arterial hpt

788 Current Drug Targets, 2009, 10, 788-798

1389-4501/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Acute Severe Arterial Hypertension: Therapeutic Options

A.R. De Gaudio†,*

, C. Chelazzi+, G. Villa

+ and F. Cavaliere

#

†University of Florence, Department of Critical Care, Section of Anesthesiology and Intensive Care. Azienda

Ospedaliero-Universitaria Careggi, Viale Morgagni 85, 50134 Florence Italy

+University of Florence, Department of Critical Care Medicine, Section of Anesthesiology, Florence, Italy

#Institute of Anaesthesia and Intensive Care of Catholic University of Rome, Rome, Italy

Abstract: Arterial hypertension is a very common condition. Cerebral, coronary and renal vessels are mainly affected by

the deleterious effect of this condition, and both acute and chronic organ failure may ensue. Exacerbation of underlying

pathophysiologic conditions or new precipitating factors can lead to hypertensive crisis, either urgencies or emergencies.

During hypertensive emergencies, a quick raise in arterial pressure may lead to acute and significant organ dysfunction,

such as aortic dissection, acute myocardial infarction, intracranial bleeding or acute renal failure. Perioperative

hypertension often takes the shape of a crisis and it can be related to hypothermia, pain, neuro-hormonal response to

surgical trauma or antihypertensive drugs withdrawal. Treatment for hypertensive crisis should achieve a progressive

control of blood pressure, avoiding any abrupt decrease in organ blood supply. Therapeutic options are many and different

in terms of pharmacokinetics and pharmacodynamic profiles. The best option should be based upon the characteristics of

the patient and the pathophysiology of the hypertensive crisis . Of particular interest, some agents are metabolized by

blood esterase and have a very short half life (e.g., clevidipine). This allows tight titration of their effect, which is

advisable when carefully lowering blood pressure. This is of particular importance when treating hypertensive crisis in

surgical patients both intra-operatively or in critical care.

Keywords: Cardiovascular homeostasis, perioperative hypertension, antihypertensive treatment, hypertensive emergency.

INTRODUCTION

According to the seventh Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC 7), arterial hypertension is defined as a systolic blood pressure (SBP) 140 mmHg or a diastolic blood pressure (DBP) 90 mmHg (Table 1) [1]. Patients with systolic values between 139 and 120 mmHg or diastolic values between 89 and 80 mmHg are considered as having pre - hypertension, and will have a tendency to develop hypertension later during lifetime.

Table 1. Blood Pressure Definitions

BP Definitions Systolic BP Diastolic BP

Normal <120 mmHg <80 mmHg

Pre-hypertension 120-139 mmHg 80-89 mmHg

Hypertension >140 mmHg >90 mm Hg

Hypertensive crisis >180 mmHg >120 mmHg

Hypertension affects an estimated 72 million people in United States and its prevalence in the US population aged more than 20 is 30% [2, 3]. Worldwide, one billion people

*Address correspondence to this author at the University of Florence,

Department of Critical Care, Section of Anesthesiology and Intensive Care.

Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni 85, 50134

Florence Italy; E-mail: [email protected]

are affected, while 7.1 million deaths are related to it. Of all the affected population, it is proved that 1% will develop an hypertensive crisis during the disease course [4]. Following JNC 7 definitions, an hypertensive crisis occurs when SBP raises above 180 mmHg or a DBP above 120 mmHg. Those crisis can be further distinguished in hypertensive urgencies, if there is no evidence of ongoing end-organ damage, and hypertensive emergencies, when the raise in blood pressure is associated to organ damage or pending organ failure.

However it is not always possible to recognize a precise cause of hypertension and hypertensive crisis, many secondary causes need to be ruled out (Table 2) [5]. These secondary forms of hypertension expose affected patients to develop hypertensive crisis more easily than essential forms [6]. The aim of this paper is to review literature data about the complex physiopathology which leads from the chronic hypertensive state to an acute crisis and the appropriate therapies available for these conditions.

Physiopathology of Arterial Hypertension

Blood pressure is the driving force of tissue perfusion. It is defined as the product of cardiac output (CO) and peripheral vascular resistance. Main determinants of CO are cardiac preload and afterload, myocardial contractility and heart rate, while vascular resistance is regulated by a highly integrated system including sympathetic activity and renin-angiotensin-aldosterone (RAA) system [7]. Endothelial function plays a major role in tightly regulating tissue perfusion pressures and oxygen supply [8].

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Acute Severe Arterial Hypertension Current Drug Targets, 2009, Vol. 10, No. 8 789

Table 2. Causes of Secondary Hypertension

• Autonomic hyperactivity (spinal cord injury, Guillain-Barré

syndrome, diabetes mellitus)

• Intracranial hypertension and brain edema

• Pheochromocytoma

• Tumors secreting renin or aldosterone

• Eclampsia and preeclampsia

• Vasculitis and scleroderma

• Parenchymal renal disease (e.g., acute glomerulonephritis)

• Renal vascular disease (e.g., renal artery stenosis or thrombosis)

• Drugs (e.g., cocaine, amphetamine, phencyclidine)

• Drug interaction (e.g., monoamine oxydase inhibitor with

tyramine, tryciclics antidepressants or sympathomimetics)

• Abrupt withdrawal of anti-hypertensive drugs (e.g., clonidine)

• Alcohol withdrawal

Sympathetic Activity

Noradrenaline and adrenaline, either from sympathetic neurons or epirenal medullar cells, interact with peripheral smooth cell- 1 adrenergic receptors increasing vascular tone at pre-capillary level. They also increase heart rate and contractility through interaction with cardiac- 1 adrenergic receptors. The net effect of sympathetic stimulation is an

increase in CO (Fig. 1) [9]. Chronic adrenergic stimulation induces vascular remodelling and smooth muscular cells proliferation, thus increasing diastolic pressure, while arterial vessels thicken and stiffen due to lipid, calcium and collagen accumulation and deposition in vascular walls [7]. Moreover, chronically increased vascular tone leads to increased myocardial mass (e.g., left ventricular hypertro-phy) and oxygen consumption, which in turn can lead to chronic ischemia or acute myocardial infarction. At renal level, increased sympathetic activity enhances sodium and water retention, further contributing to maintain elevated blood pressure.

Renin-Angiotensin-Aldosterone System

The RAA system greatly influences cardiovascular homeostasis (Fig. 2). Angiotensin II (AT-II) acts as direct vasoconstrictor on systemic and renal vessels, thus contributing to initiate and maintain elevated blood pressure. Moreover, AT-II stimulates adrenaline and noradrenaline release at pre-synaptic level. It also contributes to left ventricular hypertrophy and myocardial ischemia through increased left ventricular wall tension. On renal vessels, AT-II-induces alterations of arterial and capillary walls and leads to progressive glomerular ischemia, parenchymal damage, proteinuria and end-stage renal failure [10]. AT-II stimulates aldosterone and antidiuretic hormone release, which both contribute to hypervolemia and hypertension. This condition

Fig. (1). Effect of increased sympathetic activity cardiovascular homeostasis.

Sympatetic activity

Increases

heart rate

and

contractility

Increase

cardiac output

Increases

vascular tone at

precapillary

level

Vasoconstriction

increasing

peripheral vascular

resistances

Increases

sodium and

water

reabsorption

Induces

vascular

remodelling

Increase

diastolic

pressure

Increased left

ventricular

hypertrofy and

oxygen

consumption

Chronic

Ischemia

and AMI Increase BP

790 Current Drug Targets, 2009, Vol. 10, No. 8 De Gaudio et al.

contributes to myocardial remodelling and cell fibrosis. Aldosterone leads to increased sodium and water renal retention, with hypokalemia and metabolic alkalosis [7]. Hyperaldosteronism “per se” promotes renal vessel inflam-mation and fibrosis, leading to microvascular renal injury [11, 12]. Furthermore, during hypertensive crisis, abrupt increase in renal vessels shear forces leads to reflex glomerular capillary constriction and renal hypoperfusion which, in turn, can be responsible for a further increase of RAA system activity with sudden worsening of renal function [13].

Endothelial Function

Vascular endothelium plays a role in regulating microvascular tone (Fig. 3). Nitric oxide exhibits vasodilating activity, while endothelin-1 is a powerful vasoconstrictor. In physiological condition the two effects are well balanced. In hypertensive patients, increase in arteriolar and capillary shear forces, due to peripheral transmission of elevated blood pressure, leads to an increased endothelin-1 release by the endothelium, with a progressive increase in vasoconstriction. The consequent reduction in blood-oxygen supply can lead to tissue hypoperfusion/ischemia and organ dysfunction [8]. In insulin resistant patients hyperinsulinemia inhibits endothelial nitric oxide release thus leading to a predominant endothelin-1 effect [14]. Vasoconstrictive endothelial tone might contri-bute to maintain high blood pressure and precipitate renal injury [13]. During hypertensive emergencies, an abrupt

increase of blood pressure raises shear stress on arteriolar and capillary vessels and leads to endothelial inflammation and fibrosis with altered permeability [10]. In sustained crisis, endothelial damage occurs, and coagulation cascade activates [15]. This can further impair tissue hypoperfusion and precipitate acute organ damage.

End-Organ Damage in Hypertensive Crisis

Hypertensive associated end-organ damage can be the acute complication of chronic hypertension or the clinical manifestation of a hypertensive emergency (Table 3).

Table 3. End Organ Damage in Arterial Hypertension

• Hypertensive encephalopathy

• Stroke

• Subarachnoid and intraparenchymal haemorrhage

• Hypertensive retinopathy

• Myocardial ischemia

• Acute congestive heart failure and pulmonary oedema

• Aortic dissection

• Renal injury and chronic renal failure

• Eclampsia

Fig. (2). Effect of renin-angiotensin system on cardiovascular homeostasis.

Renin

Angiotensin II

AldosteroneVasoconstriction

on systemic and

renal vassels

Left ventricular

hypertrophy and

myocardial

ischemia

Increase left

ventricular wall

tension

Alteration of renal

arterial and capillary

vessels’ wall

Glomeruar ischemia,

parenchymal damage,

proteinuria, end-stage

renal failure

ADH

Sodium and

water renal

retention

hypervolemia

Increase BP

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Brain and Retina

Normotensive individuals maintain a normal cerebral blood flow between mean arterial pressures (MAP) of 60 and 120 mm Hg [16]. A chronically high MAP induces cerebral microvascular thickening and stiffening, increasing cerebral vascular resistance. Consequently hypertensive patients are more prone to suffer from cerebral hypoperfusion when blood pressure lowers [17]. On the other hand, an abrupt increase in blood pressure leads to elevated cerebral blood flow and intracranial pressure, with consequent blood brain barrier disruption, fluid leakage and brain oedema [7, 18]. Clinical manifestation of such hypertensive encephalopathy is an acute neurologic syndrome associated to severe hyper-tension. Clinical manifestations include headache, nausea and vomiting which are associated to elevated blood pressure. If the syndrome is left untreated, confusion, delirium or seizures can manifest, and risk of stroke or cerebral haemorrhage is high [13]. On the retina, chronic hypertension leads to arterial narrowing and intimal thickening. In hypertensive crisis, blood-retina disruption occurs, with necrosis, retinal ischemia and optic disk oede-ma. Fundoscopic examination reveals haemorrhage, “cotton wool spots” and papilledema [19].

Heart

Chronically elevated peripheral vascular resistance leads to increased left ventricular mass because of the increased left wall tension [7]. Aldosterone and angiotensin II can directly stimulate left ventricular hypertrophy and remodelling. Thickening of the ventricular wall increases myocardial oxygen consumption, limiting diastolic blood flow and myocardial oxygen delivery. These phenomena lead to a chronic myocardial ischemia, with progressive wor-sening of left ventricular function and deposition of inters-titial collagen, with further impairment of myocardial oxy-gen delivery [20]. Left ventricular hypertrophy can lead to mitral regurgitation, left atrial dilatation and atrial fibrilla-tion, which further reduce blood flow to the coronaries. During hypertensive crisis, a raise in myocardial serum troponin-I is commonly observed as the result of impaired myocardial cells oxygen supply, even in absence of overt ischemia or infarction [21]. However, during acute crisis, shear stress on coronary walls leads to intimal damage and accelerated atherosclerosis which can precipitate plaque rupture and intravascular thrombosis causing myocardial infarction [13]. Both left ventricular hypertension and myocardial ischemia lead to left ventricular failure and congestive heart failure. In hypertensive crisis, the already

Fig. (3). Effects of hyperinsulinemia on endothelial dysfunction.

Hypertensive states

Increased shear

forces on arterioles

and capillaries

Increased endothelin-1

vasocostrictive effect

Unbalanced

vasoconstrictive tone

Organ chronic

hypoperfusion, ischemia

and dysfunction

Organ damage

Hyperinsulinemia

Endothelial

inflammation

and fibrosis

Alterated

permeability

Activation of coagulative

cascade


failing left ventricle can be overcome by acutely increased vascular resistance and acute congestive failure with pulmo-nary edema [22]. Clinically, patients are hypoxic and crack-les are heard on chest auscultation, limbs can be cool as a sign of hypo-perfusion and oedematous as fluid overload occurs [18].

Aorta

Untreated hypertension may lead to aortic dilation and intimal tearing, i.e. aortic dissection [13]. Blood flows into the aortic media and false and true aortic lumen become evident. Dissection can involve the ascending aorta (proximal, type A of Stanford) or not (distal, type B of Stanford) [23]. In type A dissection, tearing can involve carotid artery, with stroke and/or syncope as clinical manifestations. Coronary arteries can be involved, and myocardial infarction can be seen [18]. If aortic rupture occurs, massive intra - pericardial bleeding leads to cardiac tamponade, obstructive shock and cardiac arrest. When aortic valve is involved in dissection, acute regurgitation can lead to pulmonary edema and acute heart failure. In type B dissection limbs ischemia or anuria can occur as a consequence of involvement of aortic branch vessels [23].

Kidneys

Acute glomerulonephritis, renal artery stenosis or cyclosporine use in renal transplant patients, may lead to arterial hypertension and hypertensive crisis [13]. On the other hand, kidneys are usually involved as target organs of chronic hypertensive status. Afferent arterioles of hypertensive patients tend to progressively narrow in the attempt of limiting overflow to glomerular capillaries. Moreover, chronic stimulation from the adrenergic system and AT-II leads to vessel wall thickening. Vessel structural changes are seen that lead to progressive reduction of glomerular blood flow and filtration rate. Microalbuminuria is the landmark of progressive glomerular damage [10]. End-stage renal failure and need for dialysis may follow. Moreover, chronic glomerular ischemia stimulates renin release and the consequent activation of the RAA system leads to further renal vasoconstriction and fluid retention, thus maintaining and worsening hypertension [24]. As auto - regulatory renal system is lost, glomerular blood flow starts to vary directly with variations of systemic arterial pressure. At this point, any abrupt reduction in blood pressure may lead to acute renal failure.

Preeclampsia and Eclampsia

The preeclamptic syndrome is characterized by hyperten-sion associated to interstitial oedema and proteinuria, while in eclamptic syndrome, neurological signs, such as visual alterations and seizures, ensue [18, 25]. Altered trophoblast implantation seems to initiate a cascade in which placental vessels vasoconstriction induces a raise in peripheral resistances, leading to hypertension. Moreover, endothelial dysfunction, with activation of coagulative pathways and inhibition of fibrinolisis, occurs as well [26].

Postoperative Arterial Hypertension

Postoperative Arterial hypertension is defined as an hypertensive crisis which occurs within 2 hours from the end

of surgery and usually requires treatment for no more than 6 hours [27]. Cardiothoracic, vascular, head and neck surgery and neurosurgical procedures are most commonly involved [28]. Perioperative neuro-hormonal stress response leading to increased sympathetic tone is thought to be responsible [29]. Other involved factors include activation or RAA system, baroreceptor dysfunction or withdrawal of central acting antihypertensive therapies [18]. Anaesthetic factors include poorly controlled postoperative pain, hypothermia, urinary distention and discontinuation of anaesthetic drugs. Postoperative crisis require aggressive treatment in case of the fear of vascular suture leak and rupture [13, 30].

Therapeutic Options

Arterial hypertension without signs of acute organ damage can be managed conservatively [4]. Control of precipitating factors and wait for a progressive reduction of blood pressure values is the more rational approach. In already hypertensive patients, reinitiating oral therapy may be the key to restore normal blood pressure. In the postoperative period, pain, anxiety, hypothermia, hypoxia, hypercapnia and hypoglycaemia have all to be ruled out and treated in order to control the hypertensive status that can be associated to them [18]. Because of the risk of organ hypoperfusion associated to the use of parenteral hypotensive drugs, postoperative volume status should be optimized before starting the intravenous therapy [28].

In the setting of hypertensive emergencies, when organ damage is pending or actual, there is a general consensus that lowering blood pressure may limit damage [4, 13]. However, even in this case, arterial pressure should be lowered slowly, targeting a 20% reduction in mean arterial pressure over several minutes-hours [6]. To rapidly lower high blood pressure values, can be harmful in chronic hypertensive patients, where autoregulation thresholds of the brain are higher than normotensive individuals. In this case, brain hypoperfusion can complicate institution of anti-hyperten-sive therapy [17]. Moreover, there is not enough evidence that anti-hypertensive treatment reduces mortality or associa-ted morbidity in hypertensive emergencies [31]. The only situation in which blood pressure should be quickly lowered, is aortic dissection, in order to reduce tearing forces on aortic wall, thus limiting the extension of dissection itself [23]. Many different pharmacological options are available, and each patient should have the treatment tailored to the aim of lowering blood pressure in a safe manner. Evidence in terms of best drug and best infusion regimen is still lacking [31].

Calcium Antagonists: Nicardipine and Clevidipine

Nicardipine is a second-generation dihydropyridine calcium-channel antagonist (Table 4). It shows high vascular selectivity and a strong cerebral and coronary vasodilatory activity, with no negative inotropic properties. Nicardipine reduces both cardiac and cerebral ischemia [32]. Nicardipine increases stroke volume and coronary blood flow, thus contributing to a better oxygen supply to the heart [4]. This might be useful in patients suffering from coronary heart diseases and congestive heart failure. Its use has been advocated in hypertensive patients undergoing vascular surgery, either abdominal, neuro- or cardiovascular [33]. Moreover, it has been used to prevent cerebral vasospasm in

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subarachnoid hemorrhage. Nicardipine has been recommen-ded as agent of choice to reduce blood pressure in patients with ischemic stroke when DBP > 120 mmHg or SBP > 220 mmHg [34]. When administered intravenously, nicardipine’s onset ranges from 5 to 15 minutes, and its action lasts between 4 to 6 hours [4]. Patient weight does not influence nicardipine dose, which starts from 5mg/h, up to a 15 mg/h, with an increasing rate of 2.5 mg/h every 5 minutes (Table 5). The main adverse effect is abrupt reduction in blood pressure and reflex tachycardia, which can be harmful in patients with coronary heart disease.

Clevidipine is a third-generation dihydropyridine calcium-channel antagonist [4, 35] (Table 4). Acting as arteriolar smooth muscle cells relaxant, clevidipine reduces peripheral vascular resistance. As a result, blood pressure lowers and cardiac output increases. Being metabolized by the esterases of red blood cells, it exhibits an ultra short activity, with an half life of about 2 minutes (Table 5). This makes clevidipine very suitable in those conditions when blood pressure needs to be tightly controlled, such as in intensive care and perioperative care [35]. Moreover, clevidipine exerts a protective role in ischemic tissues limiting reperfusion injury, either scavenging oxygen free radicals or reducing intracellular calcium overflow toxicity [36]. Clevidipine is effective in reducing blood pressure in hypertensive crises in surgical and intensive care patients and at the emergency department [37]. In hypertensive patients scheduled for cardiac surgery, pre-operative clevidipine was given to control high blood pressure [38]. It showed to rapidly decrease blood pressure without significant increases in heart rate (median of 6 minutes, CI 95% 6-8 min.). This last effect must be taken as an

advantage when treating patients suffering from ischemic heart disease, in whom any reflex tachycardia can increase myocardial oxygen consumption. Similarly, clevidipine was found to reduce blood pressure without influencing cardiac index or filling pressures [39]. The drug showed both a rapid onset and offset in patients admitted to postoperative intensive care. Authors concluded that clevidipine may be useful in treatment of acute postoperative hypertension. The same results were found in the ECLIPSE trials on acute hypertension treatment in cardiac surgery patients [40]. Clevidipine showed to be more effective than nitroglycerin (p=0.0006) and sodium nitroprusside (p=0.003) in maintai-ning a blood pressure target. Compared to nicardipine, it showed the same efficacy, but more stability in terms of less blood pressure excursions. No differences were found in the incidence of myocardial infarction, stroke or postoperative renal dysfunction.

Alpha-Adreno Receptors Agonists and Antagonists: Urapidil, Phentolamine and Clonidine

Urapidil acts as a peripheral 1 post-synaptic receptor antagonist and as a central 5-hydroxytryptamine receptor agonist [4, 41] (Table 4). It induces a reduction in both preload and afterload, thus lowering cardiac output and blood pressure, without reflex effects on heart rate (Table 5). It is used to control hypertensive crisis either in surgical patients or during pregnancy [41]. Urapidil has been compared to nitroprusside in its efficacy in reducing blood pressure during hypertensive emergencies [42]. It showed to be as effective as nitroprusside, with a slower effect and a lower incidence of adverse hypotensive events. In light of this, Authors recommended its use in patients with

Table 4. Drugs Receptor Interaction and Mechanism of Action

Calcium Channel Alfa 1 Alfa 2 Beta 1 Beta 2 D1 5-HT NO

Nicardipine Antagonist

Clevidipine Antagonist

Urapidil Antagonist

(+++) Partial Agonist

(++) Antagonist

(+) Agonist

(++)

Clonidine Agonist

(+++)

Agonist

(+)

Agonist

(+)

Phentolamine Antagonist

(+++)

Antagonist

(+++)

Antagonist

(+)

Labetalol Antagonist

(+++++++)

Antagonist

(+++++++)

Antagonist

(+)

Antagonist

(+)

Esmolol Antagonist

Nitroglycerine Donors

Sodium

Nitroprusside Donors

Fenoldopam Antagonist

(+)

Antagonist

(+)

Agonist

(+++)


cerebrovascular and cardiovascular diseases, in whom a gradual and cautious reduction of blood pressure is indicated. Urapidil-mediated 1-block proved to be useful in patients undergoing laparoscopic surgery for pheocromo-cytoma. The drug prevented cathecolaminergic crises during gland manipulation and resection [43]. Urapidil use is contraindicated in aortic stenosis [18].

Phentolamine is a competitive receptor antagonist that shows affinity for both -1 and -2 adreno-receptors (Table 4). It exerts also an 5-HT and K+ channels blocking effect. Phentolamine has an half-life of 19 minutes following intravenuos administration and approximately 13 % of a single intravenous dose appears in the urine as unchanged

drug. Phentolamine can be used for short-term control of hypertension in patients with Pheochromocytoma [44]. To control high blood pressure, 5 mg of the drug are injected intravenously 1 or 2 hours before surgery and repeated if necessary (Table 5). Tachyphylaxis, reflex thachycardia and an increase in circulating levels of noradrenaline counter indicate its use for prolonged blood pressure control in peri-operative period [45].

Rapid infusions of phentolamine may cause severe hypotension, and the drug should be administered cautiously. In addition, reflex cardiac stimulation may cause alarming tachycardia, cardiac arrhythmias, and ischemic cardiac events, including myocardial infarction. GI stimulation may

Table 5. Antihypertensive Agents’ Synopsis

Drug Dynamic Dose Onset (min) Metabolism Offset Adverse Effects

Nicardipina calcium-channel

antagonist

5mg/h, up to a 15 mg/h, with

an increasing rate of 2.5 mg/h every 5 minutes

5-15 hepatic 4-6 h

abrupt reduction in blood pressure

and reflex tachycardia

Clevidipine calcium-channel

antagonist

0.4 g/kg/min doubling

every 90 seconds to a maximum of 8 g/kg/min

1-2 esterases of

red blood cells

5-15 min

Urapidil

peripheral 1 post-

synaptic receptor

antagonist and central

5HT receptor agonist

bolus of 10-50 mg or 2

mg/min titrated up to 9 mg/min

2-5 hepatic 1-2 h hypotension, cardiac arrhythmias

Phentolamine

-1 and -2

adrenoreceptors

antagonist

2-5 mg 1-2 hours before

pheochromocytoma surgery

repeating if necessary

1-2 hepatic 15-30 min

tachyphylaxis, reflex thachycardia,

an increase of circulating levels of

noradrenaline cardiac arrhythmias,

ischemic cardiac events abdominalpain, nausea

Clonidine 2-adrenergic receptors

agonist

starting at 0.2 mg/kg/min

and titrated up to a maximum of 0.5 mg/kg/min

5-10 hepatic 6-8 h bradycardia and hypotension, dry

mouth and sedation

Labetalol

1-adrenergic and

nonselective -

adrenergic blocking agent

initial dose of 20 mg,20-80

mg can follow every 10

minutes. Continuous

infusion starting at 1-2

mg/hrs after the loading doseof 20mg

2-5 hepatic 2-4 h bradycardia and bronchospasm

Esmolol 1-adrenergic

blocking agent

bolus of 0.5 to 1 mg/kg

followed by a

continuous infusion starting

at 50 g/kg/min and titratedup

to 300 g/kg/min

1

red blood

cells esterases

10-20 min bradycardia and bronchospasm

Nitroglycerine NO donors

5 g/min, titrated by 5

g/min every 5-10 min to maximum of 60 g/min

2-5 hepatich 10-20 min

hypotension, tachycardia,

hypoxemia , tachyphylaxis and headache

Sodium

Nitroprusside NO donors

starting at 0.5 g/kg/min,

and titrated up to a maximum of 2 g/kg/min

<1breaken down

in erythrocyte1-2 min

cyanide toxicity

Fenoldopam dopamine-1 receptor

agonist

starting dose of 0.1

g/kg/min 5 hepatic 40 min

increase intraocular

pressure,tachycardia, hypotensionand hypokaliemia


result in abdominal pain, nausea, and exacerbation of peptic ulcer.

Clonidine is a direct and selective agonist of 2-adrenergic receptors (Table 4). Intravenous administration of clonidine leads to an acute and transient elevation in blood pressure, due to peripheral post-sinaptic 2-adrenergic stimulation [46]. However this effects is followed by a prolonged hypotensive effect which is related to its adrenergic stimulation on brain stem receptors. Both heart rate and contractility are reduced by clonidine. Secondary effects are linked to excessive sympathetic block, such as bradycardia and hypotension (Table 5). Clonidine exerts analgesic and sedative effects [47]. Those combined effects make clonidine useful in controlling the postoperative hypertension associated to pain and agitation [46]. Moreover it has shown to reduce anesthetic requirements both in non cardiac and cardiac surgery [48, 49]. Clonidine infusion leads to hemodynamic stability due to the sympathetic block and it seems to reduce perioperative cardiac risk for patients undergoing non cardiac surgery [50]. Interestingly, patients undergoing regional anesthesia for carotid endoarterectomy treated with clonidine had a significantly reduced cortisol, epinephrine and norepinephrine plasma concentration (p<0.05) [51]. Same results were observed in hypertensive patients undergoing general anesthesia for major vascular surgery [52], in whom clonidine showed to reduce anesthetic requirements and plasma level of adrenergic stress mediators. This blunt in adrenergic response to surgical stress, might be helpful when managing peri-operative hypertensive crises.

Beta-Blockers: Labetalol and Esmolol

Labetalol is a -blocker with selective 1 -adrenergic and nonselective -adrenergic blocking activity, with a / -blocking ratio of 1:7 [53] (Table 4). Following intravenous administration, labetalol exerts its effects in 2-5 minutes, peaking at 5-15 minutes and lasting 2-4 hrs (Table 5). Reflex tachycardia is blunt by the -blocking effect, and heart rate can also be slightly reduced [54]. Labetalol reduces the systemic vascular resistance without, thus increasing cardiac output. Moreover, it maintains cerebral, renal, and coronary blood flow [55]. Its use is safe in pregnancy, due to little placental transfers [55]. Labetalol is administered as an initial dose of 20 mg. Next doses of 20-80 mg can follow every ten minutes, targeting a desired BP. Continuous infusion is suitable as well, starting at 1-2 mg/hr after the loading dose of 20 mg, and titrating it to the desired blood pressure values [4, 53]. Adverse effects include bradycardia and bronchospasm, while caution must be used in treating patients with congestive heart failure to avoid acute heart failure [18].

Esmolol is cardioselective, -adrenergic blocking agent (Table 4). Following its administration, the effect starts within one minute and lasts up to 10-20 minutes [56] Table 5. Esmolol reduces blood pressure reducing heart rate and myocardial contractility, thus reducing cardiac output. However, peripheral blood flow is maintained. Esmolol exerts no vasodilating effect [56]. Being metabolized by the red blood cells esterases, its elimination is not dependant on hepatic or renal function. However, any reduction in the number of circulating red cells might prolong its half-life.

Due to the rapid onset and offset, esmolol is considered as the anti-hypertensive of choice in intensive care and postoperatively, when a tight control on blood pressure has to be kept [53]. This hemodynamic stabilizing effect was recently evidenced in neurosurgical patients treated with esmolol during emergence from general anesthesia [57]. Authors found that a loading dose of the drug followed by a continuous infusion, effectively treated tachycardia and hypertension (p<0.05). The same effect has been observed during endotracheal intubation or skin incision, when esmolol can prevent any raise in intracranial pressure associated to excessive adrenergic stimulation [58]. A “myocardial sparing effect” has been observed in brain dead organ donors, in whom esmolol can be used to avoid the effect of associated “autonomic storm” [59].

As an antiarrhythmic drug, esmolol has been employed to reduce heart rate in supraventricular tachyarrhtymias [60] and its use has been recommended particularly in decreasing ventricular rate in high rate atrial fibrillation in post-CABG patients [61].

Perioperatively, esmolol infusion contributes to a better pain control, reducing opioid requirements. Recently, it has been used as a continuous infusion in hypertensive patients undergoing laparoscopic cholecystectomy [62]. In this trial, Authors found that esmolol exerted an opiod-sparing effect, both intraoperatively (p=0.001) and post-operatively (p=0.012). Esomolol is administered as a slow (one minute long) bolus of 0.5 to 1 mg/kg, followed by a continuous infusion starting at 50 g/kg/min and titrated up to 300

g/kg/min, targeting a desired blood pressure [4]. As with labetalol, bradycardia and bronchospasm may follow its administration, and its use in congestive heart failure must be judicious [18].

Nitroglycerin

Nitroglycerin is a venous dilator which reduces dilate arterioles only at high doses [63] (Table 4). It reduces blood pressure reducing preload and, thus, cardiac output. Nitroglycerin onset starts in 2-5 minutes after administration, and lasts 10-20 minutes after withdrawal [4, 53]. Its elimination is hepatic (Table 5). When administered to volume depleted patients (e.g., postoperative patients), Nitroglycerin tends to cause hypotension and reflex tachycardia, particularly harmful in the setting of coronary heart disease [27]. Moreover, reduction of cardiac output can impair peripheral blood flow, particularly to kidneys and brain. Due to its potential detrimental effects, use of nitroglycerin in critical care patients must be cautious, and a low-dose administration is advised only in patients with hypertensive emergencies associated with acute coronary syndromes or acute pulmonary edema [18]. Dosing regimens start at 5 g/min, titrated by 5 g/min every 5-10 min to maximum of 60 g/min [4]. Adverse effect include hypotension and tachycardia, hypoxemia due to ventilation-perfusion mismatch (it blunts hypoxemic vasoconstriction in lungs), tachyphylaxis and headache.

Sodium Nitroprusside

Sodium nitroprusside acts as arterial and venous vasodilator, decreasing cardiac after-load and preload [4, 64] (Table 4). Nitroprusside is a very effective anti-hypertensive


agent. Its effect begins seconds after starting the intravenous infusion and lasts for 1-2 minutes after its withdrawal. Nitroprusside use should be limited to manage very severe hypertensive crisis, starting as an infusion rate of 0.5

g/kg/min, and up to a maximum of 2 g/kg/min [4, 18] Table 5. Due to its direct vasodilatory effects, nitroprusside tends to decrease peripheral blood flow to tissues. This effect may be detrimental in coronary heart disease, where a “steal” of blood can occur from ischemic to healthy myocardium [64]. In patients with compromised brain autoregulatory system, such as following intracranial hemorrhage or trauma, nitroprusside-associated hypotension can dangerously lower cerebral blood flow, precipitating ischemic damage [65]. Moreover, nitroprusside raises intracranial pressure via an increased cerebral blood flow [66].

Main adverse affect of nitroprusside is cyanide toxicity [53]. Cyanide is released at a dose related rate during nitroprusside infusion. Cyanide accumulation, interfering with cellular respiratory pathways, can lead to coma, encephalopathy, convulsions, irreversible focal neurologic abnormalities or sudden cardiac death [18]. Liver metabo-lizes cyanide in to thiocyanate, which is then excreted by kidneys [64]. In order to detoxificate cyanide, a continuous supply of thiosulfate to liver is necessary [4]. Moreover, normal liver and renal functions are required. Considering the potential for severe toxicity and harmful effects on peripheral blood flow, nitroprusside should be used in a very cautious way, limiting length of infusion and associating a continuous infusion of hydroxocobalamin [18].

Fenoldopam

Fenoldopam is a dopamine-1 receptor agonist which induces vasodilatation, thus lowering peripheral vascular resistance and blood pressure [4, 67] (Table 4). Its effect begins within 5 minutes after starting the infusion and peaks in 15minutes. At infusion withdrawal, fenoldopam effects last for about 40 minutes [67]. The rapid fenoldopam metabolism is hepatic and it does not involve the cytochrome P-450. An initial starting dose of 0.1 g/kg/min is recommended [18] (Table 5). Due to its dopamine-1 effect, fenoldopam increases renal blood flow, improving urine flow, creatinine clearance and sodium excretion in patients with or without impaired renal function [68]. This makes fenoldopam infusion appealing to treat hypertensive patients with worsening renal function, as those undergoing renal transplant and receiving cyclosporine [69] or in those who need radiocontrast to prevent associated nephrotoxicity [70]. Moreover, experimental data support its use in patients receiving amphotericin-B [71]. Being a pure vasodilator, fenoldopam infusion can be followed by a reflex tachycardia. This mandates caution when used in patients at risk for myocardial ischemia [72]. Fenoldopam raises intraocular pressure, and it should be given with caution, if it all, to patients suffering from glaucoma or elevated intracranial pressure [72].

CONCLUSIONS

Due to the high prevalence of arterial hypertension, hypertensive crisis are commonly observed. While hypertensive urgencies can be conservatively managed, emergencies challenge the clinician with the target of

reducing blood pressure while maintaining organ blood flow, e.g., avoiding coronary, brain or renal hypo-perfusion. In order to do so, many different agents are suitable, and therapeutic strategies must be undertaken considering both severity of the crisis and clinical features of the single patients. Faster agents, like clevidipine, might be of particular benefit when arterial pressure control must be achieved quickly.

REFERENCES

[1] Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA,

Izzo JL Jr, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,

National Heart, Lung, and Blood Institute, National High Blood Pressure Education Program Coordinating Committee. Seventh

report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Hypertension

2003; 42(6): 1206-52. [2] Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et

al. Heart disease and stroke statistics: 2007 update. A report from the American Heart Association Statistics Committee and Stroke

Statistics Sub-committee. Circulation 2007; 115(5): 69-171. [3] Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment,

and control of hypertension in the United States, 1988-2000. JAMA 2003; 290 (2): 199-206.

[4] Varon J. Treatment of acute severe hypertension. Current and newer agents. Drugs 2008; 68(3): 183-297.

[5] Taler SJ. Secondary causes of hypertension. Prim Care Clin Off Pract 2008; 35: 489-500.

[6] Flanigan JS, Vitberg D. Hypertensive emergencies and severe hypertension: What to treat, who to treat, and how to treat. Med

Clin N Am 2006; 90: 439-51. [7] Heilpern K. Pathophysiology of hypertension. Ann Emerg Med

2008; 51: S5-6. [8] Vaughan CJ, Elanty N. Hypertensive emergencies. Lancet 2000;

356: 411-7. [9] Kim JR, Kiefe CI, Liu K, Williams OD, Jacobs DR Jr, Oberman A.

Heart rate and susbequent blood pressure in young adults: the CARDIA study. Hypertension 1999; 33: 640-6.

[10] Ritz E. Heart and kydneys: fatal twins? Am J Med 2006; 119(5): S31-S9.

[11] Jandelet-Dahm K, Cooper ME. Hypertension and diabetes: role of renin-angiotensin system. Endocrinol Metab Clin N Am 2006; 35:

469-90. [12] Hostetter TH, Rosenberg ME, Ibrahim HN, Juknevicius I.

Aldosterone in renal disease. Curr Opin Nephrol Hypertens 2001; 10(1): 105-10.

[13] Aggarawal M, Khan IA. Hypertensive crisis: hypertensive emergencies and urgencies. Cardiol Clin 2006; 24: 135-46.

[14] Sarafidis PA, Bakris GL. Insulin and endothelin: an interplay contributing to hypertesnion development? J Clin Endocrinol

Metab 2007; 92(2): 379-85. [15] Ault MJ, Ellrodt AG. Pathophysiological events leading to the end-

organ effects of acute hypertension. Am J Emerg Med 1985; 6: 10-5. [16] Strandgaard S, Paulson OB. Cerebral autoregulation. Stroke 1984;

15(3): 413-6. [17] Immink RV, van den Born BJ, van Montfrans GA, Koopmans RP,

Karemaker JM, van Lieshout JJ. Impaired cerebral autoregulation in patients with malignant hypertension. Circulation 2004; 110(15):

2241-5. [18] Slama M, Modeliar SS. Hypertension in the intensive care unit.

Curr Opin Cardiol 2006; 21: 279-87. [19] Wong TY, Mitchell P. Hypertensive retinopathy. N Engl J Med

2004; 351: 2310-7. [20] London GM, Marchais SJ, Guerin AP, Pannier B. Arterial stiffness:

pathophysiology amd clinical impatc. Clin Exp Hypertens 2004; 26: 689-99.

[21] Mahajan N, Mehta Y, Rose M, Shani J, Lichstein E. Elevated troponin level is not synonymous with myocardial infarction. Int J

Cardiol 2006; 111: 442-9. [22] Ghoeghiade M, De Luca L, Fonarow GC, Filippatos G, Metra M,

Francis GS. Pathophysiologic targets in the early phase of acute heart failure syndromes. Am J Cardiol 2005; 96: 11G-7G.


[23] Kamalakannan D, Rosman HS, Eagle KA. Acute aortic dissection.

Crit Care Clin 2007; 26: 779-800. [24] Smith HT. Hypertension and the kidney. Am J Hypertens 1993;

6(4): 119S-22S. [25] Lenfant C. National Education Program Working Group on High

Blood Pressure in Pregnancy. Working group report on high blood pressure in pregnancy. J Clin Hypertens 2001; 3(2): 75-88.

[26] Frishman WH, Schlocker SJ, Awad K, Tejani N. Pathophysiology and medical management of systemic hypertension in pregnancy.

Cardiol Rev 2005; 13(6): 274-84. [27] Haas CE, LeBlanc JM. Acute postoperative hypertension: a review

of therapeutic options. Am J Health Syst Pharm 2004; 61(16): 1661-73.

[28] Varon J, Marik PE. Perioperative hypertension management. Vasc Health Risk Manage 2008; 4(3): 615-27.

[29] Roberts AJ, Niarchos AP, Subramanian VA, Abel RM, Herman SD, Sealey JE, et al. Systemic hypertension associated with

coronary artery bypass surgery. Predisposing factors, hemodynamic chracteristics, humoral profile, and treatment. J Thorac Cardiovasc

Surg 1977; 74: 846-59. [30] Goldberg ME, Larijani GE. Perioperative hypertension.

Pharmacotherapy 1998; 18: 911-4. [31] Perez MI, Musini VM. Pharamcological interventions for

hypertensive emergencies. Cochrane Database Syst Rev 2008; 23(1): CD003652.

[32] Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest 2000; 118: 214-27.

[33] Curran MP, Robinson DM, Keating GM. Intravenous nicardipine: its use in the short term treatment of hypertension and various other

indications. Intravenous nicardipine: its use in the short term treatment of hypertension and various other indications. Drugs

2006; 13 (66): 1755-82. [34] Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger

D, et al. American Heart Association/American Stroke Association Stroke Council, American Heart Association/American Stroke

Association High Blood Pressure Research Council, Quality of Care and Outcomes in Research Interdisciplinary Working Group.

Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American

Heart Association/American Stroke Association Council, High Blood Pressure Research Council, and the Quality of Care and

Outcomes. Stroke 2007; 38: 2001-23. [35] Rodriguez G, Varon J. Clevidipine. A unique agent for the critical

care practiotioner. Crit Care Shock 2006; 2 (9): 37-41. [36] Segawa D, Sjoquist PO, Wang QD, Gonon A, Rydén L. Time-

dependent cardioprotection with calcium anatagonist and experimental studies with clevidipine in ischemic-reperfused pig

hearts: part II. J Cardiovasc Pharmacol 2002; 36: 338-42. [37] Noviawaty I, Uzun G, Qureshi AI. Drug evaluation of clevidipine

for acute hypertension. Expert Opin Pharmacother 2008; 14(9): 2519-29.

[38] Levy JH, Mancao MY, Gitter R, Kereiakes DJ, Grigore AM, Aronson S, et al. Clevidipine effectively and rapidly controls blood

pressure preoperatively in cardiac surgery patients: the results of the randomized, placebo-controlled efficacy study of clevidipine

assessing it preoperative effect in cardiac surgery-1. Anesth Analg2007; 105: 918-25.

[39] Bailey JM, Lu W, Levy JH, Ramsay JG, Shore-Lesserson L, Prielipp RC, et al. Clevidipine in adult cardiac surgical patients.

Anesthesiology 2002; 96: 1086-94. [40] Aronson S, Dyke CM, Stierer KA, Levy JH, Cheung AT, Lumb

PD, et al. The ECLIPSE trials: comparative studies of clevidipine to nytroglicerin, sodium nitroprusside and nicardipine for acute

hypertension treatment in cardiac surgery patients. Anesth Analg 2008; 107: 1110-21.

[41] Dooley M, Goa KL. Urapidil: a reappraisal of its use in the management of hypertension. Drugs 1998; 5(56): 929-55.

[42] Hisrchl MM, Binder M, Bur A, Herkner H, Müllner M, Woisetschläger C, et al. Safety and efficacy of urapidil and sodium

nitroprusside in the treatment of hypertensive emergencies. Intensive Care Med 1997; 23: 885-8.

[43] Tauzin-Fin P, Sesay M, Gosse P, Ballanger P. Effects of perioperative alpha1 block on haemodynamic control during

laparoscopic surgery for phaeochromocytoma. Br J Anaesth 2004; 4 (93): 512-7.

[44] Koba SL, Paran E, Jamali A, Mizrahi S, Siegel RJ, Leor J.

Pheohromocytoma:cyclic attacks of hypertension alternating with hypotension. Nat Clin Pract Cardiovasc Med 2008; 5: 53-7.

[45] Feneck R. Drugs for the perioperative control of hypertension curren issues and future directions. Drugs 2007; 14(67): 2023-44.

[47] Sica DA. Centrally acting antihypertensive agents: an update. J Clin Hypertens (Greenwich) 2007; 5(9): 399-405.

[47] Giovannoni MP, Ghelardini C, Vergelli C, Dal Piaz V. Alpha2-agonists as analgesic agents. Med Res Rev 2009; 2(29): 339-68.

[48] Sollazzi L, Modesti C, Vitale F, Sacco T, Ciocchetti P, Idra AS, et al. Preinductive use of clonidine and ketamine improves recovery

and reduces postoperative pain after bariatric surgery. Surg Obes Relat Dis 2009; 1(5): 67-71.

[49] Mandke A, Mevada H, Borkar S, Mandke N. Clinical efficacy of clonidine as an adjunct to anaesthesia for coronary artery bypass

graft surgery. Ann Card Anaesth 1999; 1(2): 22-7. [50] Mercado DL, Ling DY, Smetana GW. Perioperative cardiac

evaluation: novel interventions and clinical challenges. South Med J 2007; 5(100): 486-92.

[51] Schneemilch C, Bachmann H, Ulrich A, Elwert R, Halloul Z, Hachenberg T. Clonidine decreases stress response in patients

undergoing carotid endarterectomy under regional anesthesia: a prospective, randomized, double-blinded, placebo-controlled study.

Anesth Analg 2006; 103: 297-302. [52] Quintin L, Bouilloc X, Butin E, Bayon MC, Brudon JR, Levron JC,

et al. Clonidine for major vascular surgery in hypertensive patients: a double-blind, controlled, randomized study. Anesth Analg 1996;

83: 687-95. [53] Marik PE, Varon J. Hypertensive crises challenges and

management. Chest 2007; 6(131): 1949-62. [54] Olsen KS, Svendsen LB, Larsen FS, Larsen FS, Paulson OB. Effect

of labetalol on cerebral blood flow, oxygen metabolism and autoregulation in healthy humans. Br J Anaesth 1995; 75: 51-4.

[55] Pearce CJ, Wallin JD. Labetalol and other agents that block both -and -adrenergic receptors. Cleve Clin J Med 1994; 61: 59-69.

[56] Reynolds RD, Gorczynski RJ, Quon CY. Pharmacology and pharmacokinetics of esmolol. J Clin Pharmacol 1986; 26: A3-A14.

[57] Bilotta F, Lam AM, Doronzio A, Cuzzone V, Delfini R, Rosa G. Esmolo blunts postoperative hemodynamic changes after propofol-

remifentanil total intravenous fast track neuroanesthesia for intracranial surgery. J Clin Anesth 2008; 20: 426-30.

[58] Ugur B, Ogurlu M, Gezer E, Nuri AO, Gursoy F. Effects of esmolol, lidocaine and fentanyl on haemodynamic responses to

endotracheal intubation: a comparative study. Clin Drug Investig 2007; 4(27): 269-77.

[59] Audibert G, Charpentier C, Seguin-Devaux C, Charretier PA, Grégoire H, Devaux Y, et al. Improvement of donor myocardial

function after treatment of autonomic storm during brain death. Transplantation 2006; 8(82): 1031-6.

[60] Kanji S, Stewart R, Fergusson DA, McIntyre L, Turgeon AF, Hébert PC. Treatment of new-onset atrial fibrillation in noncardiac

intensive care unit patients: A systematic review of randomized controlled trials. Crit Care Med 2008; 5(36): 1620-4.

[61] Hilleman DE, Reyes AP, Mooss AN, Packard KA. Esmolol versus diltiazem in atrial fibrillation following coronary artery bypass

graft surgery. Curr Med Res Opin 2003; 5 (19): 376-82. [62] Ozturk T, Kaya H, Aran G, Aksun M, Savaci S. Postoperative

beneficial effects of esmolol in treated hypertensive patients undergoing laparoscopic cholecystectomy. Br J Anaesth 2008; 2

(100): 211-4. [63] Bussmann WD, Kenedi P, von Mengden HJ, Nast HP, Rachor N.

Comparison of nitroglycerin with nifedipine in patients with hypertensive crisis or severe hypertension. Clin Investig 1992;

1085-8. [64] Friederich JA, Butterworth JF. Sodium nitroprusside: twenty years

and counting. Anesth Analg 1995; 81: 152-62. [65] Hartmann A, Buttinger C, Rommel T, Czernicki Z, Trtinjiak F.

Alteration of intracranial pressure, cerebral blood flow, autoregulation and carbon dioxide-reactivity by hypotensive agents

in baboons with intracranial hypertension. Neurochirurgia 1989; 32: 37-43.

[66] Anile C, Zanghi F, Bracali A, Maira G, Rossi GF. Sodium nitroprusside and intracranial pressure. Acta Neurochir 1981; 58:

203-11.


[67] Bodmann KF, Troster S, Clemens R, Schuster HP. Hemodynamic

profile of intravenous fenoldopam in patients with hypertensive crisis. Clin Investig 1993; 72: 60-4.

[68] Shusterman NH, Elliott WJ, White WB. Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive

patients with impaired renal function. Am J Med 1993; 95: 161-8. [69] Jorkasky DK, Audet P, Schusterman N, Ilson B, Dafoe D, Hedrich

D, et al. Fenoldopam reverses cyclosporine-induced renal vasoconstriction in kydney transplant recipients. Am J Kidney Dis

1992; 19: 567-72.

[70] Bakris GL, Lass NA, Glock D. Renal hemodynamics in

radiocontrast medium-induced renal dysfunction: a role for dopamine receptors. Kidney Int 1999; 56: 206-10.

[71] Brooks DO, Mitchell MP, Short BG, Ruffolo RR Jr. The effect of fenoldopam on the acute and subacute nephrotoxicity produced by

amphotericin-B in the dog. J Pharmacol Exp Ther 1992; 260: 269-74.

[72] 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(21): 1548-57.

Received: March 28, 2009 Revised: March 31, 2009 Accepted: March 31, 2009

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