Inotropes

Background

Indications

Intotropes are indicated for patients with LV systolic dysfunction, low CO, and low SBP (e.g. < 90 mmHg) resulting in end organ hypoperfusion (i.e. cardiogenic shock). - Short term hemodynamic support - Bridge therapy to MCS/ECLS/Transplant - Limited use in long-term hemodynamic support

Caution

Inotropes can cause sinus tachycardia, increase RVR in AF (increased AVN conduction), induce myocardial ischemia and arrythmias, and increase mortality.

Inotropic Agents

Agent	Class	MOA	Dosing	Notes
Dobutamine	Beta agonist (synthetic)	B1/B2 agonist. Variable A1 activity.	2-20 mcg/kg/min
Dopamine	Beta agonist (endogenous)	Dose-dependent delta->beta->alpha affects. Introtropy, arteriovenous constriction.
Isoproterenol	Nonselective beta agonist	Beta 1/2 agonism.	2-10 mcg/min	Used for bradyarrhythmias (especially TdP), Brugade syndrome
Milrinone	PDE inhibitor	PDE-3 inhibitor, decreases cAMP degradation distally to beta receptor. Increases Ca++ influx to cell. Vasodilation via vascular PDE inhibition.	0.375–0.75 mcg/kg/min
Levosimendan	Ca-sensitizing agent	Increases myocardial contraction with Ca++. PDE-3 inhibition.

Specific Use Cases

Setting	Guidance
Hypotension	Dobutamine preferred over PDE-3 inhibitors or Ca-sensitizing agents due to less vasodilatory effects.
Renal insufficiency	Dobutamine preferred to milrinone. Dose adjustment necessary with milrinone.
Recent beta-blockade	PDE-3 inhibitor preferred due to different MOA. Alternatively, use high-dose dobutamine.
AFRVR	Avoid dobutamine and dopamine if possible.

Dobutamine

Dobutamine is a synthetic catecholamine that acts as a β1- and β2-receptor agonist.

binds β1:β2 at a 3:1 ratio, therefore is a potent inotrope with weaker chronotropic effect
vascular smooth muscle binding and β2 stimulation lead to mild vasodilation, particularly at lower doses (<5 mcg/kg/min). This effect is ameliorated at higher doses where vasoconstriction dominates
increases myocardial oxygen consumption significantly despite its mild chronic effects at low-medium doses. "Exercise-mimicking effect" makes it also useful for diagnostic cardiac perfusion imaging.
risk of malignant ventricular arrhythmias can be observed at any dose
rare risk of hypersensitivity myocarditis (eosinophilic) in 2-20% of patients. Dose-dependent risk.

Milrinone

Milrinone is a phosphodiesterase 3 inhibitor that increases cardiac inotropy, lusitropy, and peripheral vasodilatation. Preference is often given to using milrinone in patients with severe pulmonary hypertension because of a purported mechanism of reducing pulmonary-artery pressures and improving right ventricular function.

Causes hypotension - avoid a loading dose.
Avoid in CAD given negative outcomes in OPTIME-HF trial.
Most beneficial in nonischemic CM.
Potentially negative mortality benefit compared to nitroglycerin/nesiritide.

Isoproterenol

Isoproterenol is a potent, nonselective, synthetic β-adrenergic agonist with very low affinity for α-adrenergic receptors.

powerful chronotropic and inotropic properties
potent systemic and mild pulmonary vasodilatory effects
stimulatory impact on stroke volume is counterbalanced by a β2-mediated drop in SVR, which results in a net neutral impact on CO.

Dopamine

Dopamine, an endogenous central neurotransmitter, is the immediate precursor to norepinephrine in the catecholamine synthetic pathway.

Pharmacokinetics: Half-life 2-3 minutes, metabilized by MAO and COMT.
MOA: 1) D1/2 receptor agonism at lowest doses (0.5-2 mcg/kg/min) which causes vasodilation in coronary, renal, mesenteric, and cerebral beds. Also causes natriuresis via renal tubular action. 2) Predominantly weak beta-1 agonism at low doses (2-10 mcg/kg/min) which promotes norepinephrine release. 3) Increasing alpha1-mediated vasoconstriction as dose escalates (>10 mcg/kg/min).
Dosing: 1) 1-5 mcg/kg/min IV (low dose) "renal dosing" 2) 5-15 mcg/kg/min IV (medium dose) "inotrope" 3) 20-50 mcg/kg/min IV (high dose) "vasopressor"
Caution: arrhythmogenic at the highest doses. Increases myocardial oxygen demands. No evidence for any renoprotective effects.

Levosimendan

Not routinely available in Canada or the USA.

Evidence Base

DOREMI (NEJM 2021)

Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock | NEJM

Question: Is milrinone safer or more effective than dobutamine in the treatment of cardiogenic shock?
Design: Single-centre blinded, 1:1 randomized and controlled, superiority trial
Population: Consecutive adult patients admitted to the Ottawa CCU with cardiogenic shock (SCAI Stage B, C, D, E).
Intervention: Milrinone (blinded)
Comparator: Dobutamine (blinded)
Outcomes:
- Primary: Composite of in-hospital mortality, resuscitated IHCA, cardiac transplant or MCS, nonfatal MI, TIA/stroke, RRT
Results:
- N=192. Primary outcome: 49% vs 54% (RR 0.90, P=0.47). No difference in subgroups, time-to-event analysis
- Secondary outcomes: No differences in sub-primaries, CCU LOS, hospital LOS, NIV, invasive ventilation, AKI, biochemistry, arrhythmias, dose of other Vasopressors.
Takeaway:
- No significant advantage of milrinone over dobutamine. Trend towards slightly reduced primary outcome. No differences in safety profile
- Underpowered study with some bias, and cannot rule out milrinone being better. For now, use either one -- whichever you are more comfortable with.