Intraoperative use of vasoactive agents

INTRODUCTION — Intraoperative episodes of hypotension and hypertension are common due to the effects of anesthetic agents and techniques, surgical manipulations, and the patient's medical comorbidities. This topic discusses the vasoactive agents (eg, vasopressors, inotropes, antihypertensive agents) that are commonly used to treat these intraoperative episodes.

A separate topic discusses the physiologic principles, complications, and controversies surrounding use of intravenous (IV) vasopressors and inotropes. (See "Use of vasopressors and inotropes" and "Drugs used for the treatment of hypertensive emergencies", section on 'Parenteral drugs'.)

Use of IV antihypertensive agents to treat hypertensive emergencies in other settings is discussed in a separate topic. (See "Use of vasopressors and inotropes" and "Drugs used for the treatment of hypertensive emergencies", section on 'Parenteral drugs'.)

Prevention, diagnosis, and treatment of intraoperative hemodynamic aberrations (eg, hypotension, hypertension, tachycardia, bradycardia) are discussed separately. (See "Hemodynamic management during anesthesia in adults".)

VASOPRESSOR AND POSITIVE INOTROPIC AGENTS

Overview — Bolus doses or continuous infusions of vasopressor or inotropic agents are administered to treat hypotension that does not immediately respond to decreasing anesthetic depth administration of fluid (table 1 and table 2) [1] (see "Hemodynamic management during anesthesia in adults", section on 'Hypotension: Prevention and treatment'). Vasopressors raise blood pressure (BP) by increasing systemic vascular resistance (SVR), whereas inotropic (and positive chronotropic) agents increase contractility and heart rate (HR) to increase cardiac output (CO). Many agents have both vasopressor and inotropic effects. However, the anesthesiologist is not directly measuring effects on CO unless a pulmonary artery catheter or other CO monitoring device is in place. (See "Pulmonary artery catheterization: Interpretation of hemodynamic values and waveforms in adults", section on 'Calculation of cardiac output' and "Novel tools for hemodynamic monitoring in critically ill patients with shock", section on 'Cardiac output'.)

Although agents that increase BP may be necessary to treat hypotension, other causes of hypotension (eg, hypovolemia) should be identified and treated to minimize dosing and duration of vasopressor/inotropic agent administration [2,3].

Notably, agents such as ephedrine and epinephrine that increase HR, CO, and BP may be detrimental in selected patients with ischemic heart disease (table 3), or left ventricular (LV) outflow tract obstruction. (See "Anesthesia for noncardiac surgery in patients with ischemic heart disease", section on 'Prevention of ischemia' and "Anesthesia for patients with hypertrophic cardiomyopathy undergoing noncardiac surgery".)

Adrenergic agents — (See "Use of vasopressors and inotropes", section on 'Adrenergic agents'.)

Ephedrine

●General considerations – Ephedrine is administered in 5 to 10 mg bolus doses. It is often selected as a first-line agent to treat acute decreases in BP, particularly if bradycardia is present. Ephedrine stimulates alpha, beta₁, and beta₂ receptors; thus, it has vasopressor, inotropic, and chronotropic properties. These are primarily indirect effects that include presynaptic release of norepinephrine, as well as postsynaptic release and inhibition of norepinephrine uptake [4-6].

●Advantages

•Increases in BP, HR, and CO are beneficial in most patients with hypotension, particularly if bradycardia originating within or above the atrioventricular node is present (eg, due to beta blocking agents).

•Bronchodilating beta₂ effects are beneficial if bronchospasm is present [7].

•Duration of action is typically longer than equipotent small bolus doses of epinephrine.

•Cerebral blood flow and cerebral oxygenation are better preserved compared with phenylephrine [8-11].

●Disadvantages

•Tachyphylaxis may occur with repeated doses or in patients with depleted stores of endogenous norepinephrine (eg, those with hemorrhagic shock). Typically, another agent is added or substituted for ephedrine after 50 to 60 mg have been administered [12].

•Attenuation of the cardiovascular effects of ephedrine occurs if it is coadministered with agents that block ephedrine uptake into adrenergic nerves (eg, cocaine) or deplete norepinephrine reserves (eg, prazosin).

•An exaggerated hypertensive response or life-threatening dysrhythmias may occur following administration of ephedrine to patients chronically receiving:

-Monoamine oxidase inhibitors – (See "Perioperative medication management", section on 'Monoamine oxidase inhibitors'.)

-Methamphetamines – (See "Anesthesia for patients with substance use disorder or acute intoxication", section on 'Amphetamines and similar agents'.)

-Selected hallucinogens – (See "Anesthesia for patients with substance use disorder or acute intoxication", section on 'Hallucinogens and dissociative drugs'.)

Thus, ephedrine is avoided or administered in very small incremental doses of 2.5 mg in these patients.

•Use in obstetrical anesthesia may be associated with increased risk of fetal acidosis. (See "Anesthesia for cesarean delivery", section on 'Vasopressors'.)

•Rare allergic reactions such as delayed severe dermatitis may occur following intravenous (IV) injection [13].

•Administration as a continuous infusion is not possible.

Phenylephrine

●General considerations – Phenylephrine may be administered in bolus doses (eg, 50 to 100 mcg) or as a continuous infusion at 10 to 100 mcg/minute. It is often selected to treat hypotension if normal or elevated HR is present. Phenylephrine causes vasoconstriction by exclusively stimulating alpha₁-adrenergic receptors and is usually associated with baroreceptor reflex-mediated decreases in HR. It is the most commonly selected intraoperative vasopressor in the United States.

●Advantages

•A decreased or stable HR is desirable in patients with ischemic heart disease (table 3) [14-16]. (See "Anesthesia for noncardiac surgery in patients with ischemic heart disease", section on 'Prevention of ischemia'.)

•Vasoconstrictor agents with primarily alpha₁ agonist properties such as phenylephrine do not have positive inotropic or chronotropic properties. Such agents are the best initial treatment options for hypotension in patients with LV outflow tract obstruction, aortic stenosis, or tetralogy of Fallot. (See "Anesthesia for patients with hypertrophic cardiomyopathy undergoing noncardiac surgery" and "Anesthesia for noncardiac surgery in patients with aortic or mitral valve disease", section on 'Hemodynamic management' and "Anesthesia for adults with congenital heart disease undergoing noncardiac surgery", section on 'Right-to-left shunt with cyanosis'.)

•Phenylephrine may be administered in bolus doses or as a continuous infusion.

●Disadvantages

•Individual responses may be variable due to variations in vascular responsiveness to phenylephrine [17-19]. For example, genomic studies of polymorphisms of the beta₂-adrenergic receptor suggest that selected patients (eg, Gly16 carriers) may require larger doses of intraoperative vasopressors such as phenylephrine or ephedrine due to association of the Gly16 allele with vasodilation and higher CO compared with other genotypes [20].

•Alpha₁ receptor-mediated vasoconstriction caused by phenylephrine may reduce CO due to decreased stroke volume and arterial compliance [21-23]. Although ephedrine and norepinephrine also cause arterial vasoconstriction, these agents also have positive inotropic effects and ephedrine may also increase HR, with likely increases in CO [21,24-27]. (See "Intraoperative fluid management", section on 'Dynamic parameters to assess volume responsiveness'.)

•Vasoconstriction with decreases in HR is detrimental in selected patients (eg, those with aortic or mitral regurgitation). (See "Anesthesia for noncardiac surgery in patients with aortic or mitral valve disease", section on 'Aortic regurgitation' and "Anesthesia for noncardiac surgery in patients with aortic or mitral valve disease", section on 'Mitral regurgitation'.)

•Effectiveness may be limited in patients with impaired ventricular function and chronic heart failure due to decreased alpha₁ receptor responsiveness.

•The effects of alpha-mediated vasoconstriction on splanchnic blood volumes and venous return are complex and may not always be beneficial [22,23].

•As with ephedrine, rare localized allergic reaction may occur.

Norepinephrine — Norepinephrine is an endogenous catecholamine that may be administered in bolus doses of 4 to 8 mcg or as a continuous infusion at 1 to 20 mcg/minute. It is used for treatment of most types of shock and is commonly used in patients undergoing cardiac surgery (see "Intraoperative management of shock in adults", section on 'Initial resuscitation' and "Intraoperative problems after cardiopulmonary bypass", section on 'Vasoactive drug therapy'). Furthermore, its use as a first-line agent during noncardiac surgery is increasing as infusion via a peripheral IV catheter has become more widely accepted [12,28-33].

●Advantages

•Norepinephrine has positive inotropic effects that maintain or increase CO in most patients, while simultaneously causing arterial vasoconstriction and increasing BP [25,29].

•Compared with phenylephrine, 8 mcg norepinephrine is approximately equipotent to 100 mcg of phenylephrine [34]. At comparable doses, norepinephrine is more likely to increase BP without significantly decreasing stroke volume or arterial compliance [21,25,35].

•Limited data also support the safety and efficacy of norepinephrine in obstetrical anesthesia [36]. (See "Anesthesia for cesarean delivery", section on 'Vasopressors'.)

•Norepinephrine may be administered in bolus doses or as a continuous infusion.

●Disadvantages

•Like phenylephrine, norepinephrine-induced alpha₁ receptor-mediated vasoconstriction may reduce CO in some patients. However, in patients who demonstrate fluid responsiveness (see "Intraoperative fluid management", section on 'Dynamic parameters to assess volume responsiveness'), administration of norepinephrine can increase CO due to greater venous return leading to increased preload [25], as well as its positive inotropic effects.

•A central venous catheter (CVC) or peripherally inserted central catheter is usually employed for prolonged administration of norepinephrine due to concern regarding tissue damage if peripheral extravasation occurs. However, since small doses of norepinephrine may be effective for initial treatment of hypotension, dilute solutions containing norepinephrine 4 to 8 mcg/mL can be administered as a bolus when necessary [34,37]. One randomized trial that included 3626 patients compared administration of norepinephrine in a concentration of 8 to 32 mcg/mL versus phenylephrine 100 mcg/mL as the first-line vasopressor to be infused for treatment of hypotension whether the patient had a CVC [33]. Cardiovascular and renal outcomes were similar between the groups. No episodes of extravascular extravasation were reported. A larger retrospective study that included 14,385 patients who received a norepinephrine infusion of 20 mcg/mL via peripheral IV catheters noted a low incidence of extravasation in five patients (0.035 percent); none required surgical or medical intervention [38]. Other reviews have also noted that dilute solutions of norepinephrine and other vasopressors rarely cause tissue damage when administered through a free-flowing peripheral IV catheter [39-41].

The optimal position in the arm for a peripheral IV catheter is the basilic or cephalic vein. In a systematic review of 325 extravasation and local tissue injury events that occurred during vasopressor infusions in critically ill patients, more than 85 percent occurred at an infusion site located distal to the antecubital fossa in the upper extremity, or distal to the popliteal fossa in the lower extremity [39]. However, catheterization of the basilic or cephalic vein directly in the antecubital fossa is avoided if possible since this position has the potential for penetration of the vein with arm flexion [40].

Epinephrine — Epinephrine is an endogenous catecholamine, which is converted from norepinephrine by phenylethanolamine-N-methyltransferase in the adrenal medulla. It is used as a first-line agent to treat severe intraoperative hypotension due to anaphylaxis or cardiac arrest (table 4 and algorithm 1). (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management" and "Advanced cardiac life support (ACLS) in adults".)

Epinephrine may also be safely used in low bolus doses of 8 to 16 mcg to treat less severe episodes of intraoperative hypotension occurring during cardiac or noncardiac surgery. Notably, epinephrine is more typically administered as an infusion, particularly if repeated bolus doses are necessary. In low-dose infusions of approximately 1 to 2 mcg/minute (ie, 0.01 to 0.02 mcg/kg per minute in a 100 kg patient), epinephrine has primarily beta₂-adrenergic effects with beneficial bronchodilator effects and arterial vasodilation rather than vasoconstriction. Intermediate dose ranges of approximately 2 to 10 mcg/minute (ie, 0.02 to 0.1 mcg/kg per minute) primarily cause predominant beta₁ and beta₂-adrenergic effects as well as some alpha-adrenergic effects, resulting in increased BP and HR, as well as bronchodilation. At higher doses of approximately 10 to 100 mcg/minute (ie, 0.1 to 1 mcg/kg per minute), epinephrine has primarily alpha-adrenergic effects causing vasoconstriction with possible hypertension. Notably, individual responses to dose-related effects are variable.

●Advantages

•As a first-line therapy for cardiac arrest and for anaphylaxis, epinephrine may be administered via an intramuscular (IM) route or through an endotracheal tube if IV access is unavailable or lost during such emergencies. (See "Anaphylaxis: Emergency treatment", section on 'Epinephrine'.)

•Epinephrine may be administered in bolus doses or as a continuous infusion.

●Disadvantages

•Titrating the balance between the alpha and beta receptor effects of epinephrine can be challenging due to interindividual variability in dose-related responses.

•Large bolus doses of epinephrine may cause profound hypertension primarily owing to its alpha effects.

•Adverse metabolic effects of excessive beta₂ stimulation include hyperglycemia, lipolysis, and metabolic acidosis (due to type B lactic acidosis) [42,43].

Vasopressin — Vasopressin (antidiuretic hormone [ADH]) is typically used to treat hypotension that is refractory to administration of adrenergic agents, particularly for patients with vasoplegia (eg, septic shock) (table 5). Vasopressin is a naturally occurring nonapeptide essential for maintenance of plasma osmolality due to its antidiuretic actions. It also acts as a vasoconstrictor by stimulating the nonadrenergic V1 receptor if administered in supraphysiologic concentrations (eg, bolus doses of 1 to 4 units or as a continuous infusion at 0.01 to 0.04 units/minute). It is often added as a supplementary agent after an inadequate response to other vasopressors. Higher vasopressin doses up to 0.1 units/minute are reserved for instances when a mean arterial BP goal cannot be achieved with lower vasopressin doses in combination with other vasopressor agents [44].

Although efficacy of vasopressin is relatively equivalent to equipotent doses of epinephrine in producing profound arterial vasoconstriction, epinephrine is strongly preferred as the first-line vasopressor during advanced cardiovascular life support during cardiac arrest (algorithm 1). (See "Use of vasopressors and inotropes", section on 'Vasopressin and analogs' and "Intraoperative management of shock in adults", section on 'Distributive shock management'.)

●Advantages

•Vasopressin is effective for treatment of hypotension refractory to administration of adrenergic agents (eg, ephedrine, phenylephrine, norepinephrine, epinephrine (table 5)). Examples include vasoplegia due to sepsis, chronic administration of angiotensin-converting enzyme inhibitors, or prolonged cardiopulmonary bypass (CPB) [44,45]. (See "Intraoperative problems after cardiopulmonary bypass", section on 'Vasoplegia' and "Intraoperative management of shock in adults", section on 'Distributive shock management'.)

•Vasopressin has no direct effects on HR; a slower HR is desirable in patients with ischemic heart disease (table 3). (See "Anesthesia for noncardiac surgery in patients with ischemic heart disease", section on 'Prevention of ischemia'.)

•Vasopressin has no vasoconstrictive effect on pulmonary arteries; thus, it is the preferred agent in patients with pulmonary hypertension [46-48]. (See "Anesthesia for noncardiac surgery in patients with pulmonary hypertension or right heart failure", section on 'Vasopressors and inotropes'.)

•An agent with pure vasoconstrictor activity such as vasopressin is the best option for patients with LV outflow tract obstruction, aortic stenosis, or tetralogy of Fallot when treatment with a vasopressor is necessary:

-(See "Anesthesia for patients with hypertrophic cardiomyopathy undergoing noncardiac surgery", section on 'Hemodynamic goals and management'.)

-(See "Anesthesia for noncardiac surgery in patients with aortic or mitral valve disease", section on 'Hemodynamic management'.)

-(See "Anesthesia for adults with congenital heart disease undergoing noncardiac surgery", section on 'Right-to-left shunt with cyanosis'.)

•Vasopressin may be administered in bolus doses or as a continuous infusion.

●Disadvantages

•Peripheral extravasation of vasopressin can cause skin necrosis [49].

•The half-life of vasopressin is longer than that of phenylephrine or the catecholamines (norepinephrine and epinephrine). Thus, vasopressin is more difficult to titrate.

•Vasopressin is usually avoided in patients with neurologic injury and in those undergoing craniotomy because it can cause cerebral vasoconstriction [50]. However, it may be used if hypotension is refractory to adrenergic agents. (See "Anesthesia for craniotomy in adults", section on 'Vasoactive drugs'.)

•Since vasopressin may cause selective splanchnic arteriolar vasoconstriction, it is used cautiously in patients at risk for splanchnic hypoperfusion [44].

Other agents to treat refractory vasoplegia — Infusions of other vasopressors may be necessary to treat vasoplegia that is unresponsive to high doses of norepinephrine and/or vasopressin [51]. These include methylene blue [52-54], angiotensin II [52,55-57], vitamin C [52,58,59], and hydroxycobalamin (table 5) [52-54]. However, none of these are the first-line treatment for intraoperative hypotension. (See "Intraoperative management of shock in adults", section on 'Distributive shock management'.)

Other inotropic agents — Infusions of other inotropic drugs may be used to support the circulation in selected patients. These are not first-line vasoactive agents for treatment of intraoperative hypotension or other hemodynamic abnormalities in the intraoperative setting. Examples include:

●Other adrenergic agents (table 1):

•Dopamine – The hemodynamic effects of dopamine are dose dependent. Its predominant actions are on dopamine-1 receptors resulting in selective vasodilation at low doses, on beta₁-adrenergic receptors resulting in inotropic and chronotropic effects at higher doses, and on alpha-adrenergic receptors resulting in vasoconstriction at the highest doses. Dopamine may be selected as a second-line alternative to norepinephrine in patients with bradycardia. Details are discussed in separate topics. (See "Use of vasopressors and inotropes", section on 'Dopamine' and "Inotropic agents in heart failure with reduced ejection fraction", section on 'Dopamine'.)

•Dobutamine – Dobutamine is an adrenergic agent that has inotropic, chronotropic, and overall vasodilatory properties. Details are discussed in separate topics. (See "Use of vasopressors and inotropes", section on 'Dobutamine' and "Inotropic agents in heart failure with reduced ejection fraction", section on 'Dobutamine'.)

•Isoproterenol – Isoproterenol is an inotropic and chronotropic agent that is not a vasopressor. Mechanisms of action, indications, and contraindications are discussed separately. (See "Use of vasopressors and inotropes", section on 'Isoproterenol'.)

●Other inodilator agents that decrease rather than increase BP (eg, milrinone, levosimendan) as discussed below (table 1). (See 'Inodilators' below.)

ANTIHYPERTENSIVE AGENTS

Overview — Bolus doses and/or continuous infusions of antihypertensive agents may be administered to treat hypertension (table 6) if there is insufficient response to rapid increases in anesthetic depth, administration of analgesic agents, or removal of noxious stimuli (eg, surgical pain, presence of an endotracheal tube). If increases in blood pressure (BP) are thought to be due to interruption of the patient's chronic antihypertensive regimen on the day of surgery, treatment with an intravenous (IV) equivalent of the missed medication is ideal, particularly if that medication was a beta blocker or clonidine. (See "Anesthesia for patients with hypertension", section on 'Antihypertensive medication withdrawal' and "Perioperative management of hypertension", section on 'Withdrawal syndromes'.)

Caution is exercised during administration of any antihypertensive agents to:

●Patients with hypovolemia. Precipitous hypotension may result after administration of any antihypertensive agent, particularly those that reduce preload (eg, nitroglycerin, nitroprusside).

●Patients with increased intracranial pressure (ICP). Most vasodilating agents (eg, nitroprusside, nitroglycerin, hydralazine, calcium channel blockers, fenoldopam) dilate the cerebral circulation and can increase cerebral flow and ICP. (See "Anesthesia for craniotomy in adults", section on 'Vasoactive drugs'.)

Beta blockers — Hypertension associated with increased heart rate (HR) and/or cardiac output (CO) is typically treated with bolus doses of a beta blocker (eg, labetalol, esmolol, metoprolol) (table 6). (See "Drugs used for the treatment of hypertensive emergencies", section on 'Adrenergic-blocking agents'.)

●Advantages

•Decreases in HR and BP are beneficial in patients with ischemic heart disease if tachycardia and/or hypertension are present (table 3). (See "Anesthesia for noncardiac surgery in patients with ischemic heart disease", section on 'Prevention of ischemia'.)

•For patients chronically receiving a beta blocker as part of an antihypertensive or antianginal regimen, administration of a beta blocker is an effective first-line treatment. Notably, if a beta blocker dose was missed on the day of surgery, rebound hypertension may occur. (See "Tapering and discontinuing antihypertensive medications" and "Perioperative management of hypertension", section on 'Withdrawal syndromes'.)

●Disadvantages

•Beta blockers should be avoided in patients with:

-Significant hypovolemia or acute hemorrhage causing anemia [60,61].

-Decompensated heart failure. (See "Treatment of acute decompensated heart failure: Specific therapies", section on 'Approach to long-term therapy in hospitalized patients'.)

-Acute or severe bronchospastic lung disease. (See "Management of the patient with COPD and cardiovascular disease", section on 'Effects of beta-blockers on mortality and COPD exacerbations'.)

-Severe sinus bradycardia or a markedly impaired cardiac conduction system (eg, sinus node dysfunction or advanced atrioventricular block).

•Beta blockers are relatively contraindicated in patients with cocaine intoxication owing to the risk of inducing unopposed alpha-adrenergic stimulation, which may lead to hypertension and myocardial ischemia from coronary vasoconstriction. (See "Cocaine: Acute intoxication", section on 'Use of beta adrenergic antagonists (beta blockers)'.)

Labetalol — Labetalol administered in 5 to 10 mg boluses up to 25 mg is a particularly good choice in patients with concomitant tachycardia and hypertension because it causes nonselective blockade of beta-adrenergic receptors and selective blockade of postsynaptic alpha₁-adrenergic receptors [62]. It is often selected to treat myocardial ischemia due to tachycardia when BP is elevated. Continuous infusions of labetalol are generally reserved for hypertensive emergencies. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Labetalol'.)

However, labetalol is relatively contraindicated for patients with severe asthma, chronic obstructive lung disease, heart failure, or bradycardia without hypertension. Furthermore, labetalol is avoided in hyperadrenergic states caused by pheochromocytoma or cocaine or methamphetamine overdose due to risk of severe hypertension from incomplete alpha blockade.

Esmolol — Esmolol may be administered in 10 to 50 mg boluses. For persistent tachycardia and hypertension, an esmolol infusion at 50 to 300 mcg/minute is appropriate. Esmolol is a very cardioselective beta₁ blocker that has rapid onset, short duration of action, and clinical effects lasting approximately 10 to 15 minutes [63]. Clearance is not dependent on renal or hepatic function because rapid metabolism by plasma esterases results in a short duration of action after discontinuation of the infusion. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Esmolol'.)

Metoprolol — Another option to treat persistent tachycardia and hypertension is administration of boluses of 1 to 5 mg of the longer-acting cardioselective beta₁ blocker metoprolol, followed by 2.5 to 15 mg every 3 to 6 hours. However, metoprolol cannot be administered as an infusion and does not have rapid offset. These properties may be a disadvantage if conditions are unstable during the intraoperative period (eg, due to bleeding). Nevertheless, metoprolol is often the preferred agent during the early postoperative period because of its longer duration of action compared with other IV beta blockers and the convenience of bolus dosing.

Landiolol — Landiolol is a short-acting IV beta blocker with similar kinetics but greater negative chronotropic effects than esmolol due to more selective beta₁ effects; however, landiolol is not available in the United States [63,64].

Calcium channel blocking agents — Selective dihydropyridine-type calcium channel blockers (eg, nicardipine, clevidipine) inhibit calcium influx to provide selective arteriolar smooth muscle relaxation (table 6).

●Advantages – Calcium channel blockers effectively treat increased BP due to increased systemic vascular resistance (SVR); they are used in the absence of tachycardia. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Calcium channel blockers'.)

●Disadvantages – These agents have no atrioventricular nodal blocking properties, so they do not slow HR if tachycardia is present.

Nicardipine — Nicardipine has no major impact on preload or CO, and only minor negative inotropic action [65]. It can be administered either by IV bolus (eg, 100 to 500 mcg increments) or by continuous infusion at 5 to 15 mg/hour. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Nicardipine'.)

Nicardipine has been widely used in a variety of surgical settings, including cardiac and neurosurgical settings [62]. One study comparing nicardipine with esmolol for control of postcraniotomy emergence hypertension noted similar efficacy but a greater need for a second "rescue" agent in patients receiving esmolol [66]. Another study comparing continuous infusions of nicardipine or labetalol to manage hypertension after acute stroke noted similar safety and efficacy for both agents [67].

Clevidipine — Clevidipine is a short-acting IV calcium channel blocker that is only administered by continuous infusion (eg, beginning at 1 to 2 mg/hour with titration up to 16 mg/hour). Clevidipine has rapid onset and rapid offset due to metabolism by plasma esterases, and clearance is not dependent on renal or hepatic function. These properties may confer an advantage over either nicardipine or nitroglycerin in patients requiring tight BP control within a narrow range [68,69]. Efficacy in controlling BP in stroke patients is similar to nicardipine [70-72]. However, clevidipine is more expensive than nicardipine, and data regarding bolus dosing are lacking. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Clevidipine'.)

Direct vasodilators — Direct vasodilators (eg, hydralazine, nitroglycerin, nitroprusside) relax vascular smooth muscle (table 6). Although the precise mechanisms causing vasodilation are not well established, these probably include opening of K+ channels, inhibition of inositol 1,4,5 triphosphate-induced release of calcium from smooth muscle sarcoplasmic reticulum, and stimulation of nitric oxide formation by the vascular endothelium.

●Advantages

•Hypertension is effectively treated due to decreases in SVR, and this may result in a reflex increase in HR that may be desirable in a patient with bradycardia.

•Decreased venous return to the heart reduces preload.

●Disadvantages

•In patients with tachycardia, HR is not decreased; instead, baroreceptor-mediated reflex tachycardia may lead to undesirable further increases in HR.

•During continuous infusion of nitroprusside or nitroglycerin, an intra-arterial catheter is necessary to continuously monitor BP.

•Splanchnic blood flow may be decreased.

Hydralazine — Bolus doses (eg, 2.5 mg) of hydralazine are often used to treat increased BP when bradycardia is present. Repeated doses may be administered every 5 minutes up to 20 mg. Hydralazine is highly selective for arterial resistance vessels, with minimal or no effect on the venous circulation [73]. HR may increase slightly due to activation of the baroreceptor reflex. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Hydralazine'.)

Disadvantages of hydralazine include its relatively slow onset compared with other IV antihypertensive agents and its less predictable antihypertensive response. Also, hydralazine cannot be administered as a continuous infusion.

Nitroglycerin — Nitroglycerin is commonly selected for patients with known or suspected ischemic heart disease because it decreases BP and preload. Nitroglycerin may be administered as an IV bolus, a continuous infusion, a sublingual dose, or by application of a paste. Small bolus doses (eg, 10 to 40 mcg) or the paste formulation of nitroglycerin primarily cause venodilation, thereby reducing preload. Higher doses administered as repeated boluses or by continuous infusion at 10 to 200 mcg/minute (approximately 0.1 to 3 mcg/kg per minute) result in arteriolar dilation, thereby reducing SVR. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Nitroglycerin'.)

Disadvantages include the need for placement of an intra-arterial catheter to continuously monitor BP when a continuous infusion is administered, even though nitroglycerin is rapidly titratable. Also, nitroglycerin is not appropriate for patients with hypovolemia since venodilation further reduces preload. In addition, reflex increase in HR may occur. Increased intrapulmonary shunt has also been reported [74].

Nitroprusside — Nitroprusside is a direct arterial vasodilator that is less commonly selected to treat severe hypertension in the intraoperative setting because safer alternative agents have been developed. It is administered by continuous infusion at 10 to 200 mcg/minute (or 0.1 to 3 mcg/kg per minute). Advantages include its potency, balanced venous and arteriolar effects, and extremely rapid onset and offset.

Disadvantages include the absolute need for an intra-arterial catheter to continuously monitor BP during nitroprusside infusion due to its extreme potency and rapid onset of action. Also, nitroprusside should not be administered in bolus dose(s) due to the risk for precipitous severe hypotension. Also, reflex tachycardia occurs with nitroprusside administration. Other concerns include risk for cyanide accumulation from its metabolic breakdown. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Nitroprusside'.)

Inodilators — Inodilators are used in the management of acutely decompensated congestive heart failure and during and after weaning from cardiopulmonary bypass (CPB), as discussed in separate topics:

●(See "Inotropic agents in heart failure with reduced ejection fraction".)

●(See "Treatment of acute decompensated heart failure: Specific therapies", section on 'Inotropic agents'.)

●(See "Intraoperative problems after cardiopulmonary bypass", section on 'Left ventricular dysfunction'.)

●(See "Intraoperative problems after cardiopulmonary bypass", section on 'Right ventricular dysfunction'.)

These agents are not used as first-line vasoactive therapy in other intraoperative settings but may be selected to improve support of the circulation in patients with specific hemodynamic abnormalities (table 1).

Dobutamine — Dobutamine is an adrenergic agent that acts predominantly on beta₁-adrenergic receptors resulting in inotropic, chronotropic, and overall vasodilation that reduces preload, afterload, and myocardial work, with or without a small reduction in BP. Details are discussed in separate topics. (See "Use of vasopressors and inotropes", section on 'Dobutamine' and "Inotropic agents in heart failure with reduced ejection fraction", section on 'Dobutamine'.)

Milrinone — The inodilator milrinone is a phosphodiesterase inhibitor that works independently of beta-adrenergic receptors, producing positive inotropic effects by slowing hydrolysis of cyclic adenosine monophosphate [75,76]. Since administration of milrinone may result in significantly reduced SVR, concomitant use of an arterial vasoconstrictor (eg, phenylephrine, vasopressin, norepinephrine) is typically necessary. Details are discussed in separate topics. (See "Use of vasopressors and inotropes", section on 'PDE inhibitors' and "Inotropic agents in heart failure with reduced ejection fraction", section on 'Intravenous phosphodiesterase-3 inhibitors'.)

Levosimendan — Levosimendan is a calcium sensitizer that acts as an inodilator by:

●Increasing myocardial sensitivity to calcium, which increases cardiac contractility.

●Opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle cells, causing vascular dilation that reduces preload, afterload, and myocardial work.

This agent has not been approved for use in the United States. Details are discussed in a separate topic. (See "Inotropic agents in heart failure with reduced ejection fraction", section on 'Intravenous calcium-sensitizing agents'.)

Other antihypertensive agents — Other agents are less commonly used to lower BP in the intraoperative setting.

Dexmedetomidine and clonidine — Clonidine and dexmedetomidine are alpha₂-adrenoreceptor agonists with antihypertensive effects (table 6).

●Dexmedetomidine – Dexmedetomidine is commonly administered as a continuous infusion during monitored anesthesia care (MAC) or as part of a total intravenous anesthesia (TIVA) technique during general anesthesia. (See "Monitored anesthesia care in adults", section on 'Dexmedetomidine' and "Maintenance of general anesthesia: Overview", section on 'Dexmedetomidine'.)

Due to its sympatholytic effects, both BP and HR are typically decreased [77,78]. For these reasons, dexmedetomidine may be selected to adjust anesthetic depth in a patient with hypertension and tachycardia. For example, dexmedetomidine is a good choice if it is prudent to avoid beta blocking agents. If intraoperative clonidine withdrawal is suspected, a dexmedetomidine infusion could be initiated or clonidine 0.1 mg could be administered via an orogastric tube (with repeat dosing as necessary). (See "Tapering and discontinuing antihypertensive medications" and "Perioperative management of hypertension", section on 'Withdrawal syndromes'.)

Disadvantages include potent bradycardic effects such that dexmedetomidine should be used with caution during a high spinal or epidural block and in patients receiving beta blockers. Also, decreases in HR and BP resolve slowly and may persist even after emergence from general anesthesia [77]. (See "Maintenance of general anesthesia: Overview", section on 'Dexmedetomidine' and "Emergence from general anesthesia", section on 'Intravenous agents'.)

●Clonidine – For patients chronically receiving clonidine as part of an antihypertensive regimen, a missed dose on the day of surgery may result in a rebound hypertensive response. This can be avoided by application of a transdermal patch of clonidine during the preoperative period, or by selecting dexmedetomidine as an anesthetic agent, as noted above.

Fenoldopam — Fenoldopam is a selective dopamine receptor agonist that produces systemic vasodilation. It is administered by continuous infusion initially at 0.1 mcg/kg per minute and may be increased up to a maximum dose of 1.6 mcg/kg per minute. Fenoldopam has potentially beneficial effects on renal function, although there are no outcome data proving efficacy for renal protection. In some centers, it is used in high-risk vascular surgery or to treat hypertensive emergencies [79,80]. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Fenoldopam'.)

As with other vasodilators, fenoldopam is avoided in patients with increased ICP. It is also avoided in patients with high intraocular pressure (IOP) such as those with glaucoma [81].

Enalaprilat — Enalaprilat is the only available IV angiotensin-converting enzyme inhibitor. It is rarely used in the perioperative setting but may be added to other agents for hypertensive emergencies [82]. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Enalaprilat'.)

Disadvantages include an unpredictable hypotensive response. It may cause precipitous hypotension in hypovolemic patients with high plasma renin activity. Also, enalaprilat has a slow onset over 15 to 30 minutes and a long duration of effect.

Diuretics — Hypertensive patients who are hypervolemic or show signs of pulmonary edema may benefit from diuresis (eg, with administration of IV furosemide 10 to 20 mg), particularly if the morning dose of a chronically administered diuretic was missed. However, since most vasodilating agents administered in the perioperative setting will temporarily reduce preload, administration of a diuretic is not typically necessary.

SUMMARY AND RECOMMENDATIONS

●Vasopressors and inotropic agents

•Overview – Bolus doses and/or continuous infusion of vasopressor and/or inotropic agents are administered to treat hypotension that does not immediately respond to decreasing anesthetic depth and/or fluid administration (table 1). (See 'Overview' above.)

•Adrenergic agents – Adrenergic agents administered to increase blood pressure (BP) include ephedrine (administered in bolus doses), phenylephrine (administered either in bolus doses or as an infusion), and the more potent endogenous catecholamines, norepinephrine and epinephrine (administered either in low bolus doses or as an infusion) (table 2). (See 'Adrenergic agents' above.)

•Agents to treat refractory vasoplegia – Vasopressin administered either in low bolus doses or as an infusion is the agent most commonly used to treat hypotension refractory to administration of adrenergic agents (eg, patients with vasoplegia due to septic shock). Infusions of other vasopressors such as methylene blue, angiotensin II, vitamin C, or hydroxycobalamin may be necessary to treat vasoplegia unresponsive to high doses of norepinephrine and/or vasopressin (table 5). (See 'Vasopressin' above and 'Other agents to treat refractory vasoplegia' above.)

•Other inotropic agents – Infusions of other inotropic drugs may be used to improve support of the circulation in selected patients but are not first-line vasoactive agents for treatment of intraoperative hypotension or other hemodynamic abnormalities. These include the adrenergic agents dopamine, dobutamine, and isoproterenol, and inodilators such as the phosphodiesterase inhibitor milrinone and the calcium-sensitizing agent levosimendan. (See 'Other inotropic agents' above and 'Inodilators' above.)

●Antihypertensive agents

•Overview – Bolus doses and/or continuous infusions of antihypertensive agents may be administered to treat hypertension (table 6) if there is insufficient response to rapid increases in anesthetic depth, administration of analgesic agents, or removal of noxious stimuli. (See 'Overview' above.)

•Beta blockers – Beta blockers administered to decrease BP and/or heart rate (HR) include labetalol and metoprolol (administered in bolus doses), as well as esmolol (administered either in bolus doses or as an infusion). (See 'Beta blockers' above.)

•Calcium channel blockers – Calcium channel blockers that may be administered to decrease BP and systemic vascular resistance (SVR) in the absence of tachycardia include nicardipine and clevidipine (administered either in bolus doses or as an infusion). (See 'Calcium channel blocking agents' above.)

•Direct vasodilators – Direct vasodilators relax vascular smooth muscle to decrease BP by decreasing SVR and preload, which is often accompanied by a reflex increase in HR. Decreased venous return to the heart reduces preload. Direct arterial dilators include hydralazine (administered in bolus doses) and nitroprusside (administered as an infusion), while nitroglycerin is primarily a venodilator administered either in low bolus doses or as a continuous infusion. During infusion of nitroprusside or nitroglycerin, an intra-arterial catheter is necessary to continuously monitor BP. (See 'Direct vasodilators' above.)

•Other antihypertensive agents – Other classes of agents that are less commonly used to lower BP in the intraoperative setting include infusions of dexmedetomidine (an anesthetic agent and alpha₂-adrenoreceptor agonist with sympatholytic effects administered by infusion) or fenoldopam (a selective dopamine receptor agonist with potential renoprotective and vasodilatory effects). (See 'Other antihypertensive agents' above.)