Dobutamine

Dobutamine is a synthetic, sympathomimetic amine, structurally related to isoproterenol and dopamine, and is administered as racemate. The positive inotropic effect is primarily based on the agonistic effect on cardiac beta1-receptors but also on cardiac alpha1-receptors; which leads to increased contractility with an increase in stroke volume and cardiac output.

Dobutamine also has an agonistic effect on peripheral beta2-receptors and to a smaller extent on peripheral alpha2-receptors.

In accordance with the pharmacological profile, positive chronotropic effects occur as well as effects on the peripheral vascular system. These however, are less pronounced than the effects of other catecholamines. The haemodynamic effects are dose-dependent. The cardiac output increases primarily due to an increase in the stroke volume; an increase in the heart rate is observed particularly with higher dosages. There is a reduction in left ventricular filling pressure and systemic vascular resistance. With higher doses, there is also a reduction in the pulmonary resistance. Occasionally an insignificant increase of the systemic vascular resistance can be observed. The volume increase due to an increase of the cardiac output is thought to be the reason for the blood pressure elevation. Dobutamine acts directly, independent from synaptic catecholamine concentrations, does not act at the dopamine receptor site, and – unlike dopamine – has no impact on the release of endogenous noradrenaline (norepinephrine).

There is a decrease of recovery time of sinus node and the A-V conduction time. Dobutamine may cause a tendency towards arrhythmia. When administered non-stop for more than 72 hours, tolerance phenomena were observed. Dobutamine impacts the functions of thrombocytes. Like all other inotropic substances, dobutamine increases myocardial oxygen demand. Via reduction of the pulmonary vascular resistance and the hyperperfusion even of hypoventilated alveolar areas (formation of a pulmonary “Shunt”) a relatively reduced oxygen supply may occur in some cases. The increase in cardiac output and the resulting increase in coronary blood flow usually compensate these effects and cause – compared with other positive inotropic substances – a favourable oxygen supply/demand ratio.

Dobutamine is indicated for patients who require positive inotropic support in the treatment of cardiac decompensation due to depressed contractility resulting either from organic heart disease or from cardiac surgical procedures, especially when a low cardiac output is associated with raised pulmonary capillary pressure.

In cases of heart failure accompanied by acute or chronic myocardial ischaemia, administration should be performed in a manner to prevent considerable increase in heart rate or blood pressure; otherwise, particularly in patients with a relatively good ventricular function, increase of ischaemia cannot be excluded.

There are only limited data with regard to clinical outcome including long-term morbidity and mortality. So far, no data exists to support a beneficial long-term effect on morbidity and mortality.

Dobutamine has no direct dopaminergic effect on renal perfusion.

Paediatric population

Dobutamine also exhibits inotropic effects in children, but the haemodynamic response is somewhat different than that in adults. Although cardiac output increases in children, there is a tendency for systemic vascular resistance and ventricular filling pressure to decrease less and for the heart rate and arterial blood pressure to increase more in children than in adults. Pulmonary wedge pressure may increase during infusion of dobutamine in children 12 months of age or younger.

Increases in cardiac output seems to begin at iv infusion rates as low as 1.0 micrograms/kg/minute, increases in systolic blood pressure at 2.5 micrograms/kg/minute, and heart rate changes at 5.5 micrograms/kg/minute.

The increase of dobutamine infusion rates from 10 to 20 micrograms/kg/minute usually results in further increases in cardiac output.

Dobutamine stress echocardiography

Ischaemic diagnostic: Due to the positive inotropic testing and in particular due to the positive chronotropic effects under dobutamine stress, the myocardial oxygen (and substrate) demand increases. With a pre-existing coronary artery stenosis, an insufficient increase of coronary blood flow leads to local hypoperfusion, which can be demonstrated on the echocardiogram in the form of a newly developed myocardial wall motility disorder in the respective segment.

Viability diagnostic: Viable myocardium, which is hypokinetic or akinetic (due to stunning, hibernation) on the echocardiogram, has a contractile functional reserve. This contractile functional reserve is particularly stimulated by the positive inotropic effects during dobutamine stress testing at lower doses (5-20 µg/kg/min). An improvement of the systolic contractility, i.e. increase of wall motility in the respective segment, can be shown on the echocardiogram.

Onset of action is 1-2 minutes after the start of infusion; during continuing infusion, steady-state plasma levels are only reached after 10-12 minutes. Steady-state plasma levels increase dose-dependently linearly to the infusion rate. Half-life is 2-3 minutes, distribution volume is 0.2 l/kg, plasma clearance is not dependent on cardiac output and is 2.4 l/min/m². Dobutamine is mainly metabolised in the tissue and liver. It is mainly metabolised to conjugated glucuronides as well as the pharmacologically inactive 3-O-methyldobutamine. The metabolites are mainly excreted in urine (more than ⅔ of the dose), and to a lesser extent in bile.

Paediatric population

In most paediatric patients, there is a log-linear relationship between plasma dobutamine concentration and hemodynamic response that is consistent with a threshold model.

Dobutamine clearance is consistent with first-order kinetics over the dosage range of 0.5 to 20 micrograms/kg/minute. Plasma dobutamine concentration can vary as much as two-fold between paediatric patients at the same infusion rate and there is a wide variability in both the plasma dobutamine concentration necessary to initiate a hemodynamic response and the rate of hemodynamic response to increasing plasma concentrations. Therefore, in clinical situations dobutamine infusion rates must be individually titrated.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity. There are no studies concerning the mutagenic and carcinogenic potential of dobutamine. In view of the vital indications and the short duration of treatment these studies appear of minor relevance. Studies in rats and rabbits revealed no evidence of a teratogenic effect. An impairment of implantation and pre- and postnatal growth retardations were observed in rats at doses toxic to mothers. No influence on fertility was seen in rats.