Vasopressors are a powerful class of drugs that induce vasoconstriction and Inotropes increase cardiac contractility. Choice of an agent should be based upon the suspected underlying etiology of shock. This presentation deals with the practical issues and controversies surrounding the use of these agents

1. Dr. Aneesh T
Assistant Professor
Dept. of General Medicine
Inotropes
&
Vasopressors

2. Overview
Introduction
Receptor physiology
Principles
Practical issues
Adrenergic & Non adrenergic agents
Controversies
Summary

3. Introduction
 Vasopressors are a powerful class of drugs that induce
vasoconstriction and thereby elevate mean arterial pressure (MAP)
 Inotropes  increase cardiac contractility
 However, many drugs have both effects.
 Quite a few agents  only some controlled clinical trials have
directly compared these agents
 The manner in which these agents are used largely reflects…
Expert opinion
Animal data
Tissue oxygenation

4. Receptor physiology
 The main categories of receptors relevant to vasopressor &
inotropic activity are
1. α1 (Alpha 1)
2. β1 (Beta 1)
3. β2 (Beta 2)
4. Dopamine
5. Calcium
sensitizers
Located in vascular walls
Induces significant vasoconstriction
Also present in the heart - increases
duration contraction

5. Receptor physiology
 The main categories of receptors relevant to vasopressor &
inotropic activity are
1. α1 (Alpha 1)
2. β1 (Beta 1)
3. β2 (Beta 2)
4. Dopamine
5. Calcium
sensitizers
Increases in inotropy
Increases chronotropy
Minimal vasoconstriction

6. Receptor physiology
 The main categories of receptors relevant to vasopressor &
inotropic activity are
1. α1 (Alpha 1)
2. β1 (Beta 1)
3. β2 (Beta 2)
4. Dopamine
5. Calcium
sensitizers
Blood vessels
Located in several other locations
Vasodilation

7. Receptor physiology
 The main categories of receptors relevant to vasopressor &
inotropic activity are
1. α1 (Alpha 1)
2. β1 (Beta 1)
3. β2 (Beta 2)
4. Dopamine
5. Calcium
sensitizers
Renal, splanchnic, coronary, cerebral beds
Dose dependent action
Can induce noradrenaline release

8. Receptor physiology
 The main categories of receptors relevant to vasopressor &
inotropic activity are
1. α1 (Alpha 1)
2. β1 (Beta 1)
3. β2 (Beta 2)
4. Dopamine
5. Calcium
sensitizers
Increases sensitivity of myocardium to Ca2+
Also inhibit phosphodiesterase
Increase inotropy and vasodilation

9. Principles
Hypotension
Hypovolemia
Pump failure
Maldistribution of
blood flow

10. Principles
Indications
A decrease of >30 mm
Hg from baseline
systolic blood pressure
A mean arterial pressure
<60 mmHg
when
End-organ dysfunction
ensues due to
hypoperfusion
Hypovolemia should be
corrected prior to the
institution of
vasopressor therapy

11. Principles
 The rational use of vasopressors and inotropes is guided by three
fundamental concepts
One drug,
many
receptors
Dose
response
curve
Direct
versus
reflex
actions

12. Practical issues
I. Volume resuscitation
 Repletion of adequate intravascular volume - crucial prior to the
initiation of vasopressors
 Most patients in septic shock – need ~2 liters of fluids
 Else, vasopressor effect is suboptimal or even ineffective
 Fluids withheld
 Pulmonary edema
 ARDS
 Heart failure
 PCWP or IVC ultrasound for monitoring (IVC diameter <2 cm may
suggest volume depletion)

13. Practical issues
II. Selection and titration
 Choice of an initial agent  underlying etiology of shock
 Dose should be titrated up to achieve effective blood pressure or
end-organ perfusion – based on urine output or mentation
 Maximal doses of the first agent or evidences of adverse effects 
add a second agent
 A third agent may be added – no controlled trials for this approach

14. Practical issues
III. Route of administration
 Vasopressors and inotropic agents  via Central venous catheter
 CVC  Rapid delivery to the heart & peripheries & prevents
extravasation
 Peripheral IV line – A temporary measure till a central line is
achieved

15. Practical issues
IV. Tachyphylaxis
 Responsiveness to these drugs can decrease over time due to
tachyphylaxis.
 Constantly titrated to adjust for this phenomenon and for changes
in the patient's clinical condition

16. Practical issues
V. Hemodynamic effects
 Mean arterial pressure (MAP) is influenced by systemic vascular
resistance (SVR) and cardiac output (CO)
 Eg. In cardiogenic shock, increasing SVR can increase afterload on
an already failing heart  impairing CO
 Raising SVR is beneficial in septic shock, when cardiac function is
largely normal.

17. Practical issues
VI. Subcutaneous delivery of medications
 Critically ill patients often on sc medication (LMWH, insulin)
 The bioavailability of these medications - reduced during
treatment with vasopressors due to cutaneous vasoconstriction.
 A higher dose of LMWH may be required for thrombosis
prophylaxis
 May require switching to intravenous therapy

18. Practical issues
VII. Frequent re-evaluation
 Critically ill patients may undergo a second hemodynamic insult
 Could necessitates a change in vasopressor or inotrope
management
 The dosage of a given agent should not simply be increased
without reconsideration of the clinical situation and the
appropriateness of the current strategy
 Weaning
• Catechol Vasopressors are titrated quickly
• Inotropes (Inamrinone, dobutamine) are titrated over hours

19. Adrenergic agents
 Acts on both alpha1 and beta1 adrenergic receptors
 Potent vasoconstriction as well as a modest increase in cardiac
output
 Thus the mild chronotropic effect is canceled out and the heart
rate remains unchanged or even decreases slightly
 Preferred agent in septic shock
Norepinephrine (Noradrenaline)
↑ MAP↑ CO
Reflex
bradycardia

20. Adrenergic agents
Initiating
dose
Maintenance
dose
Role in therapy
8 to 12
mcg/minute
2 to 4
mcg/minute
Max : 35 - 100
mcg/minute
• Initial vasopressor of choice in
septic, cardiogenic, and
hypovolemic shock.
• Wide range of doses utilized
clinically.
Norepinephrine (Noradrenaline)

21. Adrenergic agents
Norepinephrine (Noradrenaline)
1 ampoule = 2 ml (2mg/ml) i.e 4mg
2 amps in 46 ml NS/5D = 8 mg (8000 µg) in 50 ml
1ml of infusion = 160 µg
Starting rate = 3 ml/hr
= 8 µg/min = 3 ml/hr
 40 µg/min = 15 ml/hr
160x3
60

22. Adrenergic agents
 Potent β1, moderate β2 & α1 adrenergic receptor effects.
 Clinically, low doses of ↑ CO (β1) inotropic & chronotropic effects
 While α receptor induced vasoconstriction is offset by the β2
mediated vasodilation.
 Net result (Low doses) = ↑ CO with ↓ SVR & variable effects on
MAP
 However, at higher doses the α effect predominates  increased
SVR in addition to an increased CO
Epinephrine (Adrenaline)

23. Adrenergic agents
Epinephrine (Adrenaline)
Initiating dose Maintenance
dose
Role in therapy
1 µg/minute 1 to 10
µg/minute
• Initial vasopressor of choice in
anaphylactic shock.
• Add-on agent to norepinephrine in
septic shock.
• Increases heart rate; may induce
tachyarrhythmias and ischemia.
• Elevates lactate concentrations*
• May decrease mesenteric perfusion.

24. Adrenergic agents
Adrenaline
1 ampoule = 1 ml (1:1000) i.e 1mg
1 amp in 49 ml NS/5D = 1 mg (1000 µg) in 50 ml
1ml of infusion = 40 µg
Starting rate = 1.5 ml/hr
= 1 µg/min = 1.5 ml/hr
 10 µg/min = 15 ml/hr
40x1.5
60

25. Adrenergic agents
Dopamine
 Effects depending upon the dose range administered
 2nd line agent to norepinephrine where there is a low risk of
tachyarrhythmias.
Dose Receptor action Result Clinical Effect
1 to 2 mcg/kg per
minute
Dopamine1 (D1)
receptors in
renal,
mesenteric, cerebral,
coronary beds
Selective vasodilation Increases urine output
by augmenting RBF &
GFR

26. Adrenergic agents
Dopamine
Dose Receptor action Result Clinical Effect
5 to 10 mcg/kg per
minute
Beta1
adrenergic receptors
↑ CO and SVR
↑ HR
increase in MAP
>10 mcg/kg per
minute
Alpha adrenergic
receptors
Vasoconstriction with
an ↑ SVR
increase in MAP
Max dose 20-50 mcg/kg per minute

27. Adrenergic agents
Dopamine
1 ampoule = 5 ml (40 mg/ml) i.e 200 mg
2 amps in 46 ml NS/5D = 400 mg in 50 ml
1ml of infusion = 8 mg (8000 µg)
5 µg/kg/min  starting dose
In a 70 kg pt = 5x70 = 350 µg/min
Starting rate = 3 ml/hr
= 5x70 µg/min ~ 400 µg/min = 3 ml/hr
= 35x70 µg/min ~ 18 ml/hr
8000x3
60

28. Adrenergic agents
Dobutamine
 Not a vasopressor
 An inotrope that causes vasodilation
 β1 effect increases inotropy and chronotropy & reduces LV filling
pressure
 Minimal α1 & β2 actions cause vasodilation
 The net effect  ↑ CO, ↓SVR ± small reduction in BP
 Indicated in severe, medically refractory heart failure and
cardiogenic shock
 Sepsis

29. Adrenergic agents
Dobutamine
Initiating dose Maintenance
dose
Role in therapy
0.5 to 1
mcg/kg/min
2 to 20
mcg/kg/min
• Initial agent of choice in cardiogenic
shock with low CO and maintained
blood pressure
• Add-on to norepinephrine for CO
augmentation in septic shock with
myocardial dysfunction
• High risk for tachyarrhythmias

30. Adrenergic agents
Dobutamine
1 ampoule = 5 ml (50 mg/ml) i.e 250 mg
1 amp in 45 ml NS/5D = 250mg in 50 ml
1ml of infusion = 5 mg (5000 µg)
1 µg/kg/min  starting dose
In a 70 kg pt = 70 µg/min
Starting rate = 1 ml/hr
= 83.33µg/min = 3 ml/hr
= 20x70 µg/min ~ 18 ml/hr
(1400 µg/min)
5000x1
60

31. Adrenergic agents
Phenylephrine
 Pure α  vasoconstriction with minimal cardiac inotropy or
chronotropy
 MAP is augmented by raising systemic vascular resistance
 Useful situations for its use - hyperdynamic sepsis, neurologic
disorders, anesthesia induced hypotension
 Disadvantage  reduces stroke volume (Reserved for use where
noradrenaline cannot be given i.e. tachyarrhythmias)

32. Adrenergic agents
Phenylephrine
Initiating dose Maintenance
dose
Role in therapy
100 to 180
mcg/minute
until
stabilized
20 to 80
mcg/minute
• Pure alpha vasoconstrictor
• Initial vasopressor when
tachyarrhythmias preclude use of
noradrenaline
• Alternative agent in septic shock;
despite use of 2 agents
• Useful in anesthesia related
hypotension
• May decrease stroke volume and
cardiac output in patients with
cardiac dysfunction.

33. Adrenergic agents
Vasopressin & Terlipressin
 A 2nd line agent in refractory vasodilatory shock, i.e. septic shock or
anaphylaxis
 Also used often to reduce the dose of the 1st line agent
 2 large meta-analyses revealed
 No short term mortality benefit
 However, reduced the dose of Noradrenaline
 Lesser rate of renal failure requiring replacement
 Rebound hypotension is common (needs tapering)

34. Adrenergic agents
Vasopressin
Initiating dose Maintenance
dose
Role in therapy
0.03 units
per
minute
0.03 to 0.04
units per
minute
(not titrated)
• Not recommended as a
replacement for a 1st line agent
• Pure vasoconstrictor; may
precipitate ischemia in coronary
artery disease.

35. Adrenergic agents
Vasopressin
1 ampoule = 1 ml (20U/ml) 20U
2 amps in 46 ml NS = 40 U in 50 ml
1ml of infusion = 0.8 U
0.03 U/min  starting dose
Rate of Infusion = 2.5 ml/hr = 0.033 U/min

36. Adrenergic agents
Ephedrine
Isoproterenol
Post anesthesia induced
hypotension
Hypotension secondary to
bradycardia

37. Non- Adrenergic agents
PDE inhibitors
 Inamrinone (formerly known as amrinone) and Milrinone
 inotropic and vasodilatory actions – akin to Dobutamine
 Lower risk of arrhythmias
 Used in medically refractory heart failure (limited by hypotension)

38. Non- Adrenergic agents
NOS inhibitors
 N-monomethyl – arginine (L-NMMA) in sepsis demonstrate a dose
dependent increase in SVR
 Cardiac index reduces – limits its use- even with other vasopressors
 Clinical utility - unproven
Calcium sensitizers
 Pimobendan, Levosimendan - increase myocardial contractility
 Evidence of improved outcomes with their use is lacking

39. Controversies
Stem from the relative paucity of large scale studies comparing similar
patient populations treated with different regimens.
1. Choice of agent in septic shock
 Earlier – Dopamine was used
 A paradigm shift in practice has occurred -most experts prefer to
avoid dopamine and favour noradrenaline

40. Controversies
2. "Renal dose" dopamine
 ↑ renal blood flow in normal volunteers at 1 - 3 mcg/kg/min
 A beneficial effect of low or "renal dose" dopamine - less proven in
patients with sepsis
 Most effective means of protecting the kidneys in septic shock is to
maintain MAP >60 mmHg

41. Controversies
3. Supra-normal cardiac index
 Theoretically, ↑ cardiac index with inotropes to >4.5 L/min/m2 (Supra-
normal) potentially ↑ oxygen delivery to peripheral tissues.
 May prevent tissue hypoxia and improve outcomes
 Large trials - resulted in either no improvement or worsened
morbidity or mortality
 Not advocated

42. 1. Vasopressors - powerful class of drugs that induce
vasoconstriction and elevate mean arterial pressure
2. Vasopressors - indicated for a MAP <60 mmHg, or a drop of
systolic BP >30 mmHg from baseline, when either condition
results in endorgan dysfunction due to hypoperfusion
3. Hypovolemia should be corrected prior to vasopressor therapy
for maximum efficacy - reevaluated frequently once
vasopressor therapy has been initiated
Summary and Recommendations

43. 4. Choice of an initial agent should be based upon the suspected
underlying etiology of shock
5. Complications of vasopressors hypoperfusion, dysrhythmias,
myocardial ischemia, peripheral extravasation with skin
necrosis and hyperglycemia.
Summary and Recommendations