UPDATE INOTROPES and VASOPRESSOR IN CARDIOGENIC SHOCK

1. INOTROPES aNdINOTROPES aNd
vaSOPRESSORS INvaSOPRESSORS IN
caRdIOgENIc ShOckcaRdIOgENIc ShOck
Dr. Anwar Yusr
Critical Care Consultant
University of Science and Technology
Hospital - Sana'a
USTH

2. Cardiogenic Shock
• Cardiogenic shock is defined as:
– SBP <90 mmHg for at least 30 minutes.
– which is secondary to myocardial dysfunction.
–Cardiac index (CI) < 2.2 l/min/m2.
– PCWP > 18 mmHg.
• It is associated with signs of tissue hypoperfusion:-
– decreased urine output: < 0.5ml/kg/hr.
– altered mental status: Confusion.
– peripheral vasoconstriction – sweaty, cold, pale.
– Capillary filling time >2 sec.

3. PATIENT WITH AHF
Bedside assessment to identify
haemodynamic profile
CONGESTION?
YES (95% of AHF patients) NO (5% of AHF patients)
“Wet” “Dry”
POOR PERFUSION?
NO
“Wet” & “Warm”
NO
“Dry” & “Warm”
YES
“Dry” & “Cold”
YES
“Wet” & “Cold”
Adapted from 2016 ESC HF Guildeines

4. “Wet” & “Cold”
Systolic blood pressure < 90 mmHg?
YES NO
 Inotropic agent.
 Consider vasopressor in
refractory cases.
 Diuretic (when perfusion
corrected).
 Consider mechanical
circulatory support if no
response to drugs.
 Vasodilators.
 Diuretics.
 Consider inotropic agent
in refractory cases.
Adapted from 2016 ESC HF Guildeines

5. Therapeutic Targets
• Inotrope support is indicated when there is evidence of
tissue hypoperfusion despite fluid optimisation.
• Generally recommended therapeutic targets of
haemodynamic parameters are:
1. MAP 65-75 mmHg.
2. CI > 2.5 [l/min/m2].
3. SVR 800-1000 (dyne/s/m-5).
4. SVO2 > 65%.
5. CPI > 0.6 [w/m2). (MAP x cardiac index x 0.0022).
• All of which aim to improve organ perfusion with the
minimized use of vasoactive drugs and heart rate <110
bpm.

7. Simplified schematic of postulated intracellular actions of beta -adrenergic agonists

8. Dobutamine
• β1 >>>β2>>α1 (β1: β2 = 3:1).
• Inotropic (increase CO), Mild Chronotropic and
vasodilation: < 5micg/kg/min.
(At higher doses >15, peripheral effect becomes vasoconstriction).
 Should be avoided if SBP < 80 mmHg.
 Worsening ischemia due to (increase O2 consumption).
 ? Loss of efficacy in patients on chronic beta blocker
therapy/acidosis/hypoxia.
AF, Ventricular arrhythmias (rare).
 Tolerance after 48h.
CONTRAINDICATION : Hypotension and HOCM.

9. DOPAMINE
<3 mcg 3 - 10 mcg > 10 mcg
↑Contractility
Minimal change in
HR and SVR
↑ Renal BF
↑ Splanchnic BF
Modest ↑ CO
↑ Renal BF
↓Proximal Tub.
Na Absorbtion
↑ Splanchnic BF
↑ HR,
Vasoconstriction
↑/ ↓ Renal BF
↓/↑ Splanchnic BF
 Dose Dependent effect of Dopamine.
D > β1> α1>> β2.
Tachycardia, Tachyarrythmias, and Worsening ischemia.

10. NOREPINEPHRINE
α1>>β1> β2
 Powerful vasopressor, modest
inotropic effects, Less chronotropic.
 Predominantly a vasoconstrictor and
a weak inotrope.
As a vasopressor:
100-fold more potent than dopamine.
3 to 5 times more potent than
phenylephrine for raising MAP.
 Cardiotoxic at high doses due to
apoptosis in experimental models.
( PKA mediated).

11. SOAP II trial
Norepinephrine is preferred over dopamine when blood pressure is low. (IIB/B)
Medical support with inotropes and vasopressor agents should be individualized
and guided by invasive hemodynamic monitoring. Use of dopamine in
this setting may be associated with excess hazard.
De Backer et al. NEJM 2010;369:779-789
2012 ESC Guidelines for the management of acute myocardial infarction in patients presenting with
STEMI
Comparison of norepinephrine and dopamine in the
treatment of shock (SOAP-II trial)

12. EPINEPHRINE
α1 predominantly
Vasoconstriction
↓ Renal BF.
↓ Splanchnic BF.
↑ Glucose.
β1 predominantly
↑HR.
↓ Duration of Systole.
↑ Myocardial contract
Periph. arteriolar dilt.
↑/ ↓ Renal BF.
↑ Renin secretion.
↑/ ↓ Splanchnic BF.
↑ Glucose.
Hypokalemia.
Epinephrine
Low Dose
(< 0.05-0.1 mcg/kg/min)
High Dose
(> 0.1 μg/kg/min)

13. Adrenaline Independent Predictor of
Survival curves for use of adrenaline
Mortality
Propensity score: age, gender, medical history (myocardial infarction, coronary artery bypass graft surgery, hypertension, renal insufficiency), acute
coronary syndrome as the etiology of cardiogenic shock, resuscitation prior to inclusion and initial presentation (confusion, blood lactate, creatinine,
systolic blood pressure, sinus rhythm, and left ventricular ejection fraction).
Tarvasmaki T et al. Crit Care Med 2016;20:208

14. Adrenaline Use Related to Deterioration in
Cardiac and Renal Biomarkers in CS
Tarvasmaki T et al. Crit Care Med 2016;20:208
Adrenaline use associated with markedly worse evolution of cardiac and renal biomarker levels over the
initial 96 hours; likely due to an increase in myocardial oxygen consumption, excessive vasoconstriction
and/or direct organ toxic damage due to intense adrenergic stimulation.

15. Epinephrine vs Norepinephrine in AMI Related CS
Levy B. et al. J Am Coll Cardiol. 2018;72(2):173–82
similar effects on arterial pressure and cardiac
index but a higher incidence of refractory
shock with epinephrine.

16. Phosphodiesterase inhibitor
• Bypiridine:
Amrinone.
Milrinone.
• Imidazole
 Enoximone.
 Piroximone.

17. PDIs - MILRINONE
 Vasodilation > positive inotropy..
 Inotropic, Chronotropic, Lusitropic.
Systemic circulation effects:
- Vasodilation.
- Increased organ perfusion.
- Decreased SVR.
- Decreased arterial pressure.
Cardiopulmonary effects:
- Increased contractility and heart rate.
- Increased stroke volume and EF.
- Decreased ventricular preload.
- Decreased PCWP.

18. Milrinone
Minimal ↑
in O2
demand
↓
SVR
↓
PVR
Minimal ↑ HR
↑ CO
Diastolic
Relaxation

19. Milrinone- Clinical application
The main use is in reducing RV afterload and in
advanced non-ischaemic cardiomyopathies.
 Theoretical advantages compared to β agonists :
- Chronotropic effect is less than β agonists.
- Less tachycardia for AF patients.
- Better efficacy for those on chronic BB therapy.
- Lusitropic and vasodilatory effects (esp. pulmonary).
 Loading dose: 50 mcg/kg administered over 10 minutes
followed by 0.375 mcg/kg/minute.
(However more expensive, hypotension and prolonged action).

20. CALCIUM
SENSETIZING
AGENTS

22. Pollesello P, Papp Z. J Cardiovasc Pharmacol 2007;50:257-63
Molecular targets, mechanisms of action
and pharmacological effects of levosimendan
Molecular
targets
Mechanisms of
action
Pharmacological
effects
Therapeutic
effects
Selective binding
to the calcium-
saturated form of
cardiac troponin C
Calcium sensitization
of contractile proteins
Positive inotropy Increased ejection fraction
Anti-stunning
Opening of KATP
channels on
smooth muscle
cells in vasculature
Membrane hyper-
polarization.
Vasodilation in all vascular
beds (also coronary and
peripheral circulation).
Lower pre- and afterload
Anti-ischaemic Tissue
perfusion.
Opening of KATP
mitochandria
channels in
cardiomyocytes
Protection of
mitochondria in
ischaemia-reperfusion
Pre-conditioning Anti-
apoptotic
Cardioprotection Anti-
ischaemic Long-term
benefits

23. Levosimendan - Pharmacology
• Loading :Loading : 12-24µg/kg over 10 min.12-24µg/kg over 10 min.
• Infusion:Infusion: 0.05-0.2µg/kg/min.0.05-0.2µg/kg/min.
• Active metabolite – OR-1896 (half life of 80 hours) –
responsible for prolonged action upto several days
after stopping infusion.
Side effects
• Hypotension 4%–10% of patients, depending on
the dose and use of a bolus.
• Headache.
• Arrhythmias: ventricular extra-systoles, and sinus
tachycardia, occurred mainly or exclusively at
higher doses.

25. LEVOSIMENDAN - Evidence
• Significant mortality benefit for critically ill
patients with heart failure and patients
undergoing cardiac surgery.
(Metanalysis from 11 controlled trials (2009)
• Improves mortality after coronary
revascularisation compared to standard therapy.
(Critical Care 2011)
Only intravenous positive inotrope that has had a
mortality benefit consistently.
Uniform physiological benefits for coronary, renal
and G.I systems.
“ALL THESE DATA SUPPORT THE USE OF LEVOSIMENDAN
IN POST MI CARDIOGENIC SHOCK PATIENTS FOR ITS
CALCIUM SENSITIZING , INOTROPIC AND ANTI
MYOCARDIAL STUNNING PROPERTIES”

26. COMPARISON BETWEEN LEVOSIMENDAN,
MILRINONE AND DOBUTAMINE
Feature Levosimendan Milrinone Dobutamine
Class Calcium channel Phosphodiesterase-III Catecholamine(β-
sensitizer inhibitor adrenergic agent)
↑intracellular Ca No Yes Yes
concentrations
Vasodilator Coronary and Peripheral Mild peripheral
systemic
↑Myocardial O₂ No No Yes
demand
Arrhythmogenic Rare and may be
due potential
Ventricular and Ventricular ectopic
to QTc prolongation supraventricular activity; less
arrhythmias arrhythmogenic than
milrinone
Adverse events Headache, Ventricular Tachycardia and
hypotension irregularities, increased SBP on
hypotension,
headache
overdosage

28. Risks of Inotropes and Vasopressors in CS
Van Diepen S. J Am Coll Cardiol. 2018;72(2):183

29. What Do The ESC Guidelines 2016 Say?
Recommendations for inotropic agents and vasopressors in patients
with cardiogenic shock
Short-term, i.v. infusion of inotropic agents may be
considered in patients with hypotension (SBP <90 mmHg)
and/or signs/symptoms of hypoperfusion despite
adequate filling status, to increase cardiac output, increase
blood pressure, improve peripheral perfusion and maintain
end-organ function.
IIb C
An intravenous infusion of levosimendan or a PDE III
inhibitor may be considered to reverse the effect of beta-
blockade if beta-blockade is thought to be contributing to
hypotension with subsequent hypoperfusion.
IIb C
Inotropic agents are not recommended unless the patient is
symptomatically hypotensive or hypoperfused because of
safety concern.
III A
556,
557

30. What Do The ESC Guidelines Say?
Recommendations for inotropic agents and vasopressors in patients
with cardiogenic shock
A vasopressor (norepinephrine preferably) may be
considered in patients who have cardiogenic shock, despite
treatment with another inotrope, to increase blood pressure
and vital organ perfusion.
IIb B
558
It is recommended to monitor ECG and blood pressure when
using inotropic agents and vasopressors, as they can cause
arrhythmia, myocardial ischaemia, and in the case of
levosimendan and PDE III inhibitors also hypotension.
I C
540,
559
-563
In such cases intra-arterial blood pressure measurement may
be considered. IIb? C

31. 31
Emergency Management of Complicated STEMIEmergency Management of Complicated STEMI
Administer
• Fluids
• Blood transfusions
• Cause-specific
interventions
Consider vasopressors
Arrhythmia
Bradycardia Tachycardia
Systolic BP
Greater than 100 mm Hg
Systolic BP
70 to 100 mm Hg
NO signs/symptoms
of shock
Systolic BP
70 to 100 mm Hg
Signs/symptoms
of shock
Systolic BP
less than 70 mm Hg
Signs/symptoms of shock
Dobutamine
2 to 20
mcg/kg per
minute IV
Low Output -
Cardiogenic Shock
Nitroglycerin
10 to 20 mcg/min IV
Dopamine
5 to 15
mcg/kg per
minute IV
Norepinephrine
0.5 to 30 mcg/min IV
Hypovolemia
Administer
• Furosemide IV 0.5 to 1.0 mg/kg
• Morphine IV 2 to 4 mg
• Oxygen/intubation as needed
• Nitroglycerin SL, then 10 to 20 mcg/min IV if SBP
greater than 100 mm Hg
• Dopamine 5 to 15 mcg/kg per minute IV if SBP 70 to
100 mm Hg and signs/symptoms of shock present
• Dobutamine 2 to 20 mcg/kg per minute IV if SBP 70
to 100 mm Hg and no signs/symptoms of shock
FirstlineofactionSecondlineofactionThirdlineofaction
See Section 7.7
in the ACC/AHA Guidelines for
Patients With ST-Elevation
Myocardial Infarction
Check Blood Pressure
Clinical signs: Shock, hypoperfusion, congestive heart failure, acute pulmonary edema
Most likely major underlying disturbance?
Further diagnostic/therapeutic considerations (should be considered in
nonhypovolemic shock)
Diagnostic Therapeutic
♥ Pulmonary artery catheter ♥ Intra-aortic balloon pump
♥ Echocardiography ♥ Reperfusion/revascularization
♥ Angiography for MI/ischemia
♥ Additional diagnostic studies
Acute Pulmonary Edema
Check Blood Pressure
Systolic BP
Greater than 100 mm Hg
and not less than 30 mm Hg
below baseline
ACE Inhibitors
Short-acting agent such as
captopril (1 to 6.25 mg)
Circulation 2000;102(suppl I):I-172-I-216.

32. 32Antmen, JACC, 2004;44:671

33. Inotropes and Vasopressors
ACC/AHAGuidelines
BP <70:-
 Norepinephrine (0.5-30 micg/min)
Switch to Dopamine (5-15 micg/kg/min) once SBP ≥80
 SBP 70-100
 Dopamine (5-15 micg/kg/min)
Add dobutamine (2-20 micg/kg/min) once SBP ≥90.
• Refractory hypotension + shock:
→ Amrinone or milrinone may improve cardiac output.
→ Levosimendan may be preferable if patient on chronic BB.

34. Newer
Inotropic
Agents
• Cardiac myosin activators-
Omecamtive mecarbil.
• Na/K-ATPase inhibitors-
Istaroxime.
• Ryanodine receptor stabilizers
JTV-519(K201),
S107,
S44121
• SERCA2a activators-
MYDICAR

35. Inotropic mechanisms and drugs (Hasenfuss & Teerlink, EHJ 2011)
Inotropic mechanism Drugs Comments (MSN)
Sodium-Potassium ATPase
inh.
Digoxin Mild inotrope, diastolic dysfunction, vagal, arrythmias
B-adrenoreceptor stimulation Dobutamine, Dopamine HR increase, arrythmias
A and B adrenoreceptor
stimulation
Adrenaline,
Noradrenaline
Vasoconstriction, HR and arrythmias
PDE inhibition Enoximone, milrinone HR inc, Vasodilatation, some inotropic effect,
arrythmias
Calcium sensitation Levosimendan Mild inotrope, calcium sensitisation, impr.
mitochonrial function, vasodilatation, HR may
increase, hypotension related to arrythmias
Acto-myosin cross-bridge
activation
Omecamtiv mecarpil Prolongs contractile phase, further evidence needed
SERCA activation Gene transfer Applied in chronic HF
SERCA activation +
vasodilatation
Nitroxyl donor, CLX-
1020
No study results posted at clinicaltrials.cov
Ryanodine receptor
stabilization
S44121 No studies registered
Sodium-potassium cross-
bridge activation + SERCA
activation
Istaroxime Istaroxime decreases PCWP, increases SBP, and
decreases diastolic stiffness in patients with acute
heart failure syndrome. Program ongoing, some study
withdrawals
Energetic modulation Etoximir, pyruvate No studies registered

36. New inotropic agents
Hasenfuss, et al. Eur Heart J 2011;32:1838-
1845
Istaroxime:
Inotropic effect ∼inhibition of Na-K
ATPase
Lusitropic effect ∼stimulation of SERCA 2a.
•↑ systolic blood pressure.
•↓ heart rate.
Myosin activators
(e.g. Omecamtiv mecarbil):
•↑ rate of effective myosin cross-bridge
formation.
→ ↑ duration of myocyte contraction.
•No effect on cAMP or calcium.

37. OMECANTIV
MECARBIL
Cardiac Specific Myosin
Activator.
•Stimulate myosin-ATPase
Accelerates the rate of actin-
dependent phosphate release from
the actin-myosin crossbridge
Promotes transition to the force
producing on-state of the cross
bridge
More cross-bridges activated per
unit time
Increased contractile force

38. Omecamtiv Mecarbil
[cardiac myosin activators]
Cleland JG, Teerlink JR, Senior R, et al.
The effects of the cardiac myosin activator, omecamtiv mecarbil, on
cardiac function in systolic heart failure: A double-blind, placebo-
controlled, crossover, dose-ranging phase 2 trial.
Lancet 2011
•Double blind, placebo controlled, dose ranging trial
•Infusions: 2 vs. 24 vs. 72 hr
•Plasma drug concentration measured at the end of each infusion
•Safety and tolerability assessed
•45 patients
38
Noveltherapies
Plasma concentration dependent effects
↑ ventricular ejection time with no change in dp/dt
Small ↓ in heart rate
Reduction in end-systolic and end-diastolic volumes
↑ cardiac ischemia
ATOMIC-AHF trial underway

39. 70%
60%
50%
40%
30%
20%
10%
0%
Tilarginine 48%
42%
Placebo
Tilarginine: Placebo
RR: 1.14
95% CI: 0.92-1.41
P=0.24
0 5 10 15 20 25 30
Days from randomization
JAMA. 2007;297(15):1657-1666.
30day-Mortality
Effect of Tilarginine Acetate in Patients With Acute
Myocardial Infarction and Cardiogenic Shock
The TRIUMPH Randomized Controlled Trial

40. Cyclosporine
Cyclosporine is another new drug which has been
proposed for reduction of re-perfusion injury in
cases of large size AMI complicated with CS. The
CLOTILDE trial (Cyclosporine in Acute Myocardial
Infarction Complicated by Cardiogenic Shock,
NCT01901471), tested the hypothesis that
administration of cyclosporine during the
reperfusion phase of AMI would reduce the
infarct size by 20-40%, reduce the risk of multi-
organ failure and improve the clinical status of
these patients.

41. GLUCAGON
• Increases cardiac output by approximately 20%,
which is associated with a decrease in
peripheral vascular resistance with less
myocardial oxygen demand when compared
with norepinephrine.
• Administer this agent to patients with
cardiogenic shock who do not respond to
conventional therapy or cannot tolerate other
agents because of the development of
significant arrhythmias or hematologic toxicity.

42. GENE THERAPY
• To increase sarcoplasmic reticulum calcium
pump activity by stimulating the calcium
pumps.
• Most approaches are related to reduced SR
calcium uptake, however, abnormal SR leak
has also been considered.
• It has been shown in isolated myocytes that
overexpression of the RyR-regulatory protein
FKBP12.6 increases SR calcium content and
fractional shortening.

43. Summary
 Treatment of cardiogenic shock relies mainly on
Revasuclarization and mechanical support.
 INOTROPES INDICATED Only if symptoms and signs of
congestion and hypoperfusion are present.
 INOTROPES May be useful as initial therapy bridging
to MCS + definitive therapy (Revasc, LVAD, transplant).
 Inotropes and pressors are associated with either no
benefit or worse outcomes.
 Use the lowest dose able to achieve desired targets
(resolution of hypoperfusion and end organ damage)
and for the shortest possible time.
 No RCT demonstrating clear clinical benefit for any
drug, Inotrope of choice based on local expertise.

44. Summary
 In spite of this, virtually all cardiogenic shock patients
receive treatment with catecholamines usually a
combination of inotrope and vasopressor.
 Accumulating evidence favors norepinephrine over
dopamine.
 Adrenaline (and dopamine) use seem to be associated
with increased mortality.
 PDE III inhibitors or levosimendan should be favoured
in patients on beta-blockers and levosimendan in
patients with decompensated chronic heart failure or
for postoperative cardiac stunning.
 Positive long-term effects of levosimendan on mortality
are still controversial.

45. THANK YOU