hta

Review article

Perioperative hypertension: a review of current and

emerging therapeutic agents

,

☆

,

☆☆

Paul E. Marik MD, FCCP, FCCM (Professor, Chief)

⁎

,

Joseph Varon MD, FCCM, FCCP (Professor of Critical Care Medicine, Internal Medicine,

and Pulmonology)

a

Pulmonary and Critical Care Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA

b

The University of Texas Health Science Center at Houston, Houston, TX 77030, USA

c

The University of Texas Medical Branch at Galveston, St. Luke's Episcopal Hospital, Houston, TX 77550, USA

Received 7 December 2007; revised 7 September 2008; accepted 19 September 2008

Keywords: ACE inhibitor; Beta-blocker;

Calcium channel blocker; Clevidipine;

Esmolol; Hypertension; Hypertensive crisis; Labetalol;

Nicardipine; Non-cardiac surgery; Surgery

AbstractPerioperative hypertension is a common problem encountered by anesthesiologists, surgeons, internists, and intensivists. Surprisingly, no randomized, placebo-controlled studies exist that show that the treatment of perioperative hypertension reduces morbidity or mortality. Nevertheless, perioperative hypertension requires careful management. While sodium nitroprusside and nitroglycerin are commonly used to treat these conditions, these agents are less than ideal. Intravenous beta blockers and calcium channel blockers have particular appeal in this setting.

© 2009 Elsevier Inc. All rights reserved.

1. Introduction

Hypertension is one of the most common chronic medical conditions in the United States, affecting close to 30% of the

population over the age of 20 years[1,2]. The prevalence of hypertension increases markedly with aging, affecting up to 60% to 70% of the population beyond the seventh decade of life[3,4]. The World Health Organization has estimated that by the year 2025, one third of the global population will be suffering from this illness.

Hypertension is a major risk factor for cardiovascular disease, stroke, and renal disease. It is now well established that treatment of hypertension reduces the risk of developing these conditions[5-9]. Furthermore, isolated systolic hyper-tension, which is particularly common in the elderly, is associated with an increased risk of cerebrovascular and coronary artery disease (CAD). Treatment of isolated systolic hypertension reduces the risk of these complications

[10,11]. The most recent report from the Joint National Committee on Prevention, Detection, Evaluation, and ☆ _{Funding: None.}

☆☆ _{Disclosure: Dr. Marik has received stipends and travel allowances}

for lectures at Medical Grand Rounds and National Meetings from ESP Pharma (PDL Pharmaceuticals) who market nicardipine (Cardene). Dr. Varon has received honoraria for lectures from PDL Pharmaceuticals and has served as a consultant for The Medicines Company and participated as an investigator in the Velocity trial, which was sponsored by The Medicines Company. These companies have developed and marketed nicardipine (Cardene) and clevidipine.

⁎Corresponding author. Tel.: +1 215 955 6590; fax: +1 215 923 6003.

E-mail address:paul.marik@jefferson.edu(P.E. Marik). Keywords:

ACE inhibitor; Beta-blocker;

Calcium channel blocker; Clevidipine;

Esmolol; Hypertension; Hypertensive crisis; Labetalol;

Nicardipine; Non-cardiac surgery; Surgery

Treatment of High Blood Pressure (JNC VII) recommends risk factor modification and treatment with antihypertensive agents in all patients with systolic blood pressure (SBP) greater than 140 mmHg and/or diastolic blood pressure (DBP) greater than 90 mmHg, regardless of age[2].

As chronic hypertension is extremely common in the general population, management of patients with hyperten-sion undergoing surgery is of major clinical importance. Chronic hypertension increases complications and mortality following a wide spectrum of surgical procedures. This association was first suggested by Smithwick and Thompson who, in 1953, reported that the mortality of hypertensive patients undergoing sympathectomy was sixfold higher than for normotensive patients undergoing similar operations

[12]. More recent data support the concept that patients with chronic hypertension are at increased risk of complications and death after surgery. The National Veterans Administra-tion Surgical Risk study of 83,000 patients found that hypertension was the second most common risk factor for surgical morbidity [13]. Numerous other studies have confirmed this finding [14-22]. The association between chronic hypertension and increased perioperative complica-tions in patients undergoing surgery is probably related to the fact that hypertension increases the risk of cardiovascular, cerebrovascular, and renal disease, and that these comorbid-ities increase the risk of surgery. It is not clear, however, that increased blood pressure (BP)per seincreases surgical risk or that normalization of BP preoperatively reduces these risks. Overzealous BP control may result in unnecessary postponements of elective surgery and increase the risk of ischemic organ injury and adverse drug reactions.

The controversy regarding management of preoperative hypertension dates back to the study by Prys-Roberts and colleagues, published in 1971 [23]. This study compared three groups of patients: a control group consisting of 7 elderly normotensive patients with an average mean arterial pressure (MAP) of 89 mmHg, a group of 7 hypertensive patients whose elevated BP pressure was not being treated preoperatively and who had an average MAP of 129 mmHg, and a group of 15 hypertensive patients whose high BP was treated preoperatively and who had an average MAP of 129 mmHg. Patients with untreated hypertension had the greatest absolute decrease in BP and the highest percentage of arrhythmias and ischemic episodes. This study was non-randomized; there were major imbalances between groups with respect to type of surgery performed and severity of comorbidities. Furthermore, a standard anesthetic technique was used for all patients. This controversy is further fueled by the study of Goldman and Caldera, published in 1979

[16]. These investigators compared surgical outcomes in three groups of patients: sick hypertensive patients whose high BP was treated preoperatively, less sick hypertensive patients whose high BP was“undertreated”preoperatively, and less sick, only moderately hypertensive patients, who received no treatment preoperatively. No difference in outcome between groups was found.

Weksler et al. performed a “quasi”-randomized con-trolled study (RCT) in 989 chronically treated hypertensive patients who were scheduled for noncardiac surgery and who had a preoperative DBP of between 110 and 130 mmHg [24]. These investigators excluded patients with known CAD or cerebrovascular disease, left ventricular hypertrophy, valvular disease, or conduction defects. The control group had their surgery postponed and they remained in the hospital for BP control, while the study patients received 10 mg of nifedipine intranasally prior to surgery. There was no difference in postoperative complica-tions between the two groups, which suggested that this subset of patients without significant cardiovascular comor-bidity can proceed with surgery despite elevated BP on the day of surgery. The generalizability of these findings is limited because of the absence of neurologic or cardiovas-cular complications in either group, suggesting that it was a very low-risk population. However, the use of intranasal nifedipine in this study is worrisome (see below), and the number of patients in the treatment group who developed severe hypotension after administration of the nifedipine was not reported.

2. Perioperative beta blockers

of postoperative myocardial infarction (MI) in patients undergoing noncardiac surgery; however, there were sig-nificantly more deaths in the metoprolol group[35]. These data suggest that perioperative beta blockers no longer be routinely prescribed in patients undergoing noncardiac surgery. However, beta blockers should not be stopped in patients chronically taking these agents.

3. Preoperative hypertension

Although preoperative BP is a significant predictor of postoperative morbidity, no data have established defini-tively that preoperative treatment of hypertension reduces postoperative complications. Ideally, all elective surgery patients with cardiovascular risk factors should undergo aggressive preoperative optimization, including control of BP, correction of electrolytes, glucose control, cessation of smoking, nutritional optimization (in high-risk patients), and possible treatment with statins[32,36-40]. The management plan in patients who present to the operating room with

“poorly” controlled BP should be individualized based on each patient's clinical presentation, comorbidities, and the assumed risks of surgery. Surgery should be deferred in those patients with acute end-organ hypertensive injury, ie, those with cardiac failure, myocardial ischemia, acute renal dysfunction, and papilledema/encephalopathy. In high-risk patients (eg, previous stroke, active CAD) with a SBP greater than 180 mmHg and/or DBP greater than 110 mmHg, it may be prudent to cancel surgery until BP and cardiovascular status have been optimized. In otherwise low-risk patients with a SBP greater than 180 mmHg and/or DBP greater than 110 mmHg, it may be reasonable to reduce BP (by no more than 20%) with a combination of intravenous (IV) beta-blocking agent and a benzodiazepine (for anxiolysis) prior to surgery. A beta blocker (metoprolol) or an alpha-beta blocker (labetalol) are the agents of choice. In patients with adequate beta-blockade [low heart rate (HR)] or in those patients in whom a beta blocker is contraindicated (asthma, conduction defect) may be treated with one of the IV dihydropyridine calcium channel blockers (nicardipine or clevidipine). Due to its short half-life, clevidipine is particularly useful in this setting. Agents with unpredictable hypotensive effects, namely nifedipine, hydralazine, and angiotensin-converting enzyme inhibitors (ACEs), should not be used in this situation. Although intranasal nifedipine was used by Weksler et al, use of this agent by this route is particularly hazardous as it may lead to a precipitous decrease in BP with myocardial, cerebral, and renal ischemia/infarction[41-43]. Hypertensive patients should continue to receive all their antihypertensive drugs preoperatively. However, the clini-cian should consider either discontinuing or reducing the dose of ACE inhibitors (ACEI) and angiotensin II receptor antagonists (ARA) at least 10 hours before surgery, as these agents have been associated with intraoperative hypotension

[44]. Coriat et al. found that ACE inhibitors were associated with hypotension in 100% of patients during induction ver-susabout 20% in whom ACE inhibitors were withheld on the morning of surgery[45]. Similarly, Brahant et al. reported post-induction hypotension in 100% of patients chronically treated with a ARA, 67% receiving an ACE and 60% receiving a beta blocker or calcium channel blocker[46]. In this study, hypotension refractory to ephedrine or pheny-lephrine requiring treatment with vasopressin occurred in 33% of patients in the ARA group, whereas all hypotensive patients receiving a beta blocker/calcium channel blocker responded to ephedrine or phenylephrine.

4. Intraoperative hypertension

Chronically hypertensive patients are more likely to experience labile hemodynamics intraoperatively[23]. There is evidence that postoperative cardiac complications are more likely in the presence of intraoperative hemodynamic instability (defined as fluctuations in MAP greater than 20%)

[47,48]. Achieving hemodynamic stability thus may be more important than targeting an arbitrary intraoperative BP. Many factors influence intraoperative BP, including patients' comorbidities, type of surgery, volume status, depth of anesthesia, and anesthetic agents used. The management of intraoperative BP is beyond the scope of this review; however, a short-acting beta blocker (esmolol) or calcium channel blocker (clevidipine) should be considered in patients with significant elevations in BP (see Discussion below andTable 1).

5. Acute postoperative hypertension

Acute postoperative hypertension (APH) has been defined as a significant elevation in BP during the immediate postoperative period that may lead to serious neurologic, cardiovascular, or surgical-site complications and which requires urgent management. While APH is widely recog-nized, there is no standardized definition for this disorder

It is likely that a number of overlapping pathophysiologic mechanisms are responsible for the development of APH, including activation of the sympathetic nervous and renin-angiotensin systems, alterations in intravascular volume, anxiety, pain, anesthesia emergence, shivering, drug side effects, underlying hypertension, and vascular disease. However, activation of the sympathetic nervous system appears to be a fundamental component of APH, as evidenced by elevated plasma catecholamine concentrations in these patients [52]. Type and duration of surgery as well as anesthetic technique and agents used are also likely to influence the development of APH. The primary

hemody-namic alteration observed in APH is an increase in afterload with an increase in SBP and DBP with or without tachycardia. Rose and colleagues studied the incidence and con-sequences of hypertension (defined as SBP N 20% of the preoperative reading) in 18,380 patients admitted to the postoperative anesthesia care unit (PACU) following general surgery[19]. In this study, 2% of patients developed APH; these patients were at significantly increased risk of unplanned critical care admission and they had a greater hospital mortality. Patients with intraoperative hypertension, inadequate ventilation, and excessive pain had an increased risk of APH. In a similar study, Hines and colleagues reported hypertension in 1.1% of PACU patients[53], while Moller and colleagues reported this complication in 0.6% of patients undergoing general surgery[54]. The frequency of APH is much higher in patients undergoing carotid endarterectomy, abdominal aortic surgery, radical neck dissection, and intracranial surgery, with reported frequen-cies of between 20% and 60%[49].

In cardiac surgery patients, treatment is usually suggested for BP N140/90 mmHg or MAP N 105 mmHg[49,50]. In these patients, meticulous BP control is recommended. Uncontrolled swings in BP are likely to increase risk of bleeding, myocardial ischemia, renal dysfunction, and cerebral ischemia as well as compromise vascular anasto-moses. In the noncardiac surgery patient, there is no consensus regarding the treatment threshold. Treatment of these patients is usually a clinical decision based on degree of BP elevation, nature of the surgery, patients' comorbidities, and risks of treatment. Unfortunately, no prospective study has yet evaluated the clinical benefit of aggressive BP control in the postoperative period. In addition, many of the referenced studies are now almost two decades old, with very few contemporary studies having been conducted.

Pain and anxiety are common contributors to BP elevations and should be treated before administration of antihypertensive therapy. Patients' volume status should be carefully assessed. Intravascular volume depletion increases sympathetic activity and vasoconstriction; in this setting, a volume challenge should be considered. Other potentially reversible causes of APH include hypothermia with shiver-ing, hypoxemia, hypercarbia, and bladder distension. Short-term administration of a short-acting IV agent is recom-mended when there is no identifiable treatable cause of hypertension. As increased sympathetic activity underlies the pathophysiology of APH, an alpha/beta blocker or beta blocker alone would appear to be a rational agent to use. The short-acting IV calcium channel blocking agents also have a role. Labetalol, esmolol, nicardipine, and clevidipine gene-rally are considered the agents of choice for treatment of APH. Fenoldopam, sodium nitroprusside, and enalaprilat may have a role in select circumstances. These drugs are summarized in Table 1 and briefly reviewed below. Considering the increased complications associated with APH, this condition is best prevented. Prevention may be achieved by preoperative BP control, attention to

intrao-Table 1 Dosage and adverse effects of commonly used parenteral antihypertensive medications for the management of perioperative hypertension

Agent Dosage Adverse effects

Nitroglycerin 5 ug/min, titrated by 5 ug/min every 5-10 min to maximum of 60 ug/min

Headache, dizziness, tachyphylaxis

Nitroprusside 0.5 ug/kg/min, increase to maximum of two ug/ kg/min to avoid toxicity

Thiocyanate and cyanide toxicity, headache, nausea/ vomiting, muscle spasm, flushing Enalaprilat 1.25 mg over 5 min

every 4-6 hrs, titrate by 1.25 mg increments at 12 to 24-hr intervals to maximum of 5 mg every 6 hrs

Variable response, potential hypotension in high rennin states, headache, dizziness

Fenoldopam 0.1 ug/kg/min initial dose, 0.05 to 0.1 ug/kg/ min increments to maximum of 1.6 ug/kg/min

Nausea, headache, flushing

Esmolol 500 ug/kg loading dose over one min, infusion at 25 to 50 ug/kg/min, increased by 25 ug/kg/ min every 10 to 20 min to maximum of 300 ug/kg/min

Nausea, flushing, first degree heart block, infusion site pain

Labetalol 20 mg initial bolus, 20 to 80 mg repeat boluses or start infusion at one to two mg/min with maximum 24 hr dose of 300 mg

Hypotension, dizziness, nausea/ vomiting, paresthesias, scalp tingling,

bronchospasm Nicardipine 5 mg/hr, increase at

2.5 mg/hr increments every 5 min to maximum of 15 mg/hr

Headache, dizziness, flushing, nausea, edema, tachycardia

Clevidipine Two mg/hr double every three min to effect and not to exceed l32 mg/hr

perative volume status and hemodynamics, and postopera-tive pain management and anxiolysis. Regional analgesia (eg, thoracic epidurals) and patient-controlled analgesia should be considered to control postoperative pain.

An uncommon form of postoperative hypertension that may be misdiagnosed is clonidine withdrawal syndrome

[55-58]. This syndrome occurs 18 to 24 hours after patients, who almost always were taking more than 1.0 mg/day, abruptly stop taking clonidine. Clonidine withdrawal syndrome is of particular concern in the perioperative period because there is no rapidly acting parenteral form of this drug for use in patients unable to take oral medication. Character-ized by excessive sympathetic activity with rebound hypertension, this syndrome often resembles the hypertensive crisis of pheochromocytoma. Clonidine withdrawal syn-drome may be aggravated by the simultaneous use of a non-selective beta blocker which blocks peripheral vasodilatory beta-receptors, leaving vasoconstricting alpha receptors unopposed. Dexmedetomidine, an IV rapid-acting alpha-2 adrenergic agonist, alleviates withdrawal syndrome follow-ing use of cocaine, opioids, and benzodiazepines, and it may have utility in patients with clonidine withdrawal syndrome

[59-61]. Clonidine withdrawal syndrome can be prevented by converting the patient to a clonidine patch preoperatively.

6. Agents for perioperative blood

pressure control

6.1. Nitroglycerin

Nitroglycerin is a potent venodilator and only at high doses affects arterial tone[62]. In volume-depleted patients, nitroglycerin may cause severe hypotension and reflex tachycardia, which are exacerbated by volume depletion. Nitroglycerin reduces BP by reducing preload and cardiac output (CO); this increases the severity of the hyper-adrenergic state characteristic of APH. Nitroglycerin, like nitroprusside, is commonly recommended for the treatment of APH [63]. However, due to its pharmacodynamic properties and unpredictable hypotensive effects, nitrogly-cerin is a poor agent for control of APH. However, low-dose (≤60 mg/min) nitroglycerin may be used as an adjunct to IV antihypertensive therapy in patients with APH associated with acute coronary syndromes or acute pulmonary edema.

6.2. Hydralazine

Hydralazine is a direct arteriolar vasodilator having little or no effect on the venous circulation, and it often causes reflex sympathetic stimulation[64]. Hydralazine, similar to nitroprusside, has been shown to increase circulating catecholamines [65]. Although hydralazine has a rapid onset (within 5 to 15 min), there can be an unpredictable and often precipitous decrease in BP lasting up to 12 hours

[64]. It can be very difficult to titrate BP response and this agent is best avoided in this setting. Hydralazine has been the drug of choice for the treatment of the increased BP of preeclampsia[66]. However, a recent meta-analysis suggests that, compared with other agents, hydralazine is associated with increased maternal and fetal complications[67].

6.3. Nitroprusside

Sodium nitroprusside is an arterial and venous vasodilator which decreases both afterload and preload. It is a very potent agent, with an onset of action of seconds, duration of action of one to two minutes, and a plasma half-life of three to 4 minutes. Sodium nitroprusside has been considered the drug of choice for APH, especially after cardiac surgery[63]. Apart from concern regarding cyanide toxicity[68], the drug has a number of attributes which render it less than ideal in the setting of APH. In patients with CAD, a significant reduction in regional blood flow (coronary steal) can occur

[69]. In a large, randomized, placebo-controlled trial, nitroprusside increased mortality when infused in the early hours after acute MI (mortality at 13 wks, 24.2% vs. 12.7%)

[70]. Nitroprusside decreases renal blood flow and, when compared with other agents, decreases renal function[71]. In addition, nitroprusside decreases cerebral blood flow (CBF) while increasing intracranial pressure, effects that are particularly disadvantageous following craniotomy[72-75]. Furthermore, because of its potent and labile antihyperten-sive effects, nitroprusside requires meticulous monitoring, usually invasive BP monitoring.

Nitroprusside contains 44% cyanide by weight [76]. Cyanide is released nonenzymatically from nitroprusside, the amount generated being dependent on dose of nitroprusside administered. Data suggest that nitroprusside infusion rates in excess of 4 ug/kg/min, for as little as two to three hours, may lead to cyanide levels in the toxic range

[76]. The recommended doses of nitroprusside of up to 10 ug/kg/min result in cyanide formation at a far greater rate than human beings can detoxify. In addition, hemolysis associated with cardiopulmonary bypass increases the release of free cyanide [77]. Sodium nitroprusside also causes cytotoxicity through the release of nitric oxide, with hydroxyl radical and peroxynitrite generation leading to lipid peroxidation [78-81]. Considering the potential for severe toxicity with nitroprusside, this drug should be used only when other IV antihypertensive agents are unavailable, and then only in specific clinical circumstances and in patients with normal renal and hepatic function [82]. Duration of treatment should be as brief as possible and the infusion rate should not exceed two ug/kg/min.

6.4. Enalaprilat

long-acting and the antihypertensive effects are unpredictable

[68]. However, enalaprilat has been used preemptively in patients undergoing craniotomy for the control of hyperten-sion during emergence [83]. Postoperative BP control is achieved by combining a longer-acting drug (enalaprilat) with a fast-acting drug which is easier to titrate (labetalol or nicardipine).

6.5. Fenoldopam

Fenoldopam is unique among the parenteral BP agents as it mediates peripheral vasodilation by acting on peripheral dopamine-1 receptors. Ten times more potent than dopa-mine, fenoldopam has the distinct advantage of mediating renal arterial vasodilation and activating dopamine receptors on the proximal and distal tubules, inhibiting sodium reabsorption and thereby promoting natriuresis and diuresis

[84]. Onset of action is within 5 minutes, with a maximal response achieved within 15 minutes[85-87]. Duration of action is 30 to 60 minutes and does not cause rebound hypertension when the infusion is discontinued. It is quickly and extensively metabolized by conjugation in the liver, without participation of the P450-cytochrome complex. After a starting dose of 0.1 ug/kg/min, the dose can be titrated every 15 minutes depending on BP response. Fenoldopam causes a dose-dependent BP decrease in the infusion range of 0.03 to 0.3 ug/kg/min [88]. In the postoperative setting, fenoldopam is effective in controlling BP following hypertensive episodes[89].

Fenoldopam improves creatinine clearance, urine flow rates, and sodium excretion in severely hypertensive patients with both normal and impaired renal function [71,90,91]. Consequently, fenoldopam may be particularly beneficial in patients with impaired renal function[92]. No adverse effects have been noted with its use; however, the drug is contra-indicated in patients with glaucoma.

6.6. Labetalol

Labetalol is a combined selective alpha-1 and non-selective beta-adrenergic receptor blocker with an alpha- to beta-blocking ratio of 1:7[93]. Labetalol is metabolized by the liver to form an inactive glucuronide conjugate [94]. The hypotensive effect of labetalol begins within two to 5 minutes after its IV administration, reaching a peak at 5 to 15 minutes following administration, and lasting for about two to 4 hours[94,95]. Due to its beta-blocking effects, HR is either maintained or slightly reduced. Unlike pure beta-adrenergic blocking agents, which decrease CO, labetalol maintains CO [96]. Labetalol reduces systemic vascular resistance without reducing total peripheral blood flow. In addition, cerebral, renal, and coronary blood flow are maintained[96-99].

Labetalol may be given as a loading dose of 20 mg, followed by repeated incremental doses of 20 to 80 mg

given at 10-minute intervals until the desired BP is achieved. Alternatively, after the initial loading dose, an infusion commencing at one to two mg/min and titrated up until the desired hypotensive effect is achieved, is particularly effective. Bolus injections of one to two mg/ kg produce precipitous decreases in BP and should therefore be avoided[100].

Labetalol has been evaluated for the treatment of APH following cardiac, vascular, intracranial, and general surgery. It has been found to be a safe and effective agent, with a response rate of between of 85% and 100%[101-105].

6.7. Esmolol

Esmolol is particularly useful in severe postoperative hypertension, particularly in tachycardiac patients[106-112]. Esmolol is an ultra-short-acting cardioselective, beta-adre-nergic blocking agent[113-115]. The onset of action of this agent is within 60 seconds, with a duration of action of 10 to 20 minutes [113-115]. The metabolism of esmolol is via rapid hydrolysis of ester linkages by red blood cell esterases, and it is not dependent on renal or hepatic function. Due to its pharmacokinetic properties, esmolol is considered the“ideal beta-adrenergic blocker” in postoperative patients [116]. This agent is available for IV use both as a bolus and as an infusion. Esmolol is a suitable agent in situations where CO, HR, and BP are increased. Typically, the drug is given as a 0.5-1 mg/kg loading dose over one minute, followed by an infusion starting at 50 mcg/kg/min and increasing up to 300 mcg/kg/min as necessary.

6.8. Nicardipine

Nicardipine is a second-generation, dihydropyridine-derivative calcium channel blocker with high vascular selectivity and strong cerebral and coronary vasodilatory activity. Nicardipine is 100 times more water-soluble than nifedipine and thus can be administered intravenously, rendering it an easily titratable IV calcium channel blocker

[117,118]. Onset of action of IV nicardipine occurs between 5 and 15 minutes, with a duration of action of 4 to 6 hours. Intravenous nicardipine reduces both cardiac and cerebral ischemia [119]. Nicardipine's dosage is independent of patient weight, with an initial infusion rate of 5 mg/hr, increasing by 2.5 mg/hr every 5 minutes to a maximum of 15 mg/hr, until the desired BP reduction is achieved[116].

favorably affects the balance between myocardial oxygen demand and supply[124].

6.9. Clevidipine

Clevidipine is a third-generation dihydropyridine calcium channel blocker which has been developed for use in clinical settings where tight BP control is crucial[125]. Clevidipine is an ultra-short-acting, selective arteriolar vasodilator

[126-128]. Similar to esmolol, it is rapidly metabolized by red blood cell esterases and thus its metabolism is not affected by renal or hepatic function. Clevidipine reduces BP by a direct and selective effect on arterioles, thereby reducing afterload without affecting cardiac filling pressures or causing reflex tachycardia [129]. Stroke volume and CO usually increase. Clevidipine increases coronary blood flow despite a decrease in coronary perfusion pressure, indicating that the drug is a direct coronary vasodilator[130]. Moreover, clevidipine protects against ischemia/reperfusion injury in an animal model of myocardial ischemia, and maintains renal function and splanchnic blood flow[131-133]. This agent can be safely used in end-stage renal disease patients.

Clevidipine is very effective in the control of postoperative hypertension [130,134]. The recently completed ECLIPSE (Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events) trial showed the efficacy and safety of this agent in the treatment of APH. ECLIPSE randomized 1,964 cardiac patients requiring treatment for perioperative hypertension to receive clevidipine or another agent (nitroprusside or nicardipine) [135]. Clevidipine was more effective than nitroprusside in control-ling BP, with a lower mortality (1.7% vs. 4.7%;P= 0.045) and similar efficacy and safety as nicardipine. Clevidipine has recently been approved by the Food and Drug Administration for use in the U.S.

7. Conclusions

Management of the perioperative hypertension patient is challenging at best. Several drugs may be utilized in this setting. However, most of these agents are not ultra-short-acting, rendering their titration and effects difficult to manage. Of the drugs available for clinical use, nicardipine, esmolol, and labetalol are effective and have a good safety profile. The new calcium channel blocker, clevidipine, appears promising.

Acknowledgment

The authors acknowledge the assistance of Susan Baik, RN, for her helpful critique and editorial assistance with this manuscript.

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