Transcript Vasopressors and inotropes

By:Dr. Amena Fatima
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Vasopressors are a powerful class of drugs that induce
vasoconstriction and thereby elevate mean arterial
pressure (MAP).
Vasopressors differ from inotropes, which increase
cardiac contractility; however, many drugs have both
vasopressor and inotropic effects.
Although many vasopressors have been used since the
1940s, few controlled clinical trials have directly
compared these agents or documented improved
outcomes due to their use .
Thus, the manner in which these agents are commonly
used largely reflects expert opinion, animal data, and
the use of surrogate end points such as tissue
oxygenation as a proxy for decreased morbidity and
mortality.
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Catecholamines are drugs that promote blood
flow and blood pressure by stimulating
adrenergic receptors
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Despite differences in adrenergic receptor
activation and physiological responses, no
catecholamine drug has proven superior to the
others for improving clinical outcomes.
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Dobutamine is primarily a β1-receptor agonist,
but also has weak β2- receptor agonist activity.
The β1-receptor stimulation produces an
increase in heart rate and stroke volume, while
the β2-receptor stimulation produces
peripheral vasodilatation.
Because the increase in stroke volume is
accompanied by a decrease in systemic
vascular resistance, the blood pressure is
usually unchanged or slightly increased .
The response to dobutamine, however, can
vary widely in critically ill patients.
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The cardiac stimulation produced by
dobutamine is often accompanied by an
increase in cardiac work and myocardial O2
consumption .
These effects can be deleterious in heart failure
because cardiac work and myocardial energy
needs are already heightened in the failing
myocardium.
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Dobutamine has been used to augment cardiac
output in patients with decompensated heart
failure due to systolic dysfunction.
However, the unfavorable effects of
dobutamine on myocardial energetics has
created a preference for other inodilators in
decompensated heart failure.
Dobutamine remains the preferred inotropic
agent for the treatment of myocardial
depression associated with septic shock but it
usually must be combined with a
vasoconstrictor agent (e.g., norepinephrine) to
raise the blood pressure.
Dosing Regimen
 Dobutamine is started at an infusion rate of 3–5
μg/kg/min (without a loading dose), and this
can be increased in increments of 3–5
μg/kg/min, if necessary, to achieve the desired
effect.
 The usual dose range is 5–20 μg/kg/min.
 Therapy should be driven by hemodynamic
end-points, and not by pre-selected dose rates.
Adverse Effects
 Dobutamine produces only mild increases in
heart rate (5-15 beats/min) in most patients,
but it occasionally causes significant
tachycardia (rate increases > 30 beats/min) ,
which can be deleterious in patients with
coronary artery disease.
 Like all positive inotropic agents, dobutamine
is contraindicated in patients with
hypertrophic cardiomyopathy.
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Dopamine is an endogenous catecholamine
that serves as a precursor for norepinephrine.
When given as an exogenous drug, dopamine
produces a variety of dose-dependent effects,
as described next.
Actions
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At low infusion rates (≤ 3 μg/kg/min),
dopamine selectively activates dopaminespecific receptors in the renal and splanchnic
circulations, which increases blood flow in
these regions .
Low-dose dopamine also directly affects renal
tubular epithelial cells, causing an increase in
both urinary sodium excretion (natriuresis) and
urine output that are independent of the
changes in renal blood flow .
The renal effects of low-dose dopamine are minimal
or absent in patients with acute renal failure .
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At moderate infusion rates (3 – 10 μg/kg/min),
dopamine stimulates β- receptors in the heart
and peripheral circulation, producing an
increase in myocardial contractility and heart
rate, along with peripheral vasodilatation.
The increase in stroke volume produced by
dopamine is greater than dobutamine at
equivalent infusion rates.
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At high infusion rates (> 10 μg/kg/min),
dopamine produces a dose dependent
activation of α-receptors in the systemic and
pulmonary circulations, resulting in
progressive pulmonary and systemic
vasoconstriction.
This vasopressor effect increases ventricular
afterload, and can reduce the stroke volume
augmentation produced by lower doses of
dopamine.
Clinical Uses
 Dopamine can be used to manage patients with
cardiogenic shock and septic shock, although
other measures are favored in these conditions
(i.e., mechanical assist devices are preferred for
cardiogenic shock, and norepinephrine is
preferred for septic shock).
 Low-dose dopamine is NOT recommended as
a therapy for acute renal failure.
Dosing Regimen
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Dopamine is usually started at a rate of 3 – 5
μg/kg/min (without a loading dose), and the infusion
rate is increased in increments of 3 – 5 μg/kg/min to
achieve the desired effect.
The usual dose range is 3 – 10 μg/kg/min for
increasing cardiac output, and 10 – 20 μg/kg/min for
increasing blood pressure.
Dopamine infusions should be delivered into large,
central veins, because extravasation of the drug
through peripheral veins can produce extensive tissue
necrosis.
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Adverse Effects
Sinus tachycardia and atrial fibrillation are
reported in 25% of patients receiving dopamine
infusions .
Other adverse effects of dopamine include
increased intraocular pressure , splanchnic
hypoperfusion, and delayed gastric emptying,
which could predispose to aspiration
pneumonia.
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EXTRAVASATION OF VASOPRESSORS:
The risk of tissue necrosis from extravasation of
dopamine is a concern with all vasopressor
(vasoconstrictor)drug infusions, and eliminating
this risk is the reason that large, central veins are
recommended for all vasopressor drug infusions.
If dopamine or any other vasopressor drug escapes
from a peripheral vein into the surrounding
tissues, the tendency for ischemic tissue necrosis
can be reduced by injecting phentolamine (an αreceptor antagonist) into the involved area.
The recommended injectate is a solution
containing 5 – 10 mg phentolamine in 15 mL of
isotonic saline.
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Epinephrine is an endogenous catecholamine
that is released by the adrenal medulla in
response to physiological stress.
It is the most potent natural β-agonist.
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Epinephrine stimulates both α-adrenergic and βadrenergic receptors (β1 and β2 subtypes), and
produces dose-dependent increases in heart rate,
stroke volume, and blood pressure.
Epinephrine is a more potent β1- receptor agonist than
dopamine, and produces a greater increase in stroke
volume and heart rate than comparable doses of
dopamine.
The α-receptor stimulation produces a nonuniform
peripheral vasoconstriction, with the most prominent
effects in the subcutaneous, renal, and splanchnic
circulations.
Epinephrine also has several metabolic effects,
including lipolysis, increased glycolysis, and increased
lactate production (from β-receptor activation), and
hyperglycemia from α-receptor-mediated inhibition of
insulin secretion.
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Clinical Uses
Epinephrine plays an important role in the
resuscitation of cardiac arrest and it is the drug of
choice for hemodynamic support in anaphylactic
shock.
Epinephrine is also used for hemodynamic
support in the early postoperative period
following cardiopulmonary bypass surgery.
Although epinephrine is as effective as other
catecholamines in septic shock concerns about side
effects have limited its popularity in septic shock.
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Dosing Regimen
The dosing regimens for epinephrine in cardiac
arrest is 1 mg IV every 3–5 minutes.
Vasopressor effect can increase coronary
perfusion pressure, but cardiac stimulation is
counter productive.
Dosing for anaphylactic shock is:
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Epinephrine infusions are not preceded by a
loading dose.
The initial infusion rate is usually 1 – 2 μg/min
(or 0.02 μg/kg/min), and the rate is then
increased in increments of 1 – 2 μg/min to
achieve the desired effect .
The usual dose range for augmenting cardiac
output or correcting hypotension is 5 – 15
μg/min.
Adverse Effects
 Epinephrine creates a greater risk of unwanted
cardiac stimulation (which can be deleterious in
patients with coronary artery disease) than the
other catecholamine drugs .
 Other adverse effects include hyperglycemia,
increased metabolic rate, and splanchnic
hypoperfusion (which can damage the mucosal
barrier in the bowel).
 Epinephrine infusions are accompanied by an
increase in serum lactate levels but this is not an
adverse effect because it reflects an increased rate
of glycolysis (not tissue hypoxia), and the lactate
can be used as an
alternative fuel source.
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Norepinephrine is an endogenous
catecholamine that normally functions as an
excitatory neurotransmitter.
When used as an exogenous drug,
norepinephrine functions as a vasopressor
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The principal action of norepinephrine is α-receptormediated peripheral vasoconstriction.
 However, the adrenergic response to norepinephrine is
altered in patients with septic shock .
 For example, norepinephrine infusions are usually
accompanied by a decrease in renal blood flow but in
patients with septic shock, renal blood flow is
increased by norepinephrine infusions .
 Similar alterations may also occur with splanchnic
blood flow (i.e., normally reduced, but not in septic
shock)
 Norepinephrine is also a weak β1-receptor agonist, but
the effects of norepinephrine on stroke volume and
heart rate can be comparable to dopamine (a more
potent β1-receptor agonist) in patients with septic
Shock.
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Clinical Uses
Norepinephrine is the preferred catecholamine for
circulatory support in patients with septic shock.
This preference is not based on improved outcomes,
because the mortality rate in septic shock is the same
regardless of the catecholamine used for circulatory
support.
Instead, norepinephrine is favored in septic shock
because it has fewer adverse effects
than dopamine or epinephrine .
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Dosing Regimen
Norepinephrine infusions are usually started at a
rate of 8 – 10 μg/min, and the dose rate is then
titrated upward or downward to maintain a mean
blood pressure of at least 65 mm Hg.
The effective dose rate in septic shock varies
widely in individual patients, but is usually below
40 μg/min.
Hypotension that is refractory to norepinephrine
usually prompts the addition of dopamine or
vasopressin, but there is no evidence that this
practice improves outcomes
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Adverse Effects
Adverse effects of norepinephrine include local
tissue necrosis from drug extravasation, and
intense systemic vasoconstriction with organ
dysfunction when high dose rates are required.
However, whenever high doses of a
vasoconstrictor drug are required to correct
hypotension, it is difficult to distinguish
between adverse drug effects and adverse
effects of the circulatory shock.
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Phenylephrine is a potent vasoconstrictor that has very
few applications in the ICU.
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Phenylephrine in a pure α-receptor agonist that
produces widespread vasoconstriction.
The consequences of this vasoconstriction can include
bradycardia, a decrease in cardiac stroke output
(usually in patients with cardiac dysfunction), and
hypoperfusion of the kidneys and bowel
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Clinical Uses
The principal use of phenylephrine is for the
reversal of severe hypotension produced by spinal
anesthesia.
However, pure α-receptor agonists are not
universally favored in this situation because they
can aggravate the decrease in cardiac stroke output
that occurs in spinal shock .
Phenylephrine is not recommended for
hemodynamic support in septic shock, although a
clinical study comparing phenylephrine and
norepinephrine for the early management of septic
shock showed no differences in hemodynamic
effects or clinical outcomes with the use of either
drug.
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Dosing Regimen
Phenylephrine can be given as intermittent IV
doses. The initial IV dose is 0.2 mg, which can
be repeated in increments of 0.1 mg to a
maximum dose of 0.5 mg .
Adverse Effects
The principal adverse effects of phenylephrine
are bradycardia, low car-diac output, and renal
hypoperfusion.
These effects are magnified in hypovolemic
patients.
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The following drugs can be added to vasopressor
therapy with catecholamines in selected situations.
Vasopressin
Antidiuretic hormone (ADH) is an osmoregulatory
hormone that is also called vasopressin because it
produces vasoconstriction.
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Actions
The vasoconstrictor effects of vasopressin are
mediated by specialized vasopressin (V1) receptors
located on vascular smooth muscle.
Vasoconstriction is most prominent in skin,
skeletal muscle, and splanchnic circulations .
Exogenous vasopressin does not increase blood
pressure in healthy volunteers, but it can produce
significant increases in blood pressure in patients
with hypotension caused by peripheral
vasodilatation.
This type of hypotension occurs in septic shock,
anaphylactic shock, autonomic insufficiency, and
the hypotension associated with spinal and general
anesthesia.
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Other actions of vasopressin include enhanced water
reabsorption in the distal renal tubules (mediated by
V2 receptors), and stimulation of ACTH release by the
anterior pituitary gland (mediated by V3 receptors).
These actions are clinically silent when vasopressin is
administered in the recommended doses.
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Clinical Uses
Vasopressin can be used in the following clinical
situations.
In the resuscitation of cardiac arrest, vasopressin can
be given as a single IV dose (40 units) to replace the
first or second dose of epinephrine.
In cases of septic shock that are resistant, or refractory,
to hemodynamic support with norepinephrine or
dopamine, a vasopressin infusion can be used to raise
the blood pressure and reduce the catecholamine
requirement (catecholamine sparing effect) .
Unfortunately, there is no survival benefit associated
with the this practice .
In cases of hemorrhage from esophageal or gastric
varices, vasopressin infusions can be used to promote
splanchnic vasoconstriction and reduce the rate of
bleeding.
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Dosing Regimen
The plasma half-life of exogenous vasopressin
is 5 – 20 min , so vasopressin must be given by
continuous infusion to produce prolonged
effects.
In septic shock, the recommended infusion rate
is 0.01 – 0.04 units/min, and a rate of 0.03
units/min is most popular.
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Adverse Effects
Adverse effects are uncommon with infusion
rates < 0.04 units/hr .
At higher infusion rates, unwanted effects can
include consequences of excessive
vasoconstriction (e.g., impaired renal and
hepatic function), along with excessive water
retention and hyponatremia.
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Terlipressin
Terlipressin is a vasopressin analogue that has two
advantages over vasopressin.
 First, it is a selective V1 receptor agonist, and does not
produce the
side effects associated with stimulation of the other
vasopressin receptors.
 Secondly, terlipressin has a much longer duration of
action than vasopressin, and a single IV dose of 1 – 2
mg can raise the blood pressure for 5 hours .
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The long duration of action allows terlipressin
to be given by intermittent IV dosing.
Terlipressin is a potent splanchnic
vasoconstrictor, and may prove valuable in the
management of variceal bleeding.
However, there is an increased risk of
splanchnic ischemia with terlipressin, and
ischemic effects cannot be reversed for 5 hours
after the drug is administered.
Like vasopressin, there is no survival
advantage associated with the addition of
terlipressin in patients with septic shock
Despite adequate volume replacement, if the patient is
hypotensive and perfusion of vital organs is jeopardized,
vasoactive agents may be administered to improve cardiac output
and blood pressure.
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It is useful to understand the receptors through which adrenergic
agents exert their effect.
• Three broad groups of agents may be identified:
1. Predominant b -agonists (dobutamine, dopexamine, isoprenaline)
2. Predominant a -agonists (phenylephrine)
3. Those with mixed b - and a -effects (adrenaline and noradrenaline).
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In general, when the heart is failing, and the peripheral
vascular resistance is normal, an agent with predominant
inotropic effect (especially a b -1 selective agent) would be a
good choice.
 If there is vasodilatation, a vasoconstrictor with
predominant a -agonist activity is appropriate.
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Familiarize with doses and effects of commonly used
inotropes and vasopressors.
 Consider practical aspects of vasopressor infusion:
– Infuse through large veins preferably central veins.
– Use multi-lumen catheters and use dedicated lumen for
vasopressor infusion.
– No other drug bolus or infusion should be given through the
same lumen.
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Use infusion or syringe pumps or other infusion
controllers.
Invasive arterial pressure should be measured.
Dobutamine and other inodilators may be given
through peripheral line.
Volume defi cit should always be corrected as much as
possible before resorting to vasopressors which would
lead to a false sense of security by increasing blood
pressure while underlying hypovolemia and resultant
low perfusion will lead to subsequent organ
dysfunction.
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All inotropes and vasopressors should be titrated so
that tissue perfusion is restored with the lowest dose of
drug and to the desired end points with minimal or no
side effects:
– Titrate to clinical improvements in heart rate (HR)
and mean arterial pressure (MAP).
– Titrate inotropes to desired cardiac output.
Do not aim for supranormal cardiac output:
– Titrate vasopressors to MAP of 65–70 mmHg.
– In patients with long-standing hypertension, renal
failure, recent cerebral infarct, and increased intraabdominal pressure, a higher MAP may be desirable.
– In trauma with active bleeding, a lower MAP till bleeding
source is controlled is advisable.
– Aiming for higher MAP than desired may result in
unnecessary vasoconstriction.
– Titrate to achieve adequacy of organ perfusion
• Urine output more than 0.5 mL/Kg/h
• ScvO 2 more than 70%
• Reduction in lactate levels over time (e.g., 20% over 2 h)
• Watch for side effects: tachycardia, arrhythmias, cardiac
ischemia
– It is a myo fi lament calcium sensitizer. It increases
myocardial contractility without increasing myocardial
ATP consumption, thereby improving contraction at low
energy cost.
– It causes normal or improved diastolic relaxation and
vasodilatation.
– It has been studied in acute decompensated heart failure,
during and after cardiac surgery, and postmyocardial
infarction.
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MILRINONE: Milrinone is a phosphodiesterase
inhibitor that enhances myocardial contractility and
relaxation via the same mechanism as dobutamine (i.e.,
cyclic AMP-mediated calcium influx into cardiac
myocytes).
Milrinone has similar effects on cardiac performance as
dobutamine, but
is more likely to produce hypotension .
Digitalis glycosides
– The digitalis glycosides have long been used as
inotropic agents.
– However, today their role in the treatment of acute
heart failure or cardiogenic shock is limited to control
of the ventricular rate response in fast atrial fi
brillation.
– The onset of action of effects of digoxin takes 90 min
after an intravenous loading dose, and peak effect
occurs at 2–6 h.
– The effects of digoxin are modest and unpredictable,
and it has a narrow therapeutic index
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• Agents used in septic shock
The Surviving Sepsis Campaign makes the following
evidence-based recommendations in patients with sepsis:
– Vasopressors
• Recommend to maintain MAP ³ 65 mmHg.
• Recommend noradrenaline centrally administered as the
initial vasopressors of choice.
• Suggest that dopamine, adrenaline, phenylephrine, or
vasopressin should not be administered as the initial
vasopressor in septic shock.
• Vasopressin at dose of 0.03 unit/min may be
subsequently added to noradrenaline with anticipation of
an effect equivalent to noradrenaline alone
Use adrenaline as the fi rst alternative agent in septic
shock when blood pressure is poorly responsive to
noradrenaline
 Recommend not to use low-dose dopamine for renal
protection.
 Recommend to insert an arterial catheter in patients
requiring vaso pressors, as soon as practical.
– Inotropic therapy
• Recommend the use of dobutamine in patients with
myocardial dysfunction as supported by elevated cardiac fi
lling pressures and low cardiac output.
• Do not increase cardiac index to predetermined
supranormal levels.
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• All inotropic and vasopressor drugs may increase myocardial oxygen
demand.
• Increasing blood pressure by use of vasopressors does not lead to
increased perfusion all the time; in certain circumstances like
hypovolemia, it might lead to decreased fl ow to end organs.
• Tachycardia may occur, especially in volume-depleted patients.
• Arrhythmias.
• Catecholamines also have signi fi cant neurohumoral and metabolic
effects, which might be deleterious, for example, hyperglycemia and
hyperlactatemia induced by adrenaline and suppression of prolactin by
dopamine.
All attempts should be made to treat underlying cause
of low perfusion state whenever feasible and
vasopressors should be weaned off at the earliest.
• If necessary, additional fl uid challenges may be used
judiciously in order to wean off vasopressors
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The following broad recommendations can be
made:
Smaller combined doses of inotropes and vasopressors may
be advantageous over a single agent used at higher doses to
avoid dose-related adverse effects.
The use of vasopressin at low to moderate doses may allow
catecholamine sparing, and it may be particularly useful in
settings of catecholamine hyposensitivity and after
prolonged critical illness.
In cardiogenic shock complicating AMI, current guidelines
based on expert opinion recommend dopamine or
dobutamine as first-line agents with moderate hypotension
(systolic blood pressure 70 to 100 mm Hg) and
norepinephrine as the preferred therapy for severe
hypotension (systolic blood pressure 70 mm Hg).
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Routine inotropic use is not recommended for endstage HF. When such use is essential, every effort
should be made to either reinstitute stable oral
therapy as quickly as possible or use destination
therapy such as cardiac transplantation or LV
assist device support.
Large randomized trials focusing on clinical
outcomes are needed to better assess the clinical
efficacy of these agents