Inotropes & Vasopressors management of various types of shock.
DR.MUHAMMAD ALI YOUSUF
Definitions • Inotropes Inotropes:: • Agents administered to increase increase myocardial contractility and therefore cardiac index
• Vasopressor • Agents are administered to increase vascular tone and thereby elevate mean arterial pressure (MAP).
Definitions • Inotropes Inotropes:: • Agents administered to increase 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 “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
r 4
Preload Contractility Afterload
Basic principles - Vasopressors
MAP = CO x SVR ~ 1
CO = HR x SV
r 4
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, 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, analgesia & platelet aggregation
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
β1 Adrenoceptor Adrenaline
G - Protein
Adenyl cyclase
ATP
cAMP
Increased heart muscle contractility
Sympathomimetics • Naturally occuring
• Synthetic
• Epinephrine
• Dobutamine
• Norepinephrine
• Dopexamine
• Dopamine
• Phenylephrine • Metaraminol • Ephedrine
Uses • Are used in critically ill patients with profound hemodynamic impairment to such extent that tissue perfusion is not sufficient to meet metabolic requirements. • They are administered via a large central vein . • 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
Catecholamines: • Endogenous:(adrenaline, noradrenaline, dopamine) • Synthetic:(dobutamine, Isoprenaline, phenylephrine) • mediate their cardiovascular actions predominantlythrough α1, β1, β2 and dopaminergic receptors. • The density and proportion of these receptors modulates the physiological responses of inotropes and vasopressors in individual tissues.
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. •
Stimulation of dopaminergic receptors (D1 and D2) in the kidney and splanchnic vasculature results in renal and mesenteric vasodilatation
Dopamine • Effect dose dependent • Direct • Low dose - 1 • High dose - 1
• Indirect • Stimulates norepinephrine release
• D1 receptors • Vasodilatation of mesenteric & renal circulation
Dopamine • Acts on both dopaminergic and adrenergic receptors • At low doses (0.5-3.0 μg/kg/min), dopamine acts predominantly on D1 receptors in the renal, mesenteric, cerebral and coronary beds resulting in selective vasodilation. • 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
Dopamine • At intermediate doses (3-10 μg/kg/min), also stimulates β1 receptor and increases cardiac output (CO), predominantly by increasing stroke volume with variable effect on heart rate. • At higher dose (10-20 μg/kg/min), the predominant effect is to stimulate α1-adrenergic receptors and produce vasoconstriction with an increased systemic vascular resistance (SVR),and the sum of these effects is an increase in mean arterial pressure (MAP).
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 Adrenaline • Adrenaline is a potent agonist for β1, β2 and α receptors present in cardiac and vascular smooth muscle. • Low dose of adrenaline increases cardiac output because of β1 receptor mediated inotropic and chronotropic effects. • 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.
Higher dose • α-receptor mediated vasoconstriction predominates which results increased SVR in addition to increased CO. • Arterial and venous pulmonary pressure are increased through direct pulmonary vasoconstriction and increased pulmonary blood flow and hence right ventricular after load. • Adrenaline has been shown to increase lactate concentration especially in severe infection and increases oxygen consumption. • 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.
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
Noradrenaline •
Noradrenaline is a potent α1-adrenergic receptor agonist with modest β-agonist activity.
•
However, it has shown effects on contractility in critical illness.
•
It primarily increases systolic, diastolic and pulse pressure and has a minimal net impact on CO.
•
It has minimal chronotropic effects because of which it is a drug of choice in settings where heart rate stimulation is undesirable.
•
Coronary flow is maintained to certain extent because of its vasoconstrictor effects.
•
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
Dobutamine •
Dobutamine is a synthetic analogue of dopamine, binding in a 3:1 ratio to β1 and β2 receptor respectively.
•
It is a potent inotrope with weaker chronotropic activity.
•
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).
•
Dose up to 15 μg/kg/min increase cardiac contractility without greatly affecting peripheral resistance.
•
Vasoconstriction progressively dominates at higher perfusion rates.
•
Significantly increases myocardial oxygen consumption. Based on this exercise mimicking behaviour, it is used as a pharmacological stress agent for diagnostic perfusion imaging .
Isoprenaline • Isoprenaline is a potent, relatively pure βreceptor stimulant. • It has powerful chronotropic and inotropic properties, with potent systemic vasodilator effect. • Its stimulatory effect on stroke volume is counterbalanced by drop in SVR, which results in a net neutral impact on CO.
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, although it can induce significant baroreceptor mediated reflex rate responses after rapid alterations in MAP.
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
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. • 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.
Effects •
vasopressin stimulation tends to cause constriction and increase in SVR.
•
Vasopressin modulated increase in vascular sensitivity to noradrenaline further augments its vasopressor effect.
•
Briefly, exogenously administered vasopressin may counteract its relative deficiency which is seen in established sepsis.
•
It may also directly influence the mechanisms involved in the pathogenesis of vasodilation through inhibition of ATP-activated K+ channel, attenuation of nitrous oxide production and reversal of adrenergic receptor down regulation.
•
Vasopressor effect of vasopressin is not affected by hypoxia and acidosis which commonly develop in shock of any origin.
Other Inotropes • cAMP dependent • Phosphodiesterase inhibitors • Glucagon
• cAMP independent • Digoxin • Calcium • levosimendan
Phosphodiesterase Inhibitors Adrenaline
G - Protein
Adenyl cyclase
ATP
cAMP
AMP
Increased heart muscle contractility
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. • 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. • 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. Calcium dependent binding to contractile protein enhances ventricular contractility without increasing intracellular calcium concentration. • The opening of K+channel leads to arteriolar and venous vasodilation. The combination of improved contractile performance and vasodilation is particularly beneficial during acute and chronic HF.
Primary mechanism: In diastole the binding pocket is not exposed. In systole Ca2+ binds to troponin C and exposes a hydrophobic binding pocket. 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.
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
Septic Shock • Vasopressor and inotropic agents remain the cornerstone for the management of septic shock after fluid administration. • There is no standard dosing regimen for vasopressor and inotropic agents. • Human and animal studies suggest some advantage of noradrenaline and dopamine over adrenaline. • 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.
Septic Shock: • VASST trial:
• A randomized, controlled trial comparing norepinephrine alone to norepinephrine plus vasopressin at 0.03 units/min, • patients receiving <15 μg/min norepinephrine at the time of randomization was better with vasopressin. • 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, normal, or increased cardiac outputs. • Therefore, treatment with a combined inotrope/vasopressor, such as noradrenaline or dopamine, is recommended if cardiac output is not measured.
Anaphylactic shock • The treatment of choice for anaphylaxis is adrenaline. • The recommended dose is 0.3 to 0.5 mg intramuscularly (IM) every 5 to 10 minutes for adults • Intravenous epinephrine is reserved for cases of cardiovascular collapse,refractory to IM therapy
Hemorrhagic shock • Vasopressors are rarely indicated and should be considered only when volume replacement is complete, haemorrhage is arrested and hypotension continues .
Cardiogenic shock complicating acute myocardial infarction • These agents increase myocardial oxygen consumption. • However,critical hypotension itself compromises myocardial perfusion, leading to elevated left ventricular (LV) filling pressures, increased myocardial oxygen requirements, 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.
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,hypotension along with sign of shock, Dopamine is the preferred agent • Moderate doses of combination of medications may be more effective than maximal doses of any individual medication. • In patients with systolic blood pressure <70 mm Hg and sign/symptoms suggestive of shock, use of noradrenaline is recommended • Vasopressin therapy may thus be effective in norepinephrine resistant shock
Cardiogenic shock complicating acute myocardial infarction • During early cardiogenic shock, endogenous vasopressin levels are increased significantly to maintain end organ perfusion. • As the shock continues, falling plasma vasopressin level contributes to a loss of vascular tone and worsening hypotension. • Vasopressin therapy may thus be effective in norepinephrine resistant shock. • this agent increase MAP without adversely impacting cardiac index and wedge pressure.
Congestive heart failure • Inotropic therapy is used in the management of decompensated heart failure to lower enddiastolic pressure and improve dieresis. • The most commonly recommended initial inotropic therapies (dobutamine, dopamine and milrinone) for refractory HF are used to improve cardiac output, enhance diuresis by improving renal perfusion and decreasing SVR. • 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. • Epinephrine, 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