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Inotropes
Áine Duggan
11/04/03
Aims
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Definition and classification of shock
Cardiovascular physiology
Classification of inotropic agents
Indication for inotropes
Specific agents
Vasopressin
Shock
• Failure of the circulatory system to deliver
adequate amounts of oxygen and nutrients
to the tissues
• Inappropriate or inadequate tissue
perfusion
Categorisation of causes of shock
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Fluid depletion » Hypovolemic
Flow restriction » Obstructive
Pump failure » Cardiogenic
Vascular failure » Distributive
Red cell failure » Dissociative
Example: major trauma
• Hypovolemic shock……..haemorrhage
• Obstructive shock……tension
pneumothorax
• Cardiogenic shock…….cardiac contusion
• Distributive shock……..spinal cord injury
Example: septicemia
• Hypovolemic shock……fluid loss
• Cardiogenic shock…..myopathic factors
• Distributive shock…..vessel damage
Shock: Primary assessment
• Airway
• Breathing (pneumothorax)
• Circulation cardiovascular signs (HR, capillary
refill, BP) and effects of circulatory inadequacy
(RR, skin colour and temperature, mental status)
• Disability
• Exposure
• Full history and examination and relevant
investigations
Shock: resuscitation
• A open airway
• B high flow oxygen and ventilatory support if
required
• C circulatory access; relevant blood tests; fluid
bolus if hypovolaemia suspected and repeated
depending on response (HR, BP, UO,
CVP,PAWP, peripheral perfusion, MVO2, lactate,
ABG); antibiotics; cardioversion, inotropes when
intravascular volume replenished; control of
haemorrhage
Physiology
• Blood flow……….systemic blood pressure
is monitored as a reflection of local tissue
perfusion
• Ohm’s law: Pressure = Flow (CO) x
Resistance
• Organ blood flow = MAP – organ venous
pressure/ organ vascular resistance
Physiology
• Cardiac output is influenced by : heart
rate, preload, afterload, contractility,
cardiac compliance
• Controlled by ANS and humoral
mechanisms
Physiology
• Autoregulation: the ability of an organ or
vascular bed to maintain adequate blood
flow despite varying blood pressure
• Metabolic regulation controls about 75% of
local blood flow
• Autoregulatory reserve
Inotrope
• Defined as a drug which increases stroke
work at a given preload and afterload
• General mechanism: all increase the force
of myocardial contraction by increasing the
cytosolic calcium concentration, which
promotes actin- myosin cross bridge
formation and leads to myocyte shortening
Drugs
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Catecholamines
Phosphodiesterase inhibitors
Cardiac glycosides
(Vasopressin)
Glucagon
Calcium
Thyroid hormone
Indications for inotropes
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Cardiopulmonary resuscitation
Anaphylaxis
Weaning from CPB
Cardiac failure post AMI
Septic shock
Catecholamines
• Most frequently used inotropic agent in
ICU
• All act on adrenergic receptors
Adrenergic receptor physiology
• Distinguished by response to catecholamines
• Receptors demonstrating order of potency such
that noradrenaline>adrenaline>isoprenaline are
termed alpha receptors
• Isoprenaline > adrenaline > noradrenaline are
termed beta receptors
• Receptors interacting with dopamine are called
dopaminergic
Adrenergic receptor physiology
• Beta receptor occupancy activates adenyl
cyclase to increase conversion of adenosine
triphosphate to cAMP
• Alpha 1 receptor occupancy activates
phospholipase C, which increases inositol
phosphates IP3 and IP4 and diacyl glycerol.
• These second messengers increase Ca release
and calcium membrane permeability. Protein
kinases then cause phosphorylation of substrate
proteins which leads to specific effects
Adrenergic receptor physiology
• Alpha receptors: α1, α2
• Α1 are located postsynaptically in vascular
smooth muscle, smooth muscle of
coronary arteries, uterus, skin, intestinal
mucosa, iris, splanchnic bed
• Activation causes arteriolar and venous
constriction, mydriasis, gut relaxation
• Cardiac bed α1 receptors increase
inotropy and decrease heart rate
Adrenergic receptor physiology
• α2 receptors are located pre and post
synaptically
• Activation of presynaptic α2 receptors
inhibits noradrenaline, acetylcholine,
serotonin, dopamine, and substance P
• Activation of postsynaptic α2 receptors
causes vasoconstriction, decreased
salivation, decreased insulin release
Adrenergic receptor physiology
• β1 receptors are located in the
myocardium, SA node, ventricular
conduction system, adipose tissue, renal
tissue
• Activation causes an increase in inotrophy,
chronotrophy, myocardial conduction
velocity, renin release, lipolysis
Adrenergic receptor physiology
• β2 receptors are located in vascular,
bronchial, uterine and skin smooth muscle
• Stimulation leads to vasodilation,
β2
bronchodilation, uterine
relaxation,
gluconeogenesis, insulin release, K uptake
• β3 involved in lipolysis and regulation of
metabolic rate
Adrenergic receptor physiology
• Dopaminergic 1 receptors are located
postsynaptically on renal and mesenteric
vascular muscle and mediate vasodilation
• Dopaminergic 2 receptors are presynaptic
and inhibit noradrenaline release
Adrenergic receptor physiology
• There is an inverse relationship between
receptor number and the concentration of
circulating adrenergic agonist and the
duration of exposure to that agonist
• Termed up regulation and down regulation
Adrenoreceptor receptor effects
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Α1 inotropy, vasoconstriction
Α2 inotropy, vasoconstriction
B1 chronotropy, inotropy
B2 inotropy, vasodilation,
bronchodilatation
Common agents
• Dopamine: low dose DA effects
• Dopamine: high dose β1, α1, α2, DA1 and
DA2 effects
• Noradrenaline: α1, α2, β1, (β2)
• Adrenaline: β1, β2 > α1, α2
• Dobutamine: β1> β2, (α1)
• Dopexamine: β2 > β1, DA
• Isoprenaline: β1, β2
Dopamine
• Naturally occuring in humans
• Precursor of noradrenaline
• Causes release of noradrenaline from
nerve endings
• Haemodynamic effect varies between
individual patients
• Dose related effects: low dose DA effects,
high dose β, α, DA effects
• Neurotransmitter in basal ganglia and CTZ
Dopamine
• Low dose <4 mcg/kg/min renal and splanchnic
vessel DA receptors are activated leading to
increased renal blood flow, GFR and Na
excretion
• Higher doses beta effects of increased
myocardial contractility, HR, ABP
• >10 mcg/kg/min α1 effects predominate leading
to marked increase in ABP, and decreased renal
blood flow, increased PVR and PAP
Dopamine
• Dopamine increases UO, does not prevent of
alter course of renal injury
• S/E nausea, vomiting, headache, arrhythmias,
hypertension, dyspnoea, extravasation may
cause sloughing and necrosis, low dose may
blunt hypoxic ventilatory drive, increasing shunt
fraction, increased myocardial oxygen demand,
• Useful for combination of inotropy and
vasoconstriction, septic hock, cardiogenic shock
(vasodilator)
Adrenaline
• Direct acting α and β receptor agonist
produced by the adrenal medulla
• Indications: cardiac arrest, anaphylaxis,
bronchospasm, cardiogenic shock,
prolongation of regional anaesthesia,
nebulized in airway oedema
• Beta effects predominate at lower doses,
with bronchodilation, vasodilation,
increased CO, tachycardia
Adrenaline
• Fall in diastolic pressure may be seen
because of beta 2 effects
• Increasing doses α effects predominate
and SV may fall as SVR increases
• 1-2 mcg/min beta stimulation
predominates
• 2-10 mcg/min α and β effects, >10
mcg/min mainly α
• Effects variable amongst individuals
Adrenaline
• Effects: tremor, anxiety, restlessness,
headache, respiratory stimulation,
decreased gut tone and motility,
bronchodilation, decreased RBF and GFR,
detruser relaxation and increased vesical
sphincter tone, increased blood glucose
and free fatty acids, hypokalaemia,
tachycardia, arrhythmias, myocardial
ischaemia, tissue necrosis
Noradrenaline
• Neurotransmitter of SNS, biosynthetic precursor
of adrenaline
• Major difference from adrenaline is that α1
effects are apparent at lower doses of the drug,
producing an increase in SVR; minimal effects
on β2 receptors
• Renal, hepatic and cerebral blood flow are
decreased
• Normally leading to reflex bradycardia, and CO
may be decreased; severely hypotensive pxt
reflex bradycardia not seen and CO maintained
Noradrenaline
• Indicated in severe hypotension due to
marked reduction in SVR, situations where
adequate coronary perfusion pressure
needed eg cardiogenic shock due to acute
MI, post cardiac surgery
• Needs CVL, little bronchodilator effect,
slight increase in minute volume,
peripheral ischemia
• Dose 1-30 mcg/min
Isoprenaline
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Synthetic catecholamine with pure beta activity
Increases HR, contractility, decreases SVR
Pulmonary vasodilator and bronchodilator
Indications: haemodynamically stable, atropine resistant
bradycardia, A-V block until temporary pacing instituted,
low CO requiring fast HR eg paediatric, transplant, status
asthmaticus, beta blocker overdose, right ventricular
failure
• Can give through peripheral line; S/E vasodilation,
hypotension, tachyarrhythmias, care in coronary artery
disease
• Dose 0.01-0.1 mcg/kg/min
Dobutamine
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Synthetic catecholamine
Β1, β2, α1 receptor effects
Mixture of stereoisomers
Increases myocardial contractility,
vasodilator, increases HR
• Typically increases CO, decreases SVR
with minimal effects on HR and ABP
• Decreases PVR, useful in RHF
Dobutamine
• Useful for treatment of low output states
caused by myocardial dysfunction
secondary to AMI, cardiomyopathy, or
myocardial depression post cardiac
surgery
• Diastolic relaxation even at low dose
• S/E hypotension, increased myocardial
oxygen consumption, arrhythmias
• Dose 2-10 mcg/kg/min
Dopexamine
• Newish synthetic catecholamine with marked
beta 2 activity and also DA1 and DA2 activity
• Weak beta 1 and no alpha activity
• Mild inotrope, marked vasodilator
• Greater renal, gut, and skeletal muscle blood
flow than dobutamine but less than renal blood
flow and Na excretion than dopamine
• S/E arrhythmias, hypotension
Phosphodiesterase inhibitors
• Amrinone, milrinone, enoxamone
• Increases cAMP by inhibiting the
conversion of cAMP to AMP
• Methylxanthines eg theophylline and
caffeine inhibit types 1,2 and 3 PDE
• Bypiridines inhibit type 3 eg amrinone,
milrinone, enoxamone
Phosphodiesterase inhibitors
• Increased contractility and increased rate
of diastolic relaxation (lusitrophy),
vasodilation leading to decreased SVR,
MVO2, RAP, LVEDP, PVR
• INODILATOR
• Minimal effects on HR and BP is patient is
euvolemic, have volume available for
administration of loading dose
Phosphodiesterase inhibitors
• No tolerance; place in beta receptor
downregulation
• Titration kinetics very different to
catecholamines
• Half lives can be prolonged and excretion
is renal
• Combined use with catecholamines may
be necessary and complementary to
maintain MAP
Phosphodiesterase inhibitors
• Half lives: milrinone 1hr, amrinone 3-4hr,
enoxamone 1-20hr (active metabolite)
• Risks: hypotension with loading, reversible
thrombocytopenia, inhibits platelet PDE 3,
ventricular ectopy, abnormal LFTs, fever,
GIT upset
• Use: moderate to severe ventricular
dysfunction with elevated filling pressures
Cardiac glycosides
• Mechanism: binds and inhibit Na K ATPase
leading to increased intracellular Na and then
the Na Ca exchanger is activated to remove
excess Na resulting in importation of Ca
• Vagotonic efects used to control ventricular
response in SVTs
• Direct and indirect increase in peripheral
resistance
• Neurohumoral effects eg decreases renin and
noradrenaline levels
Cardiac glycosides
• Narrow therapeutic index
• Adverse drug interactions
• DIG trial beneficial at serum levels less
than 1 ng/ml and detrimental effects at
concentrations > 1 ng/ml
• Limited role in ICU
(Vasopressin)
• Arginine vasopressin is a synthetic analogue of
ADH, which is produced by posterior pituitary
• AVP causes vasoconstriction by direct
stimulation of smooth muscle V1 receptors
• No increase in myocardial oxygen consumption
as no beta effects
• Rapid onset with duration of action of 10-20
minutes
• Administration through CVL best
• Indicated in VF cardiac arrest in dose of 40iu
once only
Vasopressin
• Relative depletion of circulating
vasopressin in established septic shock
• Immediate and sustained increase in MAP
during infusion of vasopressin (0.04U/min)
in 14/16 patients in septic shock refractory
to traditional vasopressors
• Tsuneyoshi et al Crit Care Med 2001: 29
(3) : 487-93
Glucagon
• Naturally occurring polypeptide that direcly
stimulates adenyl cyclase via receptors to
increase cAMP in myocardial cells
resulting in positive inotropy with no
myocardial excitability
• Large doses needed for effect
• Obvious metabolic S/E
• Severe beta blocker OD
Calcium
• Essential in myocardial excitation contraction
coupling
• Role in CPR and shock not established
• Deleterious effects on ischaemic brain and
myocardium
• Unpredictable and variable effects on HR, BP,
CO, effect lasts about 5mins: increases SVR
• Maybe useful post CPB
• Indicated in hyperkalaemia, hypocalcaemia,
calcium channel blocker OD
Thyroid hormone
• Required for synthesis of contractile
proteins and expression of beta receptors
• Augments myocardial contractility
• Indicated in preexisting hypothyroidism;
post cardiac transplantation as pxt may
have sick euthyroid syndrome
• Maybe r ole post routine CPB and in brain
dead organ donor
Summary
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Definition and classification of shock
Cardiovascular physiology
Classification of inotropic agents
Indication for inotropes
Specific agents
Vasopressin