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Vasoactive Agents in the PICU PCCM Faculty University of North Carolina Pediatric Critical Care Medicine Outline Developmental physiology of cardiovascular system Basic terminology review Description of most commonly used agents by site and mechanism of action What this will not teach you Will not review specific algorithms (i.e.sepsis, low cardiac output syndrome, anaphylaxis, etc) in detail Developmental Physiology Myocardial Contraction Contractility increases over 1st months of life along with: #’s of sympathetic nerve fibers within myocardium Total concentration of endogenous norepinephrine There is a greater dependence of CO on HR than contractility during this time Immature Heart Limited responsiveness to medications noncontractile content availability of releasable NE Less mature sympathetic system Underdeveloped intracellular calcium regulatory mechanisms functional reserve capacity Ionized Calcium Plays central role in maintaining myocardial contractility Effects mediated via intracellular concentration, calcium requirements of the muscle cell, sensitivity of the myofilaments to calcium 1 Vascular Smooth Muscle Calcium dependent effects Agents that increase intracellular cAMP increase intracellular calcium requirements for contraction, thus encouraging smooth muscle relaxation and vasodilation Vascular Smooth Muscle Calcium independent effects G protein mediated activation of phospholipase C results in breakdown of phosphatidylinositol bisphosphate into IP3 and DAG. IP3 releases calcium from the sarcoplasmic reticulum initiating contraction and DAG activates protein kinase C with phosphorylation of intracellular proteins Effects of Agents Pressors: increase systemic vascular resistance and increase blood pressure Inotropes: affect myocardial contractility and enhance stroke volume Chronotropic Agents: affect heart rate Lusotropic Agents: improve relaxation during diastole and decrease EDP in the ventricles Dromotropic Agents: Affects conduction speed through AV node; increases heart rate Bathmotropic Agents: affect degree of excitability Alpha-Adrenergic Agents Alpha1-adrenergic effects: Vascular smooth muscle contraction Alpha2-adrenergic effects: Vascular smooth muscle relaxation Beta-Adrenergic Agents Beta1-adrenergic effects: Direct cardiac effects Inotropy (improved cardiac contractility) Chronotropy (increased heart rate) Beta2-adrenergic effects: Vasodilation Bronchodilation Dopaminergic Agents Dopaminergic Agents Several types of receptors located throughout body (D1-D5) Certain (esp. D1-like & D2-like) dopaminergic receptors increase renal and mesenteric blood flow Catecholamines Sympathomimetic amines that contain Odihydrobenzene Dopamine, epinephrine and norepinephrine are endogenous Dobutamine and isoproterenol are synthetic Sustained use or antecedent CHF can lead to down-regulation of β-receptors and decrease efficacy Epinephrine Both an alpha- and beta-adrenergic agent 0.01 mcg/kg/min-0.3 mcg/kg/min Low-dose infusion = β activation Increase HR, contractility, decrease SVR Higher doses = activation Increased SVR and MAP Increased myocardial O2 demand EPINEPHRINE Low Dose (<0.05-0.1 mcg/kg/min) Epinephrine β1 predominantly ↑HR ↓ Duration of Systole ↑ Myocardial contract Periph. arteriolar dil. ↑/ ↓ Renal BF ↑ Renin secretion ↑/ ↓ Splanchnic BF ↑ Glucose Hypokalemia High Dose (> 0.1 μg/kg/min) α1 predominantly Vasoconstriction ↓ Renal BF ↓ Splanchnic BF ↑ Glucose Epinephrine Indications for its use as a continuous infusion are: low cardiac output state beta effects will improve cardiac function alpha effects may increase afterload and decrease cardiac output septic shock useful for both inotropy and vasoconstriction Epinephrine Adverse effects include: Anxiety, tremors,palpitations Tachycardia and tachyarrhythmias Increased myocardial oxygen requirements and potential to cause ischemia Decreased splanchnic and hepatic circulation (elevation of AST and ALT) Anti-Insulin effects: lactic acidosis, hyperglycemia Norepinephrine An epinephrine precursor that acts primarily on receptors Used primarily for alpha agonist effect increases SVR without significantly increasing C.O. Used in cases of low SVR and hypotension such as profound “warm shock” with a normal or high C.O. state- usually in combination with dopamine or epinephrine Infusion rates titrated between 0.05 to 0.3 mcg/kg/min Norepinephrine Differs from epinephrine in that the vasoconstriction outweighs any increase in cardiac output. i.e. norepinephrine usually increases blood pressure and SVR, often without increasing cardiac output. Norepinephrine Adverse Effects: Similar to those of Epinephrine Can compromise perfusion in extremities and may need to be combined with a vasodilator e.g. Dobutamine or Nipride More profound effect on splanchnic circulation and myocardial oxygen consumption Vasopressin a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure possesses antidiuretic and vasopressor properties deficiency of this hormone results in diabetes insipidus Vasopressin Vasopressin Administration intravenous, intramuscular, or intranasal routes IV is route for vasopressor activity The half-life of circulating ADH is approximately 20 minutes, with renal and hepatic catabolism via reduction of the disulfide bond and peptide cleavage Vasopressin Administration interacts with two types of receptors V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction V2 receptors are found on renal tubule cells and mediate antidiuresis through increased water permeability and water resorption in the collecting tubules Newer drug to ACLS for resuscitation Use in refractory septic shock with low SVRI in pediatrics? Dopamine Intermediate product in the enzymatic pathway leading to the production of norepinephrine; thus, it indirectly acts by releasing norepinephrine. Directly has , and dopaminergic actions which are dose-dependent. Indications are based on the adrenergic actions desired. Dopamine renal perfusion 2-5 mcg/kg/min (dopaminergic effects) by sensitivity of vascular smooth muscle to intracellular calcium (? Effects on UOP) C.O. in Cardiogenic or Distributive Shock 510mcg/kg/min ( adrenergic effects) Post-resuscitation stabilization in patients with hypotension (with fluid therapy) 1020mcg/kg/min ( adrenergic effects) peripheral vasoconstriction, SVR, PVR, HR, and BP—This dose may be needed in preterm infants for medium dose effects Dose Dependent effect of Dopamine <5 mcg 5 - 10 mcg > 10 mcg Modest ↑ CO ↑Contractility ↑ HR, ↑ Renal BF Minimal change in HR and SVR Vasoconstriction ↓Proximal Tub. Na Absorbtion ↑ Renal BF ↑ Splanchnic BF ↑ Splanchnic BF ↑/ ↓ Renal BF ↓/↑ Splanchnic BF Dobutamine Synthetic catecholamine with 1 inotropic effect (increases stroke volume) and 2 peripheral vasodilation (decreases afterload) Positive chronotropic effect 1 (increases HR) Some lusotropic effect Overall, improves Cardiac Output by above beta-agonist acitivity Dobutamine Major metabolite is 3-Omethyldobutamine, a potent inhibitor of alpha-adrenoceptors. Therefore, vasodilation is possible secondary to this metabolite. Usual starting infusion rate is 5 mcg/kg/min, with the dose being titrated to effect up to 20 mcg/kg/min. DOBUTAMINE Dobutamine L- isomer Stimulates α1 D- isomer Stimulates β1 and β2 Dobutamine Used in low C.O. states and CHF e.g. myocarditis, cardiomyopathy, myocardial infarction If BP adequate, can be combined with afterload reducer (Nipride or ACE inhibitor) In combination with Epi/Norepi in profound shock states to improve Cardiac Output and provide some peripheral vasodilatation Isoproterenol Synthetic catecholamine Non-specific beta agonist with minimal alpha-adrenergic effects. Causes inotropy, chronotropy, and systemic and pulmonary vasodilatation. Indications: bradycardia, decreased cardiac output, bronchospasm (bronchodilator). Isoproterenol Occasionally used to maintain heart rate following heart transplantation. Dose starts at 0.01 mcg/kg/min and is increased to 2.0 mcg/kg/min for desired effect. Avoid in patients with subaortic stenosis, and hypertrophic cardiomyopathy or TOF lesions because increases the outflow gradient Milrinone/Amrinone Belong to class of agents “Bipyridines” Non-receptor mediated activity based on selective inhibition of Phosphodiesterase Type III enzyme resulting in cAMP accumulation in myocardium cAMP increases force of contraction and rate and extent of relaxation of myocardium Inotropic, vasodilator and lusotropic effect Advantage over catecholamines: Independent action from -receptor activation, particularly when these receptors are downregulated (CHF and chronic catecholamine use) Milrinone Increases CO by improving contractility, decreased SVR, PVR, lusotropic effect; decreased preload due to vasodilatation Unique in beneficial effects on RV function Protein binding: 70% Half-life is 1-4 hours Elimination: primarily renally excreted Load with 50 mcg/kg over 30 mins followed by 0.25 to 0.75 mcg/kg/min No increase in myocardial O2 requirement PDE Inhibition PDE PDE 3 PDE 5 Aminophylline Milrinone Sildenefil Milrinone Minimal ↑ HR ↑ CO Diastolic Relaxation Minimal ↑ in O2 demand ↓ SVR ↓ PVR Other Vasoactive Agents NESRITIDE Recombinant hBNP Secreted by ventricles in response to ↑ wall stress and volume overload Venous and arteriolar dilator, acts on Guanylate cyclase It reduces RA pressure, PCWP and cardiac index Dose: Infusion 0.01- 0.03 mcg/kg/min Hypotension Nesiritide: Other Effects Nesiritide (recombinant human BNP) is a vasodilator with other theoretical effects including: natriuresis, neurohormonal inhibition, and reverse remodeling In the setting of Heart Failure, it has been shown to reduce pulmonary capillary wedge pressure and improve shortness of breath relative to placebo Linked to possible renal failure and increased mortality in some patient populations Vasodilators Classified by site of action Venodilators: reduce preload - Nitroglycerin Arteriolar dilators: reduce afterload Minoxidil and Hydralazine Combined: act on both arterial and venous beds and reduce both pre- and afterload Sodium Nitroprusside (Nipride) Nitroprusside Vasodilator that acts directly on arterial and venous vascular smooth muscle. Indicated in hypertension and low cardiac output states with increased SVR. Also used in post-operative cardiac surgery to decrease afterload on an injured heart. Action is immediate; half-life is short; titratable action. Nitroprusside Toxicity is with cyanide, one of the metabolites of the breakdown of nipride. Severe, unexplained metabolic acidosis might suggest cyanide toxicity. Dose starts at 0.5 mcg/kg/min and titrate to 5 mcg/kg/min to desired effect. May go higher (up to 10 mcg/kg/min) for short periods of time. Nitroglycerine Direct vasodilator as well, but the major effect is as a venodilator with lesser effect on arterioles. Not as effective as nitroprusside in lowering blood pressure. Another potential benefit is relaxation of the coronary arteries, thus improving myocardial regional blood flow and myocardial oxygen demand. Nitroglycerine Used to improve myocardial perfusion following cardiac surgery Dose ranges from 0.5 to 8 mcg/kg/min. Typical dose is 2 mcg/kg/min for 24 to 48 hours post-operatively Methemoglobinemia is potential side effect Summary Relative receptor activity of most commonly used inotropes α1 α2 β1 β2 DA Norepinephrine +++ +++ + - - Epinephrine +++ ++ +++ ++ - Dopamine ++ + ++ +++ +++ Dobutamine + - +++ + - Isoproterenol - - ++ ++ - Receptor Activity (continued)