Vasoactive Drugs and Shock Philip Marcus, MD MPH

Shock Acute, generalized, inadequate perfusion of critical organs Serious pathophysiologic consequences if continued Disturbed metabolic function at organ and cellular levels Disorder of cellular O2 utilization Usually low-flow state Maldistribution

Shock Clinical Manifestations Hypotension Oliguria Acidosis CNS dysfunction

Physiologic Measurements Pulmonary Capillary Wedge Pressure Index of LV preload Cardiac Output Systemic Vascular Resistance Index of LV afterload Mixed Venous O2 saturation (SvO2) O2 delivery = CO x caO2 O2 consumption = CO x (caO2 – cvO2)

Causes of Shock Cardiogenic Obstructive Oligemic Distributive

Cardiogenic Shock Arrhythmias Cardiac mechanical factors Regurgitant lesions Obstructive lesions LV outflow LV inflow Cardiomyopathies Impaired LV contractility Impaired LV compliance

Obstructive Shock Cardiac tamponade Constrictive pericarditis Pulmonary embolism

Oligemic Shock Hemorrhagic intravascular depletion Nonhemorrhagic intravascular depletion Vomiting Diarrhea Dehydration Peritonitis Pancreatitis ascites

Distributive Shock Abnormal vascular volume distribution Results from decreased regional vascular resistance Etiologic factors Sepsis, endotoxemia Metabolic factors Respiratory failure, renal failure, drug OD Endocrinologic factors Ketoacidosis, hyperosmolar state, hypothyroid Neurologic factors Anaphylaxis

Hemorrhage, solute loss Low Preload Shock Reduced PCWP Reduced CO Elevated SVR Reduced svO2 Treatment = Volume infusion Hemorrhage, solute loss

Cardiac Dysfunction Shock Elevated PCWP Reduced CO Elevated SVR Reduced svO2 Treatment Inotropic agents Vasodilators Volume Systolic Failure: Ischemia, infarction Diastolic Failure: Tamponade Valve Dysfunction

Sepsis, Anaphylaxis, Adrenal crisis, Toxic shock Low Afterload Shock Reduced or Normal PCWP Elevated CO Reduced SVR Elevated svO2 Treatment Volume infusion Vasoconstrictors ? Inotropic agents Sepsis, Anaphylaxis, Adrenal crisis, Toxic shock

Low preload & Cardiac Dysfunction Combined Disorders Normal PCWP Reduced CO Elevated SVR Reduced svO2 Treatment Volume infusion, then Inotropic agents Low preload & Cardiac Dysfunction

Indications for Vasopressors Decrease of > 30 mmHg from baseline systolic BP OR Mean arterial pressure (MAP) < 60 mmHg when either condition results in end-organ dysfunction due to hypoperfusion. Hypovolemia must be corrected prior to institution of vasopressor therapy.

Fundamental Concepts One drug, many receptors Dose-response curve A given drug often has multiple effects because of actions upon more than one receptor Dose-response curve Many agents have dose-response curves Primary adrenergic receptor subtype activated by the drug is dose-dependent Direct vs. reflex actions

Isoproterenol b1 + b2 activity Positive Inotropic activity Positive Chronotropic activity Increased MVO2 Increases CO, Decreases SVR Increases systolic BP, decreases diastolic BP Used in cardiac standstill and for profound bradyarrhythmias Use in hypotension limited to situations in which hypotension results from bradycardia; High affinity for β-2 receptors results in vasodilatation and a decrease in MAP

Epinephrine a1, b1 + b2 activity Positive inotropic activity Positive chronotropic activity Constricts arterioles in skin, mucosa and splanchnic circulation Increases systolic BP, decreases diastolic BP Decreases SVR via dilatation of skeletal muscle vasculature Enhances blood flow Used primarily in cardiac standstill and hypotension following cardiac surgery α receptor induced vasoconstriction offset by β-2 receptor vasodilatation

Norepinephrine Levarterenol Peripheral vasoconstrictor Arterial and venous α adrenergic activity Inotropic action β-1 action Reflex bradycardia may occur Secondary to potent pressor activity

Norepinephrine Levarterenol Used in acute hypotensive states Following sympathectomy Following removal of pheochromocytoma Spinal anesthesia Septic shock Extravasation Necrosis and sloughing Antidote…phentolamine

Phenylephrine Pure α-agonist Elevates SVR Causes reflex bradycardia Equal effectiveness as norepinephrine No chronotropic effects No inotropic effects Danger of extravasation

Dopamine Endogenous catecholamine Acts directly on α and β1 receptors Acts also on Dopamine receptors Dose-dependent effects Low-dose = dopaminergic effects Medium-dose = β effects Medium to high-dose = α and β effects High-dose = α effects

Dopamine Dopaminergic effects Vasodilatation of renal, mesenteric, coronary, splanchnic and cerebral vasculature Natriuretic effects Increases RBF and GFR Induces redistribution of intrarenal blood flow to juxtamedullary nephrons Direct tubular action Increases urinary cAMP

Dopamine β1 actions α effects Inotropic effects Increases SVR Increases CO Less chronotropic effects than isoproterenol Releases NE…further increases CO α effects Increases SVR Increases MAP Can reduce urine output Dopaminergic receptors antagonized

Dopamine Rapid onset of action Rapid metabolism 2 – 4 minutes t1/2 < 10 minutes First-order kinetics MAO + COMT

Dopamine Indications Assure adequate filling pressures Low cardiac output Compromised renal function Assure adequate filling pressures Fluid administration Use in conjunction with nitroprusside to inhibit vasoconstriction Extravasation Necrosis and sloughing Nausea and vomiting often occur

Dobutamine Direct-acting catecholamine Chemically related to dopamine Principally stimulates β1 receptors within myocardium INOTROPIC Minimal chronotropic effects No α or β2 effects No dopaminergic effects

Dobutamine

Dobutamine Increases contractility Rapid onset of action Increases CO without tachycardia No arrhythmogenic or vasodilatory effects No vasoconstriction Rapid onset of action 1 – 2 minutes Rapid metabolism t ½ ~ 2-3 minutes COMT

Dobutamine Useful in low cardiac output states Acute and chronic heart failure without hypotension Used in acute MI and following cardiac surgery IHSS contraindication Usual dose = 5-20 mcg/kg/min

Dopexamine Synthetic catecholamine Used in Europe Systemic and pulmonary vasodilator effects Lesser agonist activity at Dopamine receptors (1/3 potency of dopamine) Positive inotropic effect Increases cerebral, renal and splanchnic blood flow Augments CO in chronic LV dysfunction following CABG and acute MI with LV dysfunction