cardio vascular system 4

Diuretics For most patients, volume status should be optimized before introduction of β-blockers and ACE inhibitors. Patients with pulmonary congestion often will require a loop diuretic in addition to standard therapy. Diuretics relieve dyspnea, decrease heart size and wall stress, and correct hyponatremia of volume overload. However, overly aggressive and especially unmonitored diuretic therapy can lead to metabolic abnormalities, intravascular depletion, hypotension, and neurohormonal activation. Digoxin Digoxin continues to be useful for patients with symptomatic heart failure and left ventricular systolic dysfunction despite receiving ACE inhibitor, β-blocker, and diuretic therapy. Digoxin is the only positive inotropic drug approved for the management of chronic heart failure. Its indirect mechanism of positive inotropy begins with inhibition of the myocardial sarcolemmal Na+-K+ ATPase, resulting in increased intracellular Na+. This, in turn, prompts the Na+/Ca2+ exchanger to extrude Na+ from the cell, increasing intracellular Ca2+. The increased Ca2+ now available to the contractile proteins increases contractile function. Besides its inotropic effects, digoxin has important vagotonic and sympatholytic effects. In atrial fibrillation, digoxin slows the rate of conduction at the AV node. In heart failure patients it reduces sympathetic efferent nerve activity to the heart and peripheral circulation through direct effects on the carotid sinus baroreceptors. Digoxin increases HR variability, an additional beneficial action on autonomic function in the patient with heart failure. Although these properties are beneficial in controlling the ventricular rate in atrial fibrillation, digoxin has only a narrow therapeutic/toxicity ratio. Digoxin toxicity is dose dependent and modified by concurrent medications (non–potassium-sparing diuretics) or conditions (renal insufficiency, myocardial ischemia). Ventricular arrhythmias consequent to digoxin toxicity may be caused by calcium-dependent afterpotentials. In patients with intoxication and life-threatening arrhythmias, purified anti-digoxin FAB fragments from digoxinspecific antisera provide a specific antidote. The efficacy of digoxin for symptomatic heart failure was shown in randomized, controlled trials. The Digitalis Investigators Group (DIG) trial, enrolling more than 6500 patients with an average follow-up of 37 months, showed that digoxin reduced the incidence of heart failure exacerbations. Although the study showed no difference in survival in patients with an ejection fraction less than 45% receiving either digoxin or placebo, the combined endpoint of death or hospitalization for heart failure was significantly reduced in patients who received digoxin (27% vs. 35%; relative risk, 0.72; 95% confidence interval, 0.66 to 0.79). Efficacy of digoxin in patients with mildly symptomatic heart failure was shown in pooled results from the Prospective Randomized Study of Ventricular Function (PROVED) and the Randomized Assessment of Digoxin and Inhibitors of Angiotensin-­Converting Enzyme (RADIANCE) trials. Patients randomized to digoxin withdrawal had an increased likelihood of treatment failure compared with those who continued to receive digoxin, suggesting that patients with left ventricular systolic dysfunction benefit from digoxin (or, at least, do not benefit from digoxin withdrawal), even when they have only mild symptoms. Accordingly, digoxin is recommended for symptomatic heart failure unless contraindicated. Together with ACE inhibitors, β-blockers, and diuretics, digoxin should be added to the therapeutic armamentarium. Ideally, serum digoxin concentration should remain between 0.7 and 1.1 ng/mL. In the elderly patient with renal insufficiency, severe conduction abnormalities, or acute coronary syndromes, even a low dose of 0.125 mg/day should be used with extra caution

Future Therapy Among the promising nonpharmacologic therapies for the management of heart failure are the implantable defibrillators and biventricular pacemakers. In the COMPANION trial (The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure), cardiac resynchronization therapy with a pacemaker combined with an implantable defibrillator significantly decreased the likelihood of death from or hospitalization for heart failure when compared with conventional pharmacologic therapy

Stem cell therapy is another potential treatment of heart failure. Stem cell therapy has shown promise in the treatment of ischemic heart disease both in the laboratory and in small clinical studies. Autologous bone marrow and peripheral blood stem cells transplanted in patients with acute myocardial infarction improved cardiac function. However, until double-blind, randomized controlled trials are performed, the true benefit of this innovative treatment remains unknown. Management of Acute Exacerbations of Chronic Heart Failure Patients with chronic heart failure, despite good medical management, may experience episodes of pulmonary edema or other signs of acute volume overload. These patients may require hospitalization for intensive management if diuretics fail to relieve their symptoms. Other patients may experience exacerbations of heart failure associated with acute myocardial ischemia or infarction, worsening valvular dysfunction, infections (including myocarditis), or failure to maintain an established drug regimen. Fonarow and associates described a risk stratification system for in-hospital mortality in acutely decompensated heart failure using data from a national registry. Low-, intermediate-, and high-risk patients with mortality ranging from 2.1% to 21.9% were identified using blood urea nitrogen, creatinine, and systolic BP on admission. These patients will require all the standard medications, as outlined in previous sections, and may also require infusions of vasodilators or positive inotropic drugs.21 Vasodilators Intravenous vasodilators have long been used to treat the symptoms of low CO in patients with decompensated chronic heart failure. In general, vasodilators reduce ventricular filling pressures and SVR while increasing SV and CO. NTG is commonly used for this purpose and has been studied in numerous clinical trials. It is often initially effective at relatively small doses (20 to 40 μg/min) but frequently requires progressively increasing doses to counteract tachyphylaxis. NTG is associated with dose-dependent arterial hypotension. Nesiritide Brain natriuretic peptide (BNP) is a 32-amino acid peptide that is mainly secreted from the cardiac ventricles. Physiologically, BNP functions as a natriuretic and diuretic. It also serves as a counterregulatory hormone to Ang II, norepinephrine, and endothelin by decreasing the synthesis of these agents and by direct vasodilation. As the clinical severity of heart failure increases, the concentrations of BNP in blood also increase. As a result, measurements of BNP in blood have been used to evaluate new onset of dyspnea (to distinguish between lung disease and heart failure). BNP concentrations in blood increase with decreasing left ventricular ejection fraction; therefore, measurements of this mediator have been used to estimate prognosis.

 BNP concentrations decline in response to therapy with ACE inhibitors, Ang II antagonists, and aldosterone antagonists. In addition, recombinant BNP has been released as a drug (nesiritide) indicated for patients with acute heart failure and dyspnea with minimal activity. Nesiritide produces arterial and venous dilatation through increasing cGMP. Nesiritide does not increase HR and has no effect on cardiac inotropy. It has a rapid onset of action and a short elimination half-life (15 minutes). In clinical studies, loading doses have ranged from 0.25 to 2 μg/kg and maintenance doses have ranged from 0.005 to 0.03 μg/kg/min. Studies have shown that nesiritide reduces symptoms of acute decompensated heart failure similarly to NTG, without development of acute tolerance. Patients receiving nesiritide experienced fewer adverse events than those receiving NTG. However, the mortality rate at 6 months was higher in the patients receiving nesiritide than in the NTG group.22 Compared with dobutamine, nesiritide was associated with fewer instances of ventricular tachycardia or cardiac arrest. Inotropes Positive inotropic drugs, principally dobutamine or milrinone, have long been used to treat decompensated heart failure, despite the lack of data showing an outcome benefit to their use. In the past, some chronic heart failure patients would receive intermittent infusions of positive inotropic drugs as part of their maintenance therapy. Small studies consistently demonstrate improved hemodynamic values and reduced symptoms after administration of these agents to patients with heart failure. Studies comparing dobutamine to milrinone for advanced decompensated heart failure showed large differences in drug costs, favoring dobutamine, and only small hemodynamic differences, favoring milrinone. Nevertheless, placebo-controlled studies suggest that there may be no role whatsoever for discretionary administration of positive inotropes to patients with chronic heart failure. In one study, 951 hospitalized patients with decompensated chronic heart failure who did not require intravenous inotropic support were assigned to receive a 48-hour infusion of either milrinone or saline. Meanwhile, all patients received ACE inhibitors and diuretics as deemed necessary. Total hospital days did not differ between groups; however, those receiving milrinone were significantly more likely to require intervention for hypotension or to have new atrial arrhythmias. A subanalysis of these results found that patients suffering from ischemic cardiomyopathy were particularly subject to adverse events from milrinone (a 42% incidence of death or rehospitalization versus 36% for placebo). At the present, positive inotropic drug support can be recommended only when there is no alternative. Thus, dobutamine and milrinone continue to be used to treat low CO in decompensated heart failure, but only in selected patients

Alternate Therapies When drug treatment proves unsuccessful, heart failure patients may require invasive therapy, including ventricular assist devices, biventricular pacing, coronary artery bypass with or without surgical remodeling, or even cardiac orthotopic transplantation. Low-Output Syndrome Acute heart failure is a frequent concern of the cardiac anesthesiologist, particularly at the time of separation from cardiopulmonary bypass (CPB). The new onset of ventricular dysfunction and a low CO state after aortic clamping and reperfusion is a condition with more pathophysiologic similarity to cardiogenic shock than to
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chronic heart failure and is typically treated with positive inotropic drugs, vasopressors (or vasodilators), if needed, and/or mechanical assistance. The latter more commonly takes the form of intra-aortic balloon counterpulsation and less commonly includes one of the several available ventricular assist devices. Causes Most patients undergoing cardiac surgery with CPB experience a temporary decline in ventricular function, with a recovery to normal function in a period of roughly 24 hours. Thus, pathophysiologic explanations must acknowledge the (usual) temporary nature of the low-output syndrome after CPB. Most likely, this results from one of three processes, all related to inadequate oxygen delivery to the myocardium: acute ischemia, hibernation, or stunning. All three processes would be expected to improve with adequate revascularization and moderate doses of positive inotropic drugs, consistent with the typical progress of the cardiac surgery patient. All three processes would be expected to be more troublesome in patients with preexisting chronic heart failure, pulmonary hypertension, or arrhythmias. Risk Factors for the Low-Output Syndrome after Cardiopulmonary Bypass The need for inotropic drug support after CPB can often be anticipated based on data available in the preoperative medical history, physical examination, and imaging studies. In a series of consecutive patients undergoing elective CABG, it was observed that increasing age, decreasing left ventricular ejection fraction, female sex, cardiac enlargement (on the chest radiograph), and prolonged duration of CPB were all associated with an increased likelihood that the patient would be receiving positive inotropic drugs on arrival in the intensive care unit. Similarly, in a study of patients undergoing cardiac valve surgery, it was found that increasing age, reduced left ventricular ejection fraction, and the presence of CAD all increased the likelihood that a patient would receive positive inotropic drug support. Specific Drugs for Treating the Low-Output Syndrome Whereas all positive inotropic drugs increase the strength of contraction in noninfarcted myocardium, mechanisms of action differ. These drugs can be divided into those that increase cyclic adenosine monophosphate (cAMP) (directly or indirectly) for their mechanisms of action and those that do not. The agents that do not depend on cAMP form a diverse group, including cardiac glycosides, calcium salts, calcium sensitizers, and thyroid hormone. In contrast to chronic heart failure, cardiac glycosides are not used for this indication, owing to their limited efficacy and narrow margin of safety. Calcium salts continue to be administered for ionized hypocalcemia and hyperkalemia, which are common occurrences during and after cardiac surgery. Increased Ca2+ in buffer solutions bathing cardiac muscle in vitro unquestionably increase inotropy. Calcium sensitizers, specifically levosimendan, function by binding to troponin C in a calcium-dependent fashion. Thus, levosimendan does not impair diastolic function because its affinity for troponin C declines with Ca2+ during diastole. Although several reports have described the successful use of levosimendan in patients recovering from CABG, clinical experience with this agent remains limited and there is no consensus as to how and when this agent should be used, relative to other, better established agents.