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INTENSIVE CARE CARDIOVASCULAR PHARMACOLOGY Toni Petrillo-Albarano, MD Director, Pediatric Transport Division of Critical Care Medicine Nervous System Peripheral Nervous system Autonomic System Central Nervous System Somatic System Sympathetic Parasympathetic "Fight or Flight " "Snooze and Loose" CARDIOVASCULAR PHARMACOLOGY TERMINOLOGY REVIEW Catecholamines Naturally occurring, biologically active amines Sympathomimetic Mimics system stimulation of the sympathetic nervous CARDIOVASCULAR PHARMACOLOGY TERMINOLOGY REVIEW Adrenergic Refers Cholinergic Refers to the sympathetic nervous system to the parasympathetic nervous system Dopaminergic Dopamine receptors in renal, visceral, coronary, and cerebral areas CARDIOVASCULAR PHARMACOLOGY TERMINOLOGY REVIEW Inotropic Influencing the force of contraction Chronotropic Influencing the rate of contraction CARDIOVASCULAR PHARMACOLOGY ADRENORECEPTORS Six receptor subtypes: alpha 1 (post-synaptic) alpha 2 (pre-synaptic) beta 1 (cardiac) beta 2 (vascular/bronchial smooth muscle) DA 1 (post-synaptic) DA 2 (pre-synaptic) CARDIOVASCULAR PHARMACOLOGY ADRENORECEPTORS ALPHA 1: Vasoconstriction Mydriasis Uterine contraction Bladder contraction Insulin inhibition Glucagon inhibition ALPHA 2: Inhibition of norepinephrine release CARDIOVASCULAR PHARMACOLOGY ADRENORECEPTORS BETA 1: Inotropy Chronotropy Lipolysis BETA 2: Vasodilation Bronchodilation Uterine relaxation Bladder relaxation Insulin release Glucagon release CARDIOVASCULAR PHARMACOLOGY ADRENORECEPTORS Desensitization: 2o to Chronic exposure Mechanisms Uncoupling Down-regulation Sequestration VASOMOTOR CENTER Parasympathetic autonomic nervous system Sympathetic autonomic nervous system Baroreceptors feedback loop Hormonal Peripheral vascular Heart resistance rate Mean arterial pressure Renal blood flow/pressure Cardiac output Contractile force Stroke volume Venous return Venous tone Blood volume Aldosterone Renin Angiotensin 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 Preload Afterload Contractility O2 Content Stroke Volume x Cardiac Output O2 Delivery Heart Rate Resistance Arterial Pressure Inadequate tissue perfusion to meet the tissue demands a result of inadequate blood flow and/or inadequate oxygen delivery. MECHANICAL REQUIREMENTS FOR ADEQUATE TISSUE PERFUSION Fluid Pump Vessels Flow PHYSIOLOGY OF SHOCK Septic (Distributive) Decreased SVR Maldistributed Blood Flow Cardiogenic Myocardial Dysfunction Compensated Obstructive Myocardial Damage Uncompensated Hypovolemic Pericardial Tamponade Hemmorrhage Reduced Ventricular Filling Reduced Preload Reduced Systolic Finction High or Normal Function Low Cardiac Output Deminished Tissue Perfusion SHOCK HYPOVOLEMIC SHOCK: Inadequate Fluid Fluid Volume (decreased preload) depletion internal external Hemorrhage internal external CARDIOGENIC SHOCK: Pump Malfunction (decreased contractility) Electrical Failure Mechanical Failure cardiomyopathy metabolic anatomic hypoxia/ischemia DISTRIBUTIVE SHOCK Abnormal Vessel Tone (decreased afterload) Sepsis Anaphylaxis Neurogenesis (spinal) Drug intoxication (TCA, calcium channel blocker) OBSTRUCTIVE SHOCK OBSTRUCTED Pericardial FLOW tamponade Pulmonary embolism Pulmonary hypertension HEMODYNAMIC ASSESSMENT OF SHOCK Type of Shock Preload Afterload Contractility Cardiac Output Cardiogenic Hypovolemic Septic Early Late Obstructive Distributive ALPHA-BETA METER Dopamine Epinephrine ß CARDIOVASCULAR PHARMACOLOGY DOPAMINE Usage: activates DA1, multiple receptors 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 PHARMACOLOGY DOPAMINE 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 PHARMACOLOGY DOPAMINE Indications: Low cardiac output Hypotension with SVR Risk of renal ischemia RENAL DOSE DOPAMINE (RDD) FACT OR FICTION? SUMMARY OF THE DATA 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 Denton et al, Kidney Int. 49:4-14,1996 RENAL DOSE DOPAMINE (RDD) FACT OR FICTION? SUMMARY OF THE DATA 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 Denton et al, Kidney Int. 49:4-14,1996 CARDIOVASCULAR PHARMACOLOGY DOPAMINE Complications: activity with NE depletion PA pressure pulmonary vascular resistance Dysrhythmias Renal vasoconstriction Tissue necrosis 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) CARDIOVASCULAR PHARMACOLOGY DOBUTAMINE Synthetic catecholamine Direct beta1 weak alpha Indications: Low cardiac output in patients at risk for: Myocardial ischemia Pulmonary hypertension LV dysfunction (cardiomyopathy) DOBUTAMINE PHARMACODYNAMICS Dose 0.5-2.5 mcg/kg/min 5 7.5-10 Receptor beta 1 beta 1 beta 1 Major Effects Variably CI (15%) CI (15%) CI (30%) BP (5%) BP (15%) HR (no change) HR (5%) SVR SVR PVR PVR ISOPROTERENOL (ISUPREL) 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) DRAWBACKS Tachycardia Dysrhythmias Peripheral vasodilation Increased myocardial consumption CPK indicating myocardial necrosis Decreased coronary O2 delivery “Splanchnic steal” by skeletal muscle EPINEPHRINE INDICATIONS Pressor of choice post-arrest Shock with bradycardia unresponsiveness to other vasopressors anaphylaxis Low cardiac output syndrome EPINEPHRINE PHARMACOKINETICS Limited data available in children Plasma concentration varies linearly with infusion rate Clearance 15.6-79.2 m/kg/min EPINEPHRINE EFFECTS Most potent catecholamine Direct acting no catecholamine stores needed Prominent alpha and beta effects Increased diastolic pressures EPINEPHRINE PHARMACODYNAMICS Dose 0.02-0.08 mcg/kg/min Population Receptor Major effects 0.2-0.8 0.8-2.0 >2.0 Adults Newborn Newborn Newborn post CV animals animals animals surgery beta1, beta1, beta1, alpha1 alpha1 beta2 beta2 CI CI CI HR HR SVR BP BP PVR SVR SVR PVR PVR EPINEPHRINE Complications Renal ischemia Dysrhythmias Severe hypertension Myocardial necrosis Hyperglycemia Hypokalemia NOREPINEPHRINE LEVOPHED Leave ‘em Dead! NOREPINEPHRINE (LEVOPHED) INDICATIONS 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) EFFECTS Potent peripheral alpha agonist Little beta 1 effects Minimal to no beta 2 Produces vasoconstriction SVR, PVR increases systolic, MAP, diastolic BP NOREPINEPHRINE (LEVOPHED) COMPLICATIONS Renal vasoconstriction may be decreased with dopamine Possible cardiac function due to increased afterload Dysrhythmias Tissue necrosis MILRINONE (PRIMACOR) Mechanism of action Phosphodiesterase III inhibitor Pharmacodynamics: Almost CI Potent pure inotrope vasodilator SVR PVR Bolus: 50 mcg/kg Infusion: 0.375 - 0.75 mcg/kg/min MILRINONE (PRIMACOR) Pharmacokinetics: t 1/2 = 90 min Side effects: Hypotension Thrombocytopenia Advantages: No precipitation Short t 1/2 VASOPRESSIN 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 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 A Rational Approach to Pressor Use in the PICU Shock / Hypotension Volume Resuscitation Signs of adequate circulation Adequate MAP NO Yes NO pressors A Rational Approach to Pressor Use in the PICU Signs of adequate circulation NO Adequate MAP Dopamine?? Or perhaps now NE Inadequate MAP Norepi A Rational Approach to Pressor Use in the PICU norepinephrine adequate MAP Inadequate MAP low C.O. Good C.O epinephrine Vasopressin CO Milrinone or dobutamine Questions ???
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