Which inotrope ?
Pr Antoine Kimmoun
France
No conflict of interest
Inodilatators
Agents with both positive inotropic and vasodilator effects
Should be used in low cardiac output patients resulting in tissular
hypoperfusion with maintained diastolic arterial pressure
• Dobutamine
• Calcium sensitizer
• Type 3 Phosphodiesterase inhibitors
agonists : Dobutamine
agonists : Dobutamine
Assessment at bedside :
No study versus placebo in cardiogenic shock
Tacon C.L et al. Intensive Care Med 2012
Calcium sensitizers
Levosimendan binds on troponin c
Enhance calcium sensitization of troponin c
Increase contractility
Antoniades,C et al. Pharmacol Ther 2007
Calcium sensitizer: Levosimendan versus
Dobutamine
664 663
Mebazaa A, et al. JAMA 2007
Calcium sensitizer: Levosimendan versus
Dobutamine
664 663
Mebazaa A, et al. JAMA 2007
Calcium sensitizer: Levosimendan versus
Dobutamine
Mebazaa A, et al. JAMA 2007
Calcium sensitizer: Levosimendan versus
Dobutamine
Mebazaa A, et al. JAMA 2007
Landoni V.V et al. N Engl J Med 2017
Levosimendan just cardiac surgery (stage C)
Multicenter randomized, levosimendan vs placebo, patient in cardiogenic shock B/C after CPB, Objective: 30-d
Vasoactive-inotropic score at 13
Stopped for futility Low dose of norepinephrine: 0.07 µg/kg/min
Chollet B et al. JAMA 2017 Metha R.H et al. N Engl J Med 2017
Levosimendan before cardiac surgery (Stade A)
Multicenter randomized, levosimendan vs placebo, patients with LVEF<35% randomized before cardiac su
Objective: composite score (30-day mortality, 30-day RRT, MI by day 5, assistance by day 5
Neutral effect on the composite score Similar results in French Licorn study
Calcium sensitizer: Levosimendan versus
Dobutamine
Uhlig K et al. Cochrane Database Syst Rev 2020
Type 3 Phosphodiesterase inhibitors
PDE3
inhibitor
Adenylate PDE3
ATP
ATP
cyclase cAMP
cAMP AMP
Ca2+
Type 3 Phosphodiesterase inhibitors:
Milrinone versus dobutamine
Mathew R et al. Engl J Med 2021
Which specific inodilatator should we use?
No clear indication on which is the prefered inodilatator
Eur Heart J 2021
Which specific inodilatator should we use?
Eur Heart J 2021
Inopressors
Molecules used to induce vasoconstriction and to increase cardiac contractility
Should be used in patients with low cardiac output resulting in both tissular hypoperfusion
AND vasodilatation (inflammation)
• Dopamine
• Norepinephrine
• Epinephrine
agonists : Dopamine at intermediate and high
doses
Tyrosine
Dopa
Dopamine
1 1 2
Norepinephrine
agonists : Dopamine
Tyrosine > 2.5 μg/kg/min
< 5 μg/kg/min
Dopa
Inotropic effect
Dopamine
1 1 2
Norepinephrine
agonists : Dopamine versus norepinephrine
Tyrosine
Dopa
Dopamine
1 1 2
Norepinephrine
De Backer D, at al. NEJM 2010
agonists : Dopamine versus norepinephrine
Tyrosine
Dopa
Dopamine
1 1 2
Arrhythmias Don’t use Dopamine in cardiogenic shock
Norepinephrine
De Backer D, at al. NEJM 2010
agonists: Norepinephrine and epinephrine
agonists: Norepinephrine versus Epinephrine
Levy B et al. JACC 2018
agonists: Norepinephrine versus Epinephrine
Main outcome
No difference in MAP and CI Levy B et al. JACC 2018
agonists: Norepinephrine versus Epinephrine
Noradrénaline
Adrénaline
⬈ heart rate Similar stroke volume index
Levy B et al. JACC 2018
agonists: Norepinephrine versus Epinephrine
Norepinephrine >> Epinephrine
in CS patients
More refractory cardiogenic shock in the epinephrine group
Levy B et al. JACC 2018
agonists: Norepinephrine versus Epinephrine
Meta regression : Mortality increase
with the use of epinephrine
16 cohorts
Leopold V et al. Intensive Care Med 2018
agonists: Norepinephrine versus Epinephrine
Eur Heart J 2021
Kill the dogma!!
Norepinephrine does not decrease coronary flow
normal mammalian (ewes) Septic shock mammalian (ewes)
placebo
NE
Norepinephrine : 0.4 gamma/kg/min
Norepinephrine : 0.4 gamma/kg/min
Kill the dogma!!
Norepinephrine does not decrease coronary flow
but increase cardiac output
normal mammalian (ewes) Septic shock mammalian (ewes)
NE
placebo
Norepinephrine : 0.4 gamma/kg/min
Norepinephrine : 0.4 gamma/kg/min
In septic shock, cardiac function is
impaired
30% of patients
Initial EF <40%
Recovery at D7
70% of patients in ≈ 100%
Initial EF > 40%
Viellard Baron AJRCCM 2003
EF is not a universal marker of severity in septic
cardiomyopathy
Pré load LVEF Post load
EF <40 % = CI< 2.5 l/min/m2 Post load Post load Werdan Clin Res Cardiol 2011
Viellard Baron AJRCCM 2003
Doesn’t do the job or harmful in septic
shock
Levosimendan in multiple organ failure from septic
shock
Multicenter randomized, levosimendan vs. placebo, patient in septic shock,
primary endpoint: daily SOFA score up to 28 days
Neutral effect on SOFA score
⬈ arrythmias on levosimendan
Neutral effect on mortality
Low mortality!
Gordon A .C et al. N Engl J Med 2016
Non selective nitric oxide synthase inhibitor
increased mortality in septic shock.
Multiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy
study. Primary efficacy objective was survival at day 28
More CV death in NO group
Mortality higher in NOi group
Lopez A .C et al. Crit care Med 2004
We don’t really know if it does the job in
septic shock
Dobutamine
No RCT compared dobutamine to placebo in this population
None of the trials directly compared dobutamine combined
with norepinephrine to norepinephrine alone
We honestly still don’t know in 2024
Surviving sepsis campaign 2021
We know it does the job in septic shock
Norepinephrine or Norepinephrine +
dobutamine
Martin et al. Crit care med 1999
Epinephrine
Prospective, multicentre, randomised, double-blind study done in 330 patients with septic shock admitted to
one of 19 participating intensive care units in France. Intervention: epinephrine or norepinephrine plus
dobutamine. Primary outcome: 28-day all-cause mortality
No difference
Time to haemodynamic success
Annane et al. Lancet 2007
How to use them at bedside?
Based on very poor evidence and thus it is a personal view
The SCAI Pyramid
Baran D.A.et al. Catheter Cardiovasc Interv. 2019
Description of CS stages
Baran D.A.et al. Catheter Cardiovasc Interv. 2019
Inotrope/vasopressor use: Stage C
First line Inotrope/vasopressor
Low CI
dobutamine
Low SP
Hypoperfusion Lactate or
Sustained
signs Creatinine levosimendan/milrinone
(relatively) If betablockade
DP
Baran D.A.et al. Catheter Cardiovasc Interv. 2019
Inotrope/vasopressor use: Stage D
First line Inotrope/vasopressor
norepinephrine
Low CI
Hypoperfusion Lactate and after DP stabilization
Low SP
signs Creatinine Dobutamine (at low
Low DP
doses)
Baran D.A.et al. Catheter Cardiovasc Interv. 2019
Inotrope/vasopressor use: Stage E
First line Inotrope/vasopressor
Low CI
Hypoperfusion Lactate Low SP
Anuria Low DP
ECMO
signs
Acute liver failure Despite maximal
Baran D.A.et al. Catheter Cardiovasc Interv. 2019
treatment
Conclusion
First line Inotrope/vasopressor
Low CI
dobutamine
Low SP
Hypoperfusion Lactate or
Sustained
signs Creatinine levosimendan/milrinone
(relatively) If betablockade
DP
norepinephrine
Low CI
Hypoperfusion Lactate and after DP stabilization
Low SP
signs Creatinine Dobutamine (at low
Low DP
doses)
Low CI
Hypoperfusion Lactate Low SP
Anuria Low DP
ECMO
signs
Acute liver failure Despite maximal
Baran D.A.et al. Catheter Cardiovasc Interv. 2019
treatment
Summary for septic shock
Quality of evidence Low
Dobutamine or epinephrine
Quality of evidence Low No levosimendan
Quality of evidence Low
