1. Pharmacologic Management of Acute Circulatory Failure Suanne M. Daves, M.D. Associate Professor Department of Pediatrics

2. What you heard last week Calcium, calcium, calcium Neonates do not have well-developed SR & depend more on extracellular Ca + Neonates have a limited ability to increase stroke volume (Starling Adaptation)

3. What you will hear today Both the sympathetic nervous system & various drugs can accelerate/enhance the excitation-contraction coupling phenomenon in myocytes.

4. Circulatory Failure What is it? Metabolic demand outstrips supply. Anaerobic state leads to accumulation of lactic acid. Energy dependent cellular processes cease. Cellular edema, cellular disruption, cell death. Organ failure.

6. Formulas to Remember

7. Treatment Goals Provide adequate tissue oxygenation. Maintain vital organ function. Restore systemic blood pressure. Tailor drugs to minimize adverse side effects.

8. β1β1 β2β2 1

9. β1β2ά1β1β2ά1 β2β2 DA 1 DA 2 ά1β2ά1β2

16. PDE

19. Bohn (2006). Inotropic Agents in Heart Failure. Heart Failure in Children and Young Adults. Chang & Towbin.

20. Bohn (2006). Inotropic Agents in Heart Failure. Heart Failure in Children and Young Adults. Chang & Towbin.

21. Stevenson. Circulation 2003

22. Dobutamine Dopamine Epinephrine Isoproterenol Norepinephrine Phenylephrine Milrinone

23. Drawbacks of Catecholamines Increased myocardial O2 demand Myocardial injury Tolerance/tachyphylaxis Arrhythmiogenesis Peripheral vasoconstriction –Elevates SVR –Compromises splanchnic blood flow

24. A 4-mos-old infant presents to the ER with irritability, poor po intake, and tachypnea. The ER doc says the baby looks “shocky”. They have started an IV & given 20mL/kg NS. You go to the ER & this is what you see……. The infant is awake & quiet. HR: 170s-180s (sinus) RR: 70s BP: 90/68 He is cool peripherally. His pulses are ‘thready’ pH 7.29/pCO 2 38/pO 2 82/HCO 3 18 Lactate 4.0

25. The infant is awake & quiet. HR: 170s-180s (sinus) RR: 70s BP: 90/68 He is cool peripherally. His pulses are ‘thready’ pH 7.29/pCO 2 38/pO 2 82/HCO 3 18 Lactate 4.0 Would you begin an inotrope/pressor? Which one?

26. Same infant………. HR: 180s (sinus) RR: 70s BP: 52/44

27. Key Concepts The predominant β-AR in the heart is the β 1 -AR (<75%). The greatest concentration of β 2 -ARs is found in vascular smooth muscle. Ά 1 -ARs predominate in vascular smooth muscle although they are present in the neonatal myocardium.

28. Key Concepts Today’s inotropes may be good in the short term for hemodynamic support but most will increase myocardial oxygen demand, increase diastolic pressures, and lead to down-regulation of ARs. PDE inhibitors, while increasing intracellular Ca +, are lusiotropic and inotropic agents that do not increase myocardial O 2 demand and are not associated with tachyphylaxis.

29. Key Concepts A strategy of combining a PDE inhibitor with a catecholamine may be the best approach to support of the myocardium and circulation. Most inotropic agents to date have a common final intracellular pathway of increased intracellular Ca +, which may ultimately lead to cell (myocyte) death.

30. Key Concepts A new generation of inotropic agents known as calcium-sensitizing agents achieve their positive inotropic effects without an increase in intracelluar Ca + or myocardial O 2 consumption.

31. Bohn (2006). Inotropic Agents in Heart Failure. Heart Failure in Children and Young Adults. Chang & Towbin.