Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion

University Hospital, Limoges136 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Interventions

PlacebosDRUG

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.

DobutamineDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age \> 18 years hospitalized in ICU * \> Septic shock (Sepsis-3 definition): 1. Clinically suspected or documented acute infection 2. Responsible for organ dysfunction(s): change in SOFA ≥ 2 points 3. 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) 4. Requiring vasopressor support (Norepinephrine) to maintain steady mean arterial pressure ≥ 65 mmHg 5. 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.

Locations (21)

CHU Orléans - service de Réanimation

Orléans, Orleans, France

CHU Strasbourg - service de Réanimation

Strasbourg, Strasbourg, France

CHU Tours - Service de Réanimation

Tours, Tours, France

Angouleme Hospital

Angoulême, France

Argenteuil Hospital

Argenteuil, France

CH de Bethune

Béthune, France

University Hospital

Brest, France

CH de Brive

Brive-la-Gaillarde, France

CH de Cannes

Cannes, France

Aphp - Henri Mondor

Créteil, France

...and 11 more locations

Outcomes

Primary Outcomes

Sequential Organ Failure Assessment (SOFA) score evolution

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

Time frame: Day 0 to Day 3

Secondary Outcomes

Circulating lactate level measurement

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

Time frame: Hour 0, Hour 6, Day 1, Day 2 and Day 3

Central venous oxygen saturation (ScvO2) measurement

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

Time frame: Hour 0, Hour 6, Day 1, Day 2 and Day 3

Open-labelled Dobutamine dayly maximal dose used as rescue therapy

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

Time frame: through study completion, an average 90 days

Open-labelled Dobutamine duration used as rescue therapy

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

Time frame: through study completion, an average of 90 days

Vasopressor support duration

Requirement of organ function supports during ICU stay. Duration in days of vasopressor support

Time frame: through study completion, an average of 90 days

Vasopressor support dayly maximal dose

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

Time frame: through study completion, an average of 90 days

Invasive mechanical ventilation duration

Requirement of organ function supports during ICU stay. Duration of invasive mechanical ventilation

Time frame: through study completion, an average of 90 days

Renal replacement therapy number

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)

Time frame: through study completion, an average of 90 days

Renal replacement therapy duration

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)

Time frame: through study completion, an average of 90 days

Arterial pressure measurement

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

Time frame: Hour 0, Hour 6, Day 1, Day 2 and Day 3

heart rate measurement

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

Time frame: Hour 0, Hour 6, Day 1, Day 2 and Day 3

Central venous pressure measurement

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

Time frame: Hour 0, Hour 6, Day 1, Day 2 and Day 3

Cardiac index measurement

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

Time frame: Hour 0, Hour 6, Day 1, Day 2 and Day 3

Stroke volume measurement

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

Time frame: Hour 0, Hour 6, Day 1, Day 2 and Day 3

Hypotension measurement

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

Time frame: Hour 0, Hour 6, Day 1, Day 2 and Day 3

Supraventricular arrhythmias measurement

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

Time frame: through study completion, an average of 90 days

Ventricular arrhythmias measurement

Severe cardiovascular adverse events from inform consent to ICU discharge. Ventricular arrhythmias

Time frame: through study completion, an average of 90 days

Occurence of Acute coronary syndrome

Severe cardiovascular adverse events from inform consent to ICU discharge. Acute coronary syndrome

Time frame: through study completion, an average of 90 days

Occurence of Stroke

Severe cardiovascular adverse events during ICU stay. Stroke

Time frame: through study completion, an average of 90 days

Mortality

Number of death

Time frame: Day 90

Mortality causes

Cause of death

Time frame: Day 90

Organ function free supports

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

Time frame: Day 90

Number of days in ICU and hospital

Length of ICU and hospital stay

Time frame: Day 90

echocardiographic assessment of left ventricular systolic function

ejection fraction measurement

Time frame: Day 0 and Day 1

Leucocyte subsets level

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

Time frame: Hour 6

Cytokines level

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.

Time frame: Hour 6

LV global longitudinal strain measurement

LV segmental deformation longitudinal analysis

Time frame: Hour 6, Day 1, Day 2 AND Day 3

RV free wall strain measurement

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

Time frame: Hour 6, Day 1, Day 2 AND Day 3

LV volume measurement

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

Time frame: Hour 6, Day 1, Day 2 AND Day 3

LV ejection fraction measurement

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

Time frame: Hour 6, Day 1, Day 2 AND Day 3

RV volume measurement

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

Time frame: Hour 6, Day 1, Day 2 AND Day 3

RV ejection fraction measurement

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

Time frame: Hour 6, Day 1, Day 2 AND Day 3

Transpulmonary thermodilution measurement

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

Time frame: Hour 6, Day 1, Day 2 AND Day 3

Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion

Overview

Conditions

Interventions

Eligibility

Locations (21)

Outcomes

Primary Outcomes

Secondary Outcomes