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Table 18-4 Vasodilator Infusions

Drug Name (Trade Name)IV InfusionMechanism of Action
MixaKineticsbDose
Clevidipine (Cleviprex)25 mg/50 mL lipid emulsion (0.5 mg/mL)cO: 2-4 min
D: 5-10 min		Initial: 1-2 mg/hd
Usual: 4-8 mg/h		CCB; arterial > venous vasodilation
Nicardipine (Cardene)40 mg/200 mL (0.2 mg/mL)cO: 5-10 min
D: 0.5-8 h		Initial: 5 mg/he
Usual: 5-15 mg/h		CCB; arterial > venous vasodilation
Nitroglycerin50 mg/250 mL (400 μg/mL)O: 1 min
D: 5 min		Initial: 50 μg/minf
IV bolus: 50-100 μg		NO; venodilation
Nitroprusside (Nipride)50 mg/250 mL (200 μg/mL)O: 1-2 min
D: 5-10 min		Initial: 0.5 μg/kg/minf
Usual: 0.5-4 μg/kg/min		NO; arterial > venous vasodilation
Fenoldopam (Corlopam)10 mg/250 mL (40 μg/mL)O: 5-10 min
D: 1-4 h		Initial: 0.05 μg/kg/ming
Usual: 0.05-1.5 μg/kg/min		D1-agonism; arteriodilation

a Infusion mix in 5% dextrose in water unless otherwise specified.

b O, onset; D, duration of action.

c Manufacturer preparation.

d Double dose every 90 seconds until approaching blood pressure goal, up to maximum 21 mg/h.

e Increase dose by 2.5 mg/h every 5 to 15 min, up to maximum 15 mg/h.

f Increase dose every 5 min based on patient responsiveness, up to maximum dose of 400 μg/min.

g Increase dose by 0.05 to 0.1 μg/kg/min every 15 minutes, up to a maximum dose of 1.5 μg/kg/min.

CCB, calcium channel blocker; D1, dopamine-1 receptor; NO, nitric oxide; NR, not recommended.

  1. Calcium channel antagonists, or calcium channel blockers (CCBs), bind L-type calcium channels that regulate calcium entry into vascular smooth muscle, myocardial cells, and cardiac pacemaker cells. They decrease the vascular resistance of peripheral organs, cause coronary artery vasodilation, and are myocardial depressants. CCBs are distinguished by their relative affinities for cardiac versus vascular L-type calcium channels.
    1. Dihydropyridine (DHP) CCBs are more selective for vascular smooth muscle and are used to treat hypertension. Their physiologic effect is largely arterial vasodilation with minimal effects on venous capacitance.
      1. Clevidipine is an ultrashort-acting antihypertensive administered by IV infusion ideal for perioperative use due to its rapid onset, titration, and elimination half-life of approximately 1 minute by serum esterases. After cessation, effects last 5 to 10 minutes, with a 90% return to baseline blood pressure by 7 minutes. Infusions are started at 1 to 2 mg/h and doubled every 90 seconds until blood pressure approaches target range. Usual doses are 4 to 8 mg/h. The maximum allowable dose is 21 mg/h.
      2. Nicardipine is another short-acting antihypertensive administered in IV infusion perioperatively. Infusions are started at 5 mg/h, increased by 2.5 mg/h every 5 to 15 min until target blood pressure is reached, up to a maximum dose of 15 mg/h. Onset is within minutes. After cessation, effects may last up to 8 hours.
      3. Nifedipine is limited to oral administration for the treatment of hypertension, including hypertension associated with pregnancy, at daily doses of 30 to 90 mg.
      4. Nimodipine is an oral CCB approved for the prevention of vasospasm in subarachnoid hemorrhage at a dose of 60 mg q4h. Dose reductions are required in hepatic insufficiency.
      5. Amlodipine is a common oral antihypertensive at daily doses of 5 to 10 mg.
    2. Non-DHP CCBs are more selective for myocardial and pacemaker L-type calcium channels and are termed cardioselective. Verapamil and diltiazem are the two non-DHP CCBs in clinical use.
      1. Indications
        1. Antianginal therapy (by decreasing myocardial oxygen consumption and coronary vasospasm)
        2. Rate control (by depressing AV nodal conduction)
        3. Conversion of hemodynamically stable SVTs (by prolonging AV nodal repolarization, blocking reentry)
        4. Hypertension (by effecting vascular smooth muscle L-type calcium channels)
      2. Contraindications to CCBs are similar to those of β-blockers. CCBs are not appropriate antiarrhythmics for patients with WPW syndrome in atrial fibrillation/flutter, as they may allow for preferential conduction through the accessory pathway.
      3. Verapamil is initially dosed 2.5 to 5 mg IV over 2 minutes, with subsequent doses of 5 to 10 mg IV every 15 to 30 minutes.
      4. Diltiazem is initially dosed 10 to 20 mg IV over 2 minutes, which can be redosed up to 0.35 mg/kg after 15 minutes if needed. An infusion of 5 to 15 mg/h can be initiated in responders.
  2. Sodium nitroprusside is a direct-acting vasodilator that acts on arterial and venous smooth muscle, reducing afterload through arteriolar dilation and reducing preload through venous dilation. Both SVR and PVR decrease.
    1. Mechanism of action. Nitroprusside decomposes to release nitric oxide, an endogenous vasodilator that activates guanylate cyclase, which increases cGMP, and leads to smooth muscle relaxation.
    2. Dosing. Infusions may be started at 0.5 μg/kg/min and titrated upward based on blood pressure response every 5 minutes up to a maximum per-minute dose of 400 μg/min (note: not weight-based).
    3. Kinetics. Nitroprusside is useful perioperatively because it has a fast onset within 2 minutes and its effects dissipate within 2 minutes of discontinuation.
    4. Adverse effects
      1. Reflex tachycardia. Nitroprusside’s reduction of preload and afterload typically causes a reflex increase in heart rate and myocardial contractility and an increase in CO.
      2. Increased intracranial pressure (ICP). Nitroprusside dilates cerebral blood vessels and should be used with caution in patients with elevated ICP.
      3. Vascular steal phenomenon. Global vasodilation may give rise to unintentional imbalances in blood flow. Under normal conditions, ischemic regions are vasodilated by metabolic factors in order to maximize blood supply. Vascular steal phenomenon results when blood supply to a vasodilated ischemic region gets shunted to newly dilated nonischemic regions. This is of particular importance in the coronary vasculature where regional ischemia may be exacerbated by vasodilator-related steal, even when afterload reduction reduces overall myocardial oxygen consumption.
      4. Cyanide toxicity. Nitroprusside reacts nonenzymatically with sulfhydryl groups in hemoglobin to release five cyanide radicals. Cyanide toxicity results when cyanide radicals bind cytochrome oxidase, disrupting the electron transport chain, leading to cellular hypoxia and death even in the presence of oxygen. Cyanide radicals can be converted by tissue and liver rhodanese to thiocyanate, which is excreted in the urine. Thiocyanate accumulation in renal insufficiency can cause thiocyanate toxicity, which is characterized by abdominal pain, vomiting, and altered mental status.
        1. Clinical features. Symptoms of cyanide toxicity include fatigue, nausea, muscle spasms, angina, and confusion. Cyanide toxicity typically occurs when more than 1 mg/kg sodium nitroprusside has been administered within 2.5 hours or when the blood concentration of cyanide reaches 100 μg/dL. Metabolic acidosis and elevated mixed venous oxygen tensions are early signs of cyanide toxicity.
        2. Treatment.Sodium thiosulfate is a sulfur donor in the rhodanese reaction that converts cyanide to thiocyanate. After discontinuing nitroprusside and administering 100% oxygen, 150 mg/kg sodium thiosulfate should be administered over 15 minutes. Severe cyanide toxicity (base deficit >10 mEq, hemodynamic instability) may require the additional administration of amyl nitrate (0.3 mL by inhalation) or 3% sodium nitrite (5 mg/kg IV over 5 minutes). These two compounds create methemoglobin, which binds cyanide ion to form inactive cyanmethemoglobin.
  3. Nitroglycerin, also known as trinitroglycerin, is a potent venodilator that also relaxes arterial, pulmonary, ureteral, uterine, GI, and bronchial smooth muscles. It mediates its effect via conversion to nitric oxide. Nitroglycerin decreases MAP primarily by increasing venous capacitance.
    1. Indications. Nitroglycerin is useful for treating congestive heart failure and myocardial ischemia by increasing coronary flow and improving left ventricular performance. Nitroglycerin increases venous capacitance, decreases venous return, and consequently decreases ventricular end-diastolic volume. A decrease in end-diastolic volume is associated with a decrease in ventricular wall tension, which reduces myocardial oxygen consumption.
    2. Dosing. Nitroglycerin can be administered as an IV bolus of 50 to 100 μg. The effects of a single bolus disappear within 5 minutes. An initial test dose of 50 μg or less is often useful to gauge patient responsiveness, which varies widely. Infusions may be started conservatively at 50 μg/min and titrated based on patient responsiveness every 5 minutes up to a maximum dose of 400 μg/min. Nitroglycerin is also available in oral, sublingual, and transdermal routes.
    3. Reflex tachycardia frequently occurs and must be treated with β-blockers to avoid increasing myocardial oxygen consumption.
    4. Tachyphylaxis often develops within 24 hours of continuous infusion.
    5. Complications. Nitroglycerin is metabolized by the liver and has no known toxicity in the clinical dose range. High doses (>250 μg/min) and prolonged continuous use may produce methemoglobinemia. Nitroglycerin produces cerebral vasodilation and should be used with caution in patients at risk for elevated ICP.
  4. Hydralazine is a direct-acting vasodilator that reduces arteriolar tone in the coronary, cerebral, renal, uterine, and splanchnic beds. It is commonly used to treat hypertensive emergencies or to augment the effect of other hypotensive agents.
    1. Reflex tachycardia. The vasodilation induced by hydralazine triggers a reflex increase in heart rate and causes activation of the renin-angiotensin system. These effects can be attenuated by the concomitant use of a β-blocker.
    2. Dosing. Hydralazine can be administered as an IV bolus of 5 to 20 mg.
    3. Kinetics and pitfalls. Hydralazine’s IV time to peak effect is 20 minutes, thus a reasonable initial bolus of 5 to 10 mg can be redosed in 20 minutes if blood pressure remains elevated. With its relatively longer elimination half-life of 3 to 7 hours, a single dose of hydralazine may act for up to 12 hours. Owing to its delayed onset, hydralazine can easily be dosed in excess of intention, resulting in hours of unwanted hypotension.
  5. Enalaprilat, an active metabolite of enalapril, is currently the only ACE inhibitor available for IV use. It reduces systolic and diastolic blood pressure by inhibiting the conversion of angiotensin I to angiotensin II.
    1. Kinetics. It has an onset of action of approximately 15 minutes, peak effect of 1 to 4 hours, and overall duration of action of about 4 hours. Elimination is primarily renal.
    2. Contraindications. ACE inhibitors interfere with renal autoregulation and must be used with caution in patients with renal dysfunction.
  6. Fenoldopam is a synthetic dopamine (D1) receptor agonist that acts by selective dilation of arterial beds while maintaining renal perfusion.
    1. Uses. A continuous IV infusion may be used perioperatively for the management of severe hypertension in patients with impaired renal function.
    2. Evidence. Despite reducing the incidence of postoperative acute kidney injury (AKI), fenoldopam has not been shown to improve mortality or need for renal replacement therapy.
    3. Dosing. “Renal dose” fenoldopam at 0.1 μg/kg/min has diuretic and natriuretic properties that increase renal blood flow without greatly effecting systemic blood pressure. For hypertension, it can be dosed up to 0.3 μg/kg/min.
    4. Kinetics. Onset is within 5 to 15 minutes, and the dose should be adjusted every 15 to 20 minutes until optimal blood pressure control is achieved.
    5. Adverse effects include dose-dependent tachycardia and occasional hypokalemia. Hypotension may occur with concomitant use of β-adrenergic receptor blockade.
  7. Adenosine is a nucleoside that, in high doses, has inhibitory effects on cardiac impulse conduction through the AV node.
    1. Clinical uses
      1. Adenosine’s ability to slow conduction through the AV node aids in diagnosing and treating SVT.
      2. The transient asystole and hypotension from an adenosine bolus facilitate clipping of cerebral aneurysms by decompressing the aneurysm and improving visualization.
      3. Adenosine dilates coronary arteries. Infusions of adenosine take advantage of coronary steal in pharmacologic stress testing to diagnose myocardial perfusion defects. Regadenoson (Lexiscan) is a more stable analogue of adenosine, which is commonly used for this purpose as a bolus dose of 0.4 mg.
    2. Dosing. Because of rapid degradation by the vascular endothelium, adenosine boluses must be rapidly delivered and followed by flushes. The starting dose is 6 mg, which may be followed by up to two 12 mg boluses, if ineffective.
    3. Precautions. Adenosine may induce acute myocardial ischemia, prolonged sinus pauses, and bradyarrhythmias, thus application of pads for transcutaneous pacing and defibrillation is recommended.
    4. Contraindications. Adenosine should be avoided in patients with WPW syndrome in atrial fibrillation/flutter as it may allow for preferential conduction through the accessory pathway.
  8. α-adrenergic antagonists
    1. Phentolamine is a short-acting selective α-adrenergic receptor antagonist that causes predominantly arterial vasodilation.
      1. Dosing. It is used in 5 mg IV boluses to treat states of hypertension and catecholamine excess (eg, pheochromocytoma). It is additionally used for local infiltration to prevent tissue necrosis after extravasation of norepinephrine, phenylephrine, dopamine, or epinephrine (5-10 mg diluted in 10 mL of saline).
      2. Kinetics. Systemic doses have a rapid onset within 2 minutes and may last up to 30 minutes.
    2. Phenoxybenzamine is an irreversible, long-acting α-adrenergic receptor antagonist approved for the preoperative management of patients with pheochromocytoma. While it effectively prevents intraoperative hypertension in patients with pheochromocytoma, postoperative hypotension is common given its long duration of action of up to a few days.
    3. Selective α1-adrenergic receptor antagonists including tamsulosin, terazosin, and doxazosin are used to induce prostatic smooth muscle relaxation in the management of benign prostatic hyperplasia. Orthostatic hypotension is an adverse effect common to this class of drugs.
  9. Pulmonary vasodilators are used to treat pulmonary hypertension and right ventricular failure.
    1. Prostaglandin E1(alprostadil) is a stable metabolite of arachidonic acid that causes peripheral and pulmonary vasodilation (Appendix I).
    2. Epoprostenol (Veletri, Flolan) is a prostacyclin (PGI2) analogue with vasodilating and antiplatelet effects (Appendix I).
    3. Inhaled nitric oxide selectively delivers vasodilating nitric oxide to ventilated areas to improve V/Q matching, whereas systemic nitric oxide donors such as nitroprusside and nitroglycerin result in unselective pulmonary vasodilation.
    4. Sildenafil is a selective phosphodiesterase-5 inhibitor that decreases cGMP degradation, increasing pulmonary levels of nitric oxide. It has been shown to improve exercise capacity and hemodynamics in patients with pulmonary hypertension.
    5. Bosentan is an oral endothelin receptor antagonist that competitively blocks the binding of endothelin, a potent pulmonary vasoconstrictor. It is approved for pulmonary arterial hypertension.