Inotropes & Vasopressorsmanagement of various types of shock. DR.MUHAMMAD ALI YOUSUF Definitions • Inotropes: • Agents administered to increase myocardial contractility and therefore cardiac index • Vasopressor • Agents are administered to increase vascular tone and thereby elevate mean arterial pressure (MAP). Inotropes Vs. Vasopressors Inotropes • Drugs that affect the force of contraction of myocardial muscle • Positive or negative • Term “inotrope” generally used to describe positive effect Vasopressor • Drugs that stimulates smooth muscle contraction of the capillaries & arteries • Cause vasoconstriction & a consequent rise in blood pressure Main Goal Tissue perfusion & oxygenation . Physiological Principles MAP = CO x SVR ~ 1 CO = HR x SV r4 Preload Contractility Afterload . Basic principles .Vasopressors MAP = CO x SVR ~ 1 CO = HR x SV r4 Preload Contractility Afterload . Basic principles .Inotropes MAP = CO x SVR CO = HR x SV Preload Contractility Afterload . Mixed action drugs . Use of inotropes & vasopressors . Drug Classification • Sympathomimetics • Naturally occurring • Synthetic • Other inotropes • cAMP dependent • cAMP independent • Other vasopressors . Sympathomimetics • Drugs that stimulate adrenergic receptors • G-protein coupled receptors G .Protein Activation of intermediate messenger . Main classes of Adrenoceptor • receptors • 1 • Located in vascular smooth muscle • Mediate vasoconstriction • 2 • Located throughout the CNS. analgesia & platelet aggregation . platelets • Mediate sedation. analgesia & platelet aggregation .Main classes of Adrenoceptor • receptors • 1 • Located in vascular smooth muscle • Mediate vasoconstriction • 2 • Located throughout the CNS. platelets • Mediate sedation. Main classes of Adrenoceptor • receptors • 1 • Located in the heart • Mediate increased contractility & HR • 2 • Located mainly in the smooth muscle of bronchi • Mediate bronchodilatation . Main classes of Adrenoceptor • receptors • 1 • Located in the heart • Mediate increased contractility & HR • 2 • Located mainly in the smooth muscle of bronchi • Mediate bronchodilatation • Located in blood vessels • Dilatation of coronary vessels • Dilatation of arteries supplying skeletal muscle . Protein Adenyl cyclase ATP cAMP Increased heart muscle contractility .β1 Adrenoceptor Adrenaline G . Sympathomimetics • Naturally occuring • Epinephrine • Norepinephrine • Dopamine • Synthetic • • • • • Dobutamine Dopexamine Phenylephrine Metaraminol Ephedrine . • They are administered via a large central vein .Uses • Are used in critically ill patients with profound hemodynamic impairment to such extent that tissue perfusion is not sufficient to meet metabolic requirements. . • To explore the evidence for their use in clinical practice. Common Inotropes and Vasopressors • Catecholamines: • • • • • • Dopamine Adrenaline Noradrenaline Dobutamine Isoprenaline Phenylephrine . Common Inotropes and Vasopressors • Vasopressin • Phosphodiesterase inhibitors • Calcium sensitizing agents . β2 and dopaminergic receptors. noradrenaline. β1. phenylephrine) • mediate their cardiovascular actions predominantlythrough α1. dopamine) • Synthetic:(dobutamine. Isoprenaline.Catecholamines: • Endogenous:(adrenaline. • The density and proportion of these receptors modulates the physiological responses of inotropes and vasopressors in individual tissues. . • Stimulation of dopaminergic receptors (D1 and D2) in the kidney and splanchnic vasculature results in renal and mesenteric vasodilatation .Catecholamines: • β1 receptor is found predominantly on myocardium and stimulation of which results inenhanced myocardial contractility through Ca2+ mediated facilitation of the actin-myosin complex binding with troponin C and enhanced chronicity through Ca2+ channel activation • β2 receptor stimulation on vascular smooth muscle cells through a different intracellular mechanism results in increased Ca2+ uptake by the sarcoplasmic reticulum and vasodilation • Activation of α1 receptors on arterial vascular smooth muscle cells results in smooth muscle contraction and increase in systemic vascular resistance. 1 • High dose .Dopamine • Effect dose dependent • Direct • Low dose .1 • Indirect • Stimulates norepinephrine release • D1 receptors • Vasodilatation of mesenteric & renal circulation . Dopamine • Acts on both dopaminergic and adrenergic receptors • At low doses (0. cerebral and coronary beds resulting in selective vasodilation. mesenteric. dopamine acts predominantly on D1 receptors in the renal. • Some reports suggest that dopamine increases urine output by augmenting renal blood flow and glomerular filtration rate and natriuresis by inhibiting aldosterone and renal tubular transport • But the clinical significance of “renal-dose” dopamine is somewhat controversial because a renal protective effect has not been demonstrated .5-3.0 μg/kg/min). the predominant effect is to stimulate α1-adrenergic receptors and produce vasoconstriction with an increased systemic vascular resistance (SVR). also stimulates β1 receptor and increases cardiac output (CO). predominantly by increasing stroke volume with variable effect on heart rate.and the sum of these effects is an increase in mean arterial pressure (MAP).Dopamine • At intermediate doses (3-10 μg/kg/min). . • At higher dose (10-20 μg/kg/min). Adrenaline • Stimulates & receptors • Predominantly effects at low doses and effects at high doses • Clinical uses • • • • • Cardiac arrest Anaphylaxis Low cardiac output states Upper airway obstruction Combination with local anaesthetics . • Low dose of adrenaline increases cardiac output because of β1 receptor mediated inotropic and chronotropic effects. β2 and α receptors present in cardiac and vascular smooth muscle.Low Dose Adrenaline • Adrenaline is a potent agonist for β1. . • The α-receptor mediated vasoconstriction is often offset by the β-2 receptor mediated vasodilation. • The result is an increased cardiac output with decreased SVR and variable effect on the MAP. • The rise in lactate is of clinical importance as lactate is utilized as a marker of tissue hypo-perfusion. • The increase in serum lactate induced by adrenaline does not associated with harm. . • Arterial and venous pulmonary pressure are increased through direct pulmonary vasoconstriction and increased pulmonary blood flow and hence right ventricular after load.Higher dose • α-receptor mediated vasoconstriction predominates which results increased SVR in addition to increased CO. • Adrenaline has been shown to increase lactate concentration especially in severe infection and increases oxygen consumption. Norepinephrine • Predominantly stimulates 1 receptors • Most commonly used vasopressor in critical care • Very potent • Administered by infusion into a central vein • Uses • Hypotension due to vasodilatation • Septic shock . . diastolic and pulse pressure and has a minimal net impact on CO. • • Coronary flow is maintained to certain extent because of its vasoconstrictor effects. it has shown effects on contractility in critical illness. However. It primarily increases systolic.Noradrenaline • • • • Noradrenaline is a potent α1-adrenergic receptor agonist with modest β-agonist activity. It has minimal chronotropic effects because of which it is a drug of choice in settings where heart rate stimulation is undesirable. High doses of noradrenaline can be safely used to maintain cerebral perfusion pressure without significantly compromising the circulatory flow. Dobutamine • Synthetic • Predominantly 1 • Small effect at 2 • Uses • Low cardiac output states • Cardiogenic shock . Dose up to 15 μg/kg/min increase cardiac contractility without greatly affecting peripheral resistance. Vasoconstriction progressively dominates at higher perfusion rates. It is a potent inotrope with weaker chronotropic activity. Significantly increases myocardial oxygen consumption. Based on this exercise mimicking behaviour. binding in a 3:1 ratio to β1 and β2 receptor respectively. Combined α1 receptor agonsim and antagonism as well as β2 stimulation such that the net vascular effect is often mild vasodilation. • • • . particularly at lower dose (≤5 μg/kg/min). it is used as a pharmacological stress agent for diagnostic perfusion imaging .Dobutamine • • • Dobutamine is a synthetic analogue of dopamine. relatively pure βreceptor stimulant. • Its stimulatory effect on stroke volume is counterbalanced by drop in SVR. which results in a net neutral impact on CO. . with potent systemic vasodilator effect.Isoprenaline • Isoprenaline is a potent. • It has powerful chronotropic and inotropic properties. although it can induce significant baroreceptor mediated reflex rate responses after rapid alterations in MAP.Phenylephrine • Phenylephrine is a potent α1 receptor agonist with virtually no affinity for β-receptors. . • It is used primarily as a rapid bolus for immediate correction of sudden severe hypotension. • It has no direct effect on heart rate. Adrenoceptor dynamics • Desensitisation / down-regulation • Chronic heart failure • Prolonged use of inotrope / vasopressor • Sespis / acidosis . Other Vasopressors • Vasopressin • Exogenous form of ADH • Acts on kidney to retain water & on peripheral blood vessels to cause intense vasoconstriction • V1 receptors • Used in severe shock • Used in cardiac arrest in USA . . • It exerts its effects through V1 receptor on vascular smooth muscle and oxytocin receptors causing vasoconstriction whereas stimulation of V2 receptors mediates water reabsorption by enhancing renal collecting duct permeability.Vasopressin • Vasopressin also known as “antidiuretic hormone” is stored primarily in granules in the posterior pituitary gland and is released in response to osmotic. chemoreceptor and baroreceptor stimuli. • Vasopressor effect of vasopressin is not affected by hypoxia and acidosis which commonly develop in shock of any origin. • It may also directly influence the mechanisms involved in the pathogenesis of vasodilation through inhibition of ATP-activated K+ channel. • Vasopressin modulated increase in vascular sensitivity to noradrenaline further augments its vasopressor effect. . attenuation of nitrous oxide production and reversal of adrenergic receptor down regulation.Effects • vasopressin stimulation tends to cause constriction and increase in SVR. • Briefly. exogenously administered vasopressin may counteract its relative deficiency which is seen in established sepsis. Other Inotropes • cAMP dependent • Phosphodiesterase inhibitors • Glucagon • cAMP independent • Digoxin • Calcium • levosimendan . Phosphodiesterase Inhibitors Adrenaline G .Protein Adenyl cyclase cAMP ATP Increased heart muscle contractility PDE 3 X AMP . • PDI are most often used to treat patients with impaired cardiac function and medically refractory heart failure • These agents act by inhibiting breakdown of cAMP in cardiac and vascular smooth muscles resulting in increased myocardial contractility and peripheral vascular dilation.Phosphodiesterase inhibitors • Phosphodiesterase inhibitors (PDI). such as amrinone and milrinone are non-adrenergic drugs with inotropic and vasodilator actions. • their effects are similar to those of dobutamine but with a lower incidence of arrhythmias. • Milrinone has a longer half-life (2-4 hours) than any other inotropic medications. . Calcium sensitizing agents • Calcium sensitizers are a recently developed class of inotropic agents • Levosimendan is the most well known drug among this class • It increase calcium binding to contractile proteins and also activates ATP sensitive K+ channels. The combination of improved contractile performance and vasodilation is particularly beneficial during acute and chronic HF. • The opening of K+channel leads to arteriolar and venous vasodilation. Calcium dependent binding to contractile protein enhances ventricular contractility without increasing intracellular calcium concentration. . Levosimendan stabilizes troponin C and prolongs the binding of Ca2+ . Dual mechanism: Also has „anti-ischaemic‟ effect via ATP-dependent K+ channel activation in cardiac myocytes.Primary mechanism: In diastole the binding pocket is not exposed. In systole Ca2+ binds to troponin C and exposes a hydrophobic binding pocket. . Use of Inotropes and Vasopressors in Various Types of Shock • Non-cardiogenic shock • Septic Shock: • • • • Impaired ventricular function. Pathological vasodilation. Deranged micro-vascular flow. Increased capillary permeability and hypovolaemia . • There is no standard dosing regimen for vasopressor and inotropic agents. • Human and animal studies suggest some advantage of noradrenaline and dopamine over adrenaline.Septic Shock • Vasopressor and inotropic agents remain the cornerstone for the management of septic shock after fluid administration. . • dopamine administration is associated with greater mortality and a higher incidence of arrhythmic events • noradrenaline is more potent than dopamine and may be more effective at reversing hypotension in septic shock. or increased cardiac outputs. controlled trial comparing norepinephrine alone to norepinephrine plus vasopressin at 0. • patients receiving <15 μg/min norepinephrine at the time of randomization was better with vasopressin.Septic Shock: • VASST trial: • A randomized. treatment with a combined inotrope/vasopressor. • dobutamine is the first choice inotropic agent for patients with measured or suspected low cardiac output in the presence of adequate left ventricular filling pressure • Septic patients who remain hypotensive after fluid resuscitation may have low. such as noradrenaline or dopamine. normal.03 units/min. is recommended if cardiac output is not measured. . • Therefore. refractory to IM therapy .5 mg intramuscularly (IM) every 5 to 10 minutes for adults • Intravenous epinephrine is reserved for cases of cardiovascular collapse.3 to 0. • The recommended dose is 0.Anaphylactic shock • The treatment of choice for anaphylaxis is adrenaline. . haemorrhage is arrested and hypotension continues .Hemorrhagic shock • Vasopressors are rarely indicated and should be considered only when volume replacement is complete. leading to elevated left ventricular (LV) filling pressures. • However. and further reduction in the coronary perfusion gradient. . • The lowest possible doses of inotropic and vasopressor agents should be used to adequately support vital tissue perfusion while limiting the adverse effects. increased myocardial oxygen requirements.critical hypotension itself compromises myocardial perfusion.Cardiogenic shock complicating acute myocardial infarction • These agents increase myocardial oxygen consumption. Dopamine is the preferred agent • Moderate doses of combination of medications may be more effective than maximal doses of any individual medication. use of noradrenaline is recommended • Vasopressin therapy may thus be effective in norepinephrine resistant shock .hypotension along with sign of shock. • In patients with systolic blood pressure <70 mm Hg and sign/symptoms suggestive of shock.Cardiogenic shock complicating acute myocardial infarction • Dobutamine should be used as a first line agent if systolic blood pressure ranges in between 70-100 mm Hg without signs and symptoms of shock • In patients with. Cardiogenic shock complicating acute myocardial infarction • During early cardiogenic shock. • As the shock continues. endogenous vasopressin levels are increased significantly to maintain end organ perfusion. . • Vasopressin therapy may thus be effective in norepinephrine resistant shock. falling plasma vasopressin level contributes to a loss of vascular tone and worsening hypotension. • this agent increase MAP without adversely impacting cardiac index and wedge pressure. • The most commonly recommended initial inotropic therapies (dobutamine.Congestive heart failure • Inotropic therapy is used in the management of decompensated heart failure to lower enddiastolic pressure and improve dieresis. enhance diuresis by improving renal perfusion and decreasing SVR. . dopamine and milrinone) for refractory HF are used to improve cardiac output. • use of levosimendan is significantly associated with improved symptoms but not survival. Cardiopulmonary arrest • Inotropic and vasopressor agents are a mainstay of resuscitation therapy during cardiopulmonary arrest. with its potent vasopressor and inotropic properties. can rapidly increase diastolic blood pressure to facilitate coronary perfusion and help restore organised myocardial contractility. • The current AHA guideline have incorporated vasopressin (single bolus of 40 U) as a one-time alternative to the first or second dose of adrenaline with pulse-less electrical activity or asystole and for pulse-less ventricular tachycardia or ventricular fibrillation . • Epinephrine. That’s All Thank You .