Inotropes & Vasopressors

management 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, 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

Located mainly in the smooth muscle of bronchi Mediate bronchodilatation Located in blood vessels Dilatation of coronary vessels Dilatation of arteries supplying skeletal muscle

1 Adrenoceptor
Adrenaline

G - Protein

Adenyl cyclase

ATP

cAMP

Increased heart muscle contractility

Sympathomimetics
Naturally occuring
Epinephrine Norepinephrine Dopamine

Synthetic
Dobutamine Dopexamine 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 1, 1, 2 and dopaminergic receptors. The density and proportion of these receptors modulates the physiological responses of inotropes and vasopressors in individual tissues.

Catecholamines:
1 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 2 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 1 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 g/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 g/kg/min), also stimulates 1 receptor and increases cardiac output (CO), predominantly by increasing stroke volume with variable effect on heart rate.

At higher dose (10-20 g/kg/min), the predominant effect is to stimulate 1-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 1, 2 and receptors present in cardiac and vascular smooth muscle. Low dose of adrenaline increases cardiac output because of 1 receptor mediated inotropic and chronotropic effects. The -receptor mediated vasoconstriction is often offset by the -2 receptor mediated vasodilation. The result is an increased cardiac output with decreased SVR and variable effect on the MAP.

Higher dose
-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 1-adrenergic receptor agonist with modest -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 1 and 2 receptor respectively. It is a potent inotrope with weaker chronotropic activity. Combined 1 receptor agonsim and antagonism as well as 2 stimulation such that the net vascular effect is often mild vasodilation, particularly at lower dose (5 g/kg/min). Dose up to 15 g/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 receptor 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 1 receptor agonist with virtually no affinity for -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 cAMP

ATP

Increased heart muscle contractility

PDE 3

X
AMP

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 g/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

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