Inotrope & vasopressor

Prof. Chhuoy Meng

Intend for use
• Shock state
• Shock state = A state of cellular and tissue hypoxia due to
either
• reduced oxygen delivery,
• increased oxygen consumption,
• inadequate oxygen utilization, or a combination of these
processes
• Oxygen delivery
•
DO2  CO  Hb  SO2
2
 MAP & CO
.
DO2  CO  Hb  SO2
CO = MAP/SRV
.
DO2  MAP/SRV  Hb  SO2

MAP = contractility  HR  (Preload – Afterload)  Vaso

motricity

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 • infection
• Inflammatory

Mechanism of •
•
Neurogenic
anaphylactic

hypotension Distributive shock

Hypovolemic shock

MAP = contractility  HR  (Preload – Afterload)  Vaso

motricity • Blood lost • Autonomous Nervous
•
Cardiogenic
Heart condition.
shock • leak sd. System activity,
• Myocardial depressed • heart refilling decreased • Endothelial function
• Heart
by condition
toxic substances, • Increase venous • PE, Pulm Hypertension
• Myocardialhypoxia,
inflammation, depression by capacitate • Tamponade
inflammation, toxic,
acidosis • Increase pulmonary
chemical mediator, pressure Obstructive shock
acidosis

4
Adrenergic receptors

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Summary of adrenergic receptor
effects on arterial pressure
• Alpha (1) receptors
are peripheral vasoconstrictors to increase SVR.
• Beta-1 receptors
have mostly positive chronotropic (heart rate) and
inotropic (contractility) effects on the heart.
• Beta-2 receptors
act as vasodilators in many organ systems

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The major vasopressor & inotrope
• The major vasopressors
• phenylephrine,
• norepinephrine,
• epinephrine, and
• vasopressin.
• Vasopressor with inotrope properties
• Dopamine (dose-dependent).
• The inotropes
• Dobutamine
• Milrinone

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Adrenergic receptors
agonists

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ADRENALINE (epinephrine)
• The relative balance of α1 and β2 receptors in the
vasculature of an organ determines epinephrine’s overall
effect on blood flow to the organ.
• The net effect:
• CO distributing to skeletal muscles
• SVR increased
• Decreased renal blood flow
• Reduce smooth muscle tone of bronchial tree
ADRENALINE (epinephrine)
• Dose
• Low: effect more on β2 receptors
• High: effect predominantly on α1 receptors
• At high doses,
• vasoconstriction → afterload 
• increase afterload → reduce CO
• E.g.
• Dose: 0.01–0.30 μg/kg/min IV infusion via a central vein*
• Titrate dose according to HR, BP, cardiac output,
presence of ectopic beats and urine output.
ADRENALINE (epinephrine)
• In usual therapeutic doses,
• no significant vasoconstrictive effect on cerebral arterioles.
• Coronary blood flow is enhanced even at doses that do not alter systemic
blood pressure.
• The hemodynamic effects of epinephrine are attenuated and can
be blocked by prior administration of α- or β-adrenergic receptor
antagonists.
• Supra therapeutic doses of epinephrine may lead to
• acute heart failure,
• pulmonary edema,
• arrhythmias,
• hypertension, and
• myocardial ischemia.
ADRENALINE (epinephrine)
• Absorption after subcutaneous injection is slow because
of local epinephrine–induced vasoconstriction.
• Does not cross the blood-brain barrier
• crosses the placenta and enters breast milk.
• T½ beta: 2min
• Duration of action: 20-30min (bronchodilator)
• Elimination:
• metabolism,
• uptake by nerve endings
NORADRENALINE (norepinephrine)
• It is the immediate precursor of epinephrine.
• It stimulates β1- and α1-adrenergic receptors.
• Effect at β2 receptors is minima
• A potent α1 agonist →
• arterial and venous vasoconstriction (++) in all vascular
beds
• No vasoconstriction in the coronary arteries
• It increases MAP by
• Vascular constriction (++)
• AND increase CO (+)
NORADRENALINE
• Metabolic acidosis may occur due to peripheral
vasoconstriction
• norepinephrine dilates coronary arteries.
• Dilute in D5%
• Usual dose for refractory hypotension:
• 2 -16 μg/min by continuous infusion
• minimal metabolic effects (hyperglycemia)
NORADRENALINE
• Does not cross the blood-brain barrier but readily crosses
the placenta
• Elimination: by metabolism and re-uptake
• By IV route,
• onset of action: immediate,
• duration of action: 1-2min
NORADRENALINE vs ADRENALIN
NORADRENALINE ADRENALINE

Systemic vascular ++ +
resistance 
Diastolic arterial ++ +
pressure
Mean arterial ++ +
pressure 
Tachycardia + ++
DOPAMINE
• Low dose (0.5-3micg/kg/min),
• it stimulate D1, D2 receptors
• Dose of 3-10micg/kg/min,
• stimulation Beta1, and alpha receptor
• increased cardiac output by
• HR 
• Contractility 
• vasodilation and Afterload 
DOPAMINE
• Dose > 10micg/kg/min,
acts like a pure alpha1 agonist.
• Arterial and venous vasoconstriction,
• increased systemic vascular resistance,
• Increased blood pressure attenuating further increases in
cardiac output.
• Reflex bradycardia may also occur
• Dopamine increases myocardial oxygen consumption.
DOPAMINE
• There are a wide range of clinical responses depending
on individual variability in pharmacokinetics as well as
other variables
• The effects of dopamine cannot be predicted based on
the dose, and the drug must be titrated to effect.

• Dopamine is less dysrhythmogenic than epinephrine

DOPAMINE
• Activation of arterial and venous α1 receptors increases
systemic vascular resistance, preload, and left ventricular
afterload.
• Dopamine increases pulmonary vascular resistance,
• it may not be the preferred inotropic agents in patients
with pulmonary hypertension or right ventricular
dysfunction.
Dobutamine
• Dobutamine has potent β1-adrenergic effects with weaker
β2-adrenergic activity.
• Its effect on αlfa receptors increases at higher doses.
• Dobutamine acts primarily as a positive inotropic agent.
• Dobutamine leads to an increase in intracellular cAMP,
increasing calcium release from the sarcoplasmic
reticulum to increase contractility.
Dobutamine
• Dobutamine has weak effects on vascular tone causing
peripheral vasodilation
• Cardiac output is increased primarily by an increase in
stroke volume.
• Blood pressure usually is not significantly affected
• it may be ineffective in patients who require increased
systemic vascular resistance rather than augmentation of
cardiac output to increase systemic blood pressure.
Dobutamine

• Chronotropic effect for a unit of increase CO:

Isoprenaline > Dopamine > Dobutamine > Adrenalin

• At low doses, increases in heart rate may be minimal.

However, high doses of Dobutamine (>10 μg/kg/min IV)
may predispose the patient to tachycardia and cardiac
dysrhythmias.
• Dobutamine but not dopamine is a coronary artery
vasodilator.
Dobutamine
• improved
• increasing contractility,
tachycardia and
• decreased left

Oxygen consumption 
• myocardial ventricular end
contractility diastolic pressure
(LVEDP), and
• decreased wall
Oxygen consumption  tension

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ISUPROTÉRÉNOL
• Isoproterenol is the most potent activator of β1 and β2
receptor activity.
• It is egal to 2-3 times of activation from adrenalin, and 100
times from nor-adrenalin.
• In clinical doses, αlfa agonist effects = 0
ISUPROTÉRÉNOL
• Continuous infusion (1 to 5 μg/min) →
• heart rate,
•  myocardial contractility, and
•  cardiac automaticity,
• systemic vascular resistance (by vasodilation in skeletal muscles)
• Cardiac output may increase thereby increasing systolic
blood pressure,
• The decrease in SVR and DBP induces a decrease of MAP
ISUPROTÉRÉNOL vs Dobutamine

For the same

increase of CO Dobutamine ISUPRENALINE

Systemic vascular
resistence - ---

Mean Arterial - /+ --
pressure
Tachycardia + +++
EPHEDRINE
• Ephedrine is an indirect-acting synthetic
sympathomimetic
• Mild direct stimulation of receptors alfa1, beta1, beta2 and
• stimulation of release of endogenous norepinephrine from
the neurons (indirect-acting).
• It is an easily titratable pressor and inotrope with a short
duration of action that does not reduce placental blood
flow, and is therefore safe to administer in pregnancy
EPHEDRINE
• The cardiovascular effects of ephedrine resemble those of
Adrenaline, but
• BP elevation less but last longer (10  longer)
• increases in systolic and diastolic blood pressure,
• increases heart rate, and
• increases cardiac output.
• Renal and splanchnic blood flows are decreased,
• coronary and skeletal muscle blood flows are increased.
• Systemic vascular resistance may be altered minimally.
EPHEDRINE
• Sometimes, it may induce hyperglycemia or mydriasis

• Ephedrine, 5 to 10 mg IV administered to adults,

to increase systemic blood pressure in the presence of sympathetic
nervous system blockade produced by regional anesthesia or
hypotension due to inhaled or injected anesthetics
Receptors affinity of major
vasopressors
• Norepinephrine
alpha-1 > beta-1 > beta-2 activities
• Epinephrine
alpha-1 = beta receptors activities
• Dobutamine :
increases CO mostly by its effects on beta and alpha stimulation.
beta-1> beta-2 > alpha.
• Isoprenaline:
• Pure beta1 and beta2 agonist; at clinical dose, alfa activity = 0
• Phenylephrine:
a pure alpha-1 agonist

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Non-adrenergic
vasopressor

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Vasopressin
• Vasopressin acts on
• V-1 receptors to stimulate smooth muscle contraction of the
vessels
• V-2 receptors in the kidneys as an anti-diuretic.
• There are no inotropic or chronotropic effects. Only BP
and SVR are increased with vasopressin

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Vasopressin
• Vasopressin is released from the posterior pituitary in
response to
• increases in plasma osmolality and
• decreases in blood pressure.
• In septic shock there is a deficiency in endogenous
vasopressin, and this has been confirmed by direct
measurement of endogenous vasopressin in patients with
septic shock requiring vasopressors.
• In vitro studies show that catecholamines and vasopressin
work synergistically
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Vasopressin
• Normal plasma concentrations are less than 4 pg/ml.
• The half-life of endogenous vasopressin is 10-35 min, and it
is metabolized via renal and hepatic pathways.
• In concentrations higher than required for its antidiuretic
effect, it acts as a non-adrenergic vasoconstrictor on
peripheral vascular beds.

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Vasopressin (Pitressin, Argipressin)
ICU INDICATIONS:
• Refractory septic shock (reserve its use in cases where the
noradrenaline dose exceeds 0.3 μg/kg/min) (unlicensed)
• Severe post cardiopulmonary bypass vasoplegia.
• Administration
• IV infusion: 1–4 units/h (central line)
• Dilute 20 units (1 ml ampoule of argipressin) in 20 ml glucose 5%
(1 unit/ml) and start at 1 unit/h, increasing to a maximum of 4
units/h
• As the patient’s condition improves, the vasopressin should be
weaned down and off before the noradrenaline is stopped

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Side effects of vasopressors
• Dopamine: hypotension, tachycardia, local tissue necrosis,
and gangrene if extravasation occurs.
• Epinephrine: tachycardia, anxiety, pulmonary edema, and
local tissue necrosis with extravasation.
• Norepinephrine: similar adverse effects to epinephrine +
bradycardia and dysrhythmia.
• Phenylephrine may cause reflex bradycardia, decreased CO,
local tissue necrosis with extravasation, peripheral, renal,
mesenteric, or myocardial ischemia.
• Vasopressin may induce arrhythmias, mesenteric ischemia,
chest pain, coronary artery constriction and MI, bronchial
constriction, hyponatremia, and local tissue necrosis with
extravasation.

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Les inhibiteurs de
phosphodiesterase-3

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cm_22 39
Milrinone
• Milrinone is a phosphodiesterase inhibitor that causes
increased levels of cyclic AMP. In cardiac myocytes, this
results in cardiac stimulation and increased CO.
• cAMP has vasodilatory effects in the smooth peripheral
vessels leading to vasodilation and decreased BP
• Milrinone is used to treat low CO as in decompensated HF.

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 Milrinone
(Corotrope 10mg/10ml)

• The overall effect of selective PDE III inhibitors is to

combine positive inotropic effects with smooth muscle
relaxation in both arteriolar and venous beds.
• They have been termed inodilators.
Milrinone
• Increasing CO,
• Decreasing PCWP and SVR,
• without significant increase in HR and myocardial oxygen
consumption.
• It produces slight enhancement in AV node conduction
and may increase ventricular rate in uncontrolled AF/atrial
flutter.
• Uses in: Severe congestive cardiac failure

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Milrinone, Administration
• IV infusion: 50 μg/kg loading dose over 10 minutes, then
maintain on 0.375–0.75 μg/kg/min to a maximum
hemodynamic effect
• Requires direct arterial BP monitoring
• Adjustment of the infusion rate should be made according
to hemodynamic response

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Side effects of inotropes
• Adverse effects of inotropes include
• hypertension,
• hypotension,
• dysrhythmias,
• angina, and acute MI.
• Dobutamine: may cause hypokalemia and local tissue
necrosis with extravasation. increased myocardial oxygen
consumption (prolong use).
• Milrinone: may cause elevated LFTs, thrombocytopenia,
and increased mortality with long-term use.
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Calcium sensitizing agent

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Levosimendan
• Levosimendan acts by sensitizing the myocardium to calcium
so that a greater ventricular contraction (cardiac output) can
be achieved without increasing oxygen requirements.
• It acts independently of cAMP and has been used in beta-
blocked patients.
• It does not increase myocardial oxygen consumption. It does
not impair the baseline diastolic function and is tolerated
without arrhythmogenicity.
• It is a systemic and coronary vasodilator used for treatment of
acute decompensated congestive heart failure

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 Levosimendan
• Levosimendan has also been shown to possess ant-
inflammatory properties. (myocarditis in sepsis)
• The calcium-sensitizing and anti-inflammatory actions of
levosimendan provide a strong rationale for its use in sepsis
• Use:
• Acute decompensation of severe chronic heart failure despite
maximal standard therapy
• Low cardiac output syndrome or cardiogenic shock
• Septic shock refractory to inotropes (unlicensed). [not
recommend when hypotension was corrected]
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 Inotrope & vasopressor in Septic shock
CO: Low
CVP > 10 > 0.3micg/kg/min CO: low
Septic shock Hypotension
Hypotension hypotension hypotension

Fluid Adrenalin Milrinone

Nor-
loading Vasopressin Dobutamin Levosimend
adrenalin
e an

As soon as suspect Assessment When Without vasopressin, or else , adrenalin may

a septic shock, volemia by US or noradrenalin alone be added.
start fluids CVP. Add can not improve If possible, Dobutamine and/or adrenalin
resuscitation Noradrenaline BP, vasopressin is was add related to HR, SVR. And CO.
(30ml/kg over 3h). after 1-2L RL been indicated (if Consider Corticosteroid supplement if still
Antibiotic started. given. available). Low hypotension.
Central line and Target: dose 0.03u/min is Finally Milrinone and/or Levosimendan is
invasive monitors MAP>65mmHg use. specifically add if justified by hemodynamic
are need. data.
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Recommendation &
suggestion

cm_22 49
RECOMMENDATIONS
All shock states
Vasopressors should only be initiated with/after adequate
resuscitation is provided with crystalloids, colloids, and/or
blood products.

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Hemorrhagic Shock
1. Vasopressors are not recommended in the initial
stabilization of hemorrhagic shock.
2. Permissive hypotension may be employed until bleeding
is controlled in patients requiring emergent surgical
intervention. (damage-controlled resuscitation)
3. If hypotension persists despite adequate blood and fluid
resuscitation and surgical intervention, consider other
etiologies for shock and an appropriate vasopressor.

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Cardiogenic Shock
• Initial management is a fluid challenge of 250 to 500 mL.
Persistent hypotension requires adding inotropes or
vasopressors.
• Vasopressors and/or inotropes may be initiated earlier in
cardiogenic shock with clinical evidence of volume
overload.
• Recommendation: start Dobu + Dopa
7.5g/kg/min + 7.5g/kg/min
• if SBP still < 70 → + NorAdre
• If, no effect add vasopressin

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Neurogenic shock
• Problems of the spinal cord results in a lack of sympathetic
tone of the peripheral nerves and unopposed
parasympathetic activation.
• Uninhibited vagal tone results in vasogenic and cardiogenic
instability.
• Initial stabilization requires a fluid challenge to restore
intravascular volume. If hypotension persists, vasopressors are
indicated to maintain systolic blood pressure greater than 90
mm Hg or MAP 85 to 90 mm Hg for the first 7 days.
• Norepinephrine is recommended as the initial pressor for alpha
and beta activation. Epinephrine may be added as a
secondary pressor
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Refractory Shock
• Adrenal insufficiency of critical illness (AICI) should be
suspected in high-risk critically ill patients with a random
serum cortisol level < 20 mcg/dL.
• When AICI is present, steroid replacement should be
initiated:
• Hydrocortisone (classic model, if have to continue):
• 50mg IV q6hrs for 5ds
• 50mg IV q12h for 3ds
• 50mg IV qd for 3ds and stop
• OR 200mg /d IV infusion for 24h or 50mg IV q6h for 24h
• OR 50 mg IV bolus followed by infusion of 10 mg/h for up to 48 hs
• Fludrocortisone 50 mcg PO daily x 7 days
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Administration
• Although peripheral IVs are suitable for short-term use,
adverse effects can and do occur.
• Although the absolute necessity for immediate central
access has been recently brought into question, it is
recognized that central access is the method of choice
for administering vasoactive medications

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