Cardiovascular Drugs A better understanding of the pathophysiology and hemodynamic manifestations of circulatory failure in children has resulted in a shift away from therapy using pure inotropes aimed at improving contractility, to measures that also focus on the peripheral vasculature and the interactions between the periphery and the myocardium Current approaches are aimed at optimizing afterload and manipulating contractility with careful, not excessive, inotropic therapy, while avoiding any unwanted increases in vascular resistance or myocardial oxygen consumption Drug therapies for acute circulatory failure are generally categorized according to their pharmacologic actions and also by their physiologic effects The classes of drugs most commonly used to treat acute circulatory failure in children are catecholamines and phosphodiesterase-3 inhibitors In addition, a number of other drugs that influence cardiovascular function through very different mechanisms including sensitization to intracellular calcium, and neurohormonal effects, have also become available for clinical use in children It is important to consider some unique pharmacodynamics and pharmacokinetic factors when approaching treatment of acute circulatory failure in children In addition, a comprehensive list of frequently used vasoactive medications in the management of acute circulatory failure is presented (Table 64.3) Table 64.3 Vasoactive Medications Used for the Management of Acute Circulatory Failure Drug Dopamine RECEPTOR IV Infusion ACTIVITY Receptor Effect Organ Effect Dose α-1 β-1 β-2 Dopamine −+ − − ++ 1–5 µg/kg/min D1-like (D1↑ vascular tone ↑ contractility ++ ++ + ++ 5–10 D5): ↓ ↑ HR µg/kg/min sensitivity to ++ + ++ 10–20 postsynaptic µg/kg/min intracellular Ca2+ D2-like (D2-4): ↓ norepinephrine Potential Side Effects Arrhythmias Tachycardia Epinephrine −+ ++ + ++ ++ + ++ + 0 Levosimendan Calcium sensitizer Milrinone Type III phosphodiesterase inhibitor Nesiritide Recombinant B-type natriuretic peptide release from nerve terminal 0.01–0.03 α-1: ↑ Ca2+ µg/kg/min influx to 0.03–0.1 postsynaptic µg/kg/min cell receptor > 0.1 β-1, β-2: ↑ µg/kg/min intracellular cAMP Loading Opening of ATP6–12 µg/kg dependent for 10 min mitochondrial K+ Continuous channels in 0.05–0.1 vascular smooth µg/kg/min muscle for 24 to 48 h 0.25–1 Inhibition of µg/kg/min intracellular hydrolysis of 3′5′ cAMP 0.01–0.02 ↑ cGMP in µg/kg/min endothelial and vascular smooth muscle cells Norepinephrine ++ ++ − 0.01–1 µg/kg/min Phenylephrine ++ 0 0.15–0.75 µg/kg/min Vasopressin V1 receptor agonist 0.01–0.1 µg/kg/min α-1: ↑ Ca2+ influx to postsynaptic cell receptor α-1: ↑ Ca2+ influx to postsynaptic cell receptor IP3 signal transduction in the vascular smooth muscle Systemic Arrhythmias vasoconstriction Hypertension ↑ contractility Hyperglycemia ↑ LV afterload Systemic vasodilation Coronary vasodilation ↑ inotropy ↑ contractility ↓ LV afterload Systemic vasodilation ↑ inotropy ↑ lusotropy Systemic vasodilation Coronary vasodilation ↑ GFR ↓ Na+ reabsorption ↑ diuresis Systemic vasoconstriction ↑ LV afterload ↑ vascular tone ↑ LV afterload Arrhythmias Hypotension Hypokalemia Hypotension Renal accumulation Bradycardia Hypotension Arrhythmias Hypertension Bradycardia Hypertension Systemic Hypertension vasoconstriction ↑ LV afterload ATP, Adenosine triphosphate; Ca2+, Calcium; cAMP, cyclic-adenosine monophosphate; cGMP, cyclic guanosine monophosphate; D, Dopamine; GFR, glomerular filtration rate; HR, heart rate; IP3, Phosphatidyl inositol triphosphate; K+, Potassium; LV, left ventricle; min, minutes; Na+, Sodium; V, vasopressin; ↑, increase; ↓, decrease; ++, potent; +, moderate; −, minimal; 0, none Maturational Influences The neonatal myocardium differs significantly from the more mature heart in its innervation and contractile reserve The neonatal heart is less densely supplied with sympathetic nerve terminals than older infants and adults, resulting in reduced myocardial effects and less reuptake of catecholamines This latter factor may also predispose to the neonatal cardiotoxicity of catecholamines as previously described.30 The newborn myocardium is more sensitive to changes in intracellular calcium compared to the more mature heart Pulmonary Vasculature Pulmonary hypertension, or lability of the pulmonary vascular resistance, is commonly encountered in newborns and infants with heart disease Changes in pulmonary vascular tone can play a role in the development of acute circulatory failure in some patients Patients at increased risk of pulmonary hypertension include those with structural heart disease, resulting in excessive pulmonary blood flow, pulmonary venous hypertension, or a functionally univentricular circulation Pulmonary vascular instability can further deteriorate in the newborn transitional circulation and by cardiac surgery and cardiopulmonary bypass, which disturbs the balance between endogenous pulmonary vasodilators and constrictors.31,32 Complex Circulations Careful control of vascular tone is a prerequisite for the circulatory management of patients with more complex congenital heart lesions, in particular those with a functionally univentricular heart In these patients, sudden changes in pulmonary or systemic vascular resistance can immediately impact on the systemic oxygen delivery and can rapidly precipitate into acute circulatory failure Moreover, a stable pulmonary vascular resistance and an appropriately dilated systemic vasculature are highly desirable The presence of complex congenital cardiac disease can also impact the responsiveness of the myocardium to exogenous agents Sympathetic dysregulation is most marked in newborns and young infants with cyanotic or critical acyanotic heart disease In these patients, reduction of the density of βadrenoreceptors is associated with elevated endogenous levels of noradrenaline and a partial uncoupling of the receptor to adenylate cyclase As a result, the myocardium may be less responsive to β-adrenergic stimulation.33