With the progress of research on the pathophysiology and treatment of heart failure, the principle of treatment based on neuroendocrine inhibitors has been established, resulting in a decrease in the status of cardiotonic drugs, which are aimed at the weakening of myocardial contractility in heart failure. However, cardiotonic drugs remain an important and indispensable tool in the treatment of heart failure under certain circumstances. For example, when accompanied by rapid atrial fibrillation, digitalis is used; when accompanied by severe low cardiac output, dopamine or dobutamine is used, etc. In addition, cardiotonic drugs can significantly improve symptoms and quality of life. 1, digitalis The history of digitalis in the treatment of heart failure has been more than 200 years, is the most commonly used drugs in the treatment of heart failure. Digitalis can selectively inhibit the activity of myocardial cell membrane Na+-K+-ATPase, increase Ca2+ inward flow through the biphasic Na+-Ca2+ exchange mechanism, thereby increasing the concentration of intracellular cytoplasmic Ca2+ and exerting positive inotropic effect, thereby increasing cardiac output. After the increase of cardiac output, the left ventricular end-diastolic pressure decreases, and myocardial oxygen consumption is thus reduced; after the increase of per-beat volume, the carotid sinus and aortic arch pressure receptors are stimulated, resulting in the enhancement of vagal excitability, which leads to the slowing down of the heart rate; in addition, after the increase of per-beat volume, the renal perfusion is increased, which leads to the inhibition of the release of renin. Not only that, but the above effects of digitalis may also be related to its association with inhibition of Na+-K+-ATPase in noncardiac muscle tissue. In heart failure, the reflex sensitivity of carotid sinus and aortic arch pressure receptors decreases, sympathetic activation occurs, and plasma concentrations of norepinephrine and renin increase. Digitalis inhibits the Na+-K+-ATPase of the pressure receptor cell membrane and afferent nerves, increasing their sensitivity, and decreasing the sympathetic excitability of the central nervous system downward, so the vagal excitability is enhanced; in addition, by inhibiting the renal Na+-K+-ATPase, it reduces the reabsorption of Na+ by the renal tubule, increases the release of sodium to the renal distal convoluted tubule, and decreases the secretion of renin by the kidneys. Thus, the action of digitalis in heart failure is not just a positive inotropic effect, but also acts by reducing neuroendocrine activity. 1.1 The Place of Digitalis in the Treatment of Heart Failure Although the place of digitalis in the treatment of heart failure is controversial, its role in significantly improving symptoms in patients who meet the indications is unquestionable, especially in patients with marked enlargement of the left ventricular internal diameter and increased heart rate. A major influence on the evaluation of digoxin was the 1997 DIG trial. This was a large randomized, double-blind, placebo-controlled clinical trial. 7,788 patients were enrolled, including 6,800 patients in sinus rhythm with an EF <0.45 (3,397 with digoxin and 3,403 with placebo), with concomitant diuretics and ACEIs in both groups. an additional 988 patients with an EF >0.45 (492 in the digoxin group and 496 in the placebo group) were enrolled. The primary endpoint of observation was mortality from all causes. A mean follow-up of 37 months resulted in no significant difference in mortality between the two groups. The mortality rates in the digoxin and placebo groups were 34.8% and 35.1%, respectively (P=0.80). However, there was a trend for fewer deaths due to worsening heart failure in the former group (P=0.06); whereas those who needed to be hospitalized due to worsening heart failure were significantly fewer, 26.8% and 34.7% in the digoxin and placebo groups, respectively (P<0.001). In the subgroup analysis, the mortality and hospitalization rates due to worsening of heart failure were as high as 45.3% in those who had previously taken digoxin and were discontinued and admitted to the placebo group, compared with 32.0% in those who had not previously used digoxin. These results show that digoxin improves symptoms and cardiac function, increases exercise tolerance, improves quality of life, and reduces hospitalization rates for worsening heart failure, but does not affect overall mortality. Although the effect on mortality was neutral, it was the only one of the positive inotropic agents that did not increase mortality with long-term treatment and to which no resistance occurred. 1.2 Clinical Use of Digitalis in the Treatment of Heart Failure It is currently believed that digitalis is primarily used in congestive heart failure patients with symptomatic left ventricular hypocontractility, especially those with tachycardia or rapid atrial fibrillation. It has important benefits for controlling ventricular rate, relieving symptoms, improving exercise capacity, and improving quality of life. The Chinese chronic heart failure treatment guideline published in 2007 pointed out that the purpose of digoxin application is to improve the clinical condition of systolic heart failure, and it is suitable for patients with heart failure who have applied diuretics, ACEI (or ARB) and beta-blockers but still continue to have symptoms. Digoxin may also be used in patients with atrial fibrillation associated with a rapid ventricular rate. Because digoxin does not significantly reduce mortality in patients with heart failure, early application is not advocated and is not recommended in NYHA class I patients. It should be used with caution or not used in patients in the acute phase of acute myocardial infarction and in patients with progressive myocardial ischemia. The 2005 European Society of Cardiology Guidelines for the Diagnosis and Treatment of Chronic Heart Failure recommend that cardiac glycosides be used in patients with atrial fibrillation and any degree of symptomatic heart failure to slow the ventricular rate and improve cardiac function and symptoms (Class I recommendation, Level of Evidence B); that the combination of digoxin and a beta-blocker in patients with atrial fibrillation is preferable to either agent alone (Class IIa recommendation, Level of Evidence C); and that digoxin does not affect the mortality rate but reduces hospitalization (Class IIa recommendation, Level of Evidence A).The 2008 ESC guidelines still suggest that digoxin can be used in patients with persistent symptoms on top of other medications, as well as in combination with beta blockers to control ventricular rate in patients with heart failure combined with atrial fibrillation. The 2005 Revised U.S. Guidelines for the Diagnosis and Treatment of Chronic Heart Failure in Adults recommend that digoxin be used in combination with diuretics, ACEIs (or ARBs), and beta-blockers to improve the clinical status of patients with heart failure; digoxin can be used in patients with heart failure combined with atrial fibrillation. the 2009 ACC/AHA Heart Failure Guidelines still suggest that if a patient is on diuretics, ACEIs (or ARBs), beta-blockers and heart failure symptoms persist, digoxin may be added. Patients who are using digoxin should also not be randomly withdrawn. The therapeutic and maintenance doses of digoxin are generally 0.125 to 0.25 mg/day; patients over 70 years of age, with impaired renal function, and who are emaciated should be given a low dose (0.125 mg/day or every other day) for initial administration. The dose can be increased if the therapeutic goal is to control the ventricular rate in atrial fibrillation. When applying digoxin, it is necessary to pay attention to its contraindications: for example, bradycardia, II ° and above sinus block or atrioventricular block; allergy to digitalis is an absolute contraindication to the application of digitalis. Common adverse effects of digitalis are cardiac arrhythmias (e.g., premature ventricular contractions, conduction block), gastrointestinal symptoms (e.g., nausea, vomiting), and neurologic disorders (e.g., dizziness, yellow and green vision). Low blood potassium and low blood magnesium increase the risk of serious arrhythmia caused by digitalis Digitalis is an effective, safe, convenient and inexpensive drug for the treatment of chronic heart failure, which can improve the symptoms and clinical conditions, but it needs to be used rationally to avoid its adverse effects. 2. Non-digital positive inotropic drugs 2.1 Commonly used non-digital positive inotropic drugs 2.1.1 Dobutamine: Dobutamine is the precursor of the endogenous catecholamine norepinephrine, and its pharmacological effects are dose-dependent. Small doses (<3 μg/kg/min) can be used in patients with hypotension and decreased urine output, which can improve renal blood flow and urine output; medium doses (3-5 μg/kg/min) have positive inotropic effects; large doses (>5 μg/kg/min) can be used in patients with acute heart failure with hypotension. There is a large individual variation in patient use, usually starting with a small dose and gradually increasing the dose. Adverse reactions are mainly palpitations and ventricular arrhythmias. 2.1.2 Dobutamine: Dobutamine is a derivative of dopamine, which produces dose-dependent positive inotropic and positive chronotropic effects mainly through excitation of β1 and β2 receptors. It has a mild vasodilatory effect in small doses; in large doses it causes vasoconstriction. Short-term application of dobutamine helps to relieve symptoms.The FIRST study showed an increased rate of death in patients with severe heart failure due to sustained intravenous dobutamine infusion, mainly due to lethal arrhythmias.The FIRST study showed an increased rate of death in patients with severe heart failure due to sustained intravenous dobutamine infusion, mainly due to lethal arrhythmias. Application: Start at 2 to 3 μg/kg/min, up to a maximum dose of 20 μg/kg/min. Be sure to adjust the dose according to efficacy, and avoid high doses if small doses are effective, to avoid increased side effects. Should not be used in patients receiving beta-blockers. Adverse effects are the same as for dopamine. 2.1.3 Phosphodiesterase inhibitors: (PDEIs) The mechanism of action is to inhibit the activity of phosphodiesterase, so that intracellular cGMP degradation is blocked, thereby elevating the concentration of cGMP, so that the activity of protein kinase on the cell membrane is elevated to promote the activation of the Ca2+ channel, so as to increase the inward flow of calcium and increase the myocardial contraction force; and there is a peripheral vasodilatation effect, reducing the resistance to the body circulation. It can be used in patients being treated with beta-blockers. The commonly used drug is milrinone, with a first dose of 25 μg/kg, diluted, administered intravenously over 16-20 minutes, followed by a 0.375 to 0.75 μg/kg/min maintenance IV drip. High-dose infusion is contraindicated in persons with low blood pressure. Milrinone is metabolized by the kidneys and should be reduced in renal failure. The main adverse effects are hypotension and cardiac arrhythmia. In the OPTIME-CHF study, 951 patients with chronic heart failure in the acute decompensated phase had a mean LVEF <23%. Milrinone sedation for 48-72 hours did not reduce inpatient morbidity and mortality or 60-day morbidity and mortality, nor did it reduce the number of days of hospitalization and rehospitalization. Hypotension and arrhythmias occurred more frequently in the milrinone-treated group. 2.1.4 Levosimendan: Levosimendan is a new generation of calcium sensitizer, and its mechanism of action mainly includes:1) Increase the sensitivity of myocardial contractile proteins to Ca2+. It selectively binds to troponin C (cTNC) and promotes myocardial contraction without increasing myocardial oxygen consumption or affecting diastolic function. When the diastolic Ca2+ concentration decreases, the drug can be dissociated from cTNC, so it doesn't affect the intracellular Ca2+ concentration, so it doesn't affect the electrophysiology of cardiomyocytes, and is not easy to cause arrhythmia. ② Vasodilatation: It dilates blood vessels by opening ATP-sensitive K channels on the cell membrane, reducing the anterior and posterior load of the heart. In addition, it can enhance the activity of nitric oxide synthase (eNOS) to increase the production of NO and exert vasodilatory effects. (iii) In large doses, it has a certain inhibitory effect of phosphodiesterase III, which further promotes its positive inotropic effect. However, the dose needs to be much larger than the general application of the dose, so this effect is rarely seen. Others: anti-inflammatory, anti-oxidative stress. Clinical application: The indications for the application of levosimendan are mainly for acute heart failure with decompensated, systolic insufficiency, and poor therapeutic response for patients with other causes of heart failure. Recommended dosage: When the systolic blood pressure >100mmHg can be given a loading dose of 12～24 ug/kg, 10 minutes intravenous push. Subsequent maintenance doses are 0.05 to 0.2 ug/kg, with the dose adjusted according to blood pressure. The recommended duration of therapy is 24 hours, but the hemodynamic effect may be maintained for several days. In patients with heart failure levosimendan can act in a dose-dependent manner, not only increasing cardiac output, but also reducing pulmonary gross wedge pressure. The clearance half-life of levosimendan is 1 hour, but after acetylation in vivo to form active metabolites OR-1896, OR-1855, the half-life can be increased to 70 ~ 80 hours. Therefore, after stopping the drug, the hemodynamic effects can be maintained for several days. This drug can be combined with other drugs for heart failure (e.g., dopamine, ACEI, beta-blockers, etc.). Safety and adverse reactions: headache and hypotension are common adverse reactions with an incidence of 2%-9% and 5%. Often occurs in high dose application. The increase in heart rate with early administration is related to pressure receptor reflexes caused by vasodilators, and the increase in heart rate after continued sedation or discontinuation is related to metabolites. The occurrence of hypotension is often associated with systemic vasodilatation, especially in patients with hypovolemia. Ventricular tachyarrhythmias may occur with high dose applications. Other adverse reactions are tachycardia, and decreased erythrocyte pressure, hemoglobin, and potassium. The prognostic effect of levosimendan is controversial.The LIDO trial, CASINO trial and RUSSLAN trial have shown a reduction in mortality in addition to an improvement in hemodynamics and symptoms in patients with decompensated acute heart failure; however, the REVIVE trial and SURVIVE trial did not show a reduction in mortality. 2.2 Indications 2.2.1 Acute heart failure: The 2005 ESC recommended the use of this therapy in patients with acute left heart failure (both new-onset and acute decompensated chronic heart failure) with decreased cardiac output, peripheral hypoperfusion (hypotension, renal insufficiency), with or without circulatory stasis or pulmonary edema, and who have a poor therapeutic response despite volume control with the optimal dose of diuretics and vasodilators. The 2008 ESC guidelines still suggest that these cardiotonic agents may be used in patients with acute left heart failure who are hypotensive or have pulmonary bruits despite the use of vasodilators and/or diuretics. Note that continuous ECG monitoring is essential for early detection of serious arrhythmias and early management. 2.2.2 Chronic heart failure: In the guidelines for diagnosis and treatment of chronic heart failure issued in China in 2007, routine intravenous application of positive inotropic drugs is not recommended. For patients with refractory end-stage heart failure, they can be used as palliative treatment to relieve symptoms (Class IIb recommendation, Level C evidence); after heart transplantation, patients with acute heart failure due to myocardial depression can be applied for a short period of 3 to 5 days. 2005 ACC/AHA guidelines for chronic heart failure recommend that positive inotropic drugs should only be used for patients waiting for heart transplantation or refractory heart failure. 2009 ACC/AHA guidelines still do not advocate the use of positive inotropic drugs. The 2009 ACC/AHA guidelines still do not advocate routine, intermittent infusions of positive inotropic drugs in the long-term management of heart failure or in patients with end-stage heart failure; these drugs should be considered only when other treatments have failed. Summary: Cardiac drugs, including digitalis and non-digitalis drugs, are still an important measure in the treatment of heart failure, although there is no evidence that any of them can improve the prognosis of patients with heart failure or even increase death. The key is to master the indications, individualize treatment, and closely monitor electrocardiography, blood pressure, and side effects. Cardiotonic drugs can significantly improve symptoms and quality of life. Digitalis-like for the left ventricular endocardium significantly increased with increased heart rate, has a very good efficacy. Serious arrhythmias rarely occur as long as one ensures that low potassium and magnesium are avoided. Dopamine and dobutamine have excellent efficacy in patients with severely reduced contractility with low cardiac output and perfusion. They are safe for clinical use as long as close cardiac monitoring is performed, ventricular arrhythmias are detected early, and amiodarone is applied prophylactically or discontinued in a timely manner. Similarly, phosphodiesterase inhibitors have strong indications for use in patients with heart failure who have hypocontractility with a rapid or slow heart rate. Pay attention to cardiac and blood pressure monitoring to avoid arrhythmia and hypotension. Levosimendan is more expensive, but it is safe to apply and has a reliable efficacy in patients with acute left heart failure with hypocontractility.