Clinical trial NCT04166331: Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
Official title: Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion: a Randomized Controlled Multi-center Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Sepsis
Cardiomyopathies
Hypoperfusion
Left Ventricular Systolic Dysfunction
Keywords: sepsis
Cardiomyopathies
Hypoperfusion
Left Ventricular Systolic Dysfunction
Lead sponsor: University Hospital, Limoges
Sponsor class: OTHER
Collaborators: name: Centre d'Investigation Clinique 1415
First posted: 2019-11-18
Enrollment: 270
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Sequential Organ Failure Assessment (SOFA) score evolution
timeFrame: Day 0 to Day 3
Secondary outcomes:
measure: Circulating lactate level measurement
timeFrame: Hour 0, Hour 6, Day 1, Day 2 and Day 3
measure: Central venous oxygen saturation (ScvO2) measurement
timeFrame: Hour 0, Hour 6, Day 1, Day 2 and Day 3
measure: Open-labelled Dobutamine dayly maximal dose used as rescue therapy
timeFrame: through study completion, an average 90 days
measure: Open-labelled Dobutamine duration used as rescue therapy
timeFrame: through study completion, an average of 90 days
measure: Vasopressor support duration
timeFrame: through study completion, an average of 90 days
measure: Vasopressor support dayly maximal dose
timeFrame: through study completion, an average of 90 days
measure: Invasive mechanical ventilation duration
timeFrame: through study completion, an average of 90 days
measure: Renal replacement therapy number
timeFrame: through study completion, an average of 90 days
measure: Renal replacement therapy duration
timeFrame: through study completion, an average of 90 days
measure: Arterial pressure measurement
timeFrame: Hour 0, Hour 6, Day 1, Day 2 and Day 3
measure: heart rate measurement
timeFrame: Hour 0, Hour 6, Day 1, Day 2 and Day 3
measure: Central venous pressure measurement
timeFrame: Hour 0, Hour 6, Day 1, Day 2 and Day 3
measure: Cardiac index measurement
timeFrame: Hour 0, Hour 6, Day 1, Day 2 and Day 3
measure: Stroke volume measurement
timeFrame: Hour 0, Hour 6, Day 1, Day 2 and Day 3
measure: Hypotension measurement
timeFrame: Hour 0, Hour 6, Day 1, Day 2 and Day 3
measure: Supraventricular arrhythmias measurement
timeFrame: through study completion, an average of 90 days
measure: Ventricular arrhythmias measurement
timeFrame: through study completion, an average of 90 days
measure: Occurence of Acute coronary syndrome
timeFrame: through study completion, an average of 90 days
measure: Occurence of Stroke
timeFrame: through study completion, an average of 90 days
measure: Mortality
timeFrame: Day 90
measure: Mortality causes
timeFrame: Day 90
measure: Organ function free supports
timeFrame: Day 90
measure: Number of days in ICU and hospital
timeFrame: Day 90
measure: echocardiographic assessment of left ventricular systolic function
timeFrame: Day 0 and Day 1
measure: Leucocyte subsets level
timeFrame: Hour 6
measure: Cytokines level
timeFrame: Hour 6
measure: LV global longitudinal strain measurement
timeFrame: Hour 6, Day 1, Day 2 AND Day 3
measure: RV free wall strain measurement
timeFrame: Hour 6, Day 1, Day 2 AND Day 3
measure: LV volume measurement
timeFrame: Hour 6, Day 1, Day 2 AND Day 3
measure: LV ejection fraction measurement
timeFrame: Hour 6, Day 1, Day 2 AND Day 3
measure: RV volume measurement
timeFrame: Hour 6, Day 1, Day 2 AND Day 3
measure: RV ejection fraction measurement
timeFrame: Hour 6, Day 1, Day 2 AND Day 3
measure: Transpulmonary thermodilution measurement
timeFrame: Hour 6, Day 1, Day 2 AND Day 3
Other outcomes:
Locations:
city: Amiens
country: France
facility: University Hospital
city: Angoulême
country: France
facility: Angouleme Hospital
city: Argenteuil
country: France
facility: Argenteuil Hospital
city: Brest
country: France
facility: University Hospital
city: Brive-la-Gaillarde
country: France
facility: CH de Brive
city: Béthune
country: France
facility: CH de Bethune
city: Cannes
country: France
facility: CH de Cannes
city: Créteil
country: France
facility: Aphp - Henri Mondor
city: Dijon
country: France
facility: Dijon university hospital
city: Haguenau
country: France
facility: CH d'Haguenau
city: La Roche-sur-Yon
country: France
facility: CH de Vendée
city: La Tronche
country: France
facility: CHU de Grenoble-Alpes
city: Le Chesnay
country: France
facility: CH de Versailles
city: Le Mans
country: France
facility: Le Mans Hospital
city: Lille
country: France
facility: Lille University Hospital
city: Limoges
country: France
facility: Limoges University Hospital
city: Lyon
country: France
facility: HCL
city: Montpellier
country: France
facility: Montpellier University Hospital
city: Nancy
country: France
facility: CHU de Nancy
city: Nice
country: France
facility: Nice University Hospital
city: Orleans
country: France
facility: CHU Orléans - service de Réanimation
city: Paris
country: France
facility: Aphp - Ambroise Paré
city: Paris
country: France
facility: Hôpital Cochin - service de Réanimation
city: Poitiers
country: France
facility: Poitiers University Hospital
city: Strasbourg
country: France
facility: CHU Strasbourg - service de Réanimation
city: Toulon
country: France
facility: CH de Toulon
city: Tours
country: France
facility: CHU Tours - Service de Réanimation
Study officials:
affiliation: University Hospital, Limoges
name: VIGNON Philippe, MD
role: PRINCIPAL_INVESTIGATOR
References: