What are the guidelines for using positive and negative inotropes, such as digoxin, dobutamine, and beta-blockers (e.g. metoprolol), in patients with heart failure?

Positive and Negative Inotropes in Heart Failure

Positive Inotropes: Reserve for Severe Hypoperfusion Only

Positive inotropic agents (dobutamine, dopamine, milrinone) should be reserved exclusively for patients with severe reduction in cardiac output causing vital organ hypoperfusion—typically manifesting as hypotension, decreased renal function, or shock—and only after diuretics and vasodilators have failed at optimal doses. 1

Clinical Indications for Positive Inotropes

• Use inotropes when peripheral hypoperfusion is present (hypotension with systolic BP <90 mmHg, decreased renal function) with or without pulmonary edema refractory to diuretics and vasodilators 1
• These agents are potentially harmful as they increase myocardial oxygen demand, calcium loading, and risk of arrhythmias 1
• Long-standing concern exists that inotropes may increase mortality 1

Specific Agent Selection and Dosing

Dobutamine is the preferred first-line inotrope for cardiogenic shock:

• Start at 2-3 mcg/kg/min without a loading dose 2, 3
• Titrate up to maximum 15-20 mcg/kg/min based on hemodynamic response 1, 2, 3
• Monitor continuously for tachyarrhythmias, particularly atrial fibrillation with rapid ventricular response 2
• Tolerance develops after 24-48 hours of continuous infusion 2, 4

Dopamine should be avoided or discontinued:

• Dopamine causes significantly more arrhythmias than norepinephrine (24% vs 12%) and is associated with higher mortality in cardiogenic shock 2
• If used, dosing is effect-dependent: <3 mcg/kg/min for renal effects, 3-5 mcg/kg/min for inotropic effects, >5 mcg/kg/min for vasopressor effects 1, 3
• The American College of Cardiology recommends transitioning away from dopamine to norepinephrine plus dobutamine 2

Alternative inotropes when beta-blockade is present:

• Phosphodiesterase III inhibitors (milrinone, enoximone) or levosimendan have pharmacological rationale when counteracting beta-blocker effects 1
• Milrinone: 25-75 mcg/kg loading dose over 10-20 min, then 0.375-0.75 mcg/kg/min 1, 3
• Levosimendan: optional 12 mcg/kg loading dose over 10 min, then 0.1 mcg/kg/min (can adjust 0.05-0.2 mcg/kg/min) 1, 3

Critical Monitoring Requirements

• Insert arterial line for continuous blood pressure monitoring when titrating multiple vasoactive agents 2
• Consider pulmonary artery catheter for invasive hemodynamic assessment in patients requiring multiple agents 2
• Target parameters: cardiac index >2 L/min/m², systolic BP >90 mmHg, pulmonary capillary wedge pressure <20 mmHg 2
• Continuous ECG telemetry is mandatory to detect arrhythmias 2, 4

Escalation to Mechanical Support

If dobutamine exceeds 20 mcg/kg/min and norepinephrine exceeds 1.0 mcg/kg/min, strongly consider mechanical circulatory support rather than adding additional pharmacologic agents. 2

---

Negative Inotropes (Beta-Blockers): Cornerstone of Chronic Heart Failure

Beta-blockers (metoprolol, bisoprolol, carvedilol) are Class I, Level A recommendations for chronic heart failure and should be initiated when patients stabilize after acute decompensation—typically after 4 days. 1

Timing in Acute Heart Failure

In patients with overt acute heart failure and more than basal pulmonary rales, beta-blockers should be used with extreme caution:

• Among patients with ongoing ischemia and tachycardia, intravenous metoprolol can be considered (Class IIb, Level C) 1
• In post-MI patients who stabilize after developing acute heart failure, beta-blockers should be initiated early (Class IIa, Level B) 1
• Metoprolol in patients with pulmonary congestion and basal rales reduced mortality and morbidity in the Gothenburg study 1

Practical Initiation Protocol

• Start with small doses of bisoprolol, carvedilol, or metoprolol 1
• Increase slowly and progressively to target doses used in large clinical trials 1
• Up-titration should be adapted to individual response 1

Management During Acute Decompensation

As a general rule, patients on beta-blockers admitted with worsening heart failure should be continued on therapy unless inotropic support is needed, but the dose can be reduced if signs of excessive dosage are present (bradycardia, hypotension). 1

Critical Contraindications and Warnings

Beta-blockers are contraindicated in: 5

• Heart rate <45 beats/min
• Second- or third-degree heart block
• Significant first-degree heart block (PR interval ≥0.24 sec)
• Systolic blood pressure <100 mmHg
• Moderate-to-severe cardiac failure (acute setting)

---

Digoxin: Symptom Management Without Mortality Benefit

Digoxin is indicated for mild to moderate heart failure to improve symptoms and reduce heart failure-related hospitalizations, but has no effect on mortality. 6

Clinical Role

• Digoxin increases left ventricular ejection fraction and improves exercise capacity 6
• The DIG trial in 6,800 patients showed no mortality improvement but reduced hospitalizations for heart failure 1
• Should be used with a diuretic and ACE inhibitor when possible 6
• Appears most beneficial in patients with severe heart failure, cardiomegaly, and third heart sound 7

Positioning in Treatment Algorithm

• Use as second-line drug after diuretics, ACE inhibitors, and beta-blockers in patients with heart failure in sinus rhythm 7
• Use as first-line drug in patients with heart failure who are in atrial fibrillation for ventricular rate control 7

---

Key Pitfalls to Avoid

• Never abruptly discontinue beta-blockers in patients with coronary artery disease—severe exacerbation of angina, MI, and ventricular arrhythmias can occur; taper over 1-2 weeks 5
• Avoid prolonged oral inotropic therapy—repeated or prolonged treatment with oral inotropic agents increases mortality 1
• Do not use dopamine as first-line vasopressor—inferior outcomes and higher arrhythmia risk compared to norepinephrine 2
• Monitor for dobutamine tolerance—develops after 24-48 hours, necessitating dose adjustments or agent switching 2, 4