Management of Systemic and Pulmonary Hypertension

Abstract

The major therapeutic approach to systemic and pulmonary hypertension and vasospasm in cardiac surgery patients involves the use of parenteral agents that reverse systemic vasoconstriction and produce vasodilation. Potential pharmacologic approaches include 1) α₁-adrenergic receptor blockers, ganglionic blockers, and calcium channel blockers; 2) central α₂-adrenergic receptor agonists, dopamine₁-adrenergic receptor agonists, potassium channel modulators, and vascular cyclic nucleotide stimulators; 3) phosphodiesterase enzyme inhibitors, and 4) angiotensin-converting enzyme inhibitors. Of the currently available intravenous vasoactive therapies, the mainstay agents are the nitrovasodilators and the dihydropyridine-type calcium channel blockers. The nitrovasodilators, a diverse group of drugs that achieve vascular relaxation by stimulating cyclic nucleotides and thereby releasing nitric oxide, include nitroglycerin and sodium nitroprusside. Although these drugs are useful, rapid development of tolerance is a drawback to nitroglycerin, while nitroprusside can cause coronary steal and increase intracranial pressure. Intravenous dihydropyridine-type calcium channel blockers inhibit mechanical responses of cardiac muscle and vascular smooth muscle by blocking inward calcium currents. Nicardipine is an arterial specific vasodilator. Treatment for vasospasm is usually empiric; pharmacologic options include nitroglycerin, but dihydropyridine calcium channel blockers and phosphodiesterase inhibitors should also be considered.

Perioperative hypertension occurs in patients who undergo cardiac surgery. Control of hypertension in this setting is notably important. Blood pressure is, simply defined, the product of cardiac output and systemic vascular resistance. Therefore, there are 2 major therapeutic approaches to perioperative hypertension: modulation of systemic vascular resistance and modulation of cardiac output. Agents that decrease cardiac output include β-blockers and anesthetic agents. Deepening the level of anesthesia intraoperatively is the antihypertensive measure often preferred by anesthesiologists.¹ However, this may not be the optimal approach, especially when using depth of anesthesia monitoring.

Potential pharmacologic approaches to vasodilation include 1) α₁-adrenergic receptor blockers, ganglionic blockers, and calcium channel blockers; 2) central α₂-adrenergic receptor agonists, dopamine₁-adrenergic receptor agonists, potassium channel (KATP) modulators, and vascular cyclic nucleotide stimulators; 3) phosphodiesterase enzyme (PDE) inhibitors; and 4) angiotensin-converting enzyme inhibitors.² The mainstays of currently available intravenous (IV) vasodilator therapies include the nitrovasodilators, which stimulate cyclic nucleotides, and the calcium channel blockers, in particular, the dihydropyridines (Table I). The physiology of the vascular response to the different pharmacologic agents that produce vasodilation is considered here.

Table I. Vasodilators

Mechanisms of Vasodilation

Vascular tone is regulated by the flux of calcium into and out of vascular smooth muscle (Fig. 1). Therefore, any drug that decreases calcium entry into, or increases calcium exit from, vascular smooth muscle will cause vasodilation.² Calcium channel blockade with dihydropyridine calcium antagonists, such as nicardipine, produces vasodilation by decreasing calcium entry into vascular smooth muscle. These agents are arterial specific vasodilators; they do not produce venodilation.

Fig. 1 Mechanisms of vascular relaxation. Nitroglycerin and nitroprusside, for example, generate nitric oxide (NO), which stimulates guanosine-3′,5′-monophosphate (cyclic GMP), which in turn sequesters calcium, thereby facilitating its removal from the cell. Dihydropyridine calcium channel blockers have an inhibitory effect on the slow calcium channel in the heart and on calcium fluxes in vascular smooth muscle.

(Adapted from: Levy JH. Anaphylactic reactions in anesthesia and intensive care. 2nd ed. Stoneham (MA): Butterworth-Heinemann Publishers; 1992, with permission from Elsevier.)

Drugs that block the breakdown of cyclic nucleotides can also produce vasodilation. Increasing cyclic nucleotides—adenosine 3′,5′-cyclic monophosphate (cyclic AMP) or guanosine 3′,5′-cyclic monophosphate (cyclic GMP), by either β₂-adrenergic agonists or PDE inhibitors—in vascular smooth muscle facilitates calcium uptake by intracellular storage sites. This in turn decreases the amount of calcium available for contraction. The net effect of increasing calcium uptake is relaxation of vascular smooth muscle and, hence, vasodilation. However, most catecholamines with β₂-adrenergic agonist activity and the PDE inhibitors (for example, milrinone) have side effects that include positive inotropy and tachycardia, which thereby limit their use for perioperative hypertension.

Prostaglandin E₁ and prostacyclin stimulate vascular adenylate cyclase independently of the β₂-adrenergic receptor, which results in increased cyclic AMP and pulmonary and systemic vasodilation. Along with the PDE inhibitors, prostacyclin and prostaglandin E₁ have been used effectively to treat pulmonary hypertension and right ventricular failure. Prostaglandins are potent platelet inhibitors, which potentially limits their use perioperatively.²

The older agent hydralazine causes relaxation of arteriolar smooth muscle through mechanisms that include channel hyperpolarization of vascular smooth muscle via KATP, interfering with the mobilization of calcium. Intravenous hydralazine has been used to treat pregnancy-induced hypertension as well as perioperative hypertension.

Endothelium-Derived Relaxing Factor

The vascular endothelium is an important mechanism contributing to endogenous vasodilation by releasing prostacyclin and nitric oxide (NO), which is also known as endothelium-derived relaxing factor. A spectrum of endogenous mediators can stimulate the vascular endothelium to release NO, which activates guanyl cyclase to generate cyclic GMP.²

With aging, endothelial function may decline. The vasculature looks morphologically normal, but a variety of metabolic abnormalities can exist, such as G-protein signaling abnormality. Endothelium-dependent vascular relaxation is also abnormal in other conditions. Although the mechanisms underlying this abnormality remain incompletely understood, decreased production of NO, increased destruction of NO by superoxide, and membrane-signaling alterations have been implicated.³ Growing evidence suggests that one of the salutary effects of antihypercholesterolemic drugs is restoration of vascular endothelial function.

The Intravenous Nitrovasodilators

The nitrovasodilators are a diverse group of drugs that achieve vascular relaxation by releasing NO. In many respects, these drugs mimic endothelium-derived NO. Nitrates and sodium nitroprusside, however, generate NO directly, independent of vascular endothelium. The nitrovasodilator nitroglycerin is a selective coronary vasodilator. It has minimal effect on small intracoronary resistance vessels (those <100 μm), which lack the metabolic transformation pathway required to convert nitroglycerin into its active form, NO. Nitroglycerin preferentially dilates epicardial vessels and prevents the coronary steal phenomenon, which is often seen with use of agents that dilate the coronary resistance vessels (Fig. 2).⁴

Fig. 2 Nitroglycerin can nonenzymatically interact with several types of thiol-containing compounds to release nitric oxide (NO). The major bioconversion of nitroglycerin likely occurs via an enzymatic process, and an as-yet-unidentified process is likely responsible for the reduction of nitroglycerin to NO. Smaller vessels (especially coronary microvessels <100 μm in diameter) are limited in their ability to convert nitroglycerin to its vasoactive metabolite compared with larger vessels.

(From: Harrison DG, Bates JN. The nitrovasodilators. New ideas about old drugs. Circulation 1993;87:1461–7. Reproduced with permission from Lippincott Williams & Wilkins.)

Nitroglycerin administration, however, can produce tolerance, which is defined as the loss of hemodynamic and antianginal effects during sustained thera-py. Nitrate tolerance is a well-known occurrence, although the mechanism remains poorly understood. Hypotheses for the development of nitrate tolerance include alteration in vascular smooth muscle receptor by depletion of sulfhydryl groups and neurohormonal changes produced by a reflex release of vasoconstrictor hormones that limit the vasodilating effects of nitrates. Additional studies have shown that nitrate ad-ministration is associated with increased vascular production of superoxide anion and endothelin 1^5–7 and desensitization of coronary conductance vessels.⁸ Clinicians who use IV nitroglycerin should be aware of the potential for development of nitrate tolerance.

Nitroprusside is a nitrovasodilator in which NO is bound to a ferrous molecule and surrounded by cyanide. It is a potent nonspecific venous and arterial dilator. Nitroprusside generates NO directly, independently of vascular endothelium, and activates guanyl cyclase to generate cyclic AMP.² In terms of its hemodynamic effects, nitroprusside can be associated with a decrease in preload and therefore in cardiac output. Since it is such a potent vasodilator, it may also cause coronary steal and increase intracranial pressure due to dilation of the large intracerebral arteries. Use of nitroprusside has been associated with the need for compensatory volume replacement, as well as with toxicity and metabolic acidosis.

Intravenous Dihydropyridine Calcium Channel Blockers

Intravenous dihydropyridine-type calcium channel blockers are arterial specific and block inward calcium currents in vascular smooth muscle. They produce arterial vasodilation without negative inotropic or dromotropic (conduction) effects. Another interesting, con-sistent finding with use of dihydropyridine calcium channel blockers is the lack of reflex tachycardia.

Intravenous dihydropyridine calcium channel blockers may be useful for the treatment of perioperative hypertension. Nicardipine, a 2nd-generation IV dihydropyridine calcium channel blocker, produces coronary arterial vasodilation, as well as specific cerebral vasodilation. This drug has been shown to decrease blood pressure and cerebral perfusion pressure without increasing intracranial pressure in patients with acute cerebral hemorrhage.⁹ Therefore, nicardipine is used extensively in both cardiac and neurologic intensive care units. Nicardipine is also characterized by its lack of effect on sinoatrial and atrioventricular node conduction. Nicardipine has been consistently shown to be a selective arterial vasodilator.^10–13 Hemodynamic effects of nicardipine, when administered in a 2-mg bolus injection and followed by continuous infusion of 20 μg/min, are shown in Table II. Among the notable findings are decreases in mean arterial pressure (average, −18 mmHg) and systemic vascular resistance, an increase in cardiac output, and no changes in filling pressures.¹⁴

Table II. Mean Hemodynamic Effects of Nicardipine in 17 Men Undergoing Cardiac Angiography for Suspected Coronary Artery Disease

After IV bolus infusion, nicardipine plasma concentrations decline tri-exponentially. Nicardipine has a rapid redistribution half-life of 2.7 minutes. Its intermediate half-life is 44 minutes, and its terminal half-life after long-term infusion is much longer: approximately 14 hours. Rapid dose-related increases in nicardipine plasma concentrations are seen during the first 2 hours after the start of infusion. Plasma concentrations increase at a much slower rate after the 1st few hours and approach steady state at 24 to 48 hours. Upon termination of the infusion, nicardipine concentrations decline rapidly, with at least a 50% decrease during the first 2 hours after infusion. The effects of nicardipine on blood pressure correlate significantly with plasma concentrations.¹⁵

Pharmacodynamically, nicardipine selectively decreases arterial pressure in a dose-dependent manner. When nicardipine was administered as an IV bolus in doses of 0.25, 0.5, 1.0, and 2.0 mg in adults undergoing cardiac surgery, the maximum response occurred within 100 seconds, and recovery to half the maximum response occurred within 3 to 7 minutes. There was a relatively linear correlation between drug concentrations and decreases in mean arterial pressure, with no change in cardiac output.¹⁶ Nicardipine is the only agent that selectively decreases pure arterial resistance.

The hallmark of IV nicardipine is arterial specificity, which allows precise titration of blood pressure irrespective of intravascular volume. This property is significant in perioperative hypertension, because arterial vasoconstriction with varying degrees of intravascular hypovolemia is a central characteristic. With nicardipine, hypotension has been reported in approximately 6% of patients.¹⁵

Isradipine, another 2nd-generation dihydropyridine calcium channel blocker, has also been evaluated for use in hypertension that develops after cardiac surgery. Leslie and colleagues¹⁷ found that isradipine significantly decreased mean arterial pressure (average, −23 mmHg) during a 90-minute infusion in 177 patients who had undergone coronary artery bypass surgery. This reduction in blood pressure was achieved with slight increases in heart rate, cardiac index, and stroke volume but no clinically relevant changes in pulmonary blood pressure, capillary wedge pressure, or pulmonary vascular resistance.

Clevidipine, an ultra–short-acting, vasoselective calcium channel blocker, is being investigated for use in perioperative hypertension. It has a half-life of 1 to 3 minutes and is vasoselective. It has been shown to decrease systemic vascular resistance and mean arterial pressure without changing heart rate, cardiac index, or cardiac filling pressures.¹⁸

Internal Mammary Artery and Coronary Artery Spasm

The internal mammary artery (IMA) is a preferred conduit for coronary artery surgery, because it is an arterial vessel containing vascular endothelium that contributes to its long-term patency. However, vasospasm can occur during IMA grafting, which may compromise myocardial perfusion. The pathophysiology of vasoconstriction is complex and may include mechanical, physical, and pharmacologic contributions.¹⁹ The pathophysiology of vasospasm appears to be related to endothelial dysfunction, adherence of platelets and neutrophils, and release of thromboxane A₂, a potent vasoconstrictor.

In vitro data suggest that most of the commonly used vasodilators can reverse IMA vasospasm by acting through multiple pathways.¹⁹ In a study involving segments of IMAs obtained from 60 patients undergoing coronary artery bypass surgery, isolated vascular rings were precontracted with norepinephrine or thromboxane A₂. The segments were then exposed to nitroglycerin, milrinone, papaverine, and isradipine. All 4 vasodilators induced relaxation of the constricted segments at therapeutic doses.

Use of the radial artery for coronary artery bypass grafting has been greatly facilitated by administration of calcium channel antagonists to reverse the spasm frequently encountered during surgical dissection.²⁰ An in vitro comparative study of the effects of 4 calcium channel antagonists—nifedipine, nicardipine, verapamil, and diltiazem—on potassium-precontracted human radial arteries obtained from 25 patients undergoing bypass grafting, all 4 effectively abolished the contraction. The vessel has different sensitivities to different agents, and the dihydropyridine derivatives nifedipine and nicardipine were more potent than verapamil and diltiazem. The authors recommend the use of dihydropyridine calcium channel blockers for preventing and treating radial artery spasm.²⁰

Conclusions

Arterial vasoconstriction is characteristic of perioperative hypertension, and multiple pharmacologic agents are available to produce vasodilation via different mechanisms. Nitroglycerin tolerance is an important concern in critically ill patients, and nitroprusside can cause venodilation and coronary steal. Dihydropyridine calcium channel blockers are arterial selective vasodilators that are beneficial in the management of perioperative hypertension.