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Intensive Care Cardiovascular Pharmacology

Toni Petrillo-Albarano, MD Director, Pediatric Transport Division of Critical Care Medicine. Intensive Care Cardiovascular Pharmacology. Catecholamines Naturally occurring, biologically active amines Sympathomimetic Mimics stimulation of the sympathetic nervous system.

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Intensive Care Cardiovascular Pharmacology

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  1. Toni Petrillo-Albarano, MD Director, Pediatric Transport Division of Critical Care Medicine Intensive CareCardiovascular Pharmacology

  2. Catecholamines • Naturally occurring, biologically active amines • Sympathomimetic • Mimics stimulation of the sympathetic nervous system Cardiovascular PharmacologyTerminology Review

  3. Adrenergic • Refers to the sympathetic nervous system • Cholinergic • Refers to the parasympathetic nervous system • Dopaminergic • Dopamine receptors in renal, visceral, coronary, and cerebral areas Cardiovascular PharmacologyTerminology Review

  4. Inotropic • Influencing the force of contraction • Chronotropic • Influencing the rate of contraction Cardiovascular PharmacologyTerminology Review

  5. Six receptor subtypes: • alpha 1 (post-synaptic) • alpha 2 (pre-synaptic) • beta 1 (cardiac) • beta2 (vascular/bronchial smooth muscle) • DA 1 (post-synaptic) • DA 2 (pre-synaptic) Cardiovascular PharmacologyAdrenoreceptors

  6. Cardiovascular PharmacologyAdrenoreceptors • ALPHA 1: • Vasoconstriction • Mydriasis • Uterine contraction • Bladder contraction • Insulin inhibition • Glucagon inhibition • ALPHA 2: • Inhibition of norepinephrine release

  7. Cardiovascular PharmacologyAdrenoreceptors • BETA 1: • Inotropy • Chronotropy • Lipolysis • BETA 2: • Vasodilation • Bronchodilation • Uterine relaxation • Bladder relaxation • Insulin release • Glucagon release

  8. Desensitization: • 2o to Chronic exposure • Mechanisms • Uncoupling • Down-regulation • Sequestration Cardiovascular PharmacologyAdrenoreceptors

  9. VASOMOTOR CENTER Sympathetic autonomic nervous system Parasympathetic autonomic nervous system Autonomic feedback loop Baroreceptors Peripheral vascular resistance Contractile force Venous tone Heart rate Mean arterial pressure Cardiac output Venous return Stroke volume Blood volume Hormonal feedback loop Aldosterone Renal blood flow/pressure Renin Angiotensin

  10. Cardiac Output • C.O.=Heart Rate x Stroke Volume • Heart rate • Stroke volume: • Preload- volume of blood in ventricle • Afterload- resistance to contraction • Contractility- force applied

  11. Preload Afterload Contractility x Stroke Volume Heart Rate O2 Content Cardiac Output Resistance O2 Delivery Arterial Pressure

  12. Inadequate tissue perfusion to meet the tissue demands • a result of inadequate blood flow and/or inadequate oxygen delivery.

  13. Fluid Pump Vessels Flow Mechanical Requirements for Adequate Tissue Perfusion

  14. Septic (Distributive) Cardiogenic Obstructive Hypovolemic Physiology of Shock SHOCK

  15. Inadequate Fluid Volume (decreased preload) • Fluid depletion • internal • external • Hemorrhage • internal • external Hypovolemic Shock:

  16. Pump Malfunction (decreased contractility) • Electrical Failure • Mechanical Failure • cardiomyopathy • metabolic • anatomic • hypoxia/ischemia Cardiogenic Shock:

  17. Abnormal Vessel Tone (decreased afterload) • Sepsis • Anaphylaxis • Neurogenesis (spinal) • Drug intoxication (TCA, calcium channel blocker) Distributive Shock

  18. OBSTRUCTED FLOW • Pericardial tamponade • Pulmonary embolism • Pulmonary hypertension OBSTRUCTIVE SHOCK

  19. Hemodynamic Assessment of Shock

  20.   ß Dopamine Epinephrine Dobutamine Norepinephrine Alpha-Beta Meter Neosynephrine Isoproternol

  21. Usage: • activates multiple receptors • DA1, DA2, beta, alpha • receptors activated in dose related manner • shown to increase at low doses: • glomerular filtration rate • renal plasma flow • urinary Na+ excretion Cardiovascular PharmacologyDopamine

  22. Pharmacodynamics: • 0.5 - 2.0 mcg/kg/min - dopaminergic • 2.0 - 5.0 mcg/kg/min - beta 1 • 5.0 - 20 mcg/kg/min - alpha Cardiovascular PharmacologyDopamine

  23. Indications: • Low cardiac output • Hypotension with SVR • Risk of renal ischemia Cardiovascular PharmacologyDopamine

  24. In healthy humans and animal models, RDD augments: • RBF, GFR, and natriuresis • In experimental models of ischemia and nephrotoxic ARF, RDD augments: • RBF, GFR, and natriuresis Renal Dose Dopamine (RDD)Fact or Fiction?Summary of the Data Denton et al, Kidney Int. 49:4-14,1996

  25. Most human studies failed to demonstrate: • RDD prevents ARF in high risk patients • improves renal function or effects outcome in established ARF • The “dark side” • cardiovascular and metabolic complications Renal Dose Dopamine (RDD)Fact or Fiction?Summary of the Data Denton et al, Kidney Int. 49:4-14,1996

  26. Complications: • activity with NE depletion • PA pressure • pulmonary vascular resistance • Dysrhythmias • Renal vasoconstriction • Tissue necrosis Cardiovascular PharmacologyDopamine

  27. Is Dopamine the Devil? Dopamine administration can reduce the release of a number of hormones from the anterior pituitary gland, including prolactin which can have important immunoprotective effects Dopamine administration was associated with ICU and hospital mortality rates 20% higher than in patients with shock who did not receive dopamine Critical Care Medicine - Volume 34, Issue 3 (March 2006)

  28. Synthetic catecholamine • Direct beta1 weak alpha • Indications: • Low cardiac output in patients at risk for: • Myocardial ischemia • Pulmonary hypertension • LV dysfunction (cardiomyopathy) Cardiovascular PharmacologyDobutamine

  29. DobutaminePharmacodynamics

  30. Major indication • bradycardia • Pure beta • Potent pulmonary/ bronchial vasodilator • Increased cardiac output • Widened pulse pressure • Increased flow to non-critical tissue beds (skeletal muscle) Isoproterenol (Isuprel)

  31. Tachycardia • Dysrhythmias • Peripheral vasodilation • Increased myocardial consumption • CPK indicating myocardial necrosis • Decreased coronary O2 delivery • “Splanchnic steal” by skeletal muscle Isoproterenol (Isuprel) Drawbacks

  32. Pressor of choice post-arrest • Shock • with bradycardia • unresponsiveness to other vasopressors • anaphylaxis • Low cardiac output syndrome Epinephrine Indications

  33. Limited data available in children • Plasma concentration varies linearly with infusion rate • Clearance • 15.6-79.2 m/kg/min Epinephrine Pharmacokinetics

  34. Most potent catecholamine • Direct acting • no catecholamine stores needed • Prominent alpha and beta effects • Increased diastolic pressures Epinephrine Effects

  35. Epinephrine Pharmacodynamics

  36. Complications • Renal ischemia • Dysrhythmias • Severe hypertension • Myocardial necrosis • Hyperglycemia • Hypokalemia Epinephrine

  37. NorepinephrineLevophed Leave ‘em Dead!

  38. Indications • Sepsis with vasodilation unresponsive to volume expansion • Hypotension unresponsive to therapy • Dose: • 0.05 - 1 mcg/kg/min • t 1/2 = 2 - 2.5 min Norepinephrine (Levophed) Indications

  39. Potent peripheral alpha agonist • Little beta 1 effects • Minimal to no beta 2 • Produces • vasoconstriction • SVR, PVR • increases systolic, MAP, diastolic BP Norepinephrine (Levophed) Effects

  40. Renal vasoconstriction • may be decreased with dopamine • Possible cardiac function due to increased afterload • Dysrhythmias • Tissue necrosis Norepinephrine (Levophed) Complications

  41. Mechanism of action • Phosphodiesterase III inhibitor • Pharmacodynamics: • Almost pure inotrope • CI • Potent vasodilator • SVR • PVR • Bolus: 50 mcg/kg • Infusion: 0.375 - 0.75 mcg/kg/min Milrinone (Primacor)

  42. Pharmacokinetics: • t 1/2 = 90 min • Side effects: • Hypotension • Thrombocytopenia • Advantages: • No precipitation • Short t 1/2 Milrinone (Primacor)

  43. ADH Analog • Increases cyclic adenosine monophosphate (cAMP) which increases water permeability at the renal tubule resulting in decreased urine volume and increased osmolality • direct vasoconstrictor (primarily of capillaries and small arterioles) through the V1 vascular receptors • directly stimulates receptors in pituitary gland resulting in increased ACTH production; may restore catecholamine sensitivity Vasopressin

  44. Vasodilatory shock with hypotension unresponsive to fluid resuscitation and exogenous catecholamines • 0.0003-0.002 units/kg/minute (0.018-0.12 units/kg/hour); titrate to effect Vasopressin

  45. A Rational Approach to Pressor Use in the PICU Shock / Hypotension Volume Resuscitation Signs of adequate circulation Adequate MAP NO pressors Yes NO

  46. A Rational Approach to Pressor Use in the PICU Signs of adequate circulation Adequate MAP NO Dopamine?? Or perhaps now NE Inadequate MAP Norepi

  47. A Rational Approach to Pressor Use in the PICU norepinephrine adequate MAP Milrinone or dobutamine CO Inadequate MAP low C.O. Good C.O epinephrine Vasopressin

  48. Questions ???

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