A hint about inotropes and vasopressors

Important definitions
Inotropes: are a group of drugs that increase the myocardial contractility ,
thus increasing the cardiac output (COP) and the systolic blood pressure.
Vasopressors: are a group of drugs that produce widespread
vasoconstriction and increasing the peripheral vascular resistance and the
diastolic blood pressure through arteriolar vasoconstriction , and increasing
the venous return to the heart and thus the (COP) by venular vasoconstriction.
Cardiac output: the volume of blood pumped by one ventricle in one
minute. It equals to the stroke volume (SV) X the heart rate.
Stroke volume: it’s the volume of the blood pumped by a single ventricle in
each heart beat. It depends on the blood volume return to the heart (preload),
the vascular resistance facing it (afterload), and the contractility of the heart.
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Mean arterial blood pressure: the average blood pressure present
in the arterial tree through out the cardiac cycle. Its calculated by (diastolic
pressure+ 1/3 pulse pressure). It’s considered to be the perfusing pressure
of the body organs, and it’s widely accepted that it should be maintained
above 60 mmHg for adequate organ perfusion and oxygenation.
Circulatory shock: a medical emergency referring to inadequate tissue
perfusion. It’s typical signs are hypotension, tachycardia, cold cyanosed
peripheries, disturbed conscious level (DCL), Oliguria, metabolic
acidosis due to inadequate tissue supply of oxygen increasing anaerobic
metabolism and lactic acid levels.
Oliguria: urine output less than 0.5ml/kg/hr in adults and less than
1ml/kg/hr in infants
Mixed venous oxygen saturation (SvO2): the percentage of
oxygen present in the venous blood collected from all the body just as it
leaves the RT side of the heart and before it enters the lungs. It is normally
between 60 – 80 %.

Receptors
Alpha 1 receptors: present mainly in the smooth muscles of blood
vessels supplying the skin, gastrointestinal tract, urinary system including
the renal arteries, and the brain. Activation elevates the ABP but can
cause digital and skin gangrene , renal impairment up to renal failure.
Beta 1 receptors: present in the heart where its stimulation causes
excitatory effects (increasing heart rate , contractility & excitability), and in
the kidney increasing renin release. Activation increases the COP but can
cause tachycardia and tachyarrythmias.
Dopamine D1 receptors: present in the renal, splanchnic (mesenteric),
coronary, and cerebral vascular beds; stimulation of these receptors leads
to vasodilatation & diuresis.

The rational use of vasoactive drugs
is guided by fundamental concepts:
1. One drug, many receptors – A given drug often has multiple effects
because of actions upon more than one receptor.
2. Vasoactive drugs are not a definitive treatment. They are merely a
method to support the MAP and perfusion of vital organs till identifying
and managing the cause of the shock state.
3. Dose-response curve – Many agents have dose-response curves, such
that the primary receptor subtype activated by the drug is dose-dependent.
eg. dopamine stimulates beta-1 receptors at doses of 2 to
10 mcg/kg per minute, and alpha 1 receptors when doses exceed
10 mcg/kg per minute.
4. Direct versus reflex actions – A given agent can affect MAP both by
direct actions on adrenergic receptors and by reflex actions triggered by
the pharmacologic response. Nor adrenaline acts on beta-1 in the
heart to cause tachycardia. However, the elevated MAP from nor
epinephrine's alpha 1 receptor-induced vasoconstriction results in a
reflex decrease in heart rate. The net result may be a stable or slightly
reduced heart rate when the drug is used.

5. Correct diagnosis of the underlying cause of shock - Choice of an initial
agent should be based upon the suspected underlying etiology of shock
6. titration , gradual application and gradual withdrawal— The dose should
be titrated gradually up to achieve effective blood pressure or end-organ
perfusion. If maximal doses of a first agent are inadequate, then a second
drug should be added to the first.
7. Correction of acid-base and electrolyte imbalance is crucial for adequate
myocardial response to vasoactive drug therapy- hypocalcaemia, acidosis,
hyponatremia, hypothermia all have –ve inotropic effect.
8. Volume resuscitation — Repletion of adequate intravascular volume, when
time permits, is crucial prior to the initiation of vasopressors. Vasopressors
will be ineffective or only partially effective in the setting of coexistent
hypovolemia.
9. Continues monitoring - all patients on hemodynamic support should be
continuously monitored by invasive blood pressure if possible or NIBP, ECG,
pulse oximetry, UOP hourly, CVP /2 hours, random blood sugar /4 hours, and
clinically for the level of consciousness and peripheral cyanosis & gangrene.

10. Route of administration — Vasopressors and inotropic agents should
be administered through an appropriately positioned central venous
catheter. This facilitates more rapid delivery of the agent to the heart for
systemic distribution and eliminates the risk of peripheral
extravasations.
11. Subcutaneous delivery of medications — Critically ill patients often
receive subcutaneously injected medications, such as LMWH and
insulin. The bioavailability of these medications can be reduced during
treatment with vasopressors due to cutaneous vasoconstriction.
12. Condition of the adrenal gland functions- adrenal insufficiency should
be suspected in any critically ill pt. with “vasopressor-resistant
hypotension”. Other clues for adrenal insufficiency include failure of
weaning from mechanical ventilation, lethargy, hypoglycemia
hyponatremia & hyperkalemia. Prompt treatment with 50-100 mg
hydrocortisone IV / 8 hours is sufficient to alleviate the condition.
13. Avoid turning & limit mobilization- use other methods to avoid bed
sores and pressure ulcers (elevate heels, air mattress)
14. Give by infusion: they are all given through intravenous slow infusion as
they all posses a very short half life (minutes).
15. Correction of concurrent anemia: keep hemoglobin levels>10 gm/dl.

Calculating the desired dosage to be administered for these drugs presents
a great difficulty for most junior staff in the ICU. however these can be
simplified by following 2 rules:
o for drugs administered in nanograms per kg per minute (ng/kg/min) as
adrenaline, isoprenaline and nor adrenaline use single concentration
technique.
its done simply by (multiplying 3 x pt’s body weight in kg, then divide
the outcome by 100). The value obtained is the number of mg of the
drug added to 50 ml D5%W or NS 0.9%, . By this way each 1 ml/hr
infusion by the syringe pump equals to 10 ng/kg/min.
3 X BW in kg = number of mg of the drug added to the 50 ml syringe .
100 .
e.g. A 65 year old pt. 80 kg, presented to the ICU with hypotension Bp
70/30 mmHg, bradycardia 50 bpm. You decide to put the patient on
adrenaline infusion 100 ng/kg/min to support the circulation. How do
proceed ?

Multiply 3 x 80 = 240, then divide 240/100 = 2.4 . So 2.4 mg of adrenaline
(2.4 ml as in Egypt the ampoule conc. Is 1mg/ml) is added to 50 ml NS .
and the syringe is adjusted to infuse 10ml/hr. that is equal to 100
ng/kg/min.
o For drugs infused in microgram/kg/min (μg/kg/min) like dopamine,
dobutamine and nitroglycerine, it’s better to use the fixed dose formula. it
starts by knowing the required dose of the drug and using it to deduct the
infusion rate of the syringe pump.
infusion rate (ml/hr) = desired dose in (μg) x body weight in kg x 60
concentration in the syringe in (μg)
e.g. a 70 yr old, 75 kg pt. DM, HTN, presented to the ICU with sever
hypertensive crisis Abp 210/110 mmHg. You decide to put him on
nitroglycerine infusion 0.5 μg/kg/min. how do you proceed, knowing that
in Egypt nitroglycerine vials are 50 ml with concentration 1mg/ml ?

the volume of the drug in this case is 50 ml, so no need to add it to another
50 ml of NS, just use as it is and simply draw in the 50 ml syringe.
using the previous formula: 0.5 x 75 x 60 = 2250. and the concentration in
the syringe is 1mg/ml = 1000 μg/ml . Dividing 2250 by 1000 we get 2.25 ml
/ hr. that is the no. we insert in the syringe pump.
another e.g. a 60 yr old female, DM, HTN, 50 kg BW presented to the ICU
for postoperative care after left lower limb amputation due to wet
gangrene complicating a sever case of infected diabetic foot. Pt is toxic,
lethargic, feverish temp. 38.8°C, tachycardic P=135 Bpm, hypotensive Abp=
85/40 mmHg. You diagnose the pt. with septic shock, and start nor
adrenaline infusion at 100 ng/kg/min. after 48 hrs the nurse informs you
that the UOP of the pt. dropped from 50 ml/ hr to less than 5 ml/hr. the
consultant of the ICU orders gradual withdrawal of the nor adrenaline
infusion and introduction of dopamine infusion at a diuretic dose of 3
μg/kg/min. how to prepare both drugs ??

For nor adrenaline infusion 50 x 3 / 100 = 1.5 mg of the drug should be added
to 50 ml D5%W. since nor adrenaline ampoules are 4mg in 4 ml so take 1.5
ml from the ampoule and add to the syringe. By adjusting this syringe to
10 ml/ hr infusion rate we get 100 ng/kg/ min.
For dopamine we require 3 μg/kg/min. so 3 x 50 x 60 = 9000. divided by the
concentration of dopamine in a 50 syringe.
Dopamine ampoules are 200 mg in 4 ml. adding this 4 to 46 ml NS gives us
a solution of 50 ml with a concentration of 200/50 = 4 mg/ml = 4000
μg/ml.
so dividing 9000/4000 = 2.5 . That is the rate of infusion you need to input
in the syringe pump to get dopamine infusion at a diuretic dose of 3
μg/kg/min.

Classification of vasoactive
drugs
Catecholamines Non-Catecholamines
these include adrenaline,
noradrenalin, dopamine,
dobutamine & isoprenaline.
Both dobutamine and
isoprenaline are synthetic
Catecholamines, not present
normally in nature.
These include Phosphodiestrase
enzyme inhibitors (PDE III) as
milrinone. Calcium sensitizer
(levosemindan) and the
antidieuretic hormone
vasopressin.

Mechanism of action

Beta 1 receptors are G-protein coupled receptors, they act by activating a Gs
(G-stimulatory) protein. Gs activates adenylyl cyclase, leading to an
increase in levels of intracellular cAMP. Increased cAMP activates protein
kinase A, which phosphorylates cellular proteins. The most important of
which to our concern is the L- type calcium channel (LTCC), which opens
causing influx of Ca2 , this causes increase in cytosolic Ca2 , which in turn
causes activation of the (RyR) ryanodine receptors on the Sarcoplasmic
Reticulum (SR) causing massive release of stored Ca2 in them a
phenomenon called Calcium-induced calcium release (CICR). This Ca2
binds to cardiac troponin C (CTnc) removing the inhibitory effects of (CTnI).
This causes movement of tropomyocin which normally covers the myosin
binding sites on the actin filament. this allows actin-myosin interaction.
After the contraction ends Ca2 is pumped back to the Sarcoplasmic
reticulum through (SERCA) ATPase.
increased intracellular Ca2 in the cardiac myocytes was associated with
increased O2 consumption, increased risk of arrhythmias & increased
apoptosis.

ADRENALINE
It’s a natural catecholamine normally produced in the adrenal medulla by
methylation of nor adrenaline. It’s present as dark ampoules containing 1 ml at
concentration of 1 mg/ml.
indications:
• acute asthmatic attacks
• resuscitation of non shockable cardiac arrest (asystole & electromechanical
dissociation)
• Anaphylaxis
• sever hypotension due to any cause (e.g. POST HIGH SPINAL INJURY
ASSOCIATED WITH BRADYCARDIA)
• Post arrest as infusion unless sever tachycardia or hypertension occurs
Epinephrine is the first-line catecholamine in cardiopulmonary
resuscitation and anaphylactic shock. As a vasopressor and as an
inotrope, epinephrine is usually considered a second-line agent.

Epinephrine is a potent mixed α- and β-adrenergic agonist. Because of its
mixed properties, epinephrine increases both mean arterial BP by
vasoconstriction (α1-adrenergic effect) and cardiac output (β1-adrenergic
effect).
Dosage : from 50 ng/kg/min upto 1500 ng/kg/min. usually the starting dose is
100ng/kg/min. Doses less than 50ng/kg/min is considered purely inotropic
and can cause hypotension by activation of β2 receptors in blood vessels.
Caution in known cases of:
1. Known hypersensitivity to sympathomimetic amines.
2. coronary insufficiency (ISHD).
3. Arrhythmias.
4. Hypertension
5. Cerebral arteriosclerosis.
6. Hyperthyroidism.
7. In obstetric patients with a maternal blood pressure in excess of
130/80mmhg.

NORADRENALINE
Norepinephrine is an endogenous catecholamine that has potent α1- > β1-
adrenergic effects. The primary vasoactive effect of norepinephrine is arterial
and venous vasoconstriction. The inotropic properties of norepinephrine are
usually offset by increases in after load due to the α1 potent action which leads
to reflex bradycardia.
Indications:
First choice vasopressor, mainly used in distributive shock with marked
vasodilatation as:
SEPTIC SHOCK, POST HIGH SPINAL INJURY ASSOCIATED WITH TACHYCARDIA,
PHEOCHROMOCYTOMA SURGERY AFTER TUMOR EXCISION, TOTAL SPINAL
AFTER SPINAL ANETHESIA, MASSIVE HAEMORRAGE WITH TACHYCARDIA till
blood products are available.
Dosage:
should be added to D5%W start with 50ng/kg/min up to 4000ng/kg/min. it’s
present in dark ampoules containing 4mg/4ml.
Caution: in pt’s with mesenteric vascular occlusion, intestinal or renal
infarctions, peripheral vascular insufficiency.

DOPAMINE
Is an endogenous catecholamine, naturally present as a neurotransmitter in the
CNS. It’s used in the ICU as an infusion due to it’s multitude of actions on
different receptors according to the dose of the infusion.
 At a low dose (0.5 – 3 μg/kg/min) it activates the Dopaminergic receptors in
the splanchnic and renal vasculature leading to VD and increased GFR and
hence the UOP.
 At intermediate dose (3 – 8 μg/kg/min) activation of the cardiac beta 1
receptors occurs with +ve inotropic, chronotropic effects.
 At high doses (10 – 20 μg/kg/min) activation of alpha 1 receptors with
increased peripheral vascular resistance and afterload. At very high doses > 20
μg/kg/min. this vasoconstrictor action overwhelms the dopaminergic
vasodilator action and may compromise the blood flow to the limbs, kidney &
mesentery.
Its used mainly as a second line inotrope and vasopressor. And as a diuretic
agent to increase renal blood flow and UOP in cases where the OLIGURIA is
due to low systemic blood pressure or marked renal vasoconstriction.
It’s available as 200 mg ampoules in 5 ml.

DOBUTAMINE
It’s a synthetic catecholamine with marked β1 and very little α and β2 actions.
it’s considered the first choice inotrope in cardiogenic shock especially in
acute cases with maintained Abp. Chronic cases of heart failure show down
regulation of beta receptors which may render the dobutamine infusion
ineffective. Also, non specific activation of β2 receptors however small can
cause marked pressure drop and accentuate the shock state especially in
hypovolemic patients.
Dosage: 2 to 20 mcg/kg/minute. Maximum: 40 mcg/kg/min. Titrate to desired
response.
Side effects include tachycardia, tachyarrythmias and increased myocardial
oxygen consumption. Hypotension is another possible outcome.
Commercially it’s present as 250 mg either in 5 ml or 25 ml ampoules.

PDE3 INHIBITORS
A group of drugs that acts mainly through direct inhibition of PDE enzyme
leading to decreased destruction of CAMP. With increased CAMP levels
inside the myocytes +ve inotropy is achieved, while in the arterial blood
vessels vasodilatation occurs hence their unique action as inodilators.
amrinone (INOCOR) and milrinone (PRIMACOR) are the most commonly used
agents of this family. They are considered second line agents in cardiogenic
shock that have synergistic effects with dobutamine, especially in cases
with maintained ABP as they produce profound vasodilatation. Side effects
include tachyarrythmias especially AF, hypotension.
Dosage:
for amrinone: loading dose of 0.75-1.5 mg/kg over 5 minutes followed by
infusion of 2 – 10 μg/kg/min.
For milrinone: loading dose 50 μg/kg IV over 10min, then 0.5 μg/kg/min.

CALCIUM SENSITIZERS

These are drugs that act to increase the contractility of the heart without
increasing the concentration of cytosolic Ca++. Unlike previous inotropes
which act through the beta adrenergic receptor cascade to increase
cytosolic Ca++ and hence the myocardial oxygen consumption, the risk of
arrythmogenesis and apoptosis, this group act by binding to troponin c in
the presence of Ca++ and increasing the troponin sensitivity to Ca++ . This
stabilizes the tropomyocin changes allowing the actin –myosin interaction
to ensue at normal Ca++ levels.
it also binds to vascular ATP dependant K+ channels which results in hyper
polarization and causes vascular relaxation with reduction in both preload
& afterload.
Note that it can be used concurrently with dobutamine as they have
synergistic effects, with vasopressors in pts with low systolic blood pressure
and even with beta blockers in post myocardial infarction pts with
tachyarrythmias.
Side effects: as with other inodilators, hypotension & as with other inotropes
tachyarrythmias are still the most common side effects although less than
other agents.
Dosage: 0.05 – 1.5 μg/kg/min infusion.

ISOPRENALINE
isoprenaline is a synthetic catecholamine which stimulates both β1&2
adrenoceptors producing an increase in cardiac output by increasing
myocardial contractility and heart rate. It’s vasodilator action surpasses the
increase in the COP caused by it’s +ve inotropic action so the net result is
decreased MAP.
Indications: Isoprenaline is used to treat severe bradycardia where use of
electronic temporary pacing is not available or appropriate. Isoprenaline
can be used for cardiogenic or septic shock and acute Stokes-Adams
attacks.
Dosage: 0.5 to 5 μg/min, (0.01-0.03μg/kg/min).
Isoprenaline and adrenaline should not be administered simultaneously
because both drugs are direct cardiac stimulants and their combined
effects may induce serious arrhythmias. Beta receptor blocking agents and
isoprenaline inhibit the effects of each other. If heart rate exceeds 110
beat/min, its wise to stop the infusion and monitor the pt closely.
It’s available in the form of 0.2 mg/ml ampoules, either 1ml or 5ml volume.

VASOPRESSIN
Vasopressin or antidieuretic hormone is a potent endogenous hormone,
which is responsible for regulating plasma osmolality and volume. In high
concentrations, it also raises blood pressure by inducing moderate
vasoconstriction by stimulating V1 receptors and reducing NO activity in
the vascular smooth muscles.
Indications: mainly as an adjunct to norepinephrine to treat catecholamine
resistant shock in septic shock, post cardiac surgery & other vasodilatory
shock (Anaphylactic). It’s main usage in the ICU however remains to control
GI bleeding due to esophageal varices.
Vasopressin is available as a 20 unit/ml injection. For continuous intravenous
infusion, it should be diluted with normal saline or D5%W to a final
concentration of 0.1 to 1 unit/ml.
Dosage: infusion rates of 0.01 to 0.03 units/min can be used with other
vasopressor in shock state. In GI bleeding the dose is increased to 0.2 – 0.4
unit/min.

comparison of intravenous inotropic agents currently used in management of
heart failure, in relationship to factors that most commonly determine choice of
agents for individual patients.

EFFECTS OF SOME VASOACTIVE
AGENTS

So how do we react to a shocked patient?

A,B,C,D
Secure the airway
Maintain breathing
Establish IV access
Carful history and
examination
ABG and labs
ECG and CVP
Urinary catheter
If polytrauma plz
remember to put a
neck collar and
move the pt as one
block
If there is a surgical
cause (stuck valve,
massive hge) do
surgical
consultation
Start IV crystalloids
500ml – 1000ml
Over 30 mins
And monitor the
response
UNLESS overt
pulmonary edema
is present with
CVP>15

Measure the CVP every 10 minutes and the
MAP every 5 minutes along with other
MAP<60 &
CVP<15
cmH2O
MAP<60 but
CVP>15 cmH2O
clinical indices
REPEAT
ONCE
STOP
Still no
response
echocardiography
INOTROPES
VASOPRESSOR

WHAT IS THE END POINT OF RESUSCITATION? WHAT ARE
YOU AIMING FOR?
1) Clinical indices: normalization of MAP, pulse rate, respiratory rate,
UOP, skin warmth, conscious level & the CVP value is helpful, but they
should not be used as markers of adequate resuscitation.
2) Mixed venous O2 saturation: should be aimed to be >70%.
For samples obtained from Central venous catheter they are 5 – 10%
less. Lower than normal values indicate imbalance between oxygen
delivery and demand.
3) Base deficit: indicate ongoing acidosis and tissue hypo perfusion.
Should be less than -2 mmol/L.
4) Lactate levels: a product of anaerobic metabolism. Should be
normalized.
NB: use all parameters together not a single one as each has its
limitations. And remember the trend in these parameters is much more
important than the mere value.

ONE LAST NOTIFICATION
In case of peripheral administration in emergency situation, if subcutanuos
extravasation of a vasopressor agent occurs, plz do the following:
1. Discontinue the agent peripherally and start it immediately centrally.
2. DO NOT PULL OUT THE PERIPHERAL CANNULA
3. Administer subcutaneous phentolamine (Regitine) using the cannula.
Comes in 5 mg per 1 ml vials or 10 mg in 1 ml. dilute 1 ml in 9 ml of NS.
A dose of 0.1 to 0.2 mg/kg (up to a maximum of 10 mg) should then be
injected through the catheter and subcutaneously around the site.
Administered as soon as the extravasation is detected.
4. Consult plastic surgery.

A hint about inotropes and vasopressors

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