Neonatal Blood Pressure Support: the Use of Inotropes, Lusitropes, and Other Vasopressor Agents

Neonatal Blood Pressure Support: The Use of Inotropes, Lusitropes, and Other Vasopressor Agents Shahab Noori, MD, Istvan Seri, MD, PhD* KEYWORDS Inotropes Lusitropes Vasopressors Hemodynamic Hypotension Shock The use of inotropes, lusitropes, and vasopressors is common in neonates with cardiovascular compromise.1,2 Although the understanding of cellular mechanisms of action of these medications is well founded,3,4 there is little information on their clin- ically relevant long-term benefits in the neonatal patient population.5–7 In addition, if not appropriately titrated, these medications may induce abrupt, excessive, and potentially harmful increases in blood pressure and systemic and organ blood flow.8–11 Thus, in addition to the cardiovascular compromise,10,11 treatment by sub- optimal administration of inotropes, lusitropes, and vasopressors may contribute to short- and long-term morbidities in critically ill preterm and term neonates.6 Prompt diagnosis of neonatal cardiovascular compromise by state-of-the-art hemodynamic monitoring of blood pressure and systemic and organ blood flow12 and careful titration of the vasoactive agents to the optimal hemodynamic response8,13 are thought to be of importance in decreasing mortality and morbidity associated with shock and its treatment in preterm and term neonates.14,15 Unfortunately, there is little evidence on what vasoactive medications to use in what patient and when, at what dose to start, how to titrate the drug, and what parameters to monitor.2,6,16 Because addressing these issues is only possible by opinion- and experience-based reasoning without much evidence at present, this article focuses on describing the documented, developmentally regulated hemodynamic actions of inotropes, lusitropes, and vasopressors, and their short-term hemodynamic benefits and risks. Although there are several reasons to stay away from advocating Center for Fetal and Neonatal Medicine and the USC Division of Neonatal Medicine, Children’s Hospital Los Angeles and the LAC1USC Medical Center, Keck School of Medicine, University of Southern California, 4650 Sunset Boulevard, Mailstop #31, Los Angeles, CA 90027, USA * Corresponding author. USC Keck School of Medicine, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Mailstop #31, Los Angeles, CA 90027. E-mail address: [email protected] Clin Perinatol 39 (2012) 221–238 doi:10.1016/j.clp.2011.12.010 perinatology.theclinics.com 0095-5108/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved. 222 Noori & Seri experience-based reasoning on the use, benefits, and potential harm of these medications, the notion that experience in medicine might be best defined as “an ability to make a mistake repeatedly with increasing confidence” is one of the reasons with which few would argue. MECHANISMS OF ACTION OF INOTROPES, LUSITROPES, AND VASOPRESSORS An inotrope is a manufactured or naturally occurring substance with a primary phar- macologic effect of increasing myocardial contractility. For the classical inotropes (eg, dobutamine) or vasopressor-inotropes (eg, epinephrine and dopamine), the mechanisms of increasing myocardial contractility are primarily based on stimulating a-orb-adrenergic and dopaminergic receptors located on the cell membrane of myocardial cells. Stimulation of these receptors leads to activation of a chain of intracellular events hinging on receptor-specific cyclic adenosine monophosphate (cAMP)–dependent or independent increases in intracellular calcium availability resulting in increased actin–myosin bridge formation and thus contractility (Fig. 1).17 Fig. 1. Mechanisms of cardiomyocyte contraction. (A)Gs-andGi-protein coupled signal transduction. Ligand-induced and receptor-specific activation (b-adrenoreceptor–Gs coupling) or deactivation (muscarinic or adenosine receptor–Gi coupling) of adenylyl cyclase results in increased or decreased cAMP formation, respectively. Increases in cAMP activates protein kinase-A (PK-A) resulting in increased influx of calcium by phosphorylation and activation of L-type calcium channels and enhanced release of calcium by the sarcoplasmic reticulum in the cardiomyocyte leading to increased inotropy, chronotropy, and dromotropy. Activation of Gi-proteins by adenosine and muscarinic receptor stimulation decreases cAMP and decreases calcium entry and release and cell membrane repolarization resulting in decreased inotropy. Gi-protein effects are prevalent mostly in the sinus and atrioventricular (AV) nodes resulting in decreased sinus rate and AV conduction velocity, respectively, with only minimal effects on myocardial contractility. (B)IP3-coupled signal transduction. The IP3 pathway is linked to activation of a1-adrenoceptors, angiotensin II (AII) receptors, and endothelin-1 (ET-1) receptors and is stimulated by agonist exposure of these receptors coupled to a phospholipase C (PL-C)– linked Gq-protein. Activated PL-C then stimulates formation of inositol triphosphate (IP3)from phosphatidylinositol biphosphate (PIP2). Increased IP3 stimulates calcium release by the sarcoplasmic reticulum resulting in increases in inotropy. (Modified from Klabunde RE. Available at: http://www.cvphysiology.com/Blood%20Pressure/BP011a.htm; with permission.) Neonatal Blood Pressure Support 223 Another class of inotropes, the phosphodiesterase (PDE) inhibitors (eg, amrinone or milrinone), rather selectively decrease the activity of PDE-III, the enzyme responsible for degradation of cAMP.18 The resulting increase in intracellular cAMP concentration leads to the chain of events described for the classical inotropes with the end-result of increased myocardial contractility. A lusitrope is a manufactured or naturally occurring substance that increases the rate of myocardial relaxation. The lusitropic property depends on the compound’s ability to reduce intracellular calcium concentration by cAMP-dependent activation of the inward-pumping calcium channels on the sarcoplasmic reticulum, or to promote calcium dissociation from troponin C primarily during diastole.19,20 A vasopressor is a manufactured or naturally occurring substance that increases vascular tone. Vascular smooth muscle tone is regulated by complex cellular mechanisms involving a delicate balance between vasodilator and vasoconstrictor factors, and the availability of cytosolic calcium plays a central role in this process (Fig. 2). Vasopressors exert their peripheral vasoconstrictive effects primarily through binding to a1-adrenergic and vasopressin1A (V1a) receptors activating the enzyme phospholipase C in the vascular smooth muscle.21 Phospholipase C in Fig. 2. Regulation of vascular tone in vascular smooth muscle cells. This figure shows the simplified depiction of three pathways of importance in regulation of vascular tone. The phosphatidylinositol (PIP2) pathway is similar to that in the heart with vasopressors (norepi- nephrine [NE], epinephrine, and dopamine), angiotensin II (AII), and endothelin-I (ET-1) A acting by way of the a1-adrenergic, AII, and ET receptors, respectively, to activate phospholipase C (PL-C) to form inositol triphosphate (IP3) and diacylglycerol (DAG). Inositol triphosphate stimulates calcium release from the sarcoplasmic reticulum while DAG activates PK-C contributing to vascular smooth muscle cell contraction. The Gs-protein coupled pathway stimulates (receptor coupled with the stimulatory G protein: Gs) or inhibits (receptor coupled with the inhibitory G protein: Gi) adenylyl cyclase resulting in increased or decreased cAMP formation, respectively. Different vascular beds have a different pattern of a- and b-adrenergic receptor and dopaminergic receptor expression.3 Increases in cAMP inhibits myosin light chain kinase (MLCK) and decreases phosphorylation of smooth muscle myosin thereby pre- venting the interactions between actin and myosin and leads to vasodilation. Decreases in cAMP have the opposite effect enhancing the vasoconstrictor tone. The b2-adrenoceptor– linked mechanism in the vascular smooth muscle cell is different from that in the myocardium. The nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) pathway induces vasodilation by way of the NO-induced activation of guanylyl cyclase (GC) and the resultant increased cGMP formation. cGMP activates the cGMP-dependent protein kinase and potassium channels resulting in inhibition of IP3 formation and calcium entry into the vascular smooth muscle cell. (Modified from Klabunde RE. Available at: http://www.cvphysiology.com/Blood% 20Pressure/BP011b.htm; with permission.) 224 Noori & Seri turn increases inositol triphosphate leading to release of calcium from the sarcoplasmic reticulum. Most of the medications used for cardiovascular support in the neonatal intensive care unit have dose-dependent inotropic, lusitropic, and vasopressor effects albeit to a varying degree and, for the compounds exerting their cardiovascular actions by receptor stimulation, with various sensitivity to the cardiovascular adrenergic, dopaminergic, and vascular vasopressin receptors (Tables 1 and 2). Discussed next are the developmentally regulated mechanisms of action of these medications, their cardiovascular effects, and the specific cardiovascular pathophysiology and clinical scenarios where each medication might be beneficial. DOPAMINE Dopamine is the most commonly used cardiovascular medication in the neonatal intensive care unit. Dopamine exerts its cardiovascular effects by dose-dependent stimulation of the a- and b-adrenergic and dopaminergic

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