depending on the dose There is evidence of improved left ventricular performance at levels of less than 2.5 µg/kg per minute in immature neonates.193,194 It was previously thought that the vasoconstricting effects occur only at doses greater than 10 µg/kg per minute There is evidence of significant α-adrenergic effects in some premature infants at doses as low as 6 µg/kg per minute, with marked elevation in systemic vascular resistance leading to decreased cardiac output and decreased flow in the superior mesenteric and middle cerebral arteries.195 Although dopamine is an effective agent at increasing systemic blood pressure,196 its effects on systemic flow and end-organ perfusion are concerning Epinephrine is an endogenous catecholamine produced by the adrenal medulla with similar mixed β1-adrenergic, at low doses, and αadrenergic, at doses greater than 0.375 µg/kg per minute, effects to epinephrine It is an effective pressor agent in the first 24 hours of life and may augment cerebral flow.197 Its clinical use is normally reserved as a rescue agent, although it may be a more effective pressor agent than dopamine in septic shock or necrotizing enterocolitis High doses or prolonged treatment have been associated with ischemia and myocardial dysfunction.198,199 These effects may relate to direct β-1 adrenergic receptor mediated damage to the myocardium.200,201 Vasopressin is a 9–amino acid peptide synthesized in the posterior pituitary, commonly known as antidiuretic hormone It displays dichotomous effects through V1 receptors In the lung, it has pulmonary vasodilator properties via modulation of release of nitric oxide It acts as a systemic vasoconstrictor, acting through phospholipid complex–mediated calcium release In adults it is a promising systemic vasopressor in vasodilatory shock and cardiopulmonary resuscitation.202–204 Although there are limited neonatal data, vasopressin has been used successfully in extremely low birth weight neonates with catecholamine resistant shock205–207 and has demonstrated safety when compared with dopamine as a first-line therapy for early hypotension.208 Theoretically, it may also be of benefit in restrictive physiologies such as the septal hypertrophy or biventricular hypertrophy that occurs in infants of diabetic mothers and preterm infants with hypotension in the setting of acute pulmonary hypertension Inodilator Agents Dobutamine is a synthetic analogue of dopamine with a predominantly β-1 adrenergic mode of action and minimal α- and β-2 adrenergic properties.209 These translate into positive inotropic and afterload reducing effects, which are highly desirable in many neonatal settings (e.g., transitional period, postasphyxial insult, pulmonary hypertension, and following ductal ligation) A systematic review of five randomized controlled trials concluded that dopamine was superior at elevating systemic blood pressure, but there were no differences in survival or neonatal morbidity.196 Two randomized trials have shown that dobutamine is a more effective agent at improving systemic blood flow.210,211 In one study, dopamine was shown to lead to a decrease in left ventricular output It can be concluded that dobutamine is a more desirable agent for neonates with hypotension and clinical signs of low cardiac output Milrinone is an inhibitor of phosphodiesterase type III that acts through increasing the bioavailability of cyclic adenine monophosphate It is both a systemic and pulmonary vasodilator, with positive inotropic and lusitropic properties In infants and children undergoing cardiac surgery, it has been shown to decrease the combined end point of death and low cardiac output syndrome.212 There is also evidence of benefit in neonates with pulmonary hypertension.213–215 The pharmacokinetics of milrinone have been characterized in premature infants in the first 24 hours of life.216,217 Experimental data suggest that the myocardial effects may be developmentally regulated, with negative inotropy in some species in early gestation.218 Caution is advised when administering milrinone to neonates with hypotension because the associated reduction in systemic vascular resistance may be associated with severe hypotension, particularly in neonates where metabolism and clearance may be impacted such as those with hepatic or renal impairment Steroids These are normally considered as rescue therapy after failure of cardiotropic support A number of clinical trials have demonstrated improved cardiovascular stability facilitating weaning of cardiotropic drugs after commencement of treatment.219,220 The mechanism of action is a combination of genomic and nongenomic effects (Fig 15.11) Their merits must be considered in the context of the potential negative effects on myelination and brain maturation.221 FIG 15.11 Major mechanisms of action of hydrocortisone Hydrocortisone upregulates the genomic production of cell surface receptors and increases cellular second messenger substrate that mediates vasoconstriction eNOS, Endothelial nitric oxide synthase; VSM, vascular smooth muscle (From Giesinger RE, McNamara PJ Hemodynamic instability in the critically ill neonate: an approach to cardiovascular support based on disease pathophysiology Semin Perinatol 2016;40[3]:174–188.) In summary, the choice of a cardiovascular treatment should consider the nature of the disease, maturational factors, potential effects on both blood pressure and cardiac output (see Fig 15.9), and pharmacologic properties The complications of treatment need also be recognized, which may include tachycardia, increased myocardial consumption of oxygen, hypotension produced by vasodilator agents, regional hypoperfusion produced by vasopressors, impaired myocardial compliance, and arrhythmias Pulmonary Hypertension and Prematurity Until recently, the nature and treatment of pulmonary vascular disease in premature infants have received little attention For the purposes of this section,