Download Drug treatment of hypertensive emergencies

Drug treatment of hypertensive emergencies
Norman M Kaplan, MD
Burton D Rose, MD
UpToDate performs a continuous review of over 350 journals and other resources.
Updates are added as important new information is published. The literature review
for version 14.2 is current through April 2006; this topic was last changed on May 9,
2006. The next version of UpToDate (14.3) will be released in October 2006.
INTRODUCTION — A hypertensive emergency is considered to be present when
severe hypertension is associated with acute end-organ damage. Examples include
malignant hypertension, with or without hypertensive encephalopathy, subarachnoid
or intracerebral hemorrhage, acute pulmonary edema, aortic dissection, and rebound
after withdrawal of antihypertensive medications. Immediate but careful reduction in
blood pressure is indicated in these settings. However, an excessive hypotensive
response is potentially dangerous, possibly leading to ischemic complications such as
stroke, myocardial infarction or blindness in some cases. Thus, in patients who are
severely hypertensive but asymptomatic, slower reductions in blood pressure should
be provided with oral agents (see below).
PARENTERAL DRUGS — A number of both parenteral and oral antihypertensive drugs
can be used in these patients (show table 1A-1B) [1,2]. (See "Treatment of specific
hypertensive emergencies" for a review of the approach to therapy in the different
causes of severe hypertension).
Nitroprusside — Nitroprusside dilates both arterioles and veins and is generally
considered to be the most effective parenteral drug for most hypertensive
emergencies. Nitroprusside, administered by intravenous infusion, begins to act
within seconds and its effects disappear within minutes, thereby minimizing the risk
of hypotension. Constant monitoring of the blood pressure is required. Nitroprusside
and other nitrovasodilators (such as nitroglycerin) that provide nitric oxide appear to
induce vasodilatation via generation of cyclic GMP which then activates calciumsensitive potassium channels in the cell membrane [3].
The major limitation to the use of nitroprusside is its metabolism to cyanide, possibly
leading to the development of cyanide or rarely thiocyanate toxicity that may be fatal
[4]. This problem, which is manifested by clinical deterioration, altered mental
status, and lactic acidosis, can be minimized by using the lowest possible dose and
by careful patient monitoring. Treatment for a prolonged period (>24 to 48 hours),
underlying renal insufficiency, and the use of doses that exceed the capacity of the
body to detoxify cyanide (more than 2 µg/kg per min) increase the risk of cyanide
accumulation. The current FDA recommendation is that maximum doses of 10 µg/kg
per minute should never be given for more than 10 minutes. An infusion of sodium
thiosulfate can be used in affected patients to provide a sulfur donor to detoxify
cyanide into thiocyanate [4].
The recommended starting dose of nitroprusside is 0.25 to 0.5 µg/kg per minute. This
can be increased as necessary to a maximum dose of 8 to 10 µg/kg per minute,
although use of these higher doses should generally be avoided or limited to a
maximum duration of 10 minutes [4]. Nitroprusside should not be given to pregnant
women.
Nitroglycerin — Nitroglycerin is also administered by intravenous infusion and is
similar in action to nitroprusside except that it produces relatively greater venodilation
than arteriolar dilation. It may be most useful in patients with symptomatic coronary
disease and in those with hypertension following coronary bypass.
The initial dose of nitroglycerin is 5 µg/min, which can be increased as necessary to a
maximum of 100 µg/min. The onset of action is 2 to 5 minutes, while the duration of
action is 5 to 10 minutes. Headache (due to direct vasodilation) and tachycardia
(resulting from reflex sympathetic activation) are the primary side effects. Cyanide
accumulation does not occur.
Nicardipine — Nicardipine is a dihydropyridine calcium channel blocker (like nifedipine)
that can be given as an intravenous infusion. The initial dose is 5 mg/h and can be
increased to a maximum of 15 mg/h. Initial experience with nicardipine has been
very favorable when compared to nitroprusside [5]. The major limitation is a longer
half-time, which precludes rapid titration.
Fenoldopam — Fenoldopam is a peripheral dopamine-1 receptor agonist, and unlike
other parenteral antihypertensive agents, maintains or increases renal perfusion
while it lowers BP [6]. It maintains most of its efficacy for 48 hours of constant rate
infusion without rebound hypertension when discontinued. Fenoldopam can be safely
used in all hypertensive emergencies, and may be particularly beneficial in patients
with renal insufficiency. After a starting dose of 0.1 µg/kg per min, the dose is
titrated at 15 min intervals, depending on the BP response. Fenoldopam is
contraindicated in patients with glaucoma [6].
Labetalol — Labetalol is a combined beta-adrenergic and alpha-adrenergic blocker. Its
rapid onset of action (5 minutes or less) makes it the only ß-blocker that is useful in
the treatment of hypertensive emergencies. Labetalol is safe in patients with active
coronary disease, since it does not increase the heart rate. On the other hand,
labetalol should generally be avoided in patients with asthma, chronic obstructive
lung disease, congestive heart failure, bradycardia, or greater than first-degree heart
block.
Labetalol can be given as an intravenous bolus or infusion. The bolus dose is 20 mg
initially, followed by 20 to 80 mg every 10 minutes to a total dose of 300 mg. The
infusion rate is 0.5 to 2 mg/min.
Esmolol — Esmolol, a relatively cardioselective beta blocker, is rapidly metabolized by
blood esterases and has a short (about 9 minutes) half-life and total duration of
action (about 30 minutes). Its effects begin almost immediately, and it has found
particular use during anesthesia to prevent postintubation hemodynamic
perturbations.
Hydralazine — Hydralazine is a direct arteriolar vasodilator with little or no effect on
the venous circulation. Thus, precautions are needed in patients with underlying
coronary disease or an aortic dissection, and a ß-blocker should be given
concurrently to minimize reflex sympathetic stimulation. The hypotensive response
to hydralazine is less predictable than that seen with other parenteral agents and its
current use is primarily limited to pregnant women. (See "Treatment of hypertension in
pregnancy").
Hydralazine is given as an intravenous bolus. The initial dose is 10 mg, with the
maximum dose being 20 mg. The fall in blood pressure begins within 10 to 30
minutes and lasts 2 to 4 hours.
Enalaprilat — Enalaprilat is an intravenous preparation of the active form of the
angiotensin converting enzyme (ACE) inhibitor enalapril. The response to enalaprilat
is variable and not predictable, a reflection of the variable plasma volume and
plasma renin activity in patients with a hypertensive emergency [7]. As an example,
hypovolemic patients with a high plasma renin activity may have an excessive
hypotensive response. In addition, ACE inhibitors are generally contraindicated in
pregnancy. (See "Angiotensin converting enzyme inhibitors and receptor blockers in
pregnancy").
The usual initial dose is 1.25 mg. As much as 5 mg may be given every six hours as
necessary [7]. The onset of action begins in 15 minutes but the peak effect may not
be seen for four hours. The duration of action ranges from 12 to 24 hours.
Phentolamine — Phentolamine is an alpha-adrenergic blocker, the use of which is
limited to the treatment of severe hypertension due to increased catecholamine
activity. Examples include pheochromocytoma and tyramine ingestion in a patient
being treated with a monoamine oxidase inhibitor. (See "Clinical presentation and
diagnosis of pheochromocytoma" and see "Treatment of pheochromocytoma in adults").
Phentolamine is given as an intravenous bolus. The usual dose is 5 to 10 mg every 5
to 15 minutes as necessary.
ORAL DRUGS — Oral antihypertensive agents lower the blood pressure more slowly
than parenteral drugs. Thus, they are primarily used when parenteral agents are not
available or when there is severe hypertension without serious acute end-organ
damage. (See "Management of severe asymptomatic hypertension (hypertensive urgencies)"
for a discussion of this issue, and see "Hypertensive emergencies: Malignant hypertension
and hypertensive encephalopathy").
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REFERENCES
Chobanian, AV, Bakris, GL, Black, HR, et al. The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure: The JNC 7 report. JAMA 2003; 289:2560.
Vaughan, CJ, Delanty, N. Hypertensive emergencies. Lancet 2000; 356:411.
Archer, SL, Huang, JM, Hampl, V, et al. Nitric oxide and cGMP cause vasorelaxation by
activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase.
Proc Natl Acad Sci U S A 1994; 91:7583.
Schulz, V. Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate and
thiocyanate. Clin Pharmacokinet 1984; 9:239.
Neutel, JM, Smith, DH, Wallin, D, et al. A comparison of intravenous nicardipine and
sodium nitroprusside in the immediate treatment of severe hypertension. Am J
Hypertens 1994; 7:623.
Murphy, MB, Murray, C, Shorten, GD. Fenoldopam: a selective peripheral dopamine-
receptor agonist for the treatment of severe hypertension. N Engl J Med 2001;
345:1548.
7. Hirschl, MM, Binder, M, Bur, A, et al. Clinical evaluation of different doses of
intravenous enalaprilat in patients with hypertensive crises. Arch Intern Med 1995;
155:2217.
GRAPHICS
Drugs for HTV emergencies A
Drugs for HTV emergencies B
Treatment of specific hypertensive emergencies
Norman M Kaplan, MD
Burton D Rose, MD
UpToDate performs a continuous review of over 350 journals and other resources.
Updates are added as important new information is published. The literature review
for version 14.2 is current through April 2006; this topic was last changed on May 8,
2006. The next version of UpToDate (14.3) will be released in October 2006.
INTRODUCTION — Most patients with relatively severe hypertension (diastolic
pressure 120 mmHg), have no acute, end-organ injury. Although some propose
relatively rapid antihypertensive therapy in this setting (as with sublingual nifedipine
or oral clonidine loading), there may be more risk than benefit from such an
aggressive regimen. (See "Management of severe asymptomatic hypertension (hypertensive
urgencies)").
There are, however, hypertensive emergencies in which rapid lowering of the BP is
indicated. These disorders will be reviewed here with the exception of malignant
hypertension and hypertensive encephalopathy, which are discussed separately. ( See
"Hypertensive emergencies: Malignant hypertension and hypertensive encephalopathy").
ANTIHYPERTENSIVE DRUGS — An overview of the mechanism of action, doses, and
routes of administration of the antihypertensive drugs that may be used in this
setting is provided in Table 1 (show Table 1A-1B) [1,2]. Intravenous furosemide or
other potent diuretics are often needed to enhance the efficacy of these agents. The
pharmacology and side effects of these drugs are discussed elsewhere. ( See "Drug
treatment of hypertensive emergencies").
As will be described below, the choice of antihypertensive drug varies with the
clinical setting. Nitroprusside has been the gold standard for many hypertensive
emergencies because it begins to act within seconds and its effects disappear within
minutes, thereby minimizing the risk of hypotension. The major limitations to the use
of nitroprusside are the need for constant monitoring and its metabolism to cyanide,
possibly leading to the development of cyanide or rarely thiocyanate toxicity that
may be fatal.
Nitroprusside — an arteriolar and venous dilator, given as an intravenous infusion.
Initial dose: 0.25 to 0.5 µg/kg per min; maximum dose: 8 to 10 µg/kg per min which
should be continued for no more than 10 minutes.
Nitroglycerin — a venous and, to a lesser degree, arteriolar dilator, given as an
intravenous infusion. Initial dose: 5 µg/min; maximum dose: 100 µg/min.
Labetalol — an alpha- and ß-adrenergic blocker, given as an intravenous bolus or
infusion. Bolus: 20 mg initially, followed by 20 to 80 mg every 10 minutes to a total
dose of 300 mg. Infusion: 0.5 to 2 mg/min.
Nicardipine — a calcium channel blocker, given as an intravenous infusion. Initial
dose: 5 mg/h; maximum dose: 15 mg/h.
Fenoldopam — a peripheral dopamine-1 receptor agonist, given as an intravenous
infusion. Initial dose: 0.1 µg/kg per min; the dose is titrated at 15 min intervals,
depending upon the blood pressure response.
Hydralazine — an arteriolar dilator, given as an intravenous bolus. Initial dose: 10
mg given every 20 to 30 minutes; maximum dose: 20 mg.
Propranolol — a ß-adrenergic blocker, given as an intravenous infusion and then
followed by oral therapy. Dose: 1 to 10 mg load, followed by 3 mg/h.
Phentolamine — an a-adrenergic blocker, given as an intravenous bolus. Dose: 5 to
10 mg every 5 to 15 minutes.
Enalaprilat — an angiotensin converting enzyme inhibitor, given as an intravenous
bolus. Dose: 1.25 mg every six hours.
In general, nitroprusside is most rapid and potent. It acts within seconds and has a
duration of action of only 2 to 5 minutes. Thus, hypotension can be easily reversed
by temporarily discontinuing the infusion. The major limitation to the use of this drug
is the development of cyanide toxicity in patients treated with high doses, for a
prolonged period (>24 to 48 hours), or with underlying renal insufficiency.
Alternatives to nitroprusside include intravenous labetalol, nicardipine, and fenoldopam;
hypotension is uncommon with these drugs and cyanide toxicity is not an issue.
Intravenous fenoldopam, a dopamine agonist that acts at the vasodilator DA1
receptors, is as effective and short-acting as nitroprusside [3]; however, it has the
advantages of increasing renal blood flow and sodium excretion, of not being
associated with the accumulation of toxic metabolites, and of not requiring shielding
from light.
TREATMENT — The optimal therapy varies with the type of hypertensive emergency.
In addition to malignant hypertension, which is discussed elsewhere, the BP may be
markedly elevated in the presence of cardiovascular or neurologic symptoms in a
number of other clinical conditions [1,2]. (See "Hypertensive emergencies: Malignant
hypertension and hypertensive encephalopathy").
Ischemic stroke or subarachnoid or intracerebral hemorrhage — The benefit of
reducing the BP in these disorders must be weighed against possible worsening of
cerebral ischemia induced by the thrombotic lesion or by cerebral vasospasm. This
issue is discussed in detail separately. (See "Treatment of hypertension following a
stroke").
These cerebrovascular events are characterized by the abrupt onset of usually focal
neurologic findings. This is in contrast to the typically insidious onset of headache,
nausea, vomiting, and confusion seen in hypertensive encephalopathy, a disorder in
which rapid lowering of the BP generally leads to resolution of the symptoms within
24 to 48 hours. (See "Hypertensive emergencies: Malignant hypertension and hypertensive
encephalopathy").
Acute pulmonary edema — Hypertension in patients with acute left ventricular failure
due to systolic dysfunction should be principally treated with vasodilators.
Nitroprusside or nitroglycerin with a loop diuretic is the regimen of choice for this
problem. Drugs that increase cardiac work (hydralazine) or decrease cardiac
contractility (labetalol or other beta blocker) should be avoided. (See "Acute
decompensated heart failure (cardiogenic pulmonary edema)").
Angina pectoris or acute myocardial infarction — Acute coronary insufficiency
frequently increases the systemic blood pressure. Intravenous parenteral
vasodilators, principally nitroprusside and nitroglycerin, are effective and reduce
mortality in patients with acute myocardial infarction, with or without hypertension
[4]. Labetalol is also effective in this setting. Drugs that increase cardiac work
(hydralazine) are contraindicated. (See "Overview of the management of acute ST elevation
(Q wave) myocardial infarction" and see "Overview of the management of unstable angina
and acute non-ST elevation (non-Q wave) myocardial infarction").
Aortic dissection — With acute aortic dissection, the stresses that damage the vessel
wall are related to the mean pressure, the width of the pulse pressure, and the
maximal rate of rise of the pressure (dp/dt). Drugs that diminish dp/dt are the
optimal agents to treat a dissection [5]. The initial aim of medical therapy in such
patients is to decrease both the systemic BP (to a systolic pressure of 100 to 120
mmHg if tolerated) and cardiac contractility. These combined goals are usually
achieved by the combination of nitroprusside and an intravenous beta blocker such as
propranolol or labetalol. Nitroprusside should not be given without a beta blocker. ( See
"Management of aortic dissection").
Withdrawal of antihypertensive therapy — Abrupt discontinuation of a short-acting
sympathetic blocker (such as clonidine or propranolol) can lead to severe hypertension
and coronary ischemia due to upregulation of sympathetic receptors. Control of the
BP can be achieved in this setting by readministration of the discontinued drug and,
if necessary, phentolamine, nitroprusside, or labetalol. (See "Withdrawal syndromes with
antihypertensive therapy").
Acute increase in sympathetic activity — In addition to drug withdrawal, increased
adrenergic activity can lead to severe hypertension in a variety of other clinical
settings. These include: (1) pheochromocytoma; (2) autonomic dysfunction, as in
the Guillain-Barré syndrome or post-spinal cord injury; and (3) the use of
sympathomimetic drugs, such as phenylpropanolamine, cocaine, amphetamines,
phencyclidine, or the combination of an MAO (monoamine oxidase) inhibitor and the
ingestion of tyramine-containing foods (such as most fermented cheeses, smoked or
aged meats, Chianti, champagne, and avocados) [2,6]. (See "Designer drugs in
adults"). The rise in BP seen in the last setting is due to an MAO inhibitor-induced
decline in intestinal tyramine metabolism, followed by increased tyramine absorption
and a subsequent tyramine-induced release of endogenous catecholamines. ( See
"Clinical presentation and diagnosis of pheochromocytoma" for a more complete list of
possibly dangerous foods).
Control of the hypertension in these disorders can be achieved with phentolamine,
labetalol, or nitroprusside. Administration of a ß-blocker alone is contraindicated, since
inhibition of ß-receptor-induced vasodilation results in unopposed alpha-adrenergic
vasoconstriction and a further rise in BP [7,8].
Pregnancy — Intravenous hydralazine is the treatment of choice in pregnant women
with severe hypertension (usually due to preeclampsia or preexistent hypertension);
nicardipine or labetalol are alternatives in patients who do not achieve adequate BP
control with hydralazine. In contrast, nitroprusside (which may cause cyanide
intoxication in the fetus), angiotensin converting enzyme inhibitors (which can impair
renal function in the fetus), and angiotensin II receptor blockers are contraindicated
in this setting. (See "Treatment of hypertension in pregnancy").
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
Kaplan, NM. Management of hypertensive emergencies. Lancet 1994; 344:1335.
2. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet 2000; 356:411.
3. Murphy, MB, Murray, C, Shorten, GD. Drug therapy: Fenoldopam - A selective
peripheral dopamine-receptor agonist for the treatment of severe hypertension. N
Engl J Med 2001; 345:1548.
4. Lau, J, Antman, EM, Jimenez-Silva, J, Kupelnick, B. Cumulative meta-analysis of
therapeutic trials for myocardial infarction. N Engl J Med 1992; 327:248.
5. Pretre, R, Von Segesser, LK. Aortic dissection. Lancet 1997; 349:1461.
6. Kaplan, NM. Hypertensive crises in clinical hypertension, 8th ed. Lippincott, Williams
& Wilkins, Philadelphia, 2002, pg. 339.
7. Prichard, BN, Ross, EJ. Use of propranolol in conjunction with alpha-receptor blocking
drugs in pheochromocytoma. Am J Cardiol 1966; 18:394.
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8.
Brown, H, Goldberg, PA, Selter, JG, et al. Hemorrhagic pheochromocytoma associated
with systemic corticosteroid therapy and presenting as myocardial infarction with
severe hypertension. J Clin Endocrinol Metab 2005; 90:563.
GRAPHICS
Drugs for HTV emergencies A
Drugs for HTV emergencies B