Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion (ADAPT)

Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion: a Randomized Controlled Multi-center Trial

Sepsis induces both a systolic and diastolic cardiac dysfunction. The prevalence of this septic cardiomyopathy ranges between 30 and 60% according to the timing of assessment and definition used. Although the prognostic role of septic cardiomyopathy remains debated, sepsis-induced left ventricular (LV) systolic dysfunction may be severe and associated with tissue hypoperfusion, while it appears to fully recover in survivors. Accordingly, optimization of therapeutic management of septic cardiomyopathy may contribute to improve tissue hypoperfusion in increasing oxygen delivery, and to reduce related organ dysfunctions in septic shock patients. Echocardiography is currently the recommended first-line modality to assess patients with acute circulatory failure. Current Surviving Sepsis Campaign strongly recommends Norepinephrine as the first-choice vasopressor in fluid-filled patients with septic shock. In contrast, the use of Dobutamine is only suggested (weak recommendation, low quality of evidence) in patients with persistent tissue hypoperfusion despite adequate fluid resuscitation and vasopressor support. Levosimendan, an alternative inodilator, has failed preventing acute organ dysfunction in septic patients and has induced more supraventricular tachyarrhythmias than in the control group. Data supporting Dobutamine in this setting are scarce and primarily physiologic and based on monitored effects of this drug on hemodynamics and indices of tissue perfusion. No randomized controlled trials have yet compared the effects of Dobutamine versus placebo on clinical outcomes. In open-labelled, small sample trials, the ability of septic patients to increase their oxygen delivery during Dobutamine administration appears to be associated with lower mortality. The tested hypothesis in the ADAPT trial is that Dobutamine will reduce tissue hypoperfusion and associated organ dysfunctions in patients with septic shock and associated septic cardiomyopathy. In doing so, it may participate in improving clinical outcomes.

Placebo will initially be started at a dose of 2.5 µg/kg/min and subsequently titrated using incremental steps (predefined durations) of 2.5 µg/kg/min, up to a maximal dose of 10 µg/kg/min

Dobutamine will initially be started at a dose of 2.5 µg/kg/min and subsequently titrated using incremental steps (predefined durations) of 2.5 µg/kg/min, up to a maximal dose of 10 µg/kg/min

Placebo will initially be started at a dose of 2.5 µg/kg/min and subsequently titrated using incremental steps (predefined durations) of 2.5 µg/kg/min, up to a maximal dose of 10 µg/kg/min. Dose adaptation will be left at the discretion of attending physician.

Dobutamine will initially be started at a dose of 2.5 µg/kg/min and subsequently titrated using incremental steps (predefined durations) of 2.5 µg/kg/min, up to a maximal dose of 10 µg/kg/min. Dose adaptation will be left at the discretion of attending physician.

Evolution of a modified Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) score (no gradation of the neurologic system) between baseline (before randomization) and Day 1, Day 2 and Day 3 after randomization. Min value =0. Max value =20 . The highest score means the worst situation

Biological indices of tissue dysoxia at baseline, hour 6, Day1, Day 2 and Day 3 after initiating Dobutamine / placebo

Biological indices of tissue dysoxia at baseline, hour 6, Day1, Day 2 and Day 3 after initiating Dobutamine / placebo

Requirement of organ function supports during ICU stay. Maximal dose in mcg/kg/min of open-labelled Dobutamine used as rescue therapy

Requirement of organ function supports during ICU stay. Duration in days of open-labelled Dobutamine used as rescue therapy

Requirement of organ function supports during ICU stay. Maximal dose in mg/h by day of vasopressor support

Requirement of organ function supports during ICU stay. Number of session of renal replacement therapy (excluding hemodialysis patient for chronic renal failure at the time of randomization)

Requirement of organ function supports during ICU stay. Duration of renal replacement therapy (excluding hemodialysis patient for chronic renal failure at the time of randomization)

Systolic, diastolic and mean arterial blood pressure (in mmHg) at Baseline, h6, Day 1, Day 2 and Day3after initiating Dobutamine / placebo

Heart rate measurement in bpm at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo

Central venous pressure in cm H2O at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo

Cardiac index measurement in L/min/m2 at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo

Stroke volume measurement in mL status at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo

Severe cardiovascular adverse events from inform consent to ICU discharge : Hypotension related to worsened vasoplegia

Severe cardiovascular adverse events from inform consent to ICU discharge. Supraventricular arrhythmias with ventricular rate > 140 bpm

Number of days free from vasopressor support, invasive mechanical ventilation, renal replacement therapy from inform consent to ICU discharge

Leucocyte subsets level according to the severity of the sepsis-induced LV systolic dysfunction and hemodynamic effects of the study drug administration

tumor necrosis factor (TNF) -α, Interferon ɣ, Interleukin-6, 8 and 10 cytokines concentration will be assess according to the severity of the sepsis-induced LV systolic dysfunction and hemodynamic effects of the study drug administration. Result for each cytokine concentration will be given in picograms per milliliter.

deformation of right ventricular myocardial tissue / routinely using with echocardiography or post exam analysis

Cardiac output measurement with echocardiography Doppler (in centers routinely using transpulmonary thermodilution). Quality of left ventricular contraction

Ratio between systolic and diastolic right ventricular volume / routinely using with echocardiography

Cardiac output measurement with echocardiography Doppler (in centers routinely using transpulmonary thermodilution). Quality of right ventricular contraction

In selected centers routinely using continuous monitoring of cardiac output using transpulmonary thermodilution: agreement of cardiac output measurement with echocardiography Doppler.

Inclusion Criteria: Age > 18 years hospitalized in ICU > Septic shock (Sepsis-3 definition): Clinically suspected or documented acute infection Responsible for organ dysfunction(s): change in SOFA ≥ 2 points With persisting hypotension (systolic and/or mean arterial pressure < 90 / < 65 mmHg) despite adequate fluid resuscitation (≥ 30 mL/kg, unless presence of pulmonary venous congestion) Requiring vasopressor support (Norepinephrine) to maintain steady mean arterial pressure ≥ 65 mmHg And lactate > 2 mmol/L Septic cardiomyopathy: echocardiographically measured LV ejection fraction (EF) ≤ 40% and LV outflow tract velocity-time integral < 14 cm Informed consent Exclusion Criteria: Pregnancy or breast feeding Hypersensitivity to Dobutamine, 5% Dextrose, or to the excipients Ventricular rate > 130 bpm (sinus rhythm or not) Severe ventricular arrhythmia Obstructive cardiomyopathy with pressure gradient at rest ≥ 50 mmHg unrelated to uncorrected hypovolemia Severe aortic stenosis: mean gradient > 40 mmHg, peak aortic jet velocity > 4 m/s, aortic valve area < 1 cm² (aortic valve area index < 0.6 cm²/m²) Acute coronary syndrome Decision to limit care or moribund status (life expectancy < 24 h) Absence of affiliation to Social Security Subjects under juridical protection.