents. Diazoxide should not be administered on a long-term basis or by mouth because of its potential
C. DeGraff,
Alan
of cardiac F. Lyon, and Julian
encephalopathy” Part
II
metabolic side effects (hyperglycemia, hirsutism, and edema). Veratrum derivatives have little if any place in the treatment of accelerated hypertension. Although these drugs may be verb effective as antihypertensive agents, their therapeutic and toxic dosage ranges are very close and side effects may be quite severe following their use. Other drugs are easier to administer and generally, more effective. Trimethaphan camphorsulfonate (Arfonad), a short-acting ganglion-blocking agent, has been advanced by some investigators as the treatment of choice in hypertensive encephalopathy,. This drug is extremely useful in the treatment of congestive heart failure in patients with hypertensive encephalopathy, but because of its extremely short duration of action (5 to 15 min.), it should not be considered the agent of choice in the patient who presents without pulmonary edema. A continuous infusion must be given and blood pressures must be checked every 10 to 15 min. to avoid a hypotensive reaction. Constant blood pressure checking may produce extreme irritation and restlessness in an already agitated patient, and large doses of sedatives may have to be given. This greatly delays the time when the patient is able to start oral feedings and oral therapy. Longer-acting agents, such as pentolinium or mecamylamine, are equally effec-
‘Physician-in-clrargge of Hypertension Section, Montefiore Hos&al and Medical Center. in Clinical Medicine, Albert Einstein College of Medicine, Nnr York. IT\‘. Y.
704
;1meric:m
Fleart
Journal
Frieden
-Sew
York,
\
V.. and .\saociate
tive, are safe when used properly, and do not require the constant monitoring that is necessary when trimethaphan is used. In the presence of pulmonary edema, where acute blood pressure lowering for a short period of time is indicated, trimethaphan is effective in producing arteriolar and venodilation and venous pooling of 1)lood in the splanchnic and peripheral areas. Its action, therefore, produces a “chemical or medical” phlebotomy. In the patient with extremely high diastolic I)ressures, marked arteriolar constriction, and pulmonar\. edema, it is probably more effective -in reducing venous return and increasing cardiac output than the use of peripheral tourniquets. In these cases of severe hvpertension, it is probably the drug of choke. Trinlethaphan is adlninistered slowlp in a dosage of 500 mg. given in a liter of glucose and water, or in a Inore concentrated solution if fluid restriclion is indicated. The drug is administered - also be effective in the treatment of hypertensive encephalopathy, although experience with it is limited. Apparently-, the initial pressor response noted after intravenous administration is not observed. There is a rapid blood pressure lowering effect (within 1 to 2 hr.) when guanethidine is administered in this manner, as contrasted to the 3 to 4 day delay in antihlspertensive activity when the drug is given orally. Ten to 1.5 mg. are given imnlediately, and the dosage is repeated as necessary to keep blood pressure at acceptable levels. Duration of effect is prolonged (from 3 to 24 hr. following a single dose). Sodium nitroprusside has also been advocated in the treatment of “accelerated”
hypertension. This drug is an effective vasodilator and, when administered intravenousI)-, has been effective in lowering blood pressure. ViJe have had no experience with this agent, and it is not, at present, available for use in most hospitals. Personal experience with h>dralazinc (Apresoline) in the treatment of h!.pertensive encephalopath>y has not been entirely satisfactor:= This drug, in doses of between 15 and 40 mg. intramuscularly- or intravenously every four to six hours, is effective in the treatment of the h>-pertension associated with acute glonlerulonephritis and toxemia of pregnant\- and,/or eclampsia, but it is only occasionally useful when used alone in accelerated hypertension. We do not, therefore, use hydralazine unless the drugs reviewed above are ineffective or not readily available. There are other newer agents that have been advocated for use in the treatment of malignant hypertension, but experience with them is limited. Treatment hypertension” insufficiency
of “accelerated and renal
The s)rndrome of malignant or accelerated hypertension and uremia ma)’ represent the “end stage” of chronic glomerulonephritis or pyelonephritis, or may reflect the occurrence of malignant nephrosclerosis with fibrinoid necrosis of the small arteries and arterioles as a result of longstanding and increasingly severe essential hypertension. Regardless of the etiology-, the immediate treatment of this serious situation is essentially the same, and is extremelJr difficult. In the presence of a blood urea nitrogen in excess of 50 to 60 mg. per cent and an elevated serum creatinine level, there is somedanger in lowering the blood pressure, since this further decreases the already severely impaired renal blood flow. In addition, the benefits of blood pressure control may be limited, and may not alter the prognosis in some of these cases. Despite these objections, there are several valid reasons for attempting blood pressure lowering in these patients. Since the prognosis is extremely poor, and rapid death will occur over a three to six month period of time or lessif they are not treated,
there is little to lose by the cautious lowering of blood pressure in these individuals. Treatment is aimed at: (1) improvement in symptonls such as visual disturbances, nausea and/or vomiting, congestive heart failure, and encephalopnthy; (2,l the possil)le reversal of the severe arteriolar patholog~. of the nlalignant phase of h\-pertension. There is some pathologic evidence that suggests a disappearance of fibrinoid nlaterial from the arteries with a change to a nlorc “benign” form of pathology with intinial fibrosis following blood pressure lowering ill these cases. This may not alter the basic pathologic process, such as chronic glonleruloncphritis if this is present, but may decrease the vascular factor that, at least partiall\-, contributes to the rapidly progressive renal insufficiency. JIM patients with renal failure solely on the basis of vascular disease, reversal of necrotizing vasculitis nlay be eve11 more beneficial. The same drugs are used in the treatment of accelerated hypertension with urcrnia as in cases without renal failure. They are, however, used more cautiousI>., and an attempt is made to slowl~~ loxw l~loocl pressure only to those levels (150 to 160/100 to 110 mg. Hg) where, theoretically at least, the edenla and fibrinoitl changes of the blood vessel wall ~nay have an opportunit)to regress. ( kcasionall\. the use of parenteral hydralazine or alpha methyldopa (,Womet~ nlay be of SOIII~ theoretic advantage because of their abilit?. to lower blood pressure acutely without seriously decreasing renal blood flow. Esperience has indicated that if blood pressure is lowered, some patients lvill continue on a more benign course for a prolonged period of time. Summary
1. Patients with “accelerated” or “malignant” hypertension should he t.reatetl
vigorousl\-. If emergency treatment is wt.cessful, and azotemia is not present, longr-ange prognosis is good. 2. The pnrenteral drugs of choice arc reserpi~ie or pentoliniuni (Ansolysen). If reserpine is ineffective after several doses, intravenous diazoxide (if available) and illtravellow ethacrynic acid should be givell. 3. ‘I‘rimethaphan is the drug of choice ill ~rrati~q the patient aith “accelerated” h)~pertetlsioll and pulmonary edema. 1. ( h-al Inedication should be started as ~15 l)ossit)le after gastrointestinal s0011 syniptollis are under c.olltrol. 5. III lmtieuts with acwlerated hl,pertctisioli aii~l azoteniia, t~lootl pressure lowering is approached more cautiously, but is intlicatetl iii ;w attempt to reverse the vascular factors that ma>- mnplicatc the underlying 1rena1disease. I’rognosis in these c;lscs is qix-cltacl eve11after successful hl00tl Ijressure reductioii. 1: E: F 1: I: f.: z c 1.: 5
1. 2. 3
4. 5. 6.
7.
R> ron~, 1.‘. 13.: The pathogelwsis of hypertensive ellccphalupathy and its relation to the maligIUII~ phase of hypertellsion. I*ancet 2:201, 1954. ,S~~~JMHI, 1;‘. O., and Smirk, F. H.: The trenf melit ilf mnlignant hypertension, .4m. J. Cardiol. 9:868, 1962. Killwid-Smith, P., MckIichael, J., and Murph>., E. .‘I.: The clinical course and pathology of h>.pwten4oll with papilledema~ (mal&rnt hvlzrtensioni. Quart. 1. Med. 51:117. 1958. F;;is, E. U.: ‘:< method for adminiskring the Arch. Int. Med. alltihypertensivc agents, 98:144, 1956. RIoer, PI., and Goldman, A. (;.: Hypertensivtx v;~~cul;udisease, Philadelphia, 1967, .I. 1%. Lippincott Company. Brest. ;I. N.. and Mover. I. H.: TheraDv of hypertensive ‘emergenciks ‘iI; hypertension f reITlIt advances, Philadelphia, 1961, 1.~1 Rr l;ebiger, l’uhlkhers. (iilford, K. if‘.: Hypertensive emergencies and their treatmellt, Med. Clin. North i\meric:l ,45&l, 1961.
Treatment
and reappraisal Edited
of
(accelerated
by Arthur
“hypertensive hypertension).
A
non-diuretic benzothiadiazine drug, diazoxide (Hyperstat) , has been evaluated over the past 4 to 5 years for the treatment of “hypertensive crises.” It is not as yet commercially available. When given intravenously (250 to 350 mg. in 1.5 to 30 sec.) dramatic lowering of blood pressure usually occurs within 1 to 2 minutes. The duration of the effect is variable (from 1 to 18 hr.). Repeated injections frequently do not produce the same degree or duration of blood pressure lowering. Diazoxide presumably produces its effect by a direct action on arteriolar smooth muscle since peripheral resistance is lowered and cardiac output does not decrease despite a marked fall in blood pressure. This drug appears to be of great value in treatment where a rapid reduction in blood pressure is indicated (acute pulmonary edema or severe cerebrovascular symptoms). Diazoxide administration results in the lowering of blood pressure when the patient is in the recumbent position and usually does not produce pronounced postural blood pressure changes. Side effects include transient hyperglycemia and occasional electrocardiographic abnormalities (S-T and T wave changes) suggestive of coronary insufficiency. After several injections, the patient is usually able to begin oral therapy with other agents. Diazoxide should not be administered on a long-term basis or by mouth because of its potential
C. DeGraff,
Alan
of cardiac F. Lyon, and Julian
encephalopathy” Part
II
metabolic side effects (hyperglycemia, hirsutism, and edema). Veratrum derivatives have little if any place in the treatment of accelerated hypertension. Although these drugs may be verb effective as antihypertensive agents, their therapeutic and toxic dosage ranges are very close and side effects may be quite severe following their use. Other drugs are easier to administer and generally, more effective. Trimethaphan camphorsulfonate (Arfonad), a short-acting ganglion-blocking agent, has been advanced by some investigators as the treatment of choice in hypertensive encephalopathy,. This drug is extremely useful in the treatment of congestive heart failure in patients with hypertensive encephalopathy, but because of its extremely short duration of action (5 to 15 min.), it should not be considered the agent of choice in the patient who presents without pulmonary edema. A continuous infusion must be given and blood pressures must be checked every 10 to 15 min. to avoid a hypotensive reaction. Constant blood pressure checking may produce extreme irritation and restlessness in an already agitated patient, and large doses of sedatives may have to be given. This greatly delays the time when the patient is able to start oral feedings and oral therapy. Longer-acting agents, such as pentolinium or mecamylamine, are equally effec-
‘Physician-in-clrargge of Hypertension Section, Montefiore Hos&al and Medical Center. in Clinical Medicine, Albert Einstein College of Medicine, Nnr York. IT\‘. Y.
704
;1meric:m
Fleart
Journal
Frieden
-Sew
York,
\
V.. and .\saociate
tive, are safe when used properly, and do not require the constant monitoring that is necessary when trimethaphan is used. In the presence of pulmonary edema, where acute blood pressure lowering for a short period of time is indicated, trimethaphan is effective in producing arteriolar and venodilation and venous pooling of 1)lood in the splanchnic and peripheral areas. Its action, therefore, produces a “chemical or medical” phlebotomy. In the patient with extremely high diastolic I)ressures, marked arteriolar constriction, and pulmonar\. edema, it is probably more effective -in reducing venous return and increasing cardiac output than the use of peripheral tourniquets. In these cases of severe hvpertension, it is probably the drug of choke. Trinlethaphan is adlninistered slowlp in a dosage of 500 mg. given in a liter of glucose and water, or in a Inore concentrated solution if fluid restriclion is indicated. The drug is administered - also be effective in the treatment of hypertensive encephalopathy, although experience with it is limited. Apparently-, the initial pressor response noted after intravenous administration is not observed. There is a rapid blood pressure lowering effect (within 1 to 2 hr.) when guanethidine is administered in this manner, as contrasted to the 3 to 4 day delay in antihlspertensive activity when the drug is given orally. Ten to 1.5 mg. are given imnlediately, and the dosage is repeated as necessary to keep blood pressure at acceptable levels. Duration of effect is prolonged (from 3 to 24 hr. following a single dose). Sodium nitroprusside has also been advocated in the treatment of “accelerated”
hypertension. This drug is an effective vasodilator and, when administered intravenousI)-, has been effective in lowering blood pressure. ViJe have had no experience with this agent, and it is not, at present, available for use in most hospitals. Personal experience with h>dralazinc (Apresoline) in the treatment of h!.pertensive encephalopath>y has not been entirely satisfactor:= This drug, in doses of between 15 and 40 mg. intramuscularly- or intravenously every four to six hours, is effective in the treatment of the h>-pertension associated with acute glonlerulonephritis and toxemia of pregnant\- and,/or eclampsia, but it is only occasionally useful when used alone in accelerated hypertension. We do not, therefore, use hydralazine unless the drugs reviewed above are ineffective or not readily available. There are other newer agents that have been advocated for use in the treatment of malignant hypertension, but experience with them is limited. Treatment hypertension” insufficiency
of “accelerated and renal
The s)rndrome of malignant or accelerated hypertension and uremia ma)’ represent the “end stage” of chronic glomerulonephritis or pyelonephritis, or may reflect the occurrence of malignant nephrosclerosis with fibrinoid necrosis of the small arteries and arterioles as a result of longstanding and increasingly severe essential hypertension. Regardless of the etiology-, the immediate treatment of this serious situation is essentially the same, and is extremelJr difficult. In the presence of a blood urea nitrogen in excess of 50 to 60 mg. per cent and an elevated serum creatinine level, there is somedanger in lowering the blood pressure, since this further decreases the already severely impaired renal blood flow. In addition, the benefits of blood pressure control may be limited, and may not alter the prognosis in some of these cases. Despite these objections, there are several valid reasons for attempting blood pressure lowering in these patients. Since the prognosis is extremely poor, and rapid death will occur over a three to six month period of time or lessif they are not treated,
there is little to lose by the cautious lowering of blood pressure in these individuals. Treatment is aimed at: (1) improvement in symptonls such as visual disturbances, nausea and/or vomiting, congestive heart failure, and encephalopnthy; (2,l the possil)le reversal of the severe arteriolar patholog~. of the nlalignant phase of h\-pertension. There is some pathologic evidence that suggests a disappearance of fibrinoid nlaterial from the arteries with a change to a nlorc “benign” form of pathology with intinial fibrosis following blood pressure lowering ill these cases. This may not alter the basic pathologic process, such as chronic glonleruloncphritis if this is present, but may decrease the vascular factor that, at least partiall\-, contributes to the rapidly progressive renal insufficiency. JIM patients with renal failure solely on the basis of vascular disease, reversal of necrotizing vasculitis nlay be eve11 more beneficial. The same drugs are used in the treatment of accelerated hypertension with urcrnia as in cases without renal failure. They are, however, used more cautiousI>., and an attempt is made to slowl~~ loxw l~loocl pressure only to those levels (150 to 160/100 to 110 mg. Hg) where, theoretically at least, the edenla and fibrinoitl changes of the blood vessel wall ~nay have an opportunit)to regress. ( kcasionall\. the use of parenteral hydralazine or alpha methyldopa (,Womet~ nlay be of SOIII~ theoretic advantage because of their abilit?. to lower blood pressure acutely without seriously decreasing renal blood flow. Esperience has indicated that if blood pressure is lowered, some patients lvill continue on a more benign course for a prolonged period of time. Summary
1. Patients with “accelerated” or “malignant” hypertension should he t.reatetl
vigorousl\-. If emergency treatment is wt.cessful, and azotemia is not present, longr-ange prognosis is good. 2. The pnrenteral drugs of choice arc reserpi~ie or pentoliniuni (Ansolysen). If reserpine is ineffective after several doses, intravenous diazoxide (if available) and illtravellow ethacrynic acid should be givell. 3. ‘I‘rimethaphan is the drug of choice ill ~rrati~q the patient aith “accelerated” h)~pertetlsioll and pulmonary edema. 1. ( h-al Inedication should be started as ~15 l)ossit)le after gastrointestinal s0011 syniptollis are under c.olltrol. 5. III lmtieuts with acwlerated hl,pertctisioli aii~l azoteniia, t~lootl pressure lowering is approached more cautiously, but is intlicatetl iii ;w attempt to reverse the vascular factors that ma>- mnplicatc the underlying 1rena1disease. I’rognosis in these c;lscs is qix-cltacl eve11after successful hl00tl Ijressure reductioii. 1: E: F 1: I: f.: z c 1.: 5
1. 2. 3
4. 5. 6.
7.
R> ron~, 1.‘. 13.: The pathogelwsis of hypertensive ellccphalupathy and its relation to the maligIUII~ phase of hypertellsion. I*ancet 2:201, 1954. ,S~~~JMHI, 1;‘. O., and Smirk, F. H.: The trenf melit ilf mnlignant hypertension, .4m. J. Cardiol. 9:868, 1962. Killwid-Smith, P., MckIichael, J., and Murph>., E. .‘I.: The clinical course and pathology of h>.pwten4oll with papilledema~ (mal&rnt hvlzrtensioni. Quart. 1. Med. 51:117. 1958. F;;is, E. U.: ‘:< method for adminiskring the Arch. Int. Med. alltihypertensivc agents, 98:144, 1956. RIoer, PI., and Goldman, A. (;.: Hypertensivtx v;~~cul;udisease, Philadelphia, 1967, .I. 1%. Lippincott Company. Brest. ;I. N.. and Mover. I. H.: TheraDv of hypertensive ‘emergenciks ‘iI; hypertension f reITlIt advances, Philadelphia, 1961, 1.~1 Rr l;ebiger, l’uhlkhers. (iilford, K. if‘.: Hypertensive emergencies and their treatmellt, Med. Clin. North i\meric:l ,45&l, 1961.