Vasoactive Agents in the PICU

1. Vasoactive Agents in the PICU PCCM Faculty University of North Carolina Pediatric Critical Care Medicine

2. Outline Developmental physiology of cardiovascular system Basic terminology review Description of most commonly used agents by site and mechanism of action

3. What this will not teach you Will not review specific algorithms (i.e.-sepsis, low cardiac output syndrome, anaphylaxis, etc) in detail

4. Developmental Physiology

5. 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

6. Immature Heart • Limited responsiveness to medications •  noncontractile content •  availability of releasable NE • Less mature sympathetic system • Underdeveloped intracellular calcium regulatory mechanisms •  functional reserve capacity

7. 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

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9. Vascular Smooth Muscle • Calcium dependent effects • Agents that increase intracellular cAMP increase intracellular calcium requirements for contraction, thus encouraging smooth muscle relaxation and vasodilation

10. 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

11. 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

12. Alpha-Adrenergic Agents • Alpha1-adrenergic effects: • Vascular smooth muscle contraction • Alpha2-adrenergic effects: • Vascular smooth muscle relaxation

13. Beta-Adrenergic Agents • Beta1-adrenergic effects: • Direct cardiac effects • Inotropy (improved cardiac contractility) • Chronotropy (increased heart rate) • Beta2-adrenergic effects: • Vasodilation • Bronchodilation

14. 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

15. Catecholamines • Sympathomimetic amines that contain O-dihydrobenzene • 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

17. 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

18. EPINEPHRINE Low Dose (<0.05-0.1 mcg/kg/min) Epinephrine High Dose (> 0.1 μg/kg/min) β1 predominantly ↑HR ↓ Duration of Systole ↑ Myocardial contract Periph. arteriolar dil. ↑/ ↓ Renal BF ↑ Renin secretion ↑/ ↓ Splanchnic BF ↑ Glucose Hypokalemia α1 predominantly Vasoconstriction ↓ Renal BF ↓ Splanchnic BF ↑ Glucose

19. 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

20. 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

21. 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

22. 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.

23. 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

24. 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

25. Vasopressin

26. 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

27. 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?

28. 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.

29. 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 5-10mcg/kg/min ( adrenergic effects) • Post-resuscitation stabilization in patients with hypotension (with fluid therapy) 10-20mcg/kg/min ( adrenergic effects) peripheral vasoconstriction,  SVR, PVR, HR, and BP—This dose may be needed in preterm infants for medium dose effects

30. Dose Dependent effect of Dopamine <5 mcg 5 - 10 mcg > 10 mcg ↑ HR, Vasoconstriction ↑/ ↓ Renal BF ↓/↑ Splanchnic BF Modest ↑ CO ↑ Renal BF ↓Proximal Tub. Na Absorbtion ↑ Splanchnic BF ↑Contractility Minimal change in HR and SVR ↑ Renal BF ↑ Splanchnic BF

31. 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

32. Dobutamine • Major metabolite is 3-O-methyldobutamine, 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.

33. DOBUTAMINE Dobutamine D- isomer Stimulates β1 and β2 L- isomer Stimulates α1

34. 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

35. 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).

36. 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

37. 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)

38. 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

39. PDE Inhibition PDE PDE 3 PDE 5 Aminophylline Milrinone Sildenefil

40. Milrinone Minimal ↑ HR ↑ CO Diastolic Relaxation Minimal ↑ in O2 demand ↓ SVR ↓ PVR

41. Other Vasoactive Agents

42. 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

43. 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

44. 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)

45. 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.

46. 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.

47. 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.

48. 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

49. Summary

50. Relative receptor activity of most commonly used inotropes