Iowa Neonatology Handbook: Pharmacology

Intropic Agents

Jeffrey L. Segar, MD
Peer Review Status: Internally Peer Reviewed

Commonly used vasoactive drugs in the NICU include dopamine, dobutamine, and epinephrine. Vasodilating drugs such as tolazoline or nitroprusside are generally not used in the NICU anymore. Since these agents mediate their effects via adrenergic and dopaminergic receptors, an understanding of these receptors is essential for the proper use of vasoactive agents. The following is a brief synopsis of the various receptors, and the physiologic responses resulting from their activation.

(*DA = Dopamine receptor)

Epinephrine

Indications

Cardiac arrest, profound shock, low cardiac output, failing myocardium unresponsive to other inotropic agents.

Dose Range

Initial dose 0.05 µg/kg/min. Titrate dose to desired response, not to exceed 1.0 µg/kg/min. An epinephrine dose of 0.05 µg/kg/min. may be more effective than a dose of dopamine at > 15 µg/kg/min.

Mechanism of action

Epinephrine is an endogenous compound formed from norepinephrine. It is principally produced with stress and produces widespread metabolic and hemodynamic effects via effects on b1 , b2 , and a-adrenergic receptors. The effects of epinephrine depend on the dosage selected and the range of plasma concentration achieved in the individual patient. b1 receptors are most sensitive to epinephrine, and are affected by very low plasma concentrations resulting in inotropic and chronotropic effects (that increase myocardial oxygen consumption). Stimulation of b2 receptors leads to vasodilation of splanchnic and skeletal muscle beds. Vasoconstriction from a- receptor stimulation in skin and renal vascular beds occurs at all concentrations, while at higher concentrations, vasoconstriction effects in the pulmonary, splanchnic, skeletal muscle, cerebral, and coronary vascular beds predominate. As the concentration of epinephrine increases, myocardial irritability occurs, manifested by atrial and ventricular dysrhythmias. Metabolic effects occur at higher plasma concentrations, including hyperglycemia from a-adrenergic-mediated suppression of insulin release that leads to ketogenesis, gluconeogenesis, and accelerated glycogenolysis with resulting lactic acidemia. Hypokalemia is attributable to b2 - adrenergic receptors linked to Na+-K+ ATPase in skeletal muscle. Other effects include hypophosphatemia, and activation of lipase.

Adverse effects

Adverse effects include increased myocardial and global oxygen consumption, tachycardia, and hypertension. The extent to which the increased oxygen utilization is balanced by improved coronary blood flow depends on the state of the myocardium. Epinephrine increases pulmonary vascular resistance. In addition, pulmonary arterial and venous pressures increase because of increased systemic to pulmonary shunt, which can lead to pulmonary edema. Higher doses induce widespread vasoconstriction that may terminate in hypertensive crisis, renal failure, and gangrene of distal extremities. Infiltration into local tissues or intra-arterial injection can produce severe vasospasm and tissue injury. If extravasation is followed by pallor and other signs of impaired local perfusion, the attending physician should be notified immediately, and consideration given to local injection of phentolamine (an a-adrenergic antagonist, 0.3 - 0.5 mg of 1 mg/ml solution).

Dopamine

Indication for use

To improve cardiac output, blood pressure, and urine output in critically ill patients with shock, renal failure, and CHF.

Mechanism of action and Dose Range

To calculate a drip that infuses 10 µg/kg/min. at 1 ml/hr:

multiply weight (kg) by 30 = number of mg Dopamine to add to 50 ml IVF (D5W, D10W, NS, D5NS)

Dopamine is found in sympathetic nerve terminals, the adrenal medulla, and is a central neurotransmitter. Dopamine stimulates D1 and D2 receptors in the brain and in vascular beds of the kidney, mesentery, and coronary arteries. Higher concentrations stimulate b1 and a receptors, and may cause renal vasoconstriction. Dopamine exerts a positive inotropic effect on the myocardium, acting as a b1 agonist. Tachycardia is less prominent during infusions of dopamine than of isoproternol. Dopamine improves myocardial efficiency because coronary arterial blood flow increase more than does myocardial oxygen consumption.

Adverse effects

Through central D2 receptors, dopamine suppresses secretion of thyrotropin and prolactin. It also inhibits release of aldosterone, which may facilitate a desirable diuresis. Dopamine may depress the ventilatory response to hypoxia and hypercarbia. Its effects on insulin secretion and glucose metabolism are similar to epinephrine. A decrease in serum potassium is also frequently noted. Since dopamine promotes release of norepinephrine from synaptic terminal and is also converted to norepinephrine in vivo, even at doses as low as 1.5 µg/kg/min., severe limb ischemia has been reported; risk is particularly increased with extravasation or presence of an arterial catheter. If this occurs, notify attending physician immediately, discontinue dopamine infusion, and in severe cases consider local infiltration with phentolamine administered with a fine hypodermic needle).

Dobutamine

Indications

Inotropic support in patients with shock, hypotension, pulmonary hypertension with hypoxemia

Dose Range

2 to 20 µg/kg/min.; usually don’t need doses higher than 15 µg/kg/min.
Usual starting dose range: 2 - 5 µg/kg/min.

Adjust upward in increments of 2 - 3 µg/kg/min., based on desired increase in cardiac output / blood pressure. Doses should be individualized to the patient response is observed within 1 - 2 min., with maximal effect within 10 min. Must be administered by continous IV infusion because brief half-life.

To calculate a drip, see Dopamine section.

Mechanism of action

Dobutamine is a synthetic catecholamine that primarily produces a significant inotropic effect via b1 -receptor stimulation in the heart) and mild to moderate chronotropic effect. Systemic vascular resistance generally decreases since in the peripheral circulation the b2 effect predominates over the a effect. May see cutaneous vasodilation. It dose not activate dopaminergic receptors, and causes no renal and mesenteric vasodilation. Dobutamine improves renal blood flow by increasing cardiac output.

Adverse effects

May cause hypotension if patient is hypovolemic. Volume loading to ensure adequate preload is recommended before starting dobutamine therapy. Dobutamine usually increases myocardial oxygen demand, but coronary blood flow and oxygen supply increase to keep pace with demand. However, when dobutamine increases heart rate and decreases diastolic time for coronary artery perfusion, myocardial oxygen balance is unfavorably affected. At infusion rates between 7.5 and 10 µg/kg/min, a 10 - 20 % increase in heart rate is generally observed. In the non-asphyxiated neonate, this is generally well tolerated. Dysrhythmia can be induced or exacerbated with electrolyte imbalance, high infusion rates, or myocarditis, although the incidence of dysrhythmia is lower than that reported for dopamine or isoproterenol. Tissue ischemia may occur with infiltration.

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