1. INOTROPES AND VASOPRESSORS
PADRAIG HEADLEY ST7

2. OBJECTIVES
•
Review physiology of cardiac contraction and inotropy
•
Classify inotropes
•
Discuss their mechanism of action
•
Overview of vasopressors
•
Choosing the right one????
•
The future??

3. Positive inotropes increase the force of contraction of the
myocardium
The smallest unit functional unit of the myocardium is the
actin-myosin unit

4. Cross bridge cycle
•Ca binds troponin C and alters tropomysin uncovering actin for binding
•ATP attaches to myosin head and causes rotation and breakdown to ADP and binding to
actin
•On attachment to actin --- further rotation and displacement ADP --produces force (on
time) --- detaches and enters non force state (off time).
•This process cycles

5. The extent of the force produced per unit time depends on the amount of crossbridges activated. This depends on:
a) the amount of Ca available
b) its affinity to troponin C
c) cross bridge function and co-operativity
European Heart Journal (2011) 32, 1838–1845 doi:10.1093/eurheartj/ehr026
Removal of calcium is
also an active process

6. HOW DOES THE HEART CONTROL IT'S FORCE OF
CONTRACTION PHYSIOLOGICALLY??
•
Length dependant activation of cross bridges :- the frank
starling mechanism -- improves co-operativity and therefore
most energy efficient means
•
Frequency dependant activation - in normal hearts increase
in heart rate will result in increased intracellular calcium,
defective in disease states and other factors involved -energy dependant
•
Catecholamine mediated activation

7. Positive
inotropy
Increased work,
imbalances in
supply and
demand, risk of
arrhythmia and
ischaemia
It's increasingly recognised that the economics of these processes may mean that
some inotropes may work without increasing energy requirements.
Both contraction and relaxation are active processes reflecting types of heart
dysfunction - systolic and diastolic

8. INOTROPES

9. CLASSIFICATION

10. BETA ADRENORECEPTORS
β-1 adrenergic
β-2 adrenergic

11. CATECHOLAMINES
• Natural or synthetic
• Most commonly used agents act on multiple receptors in a
dose-dependent manner
• Have multisystem effects also - central, respiratory, endocrine,
immune

12. Natural catecholamines

13. ADRENALINE
• Potent β-1, moderate α-1 & β-2
• Low dose – chronotrope and inotrope
• Increased CO, decreased SVR, variable MAP
• High dose – α effect increases
• Increased CO, increased SVR

14. DOPAMINE
• Dose range dependent effects:
• 1 – 2 μg/kg/min dopamine-1 receptors in the renal, mesenteric, cerebral, and
coronary beds, resulting in selective vasodilation
• 5 -10 μg/kg/min β-1 stimulation – increased SV, variable effect on HR
• >10 μg/kg/min adrenergic stimulation – vasoconstriction & increased SVR

15. DOBUTAMINE
• Synthetic derivative of isoprenaline
• Overall an inotrope with vasodilatory properties
• Predominantly β-1 - inotropy, chronotropy, decreased LV filling pressure
• Minimal α and β-2 – overall vasodilation

17. PHOSPHODIESTERASE INHIBITORS
• Selective or non selective
• PDE3 inhibitors - Inotropic and vasodilatory
• Mainly in impaired cardiac function and medically refractory heart failure
• Limitations in sepsis due to vasodilatation

19. LEVOSIMENDAN
•
Inodilator
•
Enhances sensitivity of troponin C to Ca without increase in intracellular Ca
•
Only acts in presence of high Ca therefore does not affect relaxation phase
•
Opening of ATP K channels causes vasodilation and reduced afterload
•
Overload cardiac output is augmented with improved diastolic relaxation without
an increase in workload
•
In vitro PDE III inhibitor ? In vivo effect
•
Long half life due to active metabolites
•
Given as loading dose followed by 24hr infusion, effects last up to 9 days

20. OTHERS
Glucagon
Insulin

21. VASOPRESSORS

22. ALPHA ADRENORECEPTORS

23. ADRENALINE
• Potent β-1, moderate α-1 & β-2
• Low dose – chronotrope and inotrope
• Increased CO, decreased SVR, variable MAP
• High dose – α effect increases
• Increased CO, increased SVR

24. DOPAMINE
• Dose range dependent effects:
• 1 – 2 μg/kg/min dopamine-1 receptors in the renal, mesenteric, cerebral, and
coronary beds, resulting in selective vasodilation
• 5 -10 μg/kg/min β-1 stimulation – increased SV, variable effect on HR
• >10 μg/kg/min adrenergic stimulation – vasoconstriction & increased SVR

25. NORADRENALINE
• α-1 & β-1
• Potent vasoconstriction, less pronounced increase in CO
• Reflex bradycardia

26. PHENYLEPHRINE
• Purely alpha-adrenergic agonist
• Increased afterload
•
CO usually actually maintained in patients without prior cardiac dysfunction
•
CO falls in patients with impaired ventricular function

27. VASOPRESSIN
•
Nanopeptide produced by hypothalamus & released by posterior pituitary.
•
3 receptors
•
•
V2 - aquaporins insertion in renal tubules, release vWF and factor VIII
•
•
V1 – G-protein coupled - vasoconstriction
V3 - anterior pituitary release of ACTH and endorphins
Synthetic derivatives - desmopressin (high V2 effect), terlipressin longer acting

28. WHICH INOTROPE /
VASOPRESSOR??

29. WHICH AGENT?
•
Depends on individual patient and type of shock
•
Potential Pitfalls and options
•
Knowing the patient's current cardiovascular status - ? more
cardiac output monitors
•
Recognising that things can change due to multiple factors
including the natural history of the underlying process eg
phases of sepsis, tachyphylaxis to adrenergic agents therefore choice of agent may need to change during course
of illness

30. SEPSIS

32. • Vasopressin and Septic Shock Trial (VASST)
• 778 patients with septic shock randomly assigned to either low dose vasopressin (0.01 to
0.03 units per minute) norepinephrine (5 to 15 mcg per minute)
• similar 28-day and 90-day mortality rates, similar incidence of serious adverse events
•
Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM , Cook DJ, Presneill JJ, Ayers D, VASST Investigators.
Vasopressin ver sus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877

33. SEPSIS

34. • Annane et al, Lancet 2007; 370: 676–84, 330 patients with septic shock in French
ICU’s
• Titrated to maintain MAP at 70mmHg, Primary outcome 28 day mortality

35. CARDIOGENIC SHOCK
•
Little evidence to guide inotropic or vasopressor therapy. ESC guidelines suggest dobutamine
first line+/- noradrenaline if required to maintain perfusion pressures
•
Those that require these agents have a high mortality
•
Revascularisation if required is key
•
Inotropes and vasopressors may actually have a detrimental effect in longer term- everything
we know to improve outcome in heart failure works opposite in effect to these agents.
•
commonly used drugs may be less effective given changes in the myocardial cells due to the
disease state and also due to pretreatment with beta blockade - leading to theory that agents
such as PDEi may be more beneficial in these cases
•
However direct studies between PDEi and dobutamine are all small studies not showing any
difference in outcome

36. LEVOSIMENDAN
•
Little evidence base to date to direct critical care use
•
Biggest trials to date have been on Decompensated chronic
heart failure - REVIVE and SURVIVE - excluded shocked or
ventilated patients - use associated with reduction in BP
particularly with loading dose
•
Meta analysis suggested potential survival advantage compared
with dobutamine but not with placebo.... Is dobutamine actually
doing harm in these cases??

37. THE FUTURE???

39. BETA BLOCKERS PLUS INOTROPES??

40. CONCLUSIONS
•
These are commonly used agents in critical care - has
appeared as viva topic in FFICM
•
Evidence base is limited to guide use of one agent over
another, choice should be based on individual patient
characteristics
•
Our understanding of basic science behind inotropy etc is
leading to novel agents / ideas