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Thus, critically ill patients, usually those with at least some component of obstructive coronary artery disease, may develop myocardial ischemia on a hemodynamic basis, with variable contributions of increased demand and decreased supply. On the other hand, catecholamine surges, hemodynamic changes, and inflammatory processes may predispose to rupture of preexisting atherosclerotic plaques. Making the distinction is vital because the treatment is completely different. In the former case, treatment is aimed at decreasing the oxygen requirement of the myocardium by eliminating provocative stimuli and controlling heart rate and blood pressure and on optimizing oxygenation and hemoglobin concentration. Relief of myocardial ischemia by these measures usually results in prompt restoration of left ventricular function without significant cellular damage because the obstruction to flow is ordinarily fixed and not total. If plaque rupture is playing a role, then simply removing or lessening stimuli that increase myocardial oxygen requirements may not be sufficient to increase the ratio of myocardial oxygen supply to demand, and, unless attempts are made to reestablish coronary blood flow, significant myocardial damage may ensue. Antithrombotic and anticoagulant strategies should be instituted, and consideration of coronary revascularization may be indicated.
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Recognition of Myocardial Ischemia
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Myocardial ischemia is most commonly manifested as constant substernal chest tightness or pressure. The pain typically is on the left side and may radiate to the throat and jaw or to the left shoulder and left arm and is often accompanied by acute onset of dyspnea and diaphoresis. Angina occasionally may be right-sided, interscapular, or perceived in the epigastrium.
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Because other syndromes may mimic angina, it is important to consider them in the differential diagnosis. These include dissecting aortic aneurysm; pericarditis; pleuritis; pulmonary processes such as pulmonary embolism, pneumonia, and pneumothorax; gastrointestinal processes such as esophageal or peptic ulcer disease and cholecystitis; musculoskeletal pain; and costochondritis. Other heart diseases (valvular heart disease, cardiomyopathies, and myocarditis) not attributable to coronary artery stenosis may also cause substernal chest tightness and should be included in the differential diagnosis. The presentation of ischemia in postsurgical patients may be subtle. Aftereffects of surgery and medication can mimic or mask the classic features of MI such as substernal chest pain radiating to the arm, neck, or jaw, and dyspnea, nausea, and diaphoresis. The vigilant clinician must therefore maintain a high index of suspicion and a low threshold for obtaining a 12-lead electrocardiogram.
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The physical examination, although sometimes insensitive and nonspecific, especially in the patient with multisystem illness or preexisting left ventricular dysfunction, may be helpful in confirming the diagnosis. Elevated jugular veins signal right ventricular diastolic pressure elevation, and the appearance of pulmonary crackles (in the absence of pulmonary disease) indicates elevated left ventricular filling pressures secondary to depressed left ventricular function. A systolic bulge occasionally can be palpated on the precordium in the area of the apex of the heart, representing contact of an ischemic dyskinetic segment of the left ventricle with the chest wall. During the ischemic episode, auscultation of the precordium may demonstrate the presence of a fourth heart sound, indicative of a noncompliant left ventricle. With extensive myocardial dysfunction, a third heart sound may be present. A murmur of mitral regurgitation attributable to papillary muscle dysfunction may also emerge.
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The Electrocardiogram
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The ECG abnormalities in myocardial ischemia vary widely and depend in large part on the extent and nature of coronary stenosis and the presence of collateral blood flow to ischemic zones. With acute total occlusion of a coronary artery, the first demonstrable ECG changes are peaked T-wave changes in the leads reflecting the anatomic area of myocardium in jeopardy. As total occlusion continues, there is elevation of the ST segments in the same leads. With continued occlusion, there is an evolution of ECG abnormalities, with biphasic and then inverted T waves. If enough myocardium is infarcted, q waves may appear, representing unopposed initial depolarization forces away from the mass of infarcted myocardium, which has lost electrical activity and no longer contributes to the mean QRS voltage vector. The formation of q waves is accompanied by a decrease in the magnitude of the R waves in the same leads, representing diminution of voltage in the mass of infarcted myocardium. Loss of R-wave voltage, visualized by comparison with previous ECG tracings, may be the only ECG evidence for the presence of permanent myocardial damage. It is important to note that QRS voltage can be affected by multiple factors, such as lead placement, body position, QRS axis shifts, and pericardial and thoracic abnormalities that may shield the electrical activity of the heart. These conditions are frequently encountered in patients in the ICU and should be taken into consideration in interpretation of q and R waves.
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Extension of an inferior MI to the posterior segment can be detected by enhancement of R waves in the anterior chest leads because these forces are now less opposed by posterior forces. True posterior infarction can be subtle because the only signs may be prominent R waves, tall upright T waves, and depressed ST segments in leads V1 and V2. Involvement of the right ventricle in inferior MI also is not readily detected on the standard 12-lead electrocardiogram because of the small mass of the right ventricle relative to the left ventricle and because of the positioning of the standard precordial leads away from the right ventricle. Right ventricular infarction may be detected by ST elevation in recordings from right precordial leads, in particular V4R.3
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Subtotal occlusion of an epicardial coronary artery may not result in ST elevation but in T-wave changes or ST depression in the leads reflecting the involved myocardium. These findings are less specific than ST elevation for myocardial ischemia because they may also be caused by a myriad of factors other than ischemia, including cardioactive drugs, in particular digoxin, and electrolyte disorders, in particular hypokalemia. Left ventricular hypertrophy and acute left ventricular pressure overload, as might occur in hypertensive crisis, may also result in ST depression—the so-called strain pattern. Supraventricular tachycardias have also been shown to cause ST depression, even in the absence of left ventricular pressure. In the presence of preexisting T-wave abnormalities, ST-segment or T-wave changes are even less specific for ischemia. Ischemia may also be indicated by previously flattened or inverted T waves that revert to upright—the so-called pseudonormalization of T waves.
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The clinician also must be careful not to be fooled by ECG “imposters" of acute infarction, which include pericarditis, J-point elevation, Wolff-Parkinson-White syndrome, and hypertrophic cardiomyopathy. In pericarditis, ST segments may be elevated, but the elevation is diffuse and the morphology of the ST segments tends to be concave upward, whereas that of ischemia is convex. Pericarditis also may be distinguished from infarction by the presence of PR-segment depression in the inferior leads (and also by the PR segment in lead aVR).4
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Recent interest has focused on “silent” myocardial ischemia, that is, objective ECG evidence of myocardial ischemia that is not associated with angina or with anginal equivalents.5 Silent myocardial ischemia may be an incidental observation on a cardiac monitor or on a routine electrocardiogram and consists of transient ST-segment depression that may last several minutes or even hours. The frequency of episodes of ST-segment depression correlates with the severity of coronary artery disease in patients with known left ventricular pressure or a history of angina.
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Decreased left ventricular function is associated with episodes of silent ST depression.6,7 In patients monitored with pulmonary artery catheters (PACs), silent ischemia may be manifested by increased pulmonary artery occlusion pressures, reflecting increased left ventricular end-diastolic pressure. Echocardiography may demonstrate transient wall motion abnormalities and diminished diastolic compliance. These signs of left ventricular dysfunction may precede ST-segment changes.6,7
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Not all episodes of transient ST-segment depression are attributable to silent ischemia. Nevertheless, should this finding be observed on the cardiac monitor, especially in association with transient elevation of left ventricular filling pressures, it is prudent to consider the possibility of myocardial ischemia as a potential factor complicating the course of the critically ill patient.
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Measurement of enzymes released into the serum from necrotic myocardial cells after infarction can aid in the diagnosis of MI.8,9 The classic biochemical marker of acute MI is elevation of creatine phosphokinase (CPK) levels. The CPK-MB isoenzyme is found primarily in cardiac muscle, and only small amounts are present in skeletal muscle and brain. CK released from the myocardium begins to appear in the plasma 4 to 8 hours after onset of infarction, and its level peaks at 12 to 24 hours and returns to baseline at 2 to 4 days. The magnitude of the increase in serum CK level and the rate at which it rises and falls are a function of the total mass of myocardium affected, the extent and nature of coronary occlusion (e.g., total or subtotal occlusion), the rate of washout from the infarcted myocardium, and the clearance from the body. To be diagnostic for MI, the total plasma CK value must exceed the upper limit of normal, and the fraction consisting of the MB isoenzyme must exceed a certain value (which depends on the CK-MB assay used, usually >5%).
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A newer serologic test for the detection of myocardial damage uses measurement of cardiac troponins.10 Troponins T and I are constituents of the contractile protein apparatus of cardiac muscle. Whereas CPK-MB may arise from other tissues, troponins originate only from cardiac muscle, rendering them more specific than the conventional CPK-MB assays for the detection of myocardial damage. Their use is becoming more widespread and has superseded the use of CPK-MB in many settings.11 Troponins are also more sensitive for the detection of myocardial damage, and troponin elevation in patients without ST elevation (or without elevation of CPK-MB) identifies a subpopulation at increased risk for complications. Rapid point-of-care troponin assays, which have become available in the past few years, have extended the clinical utility of this marker. Troponins may not be elevated until 6 hours after an acute event, so critical therapeutic interventions should not be delayed pending assay results. Once elevated, troponin levels can remain high for days to weeks, thereby limiting their utility to detect late reinfarction.
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Lactate dehydrogenase (LDH) is also released from necrotic myocardial tissue after infarction, although elevation of this enzyme is relatively nonspecific for MI because LDH is present in many other tissues. LDH levels peak at 72 to 96 hours and may be used to detect recent infarction, which is associated with an increase in the LDH1 isoenzyme.
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To the physician confronted with a critically ill patient, echocardiography can be a key element in successful differential diagnosis.12 Echocardiography is simple, safe, and permits systemic interrogation of cardiac chamber size, left and right ventricular functions, valvular structure and motion, atrial size, and the anatomy of the pericardial space. The presence of segmental left ventricular wall motion abnormalities suggests compromise of blood flow to those segments.13 Doppler interrogation can be used for noninvasive assessment of right and left ventricular filling pressures, pulmonary artery pressures, stroke volume, and cardiac output.
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Echocardiography is particularly useful in the evaluation of patients with acute heart failure or suspected cardiogenic shock, and early echocardiography should be performed routinely.14 Expeditious evaluation of global and regional left ventricular performance is crucial for management of congestive heart failure, with or without suspected myocardial ischemia.
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Echocardiography is also extremely valuable for the rapid diagnosis of mechanical causes of shock after MI such as papillary muscle rupture and acute mitral regurgitation, acute ventricular septal defect, and free wall rupture and tamponade.14 In some cases, echocardiography may demonstrate findings compatible with right ventricular infarction. Echocardiography can also show alternative diagnoses, such as valvular abnormalities, pericardial tamponade, or hypertrophic cardiomyopathy. Acute right heart failure, manifested by a dilated and hypokinetic right ventricle without hypertrophy suggestive of chronic pulmonary hypertension, can suggest pulmonary embolism (see Chap. 26).15
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Transthoracic echocardiographic images may be suboptimal due to a poor acoustic window in critically ill patients, in particular those who are obese, have chronic lung disease, or are on positive pressure ventilation. Contrast echocardiography may be used to improve image quality.16 Transesophageal echocardiography also can provide better visualization, particularly of valvular structures, and can be performed safely at the bedside.
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Technetium pyrophosphate is deposited in irreversibly damaged regions of myocardium.17 The regions of radioactivity are detected by scintigraphy and appear as “hot spots” on imaging. The period during which technetium pyrophosphate scanning is most sensitive for the detection of infarcted myocardium is approximately 1 to 3 days after MI; if a scan performed then is positive, scans may remain positive for weeks to months thereafter. Whereas the sensitivity and specificity for detection of a transmural infarct are high with this technique, they are low to moderate for a non–Q-wave or subendocardial infarct. Therefore, the usefulness of this test is limited for the diagnosis of MIs, especially non–Q-wave infarcts, because it offers little information unavailable by other means.18
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Thallium 201 is transported into viable myocardial tissue by processes dependent on adenosine triphosphate via Na/K-ATPase. It is distributed to the myocardium on the basis of blood flow. Necrotic or scarred myocardial tissue from a new or previous MI will appear as a “cold spot” on scintigraphy. Technetium 99 sestamibi is a newer isotope preparation widely used to assess myocardial perfusion. Sestamibi also distributes to the myocardium on the basis of blood flow. The major advantage of using sestamibi instead of thallium is that the photons produced by the technetium 99 radionuclide have higher energy and therefore more readily penetrate the fat and other tissues that overlie the heart, resulting in fewer attenuation artifacts than seen with thallium 201. In addition, unlike thallium, sestamibi does not undergo significant redistribution, so perfusion defects seen on scintigraphic images do not reverse over time. Sestamibi scans at rest can be used in patients presenting to the emergency department with chest pain of unclear cause. Patients without perfusion defects do not have evidence of ongoing myocardial underperfusion and can be safely discharged, with follow-up stress testing as needed.19 A positive scan does not differentiate between new and old perfusion defects, so hospital admission and further evaluation are necessary.
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Hemodynamic Monitoring
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In patients with hemodynamic instability that does not improve relatively quickly with simple therapeutic maneuvers, pulmonary artery catheterization should be considered (see Chap. 13). Pulmonary artery catheterization provides simultaneous assessment of filling pressures and cardiac output and can be quite useful for differential diagnosis in critically ill patients. In patients with hypoxemia and pulmonary infiltrates on chest radiogram, a frequent dilemma in ICU patients, pulmonary artery catheterization may be used to differentiate cardiac from pulmonary causes. Right heart catheterization is also quite useful in the differential diagnosis of shock. Hemodynamic profiles of patients with different forms of shock are presented in Table 25-1. It is important to recognize the possibility of mixed forms of shock in the critically ill patient (see Chap. 21). For example, even in the presence of significant left ventricular dysfunction and suspected cardiogenic shock, patients with cardiogenic shock can be relatively depleted of volume, perhaps due to diaphoresis or vomiting.20,21
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Hemodynamic monitoring also can be useful in the diagnosis of mechanical complications of infarction. Right heart catheterization may show a step up in hemoglobin oxygen saturation diagnostic of ventricular septal rupture. The waveform of the pulmonary artery occlusion pressure tracing may show a prominent V wave (10 mm Hg above the mean pulmonary artery occlusion pressure is regarded as significant), suggesting severe mitral regurgitation, although V waves also may be present in acute ventricular septal rupture. Equalization of diastolic filling pressures may suggest pericardial tamponade. The hemodynamic profile of right ventricular infarction includes high right-side filling pressures in the presence of normal or low occlusion pressures.22
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Perhaps more importantly, pulmonary artery catheterization may be used to guide therapy in hemodynamically unstable patients. Infusions of vasoactive agents need to be titrated carefully in patients with myocardial ischemia to maximize coronary perfusion pressure with the least possible increase in myocardial oxygen demand. Invasive hemodynamic monitoring is often considered useful in guiding therapy in these unstable patients because clinical estimates of filling pressure can be unreliable;23 in addition, changes in myocardial performance and compliance and therapeutic interventions can change cardiac output and filling pressures precipitously. Optimization of filling pressures and serial measurements of cardiac output (and other parameters such as mixed venous oxygen saturation) allow for titration of the dosage of inotropic agents and vasopressors to the minimum dosage required to achieve the chosen therapeutic goals. This minimizes the increases in myocardial oxygen demand and arrhythmogenic potential.24
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The PAC provides hemodynamic data not easily inferred from physical examination or laboratory evaluation, but whether its use translates into definable benefits for patients has long been questioned.25 Despite the many theoretical advantages to the PAC, retrospective analyses in patients with acute myocardial ischemia have found no benefit,26 and some have found associations between catheter use and adverse outcomes. Prospective trials have shown PAC to be practical in high-risk surgical patients and in patients with septic shock and acute respiratory distress syndrome; such a trial would be interesting in patients with cardiac ischemia. Lacking prospective trials to answer the question of efficacy, we nevertheless believe the benefits of more rapid diagnosis are clear and find the catheter essential to guide supportive therapy.21 Prudence should be exercised in choosing a site for central venipuncture because many will have received or are candidates for thrombolytic and intravenous heparin therapy. Insertion sites that can be compressed easily should significant bleeding occur are preferred.
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Patients with a history of stable angina who develop chest pain while in the critical care setting are best treated by removal of provocative stimuli that increase myocardial oxygen consumption or lead to compromised coronary blood flow, if these factors can be identified. For example, correction of hypoxia, anemia, hypovolemia, tachycardia, or labile hypertension may be sufficient to control anginal episodes. Often overlooked are fever, infection, anxiety, stress, activity, and the work of breathing. Antianginal medications the patient was receiving before hospitalization should be continued, and the doses may have to be increased.
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In instances of refractory angina or when provocative stimuli cannot be ameliorated, it may be necessary to perform coronary angiography and revascularization of the culprit vessels (preferably percutaneously), especially if the myocardial ischemia is complicating further management of the patient.
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Aspirin is the best known and most widely used of the antiplatelet agents because of its low cost and relatively low toxicity. Use of salicylates to treat coronary artery disease in the United States was first reported in 1953.27 Aspirin inhibits the production of thromboxane A2 by irreversibly acetylating the serine residue of the enzyme prostaglandin H2 synthetase.
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Reduction of death or nonfatal MI in patients with unstable angina and NSTEMI has been well established in several large randomized clinical trials.28,29 In addition to its use in acute clinical settings, aspirin has been shown to be beneficial in preventing cardiovascular events when administered as secondary prevention in patients after acute MI and as primary prevention in subjects with no prior history of vascular disease.30
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The most widely used and effective dose of aspirin in cardiovascular disease is 81 to 325 mg/d. Despite the fact that small-dose aspirin preferentially blocks the conversion of thromboxane to prostacyclin and thus has a more profound antiplatelet effect, large-dose aspirin has been found to be as effective as small-dose aspirin in prevention of cardiovascular death, MI and stroke,31 which suggests that anti-inflammatory effects of aspirin also play a role.32 Once begun, aspirin likely should be continued indefinitely. Toxicity with aspirin is mostly gastrointestinal; enteric-coated preparations may minimize these side effects.
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Nitroglycerin is a mainstay of therapy for angina because of its efficacy and rapid onset of action. The most important antianginal effect of nitroglycerin is preferential dilation of venous capacitance vessels. Myocardial oxygen consumption is reduced as left ventricular volume and arterial pressure decrease.33 At larger doses, nitroglycerin also may relax arterial smooth muscle, causing a modest decrease in afterload.33 In addition, nitroglycerin can dilate epicardial coronary arteries and redistribute coronary blood flow to ischemic regions by dilating collateral vessels. Nitroglycerin also has antithrombotic and antiplatelet effects.
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The quickest route of administration of nitroglycerin is sublingual. Sublingual doses of 0.4 mg may be administered every 5 to 10 minutes to a total of three doses, if required to control pain. Topical or oral nitrates may be used for long-term therapy.
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In patients with unstable angina, if sublingual nitroglycerin does not cause chest pain to resolve completely, intravenous nitroglycerin should be administered, starting at a dose of 10 to 20 μg/min. This dose may be titrated upward as tolerated in increments of 10 to 20 μg/min every 5 to 10 minutes until pain resolves. An upper limit of 400 μg/min is usually accepted as maximal; above this dose, usually there is no further clinical response. Excessive lowering of blood pressure can compromise perfusion of the coronary vascular bed.
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Because of its hemodynamic actions, systemic blood pressure may fall after nitroglycerin administration, so frequent blood pressure checks are required. Hypotension typically responds to the Trendelenburg-position and to fluid boluses.
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The rationale for administering β blockers during ischemic episodes derives from their negative chronotropic and inotropic properties. Heart rate and contractility are two of the three major determinants of myocardial oxygen consumption. By altering these variables, myocardial ischemia can be attenuated significantly.34 These agents are particularly effective in patients with angina who remain tachycardic or hypertensive (or both) and in patients with supraventricular tachycardia complicating myocardial ischemia. Rapid control can be achieved by intravenous administration of metoprolol, a β1-selective blocker, in 5-mg increments every 5 minutes up to 15 mg. Thereafter, 25 to 50 mg every 6 hours can be given orally.
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Beta blockers should be used with caution in patients with marginal blood pressure, preexisting bradycardia, atrioventricular nodal conduction disturbances, or evidence for left ventricular failure and in those with bronchospastic disease. A short-acting intravenous β blocker, such as esmolol, may be the preferred agent in patients who have the potential for hemodynamic instability or who have relative contraindications.
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Calcium Channel Blockers
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Nondihydropyridine calcium channel blockers (verapamil and diltiazem) also have negative chronotropic and inotropic effects and can be used to control myocardial oxygen demand in patients with ischemia. Both can be given as intravenous boluses, starting with small doses (diltiazem 10 to 20 mg, verapamil 2.5 mg), and then infused continuously.
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Calcium channel blockers are particularly useful in the setting of coronary vasospasm because they cause direct dilation of coronary vascular smooth muscle. Vasospasm can produce variant angina in patients with mild or no coronary artery disease (Prinzmetal's angina) or aggravate ischemia in patients with atherosclerotic coronary stenoses that are subcritical but serve as sites of vasospasm, possibly as a consequence of abnormalities of the underlying smooth muscle or derangements in endothelial physiology.35 The illicit use of cocaine is increasingly being recognized as a cause of coronary vasospasm leading to angina and myocardial ischemia. Coronary vasospasm usually presents with ST elevation associated with chest pain and can be difficult to differentiate from vessel closure due to coronary thrombosis. Consideration of the clinical setting, rapid fluctuation of ST segments, and prompt resolution with nitrates can provide useful clues. Variant angina attributable to vasospasm responds well to treatment with calcium channel blockers.
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Angiotensin-Converting Enzyme Inhibitors
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Angiotensin-converting enzyme (ACE) generates angiotensin II from angiotensin I and catalyzes the breakdown of bradykinin. Thus ACE inhibitors can decrease circulating levels of angiotensin II and increase levels of bradykinin, which in turn stimulates production of nitric oxide by endothelial nitric oxide synthase. In the vasculature, ACE inhibition promotes vasodilation and tends to inhibit smooth muscle proliferation, platelet aggregation, and thrombosis.
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The major hemodynamic effect of ACE inhibition is afterload reduction, which is most important as an influence of myocardial oxygen demand in patients with impaired left ventricular function. A recent study, however, has demonstrated that ACE inhibition may be beneficial to prevent recurrent events in high-risk patients. The HOPE trial randomized 9297 patients with documented vascular disease or at high risk for atherosclerosis (diabetes plus at least one other risk factor) in the absence of heart failure to treatment with the tissue-selective ACE inhibitor ramipril (target dose 10 mg/d) or placebo.36 An impressive 22% reduction in the combined end point of cardiovascular death, MI, and stroke was observed, and the number of patients and effect size were sufficient so that the reduction in individual end points was significant.36 Patients were normotensive at the start of the trial, and the magnitude of benefit observed was not explained by the modest reduction in blood pressure (2 to 3 mm Hg).36 On the basis of this study, the latest American College of Cardiology/American Heart Association guidelines recommend the use of ACE inhibitors in most cases as routine secondary prevention for patients with known CAD, particularly in diabetics without severe renal disease.37
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Lipid-Lowering Agents
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There is extensive epidemiologic, laboratory, and clinical evidence linking cholesterol and coronary artery disease. Total cholesterol level has been linked to the development of CAD events with a continuous and graded relation.38 Most of this risk is due to low-density lipoprotein (LDL) cholesterol. Different large primary and secondary prevention trials have associated decreasing LDL cholesterol with a decreased risk of coronary disease events. Earlier lipid-lowering trials used bile-acid sequestrants (cholestyramine), fibric acid derivatives (gemfibrozil and clofibrate), or niacin in addition to diet. The reduction in total cholesterol in these early trials was 6% to 15% and was accompanied by a consistent trend toward a reduction in fatal and nonfatal coronary events.39
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More impressive results have been achieved by using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Statins have been demonstrated in several trials to decrease the rate of adverse ischemic events in patients with documented CAD.40–42 The goal of treatment has conventionally been an LDL cholesterol level below 100 mg/dL,37 but a recent study has shown that more aggressive LDL lowering has significantly greater protective effects. Patients were randomized within 10 days of an acute coronary syndrome to pravastatin (40 mg/d, standard therapy) or atorvastatin (80 mg/d, intensive therapy). Atorvastatin lowered LDL cholesterol more (to 62 mg/dL compared with 95 mg/dL) and significantly reduced the composite end point of death, MI, unstable angina, revascularization, and stroke.42 Maximum benefit may require management of other lipid abnormalities (elevated triglycerides and low high-density lipoprotein cholesterol) and treatment of other atherogenic risk factors.
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Intraaortic Balloon Pump Counterpulsation
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When angina remains refractory to maximal medical therapy, intraaortic balloon pump (IABP) counterpulsation may be considered. The IABP is a device that is inserted through the femoral artery into the descending thoracic aorta just distal to the aortic arch. A 40-mL balloon at the tip of the catheter is inflated in diastole by a pneumatic pump in synchrony with closure of the aortic valve and is deflated on opening of the aortic valve. Inflation and deflation are gated to the R and T waves on the electrocardiogram or to the arterial pressure recording. By deflating during ventricular systole, ventricular afterload is reduced, resulting in significant decreases in myocardial wall stress and significant decreases in myocardial oxygen requirements.43 Further, inflation during diastole augments coronary blood flow by increasing coronary perfusion pressure. The main way in which an IABP relieves myocardial ischemia is by decreasing oxygen demand through afterload reduction.44
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Use of an IABP is indicated in unstable angina when the angina and attendant ECG abnormalities are persistent and refractory to maximal pharmacologic therapy. Insertion of an IABP may improve hemodynamics and control symptoms so that coronary angiography can be performed safely. An IABP also may be inserted in patients who are stable and have undergone angiography but in whom precarious coronary lesions (e.g., left main coronary artery stenosis) have been identified. Typically, these patients are maintained on the device while awaiting surgery or angioplasty.
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Although insertion of an IABP can result in immediate and dramatic relief of myocardial ischemia, placement of this device can be associated with significant complications.43 These include aortic dissection, femoral artery lacerations, hematomas, femoral neuropathies, renal failure from renal artery occlusion, arterial thrombi and emboli, limb ischemia, and line sepsis. These potential complications must be weighed in determining whether an IABP should be inserted. Once one is inserted, the patient should be maintained on full anticoagulating doses of intravenous heparin by constant infusion. Frequent checks of peripheral pulses and surveillance for other complications should be performed routinely.
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If anginal symptoms persist despite maximal medical therapy, coronary angiography with an aim toward possible revascularization should be considered. One must keep in mind that coronary angiography is not a therapeutic intervention but a diagnostic test. Angiography is of little tangible value if there are no viable revascularization options.
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Recommendations for the timing of angiography in patients with unstable ischemic syndromes are controversial. Early angiography can identify patients with left main or severe three-vessel disease, in whom early coronary artery bypass surgery can be lifesaving. The decision to perform angiography early should be based on the frequency and severity of angina episodes and the nature and extent of ECG changes. For example, extensive ST depression in the anterior chest leads suggests stenosis of the proximal left anterior descending artery or left main coronary artery, total occlusion of which might result in sudden death. Frequent anginal episodes or episodes that are difficult to control with conventional antianginal medications also point to impending infarction. Under these circumstances, early angiography is indicated. Otherwise, in cases in which the patient is stabilized readily with pharmacologic agents, including aspirin and heparin, there is no need for early angiography. Under these circumstances, one option is to forego coronary angiography altogether and then to evaluate patients several days to weeks later when they are completely stabilized and ambulatory. That can be accomplished by exercise stress testing, which can stratify patients according to their risk for subsequent cardiac events. Our usual approach, however, is to perform coronary angiography in all patients who are appropriate candidates after they have been stabilized but before hospital discharge.
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ST-Elevation Myocardial Infarction
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Symptoms suggestive of MI are usually similar to those of ordinary angina but are greater in intensity and duration. Nausea, vomiting, and diaphoresis may be prominent features, and stupor and malaise attributable to low cardiac output may occur. Compromised left ventricular function may result in pulmonary edema with development of pulmonary bibasilar crackles and jugular venous distention; a fourth heart sound can be present with small infarcts or even mild ischemia, but a third heart sound is usually indicative of more extensive damage.
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Patients presenting with suspected myocardial ischemia should undergo a rapid evaluation and should be treated with oxygen, sublingual nitroglycerin (unless systolic pressure <90 mm Hg), adequate analgesia, and aspirin (160 to 325 mg orally).45 Narcotics should be used to relieve pain and anxiety, the salutary effects of which have been known for decades and must not be underestimated. It is also important to provide reassurance to the patient. A 12-lead electrocardiogram should be made and interpreted expeditiously.
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ST-segment elevation of at least 1 mV in two or more contiguous leads provides strong evidence of thrombotic coronary occlusion: the patient should be considered for immediate reperfusion therapy. The diagnosis of STEMI can be limited in the presence of preexisting left bundle branch block or permanent pacemaker. Nonetheless, new left bundle branch block with a compatible clinical presentation should be treated as acute MI and treated accordingly. Recent data have suggested that patients with STEMI and new left bundle branch block may gain greater benefit from reperfusion strategies than those with ST elevation and preserved ventricular conduction.46
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Early reperfusion of an occluded coronary artery is indicated for all eligible candidates. Overwhelming evidence from multiple clinical trials has demonstrated the ability of thrombolytic agents administered early in the course of an acute MI to reduce infarct size, preserve left ventricular function, and decrease short-term and long-term mortality rates.47,48 Patients treated early derive the most benefit. Indications and contraindications for thrombolytic therapy are listed in Table 25-2. Because of the small, but nonetheless significant, risk of a bleeding complication, most notably intracranial hemorrhage, the decision to give a thrombolytic agent should be undertaken with prudence and caution. That is of special importance in ICU patients who may have a predisposition to bleeding complications because of multiple factors. Contraindications can be regarded as absolute or relative. In the surgical patient, thrombolysis may pose a prohibitive risk and emergent coronary angiography (with percutaneous coronary intervention as clinically indicated) may be preferable.
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In contrast to the treatment of STEMI, thrombolytics have shown no benefit or even increased risk of adverse events when used for the treatment of unstable angina or NSTEMI.49 Based on these findings, there is currently no role for thrombolytic agents in these latter syndromes.
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Streptokinase (SK) is a single-chain protein produced by α-hemolytic streptococci. SK is given as a 1.5 million U intravenous infusion over 1 hour, which produces a systemic lytic state for approximately 24 hours. Hypotension with infusion usually responds to fluids and a decreased infusion rate, but allergic reactions are possible. Hemorrhagic complications are the most feared side effect, with a rate of intracranial hemorrhage of approximately 0.5%. SK produces coronary arterial patency approximately 50% to 60% of the time and has been shown to decrease mortality rate by 18% compared with placebo.47
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Tissue plasminogen activator (t-PA) is a recombinant protein that is more fibrin selective than SK and produces a higher early coronary patency rate (70% to 80%). The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) was a large (41,021 patients) clinical trial comparing SK with t-PA in patients with STEMI and demonstrated a small but significant survival benefit for t-PA (1.1% absolute, 15% relative reduction).50 The GUSTO angiographic substudy showed that the difference in patency rates explains the difference in clinical efficacy between these two agents.51 t-PA is usually given in an accelerated regimen consisting of a 15-mg bolus, with 0.75 mg/kg (up to 50 mg) intravenously over the initial 30 minutes and 0.5 mg/kg (up to 35 mg) over the next 60 minutes. Allergic reactions do not occur because t-PA is not antigenic, but the rate of intracranial hemorrhage may be slightly higher (∼0.7%) than that with SK.
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Reteplase is a deletion mutant of t-PA with an extended half-life and is given as two 10-mg boluses 30 minutes apart. Reteplase was originally evaluated in angiographic trials that demonstrated improved coronary flow at 90 minutes compared with t-PA, but subsequent trials showed similar 30-day mortality rates.52 Why enhanced patency with reteplase did not translate into lower mortality is uncertain.
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Tenecteplase (TNK-tPA) is a genetically engineered t-PA mutant with amino acid substitutions that result in prolonged half-life, resistance to plasminogen-activator inhibitor 1, and increased fibrin specificity. TNK-tPA is given as a single bolus adjusted for weight. A single bolus of TNK-tPA has been shown to produce coronary flow rates identical to those seen with accelerated t-PA, with equivalent 30-day mortality and bleeding rates.53 Based on these results, single-bolus TNK-tPA is an acceptable alternative to t-PA.
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Because these newer agents have equivalent efficacy and side effect profiles at no additional cost compared with t-PA, and because they are simpler to administer, they have gained popularity. The ideal thrombolytic agent has not been developed. Newer recombinant agents with greater fibrin specificity, slower clearance from the circulation, and more resistance to plasma protease inhibitors are being studied.
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Primary Percutaneous Coronary Intervention in Acute MI
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As many as 50% to 66% of patients presenting with acute MI may be ineligible for thrombolytic therapy, and these patients should be considered for primary percutaneous coronary intervention (PCI). The major advantages of primary PCI over thrombolytic therapy include a higher rate of normal (Thrombolysis In Myocardial Infarction [TIMI] grade 3) flow,48 lower risk of intracranial hemorrhage, and the ability to stratify risk based on the severity and distribution of coronary artery disease. Data from several randomized trials have suggested that PCI is preferable to thrombolytic therapy for patients with acute MI at higher risk, including those older than 75 years, those with anterior infarctions, and those with hemodynamic instability.54 The largest of these trials is the GUSTO-IIb angioplasty substudy, which randomized 1138 patients. At 30 days, there was a clinical benefit in the combined primary end points of death, nonfatal reinfarction, and nonfatal disabling stroke in the patients treated with percutaneous transluminal coronary angioplasty (PTCA) as opposed to t-PA, but there was no difference in the “hard” end points of death and MI at 30 days.55
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These trials were performed in institutions in which a team skilled in primary angioplasty for acute MI was immediately available, with standby surgical backup, allowing for prompt reperfusion of the infarct-related artery. More important than the method of revascularization is the time to revascularization.56 Procedural volume also is important.57 A recent meta-analysis comparing direct PTCA with thrombolytic therapy found lower rates of mortality and reinfarction among those receiving direct PTCA.58,59 Thus, direct angioplasty, if performed in a timely manner (ideally within 60 minutes) by highly experienced personnel, may be the preferred method of revascularization because it offers more complete revascularization with improved restoration of normal coronary blood flow and detailed information about coronary anatomy. There are certain subpopulations in which primary PCI is preferred. These subsets are listed in Table 25-3.
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Coronary Stenting and Glycoprotein IIb/IIIa Antagonists
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Primary angioplasty for acute MI results in a significant decrease in mortality rate but is limited by the possibility of abrupt vessel closure, recurrent in-hospital ischemia, reocclusion of the infarct-related artery, and restenosis. The use of coronary stents has been shown to decrease restenosis and adverse cardiac outcomes in routine and high-risk PCI.60 The Primary Angioplasty in Myocardial Infarction Stent Trial tested the hypothesis that routine implantation of an intracoronary stent in the setting of MI would reduce angiographic restenosis and improve clinical outcomes compared with primary balloon angioplasty alone. This large, randomized, multicenter trial involving 900 patients did not show a difference in mortality rate at 6 months but did show improvement in ischemia-driven target vessel revascularization and less angina in the stented patients compared to PTCA alone.61
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Glycoprotein (GP) IIb/IIIa receptor antagonists inhibit the final common pathway of platelet aggregation by blocking cross linking of activated platelets, and their use in percutaneous intervention has become routine.62 The benefits of GP IIb/IIIa inhibition and coronary stenting appear to be additive.63,64 Thus, combining GP IIb/IIIa antagonism and stenting in acute MI makes theoretical sense and has been tested in two large clinical trials. The ADMIRAL trial evaluated abciximab as an adjunct to primary PTCA and stenting in 300 patients with acute MI. Abciximab used in conjunction with stenting improved coronary patency before stenting and resulted in a nearly 50% relative risk reduction in the incidence of death, recurrent MI, and urgent revascularization at 30 days, although this was associated with an increased incidence of minor bleeding.65 The CADILLAC trial randomized 2082 patients to angioplasty alone, angioplasty plus abciximab, stenting alone, or stenting plus abciximab. The composite end point of death, reinfarction, disabling stroke, and repeat revascularization was reduced with addition of abciximab to angioplasty, and outcomes were better with stenting (but abciximab added to stenting alone did not improve outcomes, although the event rate was low).66 Based on the results of these trials, stenting has become routine for patients with PCI in the setting of acute MI, usually with the addition of GP IIb/IIIa inhibition.
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In patients who fail thrombolytic therapy, salvage PTCA is indicated, although the initial success rate is lower than that of primary angioplasty, reocclusion is more common, and mortality is higher. The RESCUE trial focused on a subset of patients with acute MI and anterior infarction and showed a reduction in the combined end point of death and congestive heart failure at 30 days in the group receiving salvage PTCA.67
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There is no convincing evidence to support empirical delayed PTCA in patients without evidence of recurrent or provocable ischemia after thrombolytic therapy. The TIMI IIB trial and other studies have suggested that a strategy of “watchful waiting” allows for identification of patients who will benefit from revascularization.68
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Adjunctive Therapies in STEMI
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Aspirin has been shown to decrease mortality rate in acute infarction to the same degree as thrombolytic therapy, and its effects are additive to thrombolytics.69 In addition, aspirin reduces the risk of reinfarction. Unless contraindicated, all patients with a suspected acute coronary syndrome (STEMI, NSTEMI, or unstable angina) should be given aspirin as soon as possible.
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Administration of full-dose heparin after thrombolytic therapy with t-PA is essential to diminish reocclusion after successful reperfusion.47,69 Dosing should be adjusted to weight, with a bolus of 60 U/kg up to a maximum of 4000 U and an initial infusion rate of 12 U/kg per hour up to a maximum of 1000 U/hr, with adjustment to keep the partial thromboplastin time between 50 and 70 seconds. Heparin should be continued for 24 to 48 hours.
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Nitrates have several beneficial effects in acute MI. They reduce myocardial oxygen demand by decreasing preload and afterload and may improve myocardial oxygen supply by increasing subendocardial perfusion and collateral blood flow to the ischemic region. Occasional patients with ST elevation due to occlusive coronary artery spasm may have dramatic resolution of ischemia with nitrates. In addition to their hemodynamic effects, nitrates also reduce platelet aggregation. Despite these benefits, the Third Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI-3) and Fourth International Study of Infarct Survival (ISIS-4) trials found no significant decrease in mortality rate from routine short- and long-term nitrate therapies.70,71 Nonetheless, nitrates remain first-line agents for the symptomatic relief of angina pectoris and when MI is complicated by congestive heart failure.
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Beta blockers are beneficial in the early management of MI and as long-term therapy. In the era before thrombolysis, early intravenous atenolol was shown to significantly decrease reinfarction, cardiac arrest, cardiac rupture, and death.72 In conjunction with thrombolytic therapy with t-PA, immediate β blockade with metoprolol resulted in a significant reduction in recurrent ischemia and reinfarction, although mortality rate was not decreased.68
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Intravenous β blockade should be considered for all patients presenting with acute MI, especially those with continued ischemic discomfort and sympathetic hyperactivity manifested by hypertension or tachycardia. Therapy should be avoided in patients with moderate or severe heart failure, hypotension, severe bradycardia or heart block, and severe bronchospastic disease. Metoprolol can be given intravenously as a 5-mg bolus, repeated every 5 minutes for a total of three doses. Because of its brief half-life, esmolol may be advantageous in situations in which precise control of heart rate is necessary or rapid drug withdrawal may be needed if adverse effects occur.
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Oral β blockade has been clearly demonstrated to decrease mortality rate after acute MI73,74 and should be initiated in all patients who can tolerate it, even if they have not been treated with intravenous β blockers. Diabetes mellitus is not a contraindication.
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Angiotensin-Converting Enzyme Inhibitors
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ACE inhibitors have been shown unequivocally to improve hemodynamics, functional capacity and symptoms, and survival in patients with chronic congestive heart failure.75,76 Moreover, ACE inhibitors prevent the development of congestive heart failure in patients with asymptomatic left ventricular dysfunction.77 This information was the spur for trials evaluating the benefit of prophylactic administration of ACE inhibitors in the period after MI. The Survival and Ventricular Enlargement trial showed that patients with left ventricular dysfunction (ejection fraction <40%) after MI had a 21% improvement in survival rate after treatment with the ACE inhibitor captopril.78 A smaller but still significant reduction in mortality rate was seen when all patients were treated with captopril in the ISIS-4 study.71 The HOPE study demonstrated that the ACE inhibitor ramipril improves survival rate when added to aspirin and β blockers.36 The mechanisms responsible for the benefits of ACE inhibitors probably include limitation in the progressive left ventricular dysfunction and enlargement (remodeling) after infarction, but a reduction in ischemic events also is seen.
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ACE inhibition should be started early, preferably within the first 24 hours after infarction. Immediate intravenous ACE inhibition with enalaprilat has not been shown to be beneficial.79 Patients should be started on small doses of oral agents (captopril 6.25 mg three times daily) and rapidly increased to the range demonstrated to be beneficial in clinical trials (captopril 50 mg three times daily, enalapril 10 to 20 mg twice daily, lisinopril 10 to 20 mg once daily, or ramipril 10 mg once daily).
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Calcium Channel Blockers
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Randomized clinical trials have not demonstrated that routine use of calcium channel blockers improves survival rate after MI. Meta-analyses have suggested that large doses of the short-acting dihydropyridine nifedipine increase mortality rate in MI. Adverse effects of calcium channel blockers include bradycardia, atrioventricular block, and exacerbation of heart failure. The relative vasodilating, negative inotropic effects, and conduction system effects of the various agents must be considered when they are used in this setting. Diltiazem is the only calcium channel blocker that has been proven to have tangible benefits by reducing reinfarction and recurrent ischemia in patients with non–Q-wave infarctions who do not have evidence of congestive heart failure.80
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Calcium channel blockers may be useful for patients whose postinfarction course is complicated by recurrent angina because these agents not only reduce myocardial oxygen demand but also inhibit coronary vasoconstriction. For hemodynamically stable patients, diltiazem can be given starting at 60 to 90 mg orally every 6 to 8 hours. In patients with severe left ventricular dysfunction, a long-acting dihydropyridine without prominent negative inotropic effects such as amlodipine, nicardipine, or the long-acting preparation of nifedipine may be preferable; increased mortality rate with these agents has not been demonstrated.
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Antiarrhythmic Therapy
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A major purpose for admitting patients with MI to the ICU is to monitor for and prevent malignant arrhythmias. Ventricular extrasystoles are common after MI and are a manifestation of electrical instability of peri-infarct areas. The incidence of sustained ventricular tachycardia or fibrillation is highest in the first 3 to 4 hours, but these arrhythmias may occur at any time. Malignant ventricular arrhythmias may be heralded by frequent premature ventricular contractions (more than five or six per minute), closely coupled premature ventricular contractions, complex ectopy (couplets, multiform premature ventricular contractions), and salvos of nonsustained ventricular tachycardia. However, malignant arrhythmia may occur suddenly without these “warning” arrhythmias.
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Based on these pathophysiologic considerations, prophylactic use of intravenous lidocaine has been advocated, even in the absence of ectopy. Even though lidocaine decreases the frequency of premature ventricular contractions and of early ventricular fibrillation, overall mortality rate is not decreased. Meta-analyses of pooled data have demonstrated increased mortality rate from the routine use of lidocaine.81 Therefore, routine prophylactic administration of lidocaine is no longer recommended.
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Nonetheless, lidocaine infusion is clearly indicated after an episode of sustained ventricular tachycardia or ventricular fibrillation and should be considered in patients with nonsustained ventricular tachycardia. Lidocaine is administered as a bolus of 1 mg/kg (not to exceed 100 mg), followed by a second bolus of 0.5 mg/kg 10 minutes later, and an infusion at 1 to 3 mg/min. Lidocaine is metabolized by the liver, so smaller doses should be given in the presence of liver disease, in the elderly, and in patients who have congestive heart failure severe enough to compromise hepatic perfusion. Toxic manifestations primarily involve the central nervous system and can include confusion, lethargy, slurred speech, and seizures. Because the risk of malignant ventricular arrhythmias decreases after 24 hours, lidocaine is usually discontinued after this point. For prolonged infusions, monitoring of lidocaine levels (therapeutic between 1.5 and 5 μg/mL) is sometimes useful.
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Intravenous amiodarone is an alternative to lidocaine for ventricular arrhythmias. Amiodarone is given as a 150-mg intravenous bolus over 10 minutes, followed by 1 mg/min for 6 hours, and then 0.5 mg/min for 18 hours.
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Perhaps the most important points in the prevention and management of arrhythmias after acute MI are correcting hypoxemia and maintaining normal serum potassium and magnesium levels. Serum electrolytes should be followed closely, particularly after diuretic therapy. Magnesium depletion is another frequently overlooked cause of persistent ectopy.82 The serum magnesium level may not reflect myocardial concentrations. Routine administration of magnesium has not been shown to decrease mortality rate after acute MI,71 but empiric administration of 2 g of intravenous magnesium in patients with early ventricular ectopy is probably a good idea.
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One possible treatment algorithm for treating patients with STEMI is shown in Fig. 25-2.
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Non–ST-Elevation Myocardial Infarction
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The key to initial management of patients with acute coronary syndromes who present without ST elevation is risk stratification. The overall risk of a patient is related to the severity of preexisting heart disease and the degree of plaque instability. Risk stratification is an ongoing process, which begins with hospital admission and continues through discharge.
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Braunwald proposed a classification for unstable angina based on severity of symptoms and clinical circumstances for risk stratification.83 The risk of progression to acute MI or death in acute coronary syndromes increases with age. ST-segment depression on the electrocardiogram identifies patients at higher risk for clinical events.83 Conversely, a normal electrocardiogram confers an excellent short-term prognosis. Biochemical markers of cardiac injury are also predictive of outcome. Elevated levels of troponin T are associated with an increased risk of cardiac events and a higher 30-day mortality rate and are more strongly correlated with 30-day survival rate than is ECG category or CPK-MB level.84 Conversely, low levels are associated with low event rates, although the absence of troponin elevation does not guarantee a good prognosis and is not a substitute for good clinical judgment.
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Aspirin is a mainstay of therapy for acute coronary syndromes. The Veterans Administration Cooperative Study Group28 and the Canadian Multicenter Trial85 showed that aspirin reduces the risk of death or MI by approximately 50% in patients with unstable angina or non–Q-wave MI. Aspirin also reduces events after resolution of an acute coronary syndrome and should be continued indefinitely.
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Clopidogrel or ticlopidine, thienopyridines that inhibit platelet activation induced by adenosine diphosphate and are more potent than aspirin, can be used in place of aspirin, if necessary. They are used in combination with aspirin when intracoronary stents are placed. Clopidogrel is generally better tolerated than ticlopidine because the risk of neutropenia is much lower.
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In the CURE trial, 12,562 patients were randomized to receive clopidogrel or placebo in addition to standard therapy with aspirin within 24 hours of unstable angina symptoms.86 Clopidogrel significantly reduced the risk of MI, stroke, or cardiovascular death from 11.4% to 9.3% (p <0.001).86 It should be noted that this benefit included a 1% absolute increase in major, non–life-threatening bleeds (p = 0.001) and a 2.8% absolute increase in major or life-threatening bleeds associated with coronary artery bypass graft (CABG) within 5 days (p = 0.07).86 These data have raised concerns about giving clopidogrel before obtaining information about the coronary anatomy.
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Clopidogrel has also been tested for secondary prevention of events. The Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events trial, a multicenter trial of 19,185 patients with known vascular disease (prior stroke, MI, or peripheral vascular disease), randomized patients to 75 mg/d of clopidogrel or 325 mg/d aspirin.87 After an average follow-up period of 1.6 years, patients treated with clopidogrel had significantly fewer cardiovascular events than did patients treated with aspirin (5.8% vs. 5.3%, a relative risk reduction of 8.7%).87
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Anticoagulant Therapy
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Heparin is an important component of primary therapy for patients with unstable coronary syndromes without ST elevation. When added to aspirin, heparin has been shown to reduce refractory angina and the development of MI,29 and a meta-analysis of the available data has indicated that addition of heparin reduces the composite end point of death or MI.88
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Heparin can be difficult to administer because the anticoagulant effect is unpredictable in individual patients; this is due to heparin binding to heparin-binding proteins, endothelial and other cells, and heparin inhibition by several factors released by activated platelets. Therefore, the activated partial thromboplastin time must be monitored closely. The potential for heparin-associated thrombocytopenia is another safety concern.
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Low-molecular-weight heparins (LMWHs), which are obtained by depolymerization of standard heparin and selection of fractions with lower molecular weights, have several advantages. Because they bind less avidly to heparin-binding proteins, there is less variability in the anticoagulant response and a more predictable dose-response curve, so the need to monitor activated partial thromboplastin time is eliminated. The incidence of thrombocytopenia is lower (but not absent, and patients with heparin-induced thrombocytopenia with anti-heparin antibodies cannot be switched to LMWH). Moreover, LMWHs have longer half-lives and can be given by subcutaneous injection. These properties make treatment with LMWH at home after hospital discharge feasible. Because evidence suggests that patients with unstable coronary syndromes may remain in a hypercoagulable state for weeks or months, the longer duration of anticoagulation possible with LMWH may be desirable.
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Several trials have documented beneficial effects of LMWH therapy in unstable coronary syndromes. The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events trial showed that the LMWH enoxaparin reduces the combined end point of death, MI, or recurrent ischemia at 14 days and at 30 days when compared with heparin.89 Similar results were found in the TIMI 11B trial comparing enoxaparin with heparin.90 A meta-analysis of these two very similar trials demonstrated a 23% 7-day and an 18% 42-day reduction in death or MI.91Dalteparin, another LMWH, is also available, but the evidence for its efficacy is not nearly as compelling as that for enoxaparin.
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Although LMWHs are substantially easier to administer than standard heparin and long-term administration can be contemplated, they are more expensive. Specific considerations with the use of LMWHs include decreased clearance in renal insufficiency and the lack of a commercially available test to measure the anticoagulant effect. LMWH should be given strong consideration in high-risk patients, but whether substitution of LMWH for heparin in all patients is cost effective is uncertain.
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Glycoprotein IIb/IIIa Antagonists
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Given the central role of platelet activation and aggregation in the pathophysiology of unstable coronary syndromes, attention has focused on platelet GP IIb/IIIa antagonists, which inhibit the final common pathway of platelet aggregation. Three agents are currently available. Abciximab is a chimeric murine-human monoclonal antibody Fab fragment that binds with relatively high affinity to platelet receptors, giving it a short plasma half-life (10 to 30 minutes) but a long duration of biologic action by virtue of the strength of the bond formed with the surface of the activated platelet. Because there is a relatively low ratio of abciximab molecules to platelets (i.e., limited plasma pool of unbound drug), platelet transfusions may be helpful in the event of a major bleeding complication. Abciximab is currently approved for elective PCI or unstable coronary syndromes with planned PCI. Tirofiban is a synthetic nonpeptide agent with a half-life of approximately 2.5 hours and a lower receptor affinity than abciximab. This drug is approved for the medical management of unstable angina or NSTEMI with or without planned PCI. Given the large ratio of drug to platelet (i.e., large plasma pool of free drug) seen with this agent and with eptifibatide, platelet transfusions are generally not regarded as helpful in the event of a major bleed. It is recommended that the drug simply be stopped and supportive therapy instituted during the relatively short biologic activity period. Eptifibatide is a cyclic heptapeptide with a 2-hour half-life. Like tirofiban, it is approved for the medical management of unstable angina with or without subsequent PCI; however, it may also be used as adjunctive therapy in elective PCI.
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The benefits of GP IIb/IIIa inhibitors as adjunctive treatment in patients undergoing percutaneous intervention have been substantial and consistently observed. Abciximab has been most extensively studied, but a benefit for eptifibatide has also been demonstrated. In acute coronary syndromes, the evidence supporting the efficacy of GP IIb/IIIa inhibitors is somewhat less impressive. Five major trials have been completed (the “4 P's” and GUSTO-IV). In the Platelet Receptor Inhibition in Ischemic Syndrome Management trial, tirofiban decreased death rate, MI, or refractory ischemia when compared with heparin, from 5.6% to 3.8% (p <0.01) at 48 hours, but there was no difference at 30 days (7.1% vs. 5.8%, p = 0.11).92 In the subsequent Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial, tirofiban added to heparin decreased death rate, MI, or refractory ischemia at 30 days, from 11.9% to 8.7% (p = 0.03).31 In the PURSUIT trial, eptifibatide decreased the rate of death or MI, from 15.7% to 14.2% (p = 0.04) at 30 days.93 The PARAGON trial with lamifiban did not show a significant benefit with GP IIb/IIIa inhibition.94 In the GUSTO-IV ACS trial, however, abciximab did not produce an improvement; death rate or MI was slightly higher in the treatment group.95 This trial included patients for whom percutaneous intervention was not planned; when patients with refractory angina and planned angioplasty were randomized to receive abciximab or placebo from 24 hours before the procedure through 1 hour after PTCA in the CAPTURE trial, the primary end point—death, MI, or urgent revascularization at 30 days—was decreased by GP IIb/IIIa inhibition, and the rate of MI before PTCA also was decreased.96 When patients were categorized as those with or without increased troponin, the benefit was confined to the positive troponin group.96
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Recent meta-analyses have found a relative risk reduction of 40% for GP IIb/IIIa therapy adjunctive to PCI, and a reduction of 11% for GP IIb/IIIa inhibitors in NSTEMI acute coronary syndromes.62 Additional analysis has suggested that GP IIb/IIIa inhibition is most effective in high-risk patients (those with ECG changes or elevated troponin).62 The benefits appear to be restricted to patients undergoing percutaneous intervention.
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Interventional Management
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Cardiac catheterization may be undertaken in patients presenting with symptoms suggestive of unstable coronary syndromes for one of several reasons: to assist with risk stratification, as a prelude to revascularization, and to exclude significant epicardial coronary stenosis as a cause of symptoms when the diagnosis is uncertain.
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An early invasive approach has been compared with a conservative approach in several prospective studies. Two earlier trials were negative. The TIMI IIIb study randomized 1473 patients to early angiography or conservative management with angiography and revascularization only for recurrent chest pain or provocable ischemia.49 No significant difference was found in the combined end point of death, MI, or positive treadmill test at 6 weeks. However, there was a high (64%) cross-over rate from the conservative to the invasive arm, and hospital stays were shorter with the early invasive approach.49 The VANQWISH trial of 920 patients with non–Q wave MI showed an increase in the primary end point of death rate or MI with an invasive strategy, although overall mortality was not significantly different.97 Difficulties with this trial included the fact that only 44% of patients randomized to the invasive arm actually underwent revascularization, compared with 33% in the conservative arm, and the entire trial had a very high surgical mortality rate (11.6%).97 It is important to realize that these trials were performed before widespread use of coronary stenting and platelet GP IIb/IIIa inhibitors, both of which have been shown to improve outcomes after angioplasty.
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More recently, a substudy of the Second Fragmin and Fast Revascularisation during Instability in Coronary Artery Disease study, which used the LMWH dalteparin, randomized 2457 patients to an early invasive or a noninvasive strategy and found a significantly lower mortality rate in the invasive group at 30 days, which was maintained at 1 year.98 The TACTICS TIMI-18 trial used aspirin, heparin, and tirofiban in 2220 patients and found a significant reduction in the combined end point of death rate, MI, or readmission for acute coronary syndrome with invasive management.99 It is important to recognize that these trials selected high-risk patients (identified on the basis of ECG changes or enzyme elevations) for inclusion. Addition of antiplatelet therapy (beyond the use of aspirin alone) to reperfusion also may have contributed to the improved outcomes with invasive strategies in these more recent trials.
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Risk stratification is the key to managing patients with NSTEMI acute coronary syndromes. One possible algorithm for managing patients with NSTEMI is shown in Fig. 25-3. An initial strategy of medical management with attempts at stabilization is warranted in patients with lower risk, but patients at higher risk should be considered for cardiac catheterization. Pharmacologic and mechanical strategies are intertwined in the sense that selection of patients for early revascularization will influence the choice of antiplatelet and anticoagulant medication. When good clinical judgment is used, early coronary angiography in selected patients with acute coronary syndromes can lead to better management and lower morbidity and mortality rates.
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Complications of Acute Myocardial Infarction
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Postinfarction Ischemia
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Causes of ischemia after infarction include decreased myocardial oxygen supply due to coronary reocclusion or spasm, mechanical problems that increase myocardial oxygen demand, and extracardiac factors such as hypertension, anemia, hypotension, or hypermetabolic states. Nonischemic causes of chest pain, such as postinfarction pericarditis and acute pulmonary embolism, should also be considered.
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Immediate management includes aspirin, β blockade, intravenous nitroglycerin, heparin, consideration of calcium channel blockers, and diagnostic coronary angiography. Postinfarction angina is an indication for revascularization. PTCA can be performed if the culprit lesion is suitable. CABG should be considered for patients with left main disease, three-vessel disease, or unsuitable for PTCA. If the angina cannot be controlled medically or is accompanied by hemodynamic instability, an IABP should be inserted.
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Ventricular Free Wall Rupture
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Ventricular free wall rupture typically occurs during the first week after infarction. The classic patient is elderly, female, and hypertensive. Early use of thrombolytic therapy decreases the incidence of cardiac rupture, but late use may actually increase the risk. Free wall rupture presents as a catastrophic event with shock and electromechanical dissociation. Salvage is possible with prompt recognition, pericardiocentesis to relieve acute tamponade, and thoracotomy with repair.100 Emergent echocardiography or pulmonary artery catheterization can help make the diagnosis.
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Ventricular Septal Rupture
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Septal rupture presents as severe heart failure or cardiogenic shock, with a pansystolic murmur and parasternal thrill. The hallmark finding is a left-to-right intracardiac shunt (“step up" in oxygen saturation from the right atrium to the right ventricle), but the diagnosis is most easily made with echocardiography.
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Rapid institution of an IABP and supportive pharmacologic measures is necessary. Operative repair is the only viable option for long-term survival. The timing of surgery has been controversial, but most authorities currently suggest that repair should be undertaken early, within 48 hours of the rupture.101
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Acute Mitral Regurgitation
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Ischemic mitral regurgitation is usually associated with inferior MI and ischemia or infarction of the posterior papillary muscle, although anterior papillary muscle rupture can also occur. Papillary muscle rupture typically occurs 2 to 7 days after acute MI and presents dramatically with pulmonary edema, hypotension, and cardiogenic shock. When a papillary muscle ruptures, the murmur of acute mitral regurgitation may be limited to early systole because of rapid equalization of pressures in the left atrium and left ventricle. More importantly, the murmur may be soft or inaudible, especially when cardiac output is low.102
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Echocardiography is extremely useful in the differential diagnosis, which includes free wall rupture, ventricular septal rupture, and infarct extension with pump failure. Hemodynamic monitoring with pulmonary artery catheterization may also be helpful. Management includes afterload reduction with nitroprusside and an IABP as temporizing measures. Inotropic or vasopressor therapy also may be needed to support cardiac output and blood pressure. Definitive therapy is surgical valve repair or replacement, which should be undertaken as soon as possible because clinical deterioration can be sudden.102,103
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Right Ventricular Infarction
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Right ventricular infarction occurs in up to 30% of patients with inferior infarction and is clinically significant in 10%.104 The combination of a clear chest radiogram with jugular venous distention in a patient with an inferior wall MI should lead to the suspicion of a coexisting right ventricular infarct. The diagnosis is substantiated by demonstration of ST-segment elevation in the right precordial leads (V3R to V5R) or by characteristic hemodynamic findings on right heart catheterization (elevated right atrial and right ventricular end-diastolic pressures with normal to low pulmonary artery occlusion pressure and low cardiac output). Echocardiography can demonstrate depressed right ventricular contractility.22 Patients with cardiogenic shock on the basis of right ventricular infarction have a better prognosis than do those with left-side pump failure.104 This may be due in part to the fact that right ventricular function tends to return to normal over time with supportive therapy.105
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In patients with right ventricular infarction, hypovolemia should be avoided because it can seriously compromise perfusion. However, most patients have elevated central venous pressures after initial resuscitation, and fluid loading is ineffective in raising perfusion further. Continued fluid loading can compromise left ventricular filling and cardiac output.105 Inotropic therapy with dobutamine is often more effective in increasing cardiac output. Serial echocardiograms may be useful to detect right ventricular overdistention.105 Maintenance of atrioventricular synchrony is also important in these patients to optimize right ventricular filling.22 For patients with continued hemodynamic instability, using an IABP may be useful, particularly because elevated right ventricular pressures and volumes increase wall stress and oxygen consumption and decrease right coronary perfusion pressure, exacerbating right ventricular ischemia.
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Reperfusion of the occluded coronary artery is also crucial. A study using direct angioplasty found that restoration of normal flow can result in dramatic recovery of right ventricular function and a mortality rate of only 2%, whereas unsuccessful reperfusion was associated with persistent hemodynamic compromise and a mortality rate of 58%.106
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Epidemiology and Pathophysiology
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Cardiogenic shock, resulting from left ventricular pump failure or from mechanical complications, represents the leading cause of in-hospital death after MI.20 Despite advances in the management of heart failure and acute MI, clinical outcomes in patients with cardiogenic shock have been frustratingly poor, with reported mortality rates ranging from 50% to 80%.107 Patients may have cardiogenic shock at initial presentation, but shock often evolves over several hours.108,109 This is important because it suggests that early treatment may potentially prevent shock.
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Cardiac dysfunction in patients with cardiogenic shock is usually initiated by MI or ischemia. The myocardial dysfunction resulting from ischemia worsens that ischemia, creating a downward spiral (Fig. 25-4). Once a critical mass of ischemic or necrotic left ventricular myocardium (usually about 40%)110 fails to pump, stroke volume and cardiac output begin to diminish significantly. Systolic dysfunction leads to decreased systemic perfusion and hypotension, which reduces coronary perfusion pressure and induces compensatory peripheral vasoconstriction and fluid retention. These compensatory mechanisms create a vicious cycle that further worsens the systolic dysfunction. Likewise, myocardial ischemia increases myocardial stiffness, thus increasing left ventricular end-diastolic pressure and myocardial wall stress at a given end-diastolic volume. Increased left ventricular stiffness limits diastolic filling and may result in pulmonary congestion, causing hypoxemia and worsening the imbalance of oxygen delivery and oxygen demand in the myocardium, resulting in further ischemia and myocardial dysfunction. The compensatory mechanisms that retain fluid to maintain cardiac output may add to the vicious cycle and further increase diastolic filling pressures. The interruption of this cycle of myocardial dysfunction and ischemia forms the basis for the therapeutic regimens for cardiogenic shock.
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Maintenance of adequate oxygenation and ventilation is critical. Many patients require intubation and mechanical ventilation, if only to reduce the work of breathing and facilitate sedation and stabilization before cardiac catheterization. Electrolyte abnormalities should be corrected, and morphine (or fentanyl, if systolic pressure is compromised) should be used to relieve pain and anxiety, thus decreasing excessive sympathetic activity and oxygen demand, preload, and afterload. Arrhythmias and heart block may have major effects on cardiac output and should be corrected promptly with antiarrhythmic drugs, cardioversion, or pacing.
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The initial approach to the hypotensive patient should include fluid resuscitation unless frank pulmonary edema is present. Patients are commonly diaphoretic and relative hypovolemia may be present in as many as 20% of patients with cardiogenic shock. Fluid infusion is best initiated with predetermined boluses titrated to clinical end points of heart rate, urine output, and blood pressure. Ischemia produces diastolic and systolic dysfunctions; hence, elevated filling pressures may be necessary to maintain stroke volume in patients with cardiogenic shock. Patients who do not respond rapidly to initial fluid boluses or those with poor physiologic reserve should be considered for invasive hemodynamic monitoring. Optimal filling pressures differ from patient to patient; hemodynamic monitoring can be used to construct a Starling curve at the bedside to identify the filling pressure at which cardiac output is maximized. Maintenance of adequate preload is particularly important in patients with right ventricular infarction.
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When arterial pressure remains inadequate, therapy with vasopressor agents may be required to maintain coronary perfusion pressure. Dopamine increases blood pressure and cardiac output and is usually the initial choice in patients with systolic pressures below 80 mm Hg. When hypotension remains refractory, norepinephrine may be necessary to maintain organ perfusion pressure. Phenylephrine, a selective α1-adrenergic agonist, may be useful when tachyarrhythmias limit therapy with other vasopressors. Vasopressor infusions need to be titrated carefully in patients with cardiogenic shock to maximize coronary perfusion pressure with the least possible increase in myocardial oxygen demand. Hemodynamic monitoring, with serial measurements of cardiac output and filling pressures (and other parameters such as mixed venous oxygen saturation), allows for titration of the dosage of vasoactive agents to the minimum dosage required to achieve the chosen therapeutic goals.24
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After initial stabilization and restoration of adequate blood pressure, tissue perfusion should be assessed. If tissue perfusion remains inadequate, inotropic support or use of an IABP should be initiated. If tissue perfusion is adequate but significant pulmonary congestion remains, diuretics may be used. Vasodilators also can be considered, depending on the blood pressure.
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In patients with inadequate tissue perfusion and adequate intravascular volume, the circulation should be supported with inotropic agents. Dobutamine, a selective β1-adrenergic receptor agonist, can improve myocardial contractility and increase cardiac output and is the initial agent of choice in patients with systolic pressures above 80 mm Hg. Dobutamine may exacerbate hypotension in some patients, especially when hypovolemia has not been corrected, and can precipitate tachyarrhythmias. Dopamine may be preferable if systolic pressure is below 80 mm Hg, although tachycardia and increased peripheral resistance may worsen myocardial ischemia. In some situations, a combination of dopamine and dobutamine can be more effective than either agent used alone. Phosphodiesterase inhibitors such as milrinone increase intracellular cyclic adenosine monophosphate by mechanisms not involving adrenergic receptors, have positive inotropic and vasodilatory actions, and are less arrhythmogenic than catecholamines. Milrinone, however, has the potential to cause hypotension and has a long half-life; in patients with tenuous clinical status, its use is often reserved for situations in which other agents have proven ineffective. Standard administration of milrinone calls for a bolus loading dose followed by an infusion, but many clinicians eschew the loading dose (or halve it) in patients with marginal blood pressure.
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Counterpulsation with an IABP reduces afterload and augments diastolic perfusion pressure, thereby increasing cardiac output and improving coronary blood flow.111 These beneficial effects, in contrast to those of inotropic or vasopressor agents, occur without an increase in oxygen demand. However, IABP does not produce a significant improvement in blood flow distal to a critical coronary stenosis and has not been shown to improve mortality when used alone, that is, without reperfusion therapy or revascularization. In patients with cardiogenic shock and compromised tissue perfusion, IABP can be an essential support mechanism to stabilize patients and allow time for definitive therapeutic measures.111,112 In appropriate settings, more intensive support with mechanical assist devices may also be implemented.
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Although thrombolytic therapy reduces the likelihood of subsequent development of shock after initial presentation,109 its role in the management of patients who have already developed shock is less certain. The number of patients in randomized trials is small because most fibrinolytic trials have excluded patients with cardiogenic shock at presentation, but the available trials (GISSI, ISIS-2, and GUSTO-1)47,50,69,113 have not demonstrated that fibrinolytic therapy decreases mortality rate in patients with established cardiogenic shock. In contrast, in the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock? (SHOCK) Registry,114 patients treated with fibrinolytic therapy had a lower in-hospital mortality rate than did those who were not (54% vs. 64%, p = 0.005), even after adjustment for age and revascularization status (odds ratio, 0.70; p = 0.027).
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Fibrinolytic therapy is clearly less effective in patients with cardiogenic shock than in those without. The explanation for this lack of efficacy appears to be the low reperfusion rate achieved in this subset of patients. The reasons for decreased thrombolytic efficacy in patients with cardiogenic shock likely include hemodynamic, mechanical, and metabolic factors that prevent achievement and maintenance of infarct-related artery patency.115 Attempts to increase reperfusion rates by increasing blood pressure with aggressive inotropic and pressor therapies and counterpulsation with an IABP make theoretical sense, and two small studies have supported the notion that vasopressor therapy improves thrombolytic efficacy.115,116 The use of an IABP to augment aortic diastolic pressure also may increase the effectiveness of thrombolytics.
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To date, emergency percutaneous revascularization is the only intervention that has been shown to reduce mortality rates consistently in patients with cardiogenic shock. Use of angioplasty in patients with cardiogenic shock grew out of its use as primary therapy in patients with MI. An analysis of the first 1000 patients treated with primary angioplasty at the Mid America Heart Institute showed a mortality rate of 44% in the subgroup of 79 patients presenting with cardiogenic shock, which was substantially lower than the 80% to 90% mortality rate in historical controls.117 Most other reported case series also showed results with percutaneous intervention that were superior to those with fibrinolytic therapy or conservative medical management (mortality rates of approximately 40% to 50%).20 Observational studies from registries of randomized trials have also reported improved outcomes in patients with cardiogenic shock selected for revascularization. Notable among these are the GUSTO-1 trial, in which patients treated with an “aggressive" strategy (coronary angiography performed within 24 hours of shock onset with revascularization by PTCA or CABG) had a significantly lower mortality rate (38% vs. 62%).118 This benefit was present even after adjustment for baseline characteristics118 and persisted to 1 year.119
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The National Registry of Myocardial Infarction 2 (NRMI-2), which collected 26,280 patients with cardiogenic shock in the setting of MI between 1994 and 1997, similarly supported the association between revascularization and survival.120 Improved short-term mortality rate was noted in those who underwent revascularization during the reference hospitalization by PTCA (12.8% vs. 43.9% mortality rate) or CABG (6.5% vs. 23.9%).120 These data complement the GUSTO-1 substudy data and are important, not only because of the sheer number of patients from whom these values are derived but also because NRMI-2 was a national cross-sectional study that more closely represents general clinical practice than carefully selected trial populations.
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This extensive body of observational and registry studies showed consistent benefits from revascularization but could not be regarded as definitive due to their retrospective design. Two randomized controlled trials have evaluated revascularization for patients with MI.
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The SHOCK study was a randomized, multicenter international trial that assigned patients with cardiogenic shock to receive optimal medical management, including IABP and thrombolytic therapy, or cardiac catheterization with revascularization using PTCA or CABG.121,122 The trial enrolled 302 patients and was powered to detect a 20% absolute decrease in 30-day all-cause mortality rates. Mortality rates at 30 days were 46.7% in patients treated with early intervention and 56% in patients treated with initial medical stabilization, but this difference did not quite reach statistical significance (p = 0.11).121 It is important to note that the control group (patients who received medical management) had a lower mortality rate than that reported in previous studies; this may reflect the aggressive use of thrombolytic therapy (64%) and IABP (86%) in these controls. These data provide indirect evidence that the combination of thrombolysis and IABP may produce the best outcomes when cardiac catheterization is not immediately available. At 6 months, the absolute risk reduction with early invasive therapy in the SHOCK trial was 13% (50.3% vs. 63.1%, p = 0.027),121 and this risk reduction was maintained at 12 months (53.3% vs. 66.4% mortality rate, p <0.03).122 Subgroup analysis showed a substantial improvement in mortality rates in patients younger than 75 years at 30 days (41.4% vs. 56.8%, p = 0.01) and 6 months (44.9% vs. 65.0%, p = 0.003).121
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The Swiss Multicenter Trial of Angioplasty for Shock (SMASH trial) was independently conceived and had a very similar design, although a more rigid definition of cardiogenic shock resulted in enrollment of sicker patients and a higher mortality rate.123 The trial was terminated early due to difficulties in patient recruitment and enrolled only 55 patients. In the SMASH trial, a similar trend in 30-day absolute decrease in mortality rate similar to that in the SHOCK trial was observed (69% mortality rate in the invasive group vs. 78% in the medically managed group; relative risk, 0.88; 95% confidence interval, 0.6 to 1.2; p = NS).123 This benefit was also maintained at 1 year.
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When the results of the SHOCK and SMASH trials are put into perspective with results from other randomized, controlled trials of patients with acute MI, an important point emerges: despite the moderate decrease in relative risk (0.72 for the SHOCK trial, with a 95% confidence interval of 0.54 to 0.95; and 0.88 for the SMASH trial, with a 95% confidence interval of 0.60 to 1.20), the absolute benefit is important, with nine lives saved for 100 patients treated at 30 days in both trials, and 13.2 lives saved for 100 patients treated at 1 year in the SHOCK trial. This latter figure corresponds to a number needed to treat of 7.6, one of the lowest figures ever observed in a randomized, controlled trial of cardiovascular disease.
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On the basis of these randomized trials, the presence of cardiogenic shock in the setting of acute MI is a class I indication for emergency revascularization by PCI or CABG.45
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Indications for Temporary Pacing in Acute Myocardial Infarction
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Damage to the impulse formation and conduction system of the heart from MI can result in bradyarrhythmias and conduction disturbances that do not respond reliably to conventional pharmacologic agents such as atropine or isoproterenol. These disturbances may lead to further hemodynamic compromise and coronary hypoperfusion. Disturbances of conduction distal to the atrioventricular node and the bundle of His are particularly worrisome, even if they are tolerated well hemodynamically. Ventricular escape rhythms in the setting of acute MI are unstable and unreliable; their discharge rate may vary widely, with abrupt acceleration to ventricular tachycardia or deceleration to asystole. It is this characteristic of subsidiary ventricular pacemakers that guides the indication for prophylactic placement of temporary transvenous pacing in acute MI (see Chap. 24). Table 25-4 lists these indications, which are based on studies documenting the progression to high-grade atrioventricular block when the indicated conduction disturbances are present. Any bradyarrhythmia unresponsive to atropine that results in hemodynamic compromises requires pacing.
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