Published on 07/02/2015 by admin
Filed under Anesthesiology
Last modified 22/04/2025
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Suneerat Kongsayreepong, MD
Nitroglycerin (glycerol trinitrate) is metabolized to NO in the vascular smooth-muscle wall and acts to stimulate cyclic guanosine monophosphate (cGMP) production. Increased cGMP leads to the reduction of cytosolic Ca2+, dephosphorylation of the myosin light chain, and smooth muscle relaxation and vasodilation. Because sulfhydryl groups are needed to produce the NO, vascular tolerance can occur when an excessive number of sulfhydryl groups are metabolized by prolonged exposure to nitroglycerin. Nitroglycerin is reported to have greater effects as a venodilator because of greater uptake in veins, as compared with arteries.
Metabolism of nitroglycerin occurs in the liver by hepatic glutathione organic nitrate reductase; inactivated metabolites are excreted by the kidney. Nitroglycerin, with a half-life of 1.9 to 2.6 min, also appears to be taken up by and metabolized in the endothelium of vessel walls.
Because of the aforementioned greater uptake of nitroglycerin by the venous endothelium, nitroglycerin acts primarily on venous capacitance vessels, causing peripheral and splanchnic pooling of blood, decreased preload, decreased cardiac ventricular wall tension, and decreased heart size. With increased concentrations of nitroglycerin, relaxation of arterial vessels occurs, first affecting conductance vessels and then the smaller resistance vessels.
The effect of nitroglycerin on cardiac performance depends on the patient’s underlying cardiac status. In patients with a normal or low ventricular filling pressure, cardiac output may decrease because of inadequate preload. In those with congestive heart failure (CHF), cardiac output increases as a result of decreased preload, reduced systolic wall tension, and, at higher doses of nitroglycerin, a decrease in afterload. For similar reasons, nitroglycerin, at high doses, also improves cardiac output in patients with mitral regurgitation. In patients with coronary artery disease, nitroglycerin causes decreased wall tension and decreased myocardial O2 demand, which, in turn, results in increased myocardial contractility and cardiac output.
Myocardial blood flow is affected indirectly via hemodynamic changes and directly by coronary arterial dilation. Coronary perfusion increases more from the lowering of left ventricular end-diastolic pressure than from improved flow during diastole. A decrease in left ventricular end-diastolic pressure also reduces extrinsic tissue compression of coronary vessels in the subendocardium. Nitroglycerin is a potent epicardial coronary vasodilator in both normal and diseased vessels. Therapeutic doses of nitroglycerin dilate large coronary arteries but not coronary arterioles, improving collateral and subendocardial blood flow to ischemic areas. Nitroglycerin produces less coronary steal than do agents that produce intense vasodilation of the small coronary resistance vessels. High doses of nitroglycerin (9-32 μg·kg−1·min−1) cause direct coronary arteriolar vasodilation, overriding any coronary autoregulation. Part of the action of nitroglycerin on coronary vasodilation may involve its effects on stimulating the production and release of prostacyclin.
Nitroglycerin causes vasodilation of pulmonary arteries and veins, resulting in a decrease in right atrial, pulmonary artery, and pulmonary artery occlusion pressure. Nitroglycerin may reduce the pulmonary artery hypertension associated with various disease states and congenital heart disease. Nitroglycerin also dilates renal arteries, cerebral arteries, and cutaneous vessels. Blood flow to the kidney and brain may decrease if adequate systemic blood pressure is not maintained.
The cause of the antianginal effects of nitroglycerin is multifactorial. The use of nitroglycerin reduces the preload and systolic wall tension, resulting in decreased myocardial O2 demand, and dilates the coronary arteries, resulting in increased O2 delivery. The benefit of nitroglycerin in patients who have a partial occlusion of the coronary arteries likely occurs through a decrease in myocardial O2 consumption; for those patients with total occlusion, the benefit occurs via redistribution of coronary artery blood flow. Nitroglycerin also relaxes vessels that are in spasm. The use of nitroglycerin was once considered to be contraindicated in patients with acute myocardial infarction because of the hypotension and tachycardia associated with its use; however, studies now show that the use of nitroglycerin increases collateral blood flow to ischemic regions and decreases infarction size. Maximum benefit is probably attained when CHF coexists. As long as hypotension is avoided, patients with acute myocardial infarction without CHF also benefit. Nitroglycerin works if it is instituted within 10 h of the ischemic event, at a starting dose of 0.5 μg·kg−1·min−1.
Perioperative indications for the use of nitroglycerin include myocardial ischemia, CHF, systemic and pulmonary hypertension, and coronary artery spasm. Preoperative oral or transcutaneous nitrates are continued until the time of the operation. Transcutaneous administration is probably not effective intraoperatively because absorption is not reliable. Intranasally administered nitroglycerin has been used to treat the pressor response to tracheal intubation and the hypertensive response that occurs after suprarenal aortic cross-clamping of abdominal aortic aneurysms. Inhaled nitroglycerin (2.5 μ/kg) has been used selectively to target pulmonary vasculature in the treatment of pulmonary hypertension—with a significant decrease in systolic, diastolic, and mean pulmonary artery pressure related to the decrease in pulmonary vascular resistance—without significant effects on systemic hemodynamics in adults and children undergoing cardiac operations.
Intraoperative indications for the intravenous administration of nitroglycerin include hypertension greater than 20% of preoperative levels in patients with coronary artery disease, left ventricular end-diastolic pressure greater than 18 to 20 mm Hg, ST-segment changes greater than 1 mm, and acute right or left ventricular dysfunction. Intraoperative doses of less than 1.0 μg·kg−1·min−1 are not considered to be effective.
In open surgical repair of an aortic aneurysm, intravenous administration of nitroglycerin maintains preaortic cross-clamp perfusion pressure and peripheral blood flow. Intravenously administered nitroglycerin also helps to control blood pressure during deployment of aortic endovascular stent grafts. Controlled hypotension to decrease blood loss during surgery can be achieved with intravenously administered nitroglycerin, either alone or combined with a drug to combat the reflex tachycardia.
The infusion of a single, intravenous, 100-μg bolus of nitroglycerin has been suggested for acute tocolysis when fetal bradycardia occurs following uterine hypertonicity after administration of combined spinal-epidural analgesia. Intravenously administered nitroglycerin can provide uterine relaxation during fetal surgery without affecting placental blood flow.
The prophylactic use of nitroglycerin has been evaluated in patients with coronary disease who have undergone a variety of operations. Although the use of nitroglycerin reduces the incidence of wall-motion abnormalities, as detected by transesophageal echocardiography, several studies have shown that the prophylactic use of nitroglycerin is ineffective in reducing the rate of ischemia, as evidenced by electrocardiography.
Polyethylene tubing is recommended for administration of nitroglycerin because polyvinylchloride tubing absorbs nitroglycerin.
A number of adverse effects are associated with the use of nitroglycerin. Nitrate tolerance may occur with a depletion of sulfhydryl groups, neurohumoral activation, volume expansion, downregulation of nitrate receptors, or any combination thereof. This tolerance may occur with all forms of nitrate administration that maintain continuous blood levels of the drug. If tolerance develops after prolonged exposure, physiologic responsiveness may be achieved with higher doses of nitroglycerin. Intermittent dosing with a nitrate-free interval each day or night can maintain a patient’s responsiveness to nitroglycerin. Cross-tolerance can occur, with a possible decreased effect in patients who previously received isosorbide dinitrate.
Discontinuation of the drug after prolonged exposure may result in a rebound phenomenon, possibly resulting in coronary vasospasm and myocardial ischemia or infarction. Metabolism of nitroglycerin by liver nitrate reductase produces a nitrite that oxidizes the ferrous iron of hemoglobin to the ferric form of methemoglobin. Nitroglycerin doses of 5 mg·kg−1·day−1 or higher should be avoided to prevent significant methemoglobinemia.
Nitroglycerin has been reported to interfere with platelet aggregation and to reduce the ability of platelets to adhere to damaged intima at doses as low as 1.19 μg·kg−1·min−1. Inhibition returns to baseline values within 15 min of discontinuation of the infusion.
The use of nitroglycerin is contraindicated in patients who have used sildenafil, vardenafil, or tadalafil within the previous 24 to 48 h. Because these drugs inhibit phosphodiesterase, which degrades cGMP, nitroglycerin-mediated vasodilatation is markedly enhanced and prolonged, resulting in cases of profound hypotension, myocardial infarction, and death. Relative contraindications to the use of nitroglycerin include increased intracranial pressure, hypovolemia, and angina associated with aortic stenosis, idiopathic hypertrophic subaortic stenosis, and tachyarrhythmias.
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