Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion

Phase 3

Recruiting

• Conditions: Sepsis; Cardiomyopathies; Hypoperfusion; Left Ventricular Systolic Dysfunction
• Interventions: Drug: Placebos; Drug: Dobutamine

• Registration Number: NCT04166331
• Lead Sponsor: University Hospital, Limoges

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-10-25
• Study First Submitted QC: 2019-11-15
• Study First Posted: 2019-11-18
• Study Start: 2020-09-20
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-16
• Last Update Posted: 2025-01-17
• Primary Completion: 2025-12-20
• Study Completion: 2025-12-20

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 270

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control	Placebos	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
Experimental	Dobutamine	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

Primary Outcome Measures

Name	Time	Method
Sequential Organ Failure Assessment (SOFA) score evolution	Day 0 to Day 3	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

Secondary Outcome Measures

Name	Time	Method
Renal replacement therapy number	through study completion, an average of 90 days	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)
Renal replacement therapy duration	through study completion, an average of 90 days	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)
Circulating lactate level measurement	Hour 0, Hour 6, Day 1, Day 2 and Day 3	Biological indices of tissue dysoxia at baseline, hour 6, Day1, Day 2 and Day 3 after initiating Dobutamine / placebo
Central venous oxygen saturation (ScvO2) measurement	Hour 0, Hour 6, Day 1, Day 2 and Day 3	Biological indices of tissue dysoxia at baseline, hour 6, Day1, Day 2 and Day 3 after initiating Dobutamine / placebo
Open-labelled Dobutamine dayly maximal dose used as rescue therapy	through study completion, an average 90 days	Requirement of organ function supports during ICU stay. Maximal dose in mcg/kg/min of open-labelled Dobutamine used as rescue therapy
Open-labelled Dobutamine duration used as rescue therapy	through study completion, an average of 90 days	Requirement of organ function supports during ICU stay. Duration in days of open-labelled Dobutamine used as rescue therapy
Vasopressor support duration	through study completion, an average of 90 days	Requirement of organ function supports during ICU stay. Duration in days of vasopressor support
Vasopressor support dayly maximal dose	through study completion, an average of 90 days	Requirement of organ function supports during ICU stay. Maximal dose in mg/h by day of vasopressor support
Invasive mechanical ventilation duration	through study completion, an average of 90 days	Requirement of organ function supports during ICU stay. Duration of invasive mechanical ventilation
Arterial pressure measurement	Hour 0, Hour 6, Day 1, Day 2 and Day 3	Systolic, diastolic and mean arterial blood pressure (in mmHg) at Baseline, h6, Day 1, Day 2 and Day3after initiating Dobutamine / placebo
heart rate measurement	Hour 0, Hour 6, Day 1, Day 2 and Day 3	Heart rate measurement in bpm at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo
Central venous pressure measurement	Hour 0, Hour 6, Day 1, Day 2 and Day 3	Central venous pressure in cm H2O at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo
Cardiac index measurement	Hour 0, Hour 6, Day 1, Day 2 and Day 3	Cardiac index measurement in L/min/m2 at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo
Stroke volume measurement	Hour 0, Hour 6, Day 1, Day 2 and Day 3	Stroke volume measurement in mL status at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo
Hypotension measurement	Hour 0, Hour 6, Day 1, Day 2 and Day 3	Severe cardiovascular adverse events from inform consent to ICU discharge : Hypotension related to worsened vasoplegia
Supraventricular arrhythmias measurement	through study completion, an average of 90 days	Severe cardiovascular adverse events from inform consent to ICU discharge. Supraventricular arrhythmias with ventricular rate \> 140 bpm
Ventricular arrhythmias measurement	through study completion, an average of 90 days	Severe cardiovascular adverse events from inform consent to ICU discharge. Ventricular arrhythmias
Occurence of Acute coronary syndrome	through study completion, an average of 90 days	Severe cardiovascular adverse events from inform consent to ICU discharge. Acute coronary syndrome
Occurence of Stroke	through study completion, an average of 90 days	Severe cardiovascular adverse events during ICU stay. Stroke
Mortality	Day 90	Number of death
Mortality causes	Day 90	Cause of death
Organ function free supports	Day 90	Number of days free from vasopressor support, invasive mechanical ventilation, renal replacement therapy from inform consent to ICU discharge
Number of days in ICU and hospital	Day 90	Length of ICU and hospital stay
echocardiographic assessment of left ventricular systolic function	Day 0 and Day 1	ejection fraction measurement
Leucocyte subsets level	Hour 6	Leucocyte subsets level according to the severity of the sepsis-induced LV systolic dysfunction and hemodynamic effects of the study drug administration
Cytokines level	Hour 6	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.
LV global longitudinal strain measurement	Hour 6, Day 1, Day 2 AND Day 3	LV segmental deformation longitudinal analysis
RV free wall strain measurement	Hour 6, Day 1, Day 2 AND Day 3	deformation of right ventricular myocardial tissue / routinely using with echocardiography or post exam analysis
LV volume measurement	Hour 6, Day 1, Day 2 AND Day 3	Ratio between systolic and diastolic left ventricular volume / routinely using with echocardiography
LV ejection fraction measurement	Hour 6, Day 1, Day 2 AND Day 3	Cardiac output measurement with echocardiography Doppler (in centers routinely using transpulmonary thermodilution). Quality of left ventricular contraction
RV volume measurement	Hour 6, Day 1, Day 2 AND Day 3	Ratio between systolic and diastolic right ventricular volume / routinely using with echocardiography
RV ejection fraction measurement	Hour 6, Day 1, Day 2 AND Day 3	Cardiac output measurement with echocardiography Doppler (in centers routinely using transpulmonary thermodilution). Quality of right ventricular contraction
Transpulmonary thermodilution measurement	Hour 6, Day 1, Day 2 AND Day 3	In selected centers routinely using continuous monitoring of cardiac output using transpulmonary thermodilution: agreement of cardiac output measurement with echocardiography Doppler.

Trial Locations

Locations (26)

University Hospital; 🇫🇷 Brest, France

Angouleme Hospital; 🇫🇷 Angoulême, France

Argenteuil Hospital; 🇫🇷 Argenteuil, France

CH de Brive; 🇫🇷 Brive-la-Gaillarde, France

CH de Bethune; 🇫🇷 Béthune, France

CH de Cannes; 🇫🇷 Cannes, France

Aphp - Henri Mondor; 🇫🇷 Créteil, France

Dijon university hospital; 🇫🇷 Dijon, France

CH d'Haguenau; 🇫🇷 Haguenau, France

CH de Vendée; 🇫🇷 La Roche-sur-Yon, France

CHU de Grenoble-Alpes; 🇫🇷 La Tronche, France

CH de Versailles; 🇫🇷 Le Chesnay, France

Le Mans Hospital; 🇫🇷 Le Mans, France

Lille University Hospital; 🇫🇷 Lille, France

Limoges University Hospital; 🇫🇷 Limoges, France

HCL; 🇫🇷 Lyon, France

Montpellier University Hospital; 🇫🇷 Montpellier, France

CHU de Nancy; 🇫🇷 Nancy, France

Nice University Hospital; 🇫🇷 Nice, France

CHU Orléans - service de Réanimation; 🇫🇷 Orleans, France

Aphp - Ambroise Paré; 🇫🇷 Paris, France

Hôpital Cochin - service de Réanimation; 🇫🇷 Paris, France

Poitiers University Hospital; 🇫🇷 Poitiers, France

CHU Strasbourg - service de Réanimation; 🇫🇷 Strasbourg, France

CH de Toulon; 🇫🇷 Toulon, France

CHU Tours - Service de Réanimation; 🇫🇷 Tours, France