Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion

Sepsis Clinical Trial

— ADAPT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04166331
• Other study ID #: 87RI18_0012 (ADAPT)
• Status: Recruiting
• Phase: Phase 3
• Start date: September 20, 2020
• Est. completion date: December 20, 2024

Study information

• Verified date: December 2023
• Source: University Hospital, Limoges
• Contact: VIGNON Philippe, MD
• Phone: 555054040
• Email: philippe.vignon[@]chu-limoges.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 270
• Est. completion date: December 20, 2024
• Est. primary completion date: December 20, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cardiomyopathies
• Hypoperfusion
• Left Ventricular Systolic Dysfunction
• Sepsis
• Systolic Murmurs
• Ventricular Dysfunction, Left

Intervention

Drug:
• 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. Dose adaptation will be left at the discretion of attending physician.
• 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. Dose adaptation will be left at the discretion of attending physician.

Locations

Country	Name	City	State
France	University Hospital	Amiens
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	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

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Limoges	Centre d'Investigation Clinique 1415

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Day 0 to Day 3
Secondary	Circulating lactate level measurement	Biological indices of tissue dysoxia at baseline, hour 6, Day1, Day 2 and Day 3 after initiating Dobutamine / placebo	Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary	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	Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary	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	through study completion, an average 90 days
Secondary	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	through study completion, an average of 90 days
Secondary	Vasopressor support duration	Requirement of organ function supports during ICU stay. Duration in days of vasopressor support	through study completion, an average of 90 days
Secondary	Vasopressor support dayly maximal dose	Requirement of organ function supports during ICU stay. Maximal dose in mg/h by day of vasopressor support	through study completion, an average of 90 days
Secondary	Invasive mechanical ventilation duration	Requirement of organ function supports during ICU stay. Duration of invasive mechanical ventilation	through study completion, an average of 90 days
Secondary	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)	through study completion, an average of 90 days
Secondary	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)	through study completion, an average of 90 days
Secondary	Arterial pressure measurement	Systolic, diastolic and mean arterial blood pressure (in mmHg) at Baseline, h6, Day 1, Day 2 and Day3after initiating Dobutamine / placebo	Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary	heart rate measurement	Heart rate measurement in bpm at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo	Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary	Central venous pressure measurement	Central venous pressure in cm H2O at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo	Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary	Cardiac index measurement	Cardiac index measurement in L/min/m2 at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo	Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary	Stroke volume measurement	Stroke volume measurement in mL status at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo	Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary	Hypotension measurement	Severe cardiovascular adverse events from inform consent to ICU discharge : Hypotension related to worsened vasoplegia	Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary	Supraventricular arrhythmias measurement	Severe cardiovascular adverse events from inform consent to ICU discharge. Supraventricular arrhythmias with ventricular rate > 140 bpm	through study completion, an average of 90 days
Secondary	Ventricular arrhythmias measurement	Severe cardiovascular adverse events from inform consent to ICU discharge. Ventricular arrhythmias	through study completion, an average of 90 days
Secondary	Occurence of Acute coronary syndrome	Severe cardiovascular adverse events from inform consent to ICU discharge. Acute coronary syndrome	through study completion, an average of 90 days
Secondary	Occurence of Stroke	Severe cardiovascular adverse events during ICU stay. Stroke	through study completion, an average of 90 days
Secondary	Mortality	Number of death	Day 90
Secondary	Mortality causes	Cause of death	Day 90
Secondary	Organ function free supports	Number of days free from vasopressor support, invasive mechanical ventilation, renal replacement therapy from inform consent to ICU discharge	Day 90
Secondary	Number of days in ICU and hospital	Length of ICU and hospital stay	Day 90
Secondary	echocardiographic assessment of left ventricular systolic function	ejection fraction measurement	Day 0 and Day 1
Secondary	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	Hour 6
Secondary	Cytokines level	tumor necrosis factor (TNF) -a, Interferon ?, 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.	Hour 6
Secondary	LV global longitudinal strain measurement	LV segmental deformation longitudinal analysis	Hour 6, Day 1, Day 2 AND Day 3
Secondary	RV free wall strain measurement	deformation of right ventricular myocardial tissue / routinely using with echocardiography or post exam analysis	Hour 6, Day 1, Day 2 AND Day 3
Secondary	LV volume measurement	Ratio between systolic and diastolic left ventricular volume / routinely using with echocardiography	Hour 6, Day 1, Day 2 AND Day 3
Secondary	LV ejection fraction measurement	Cardiac output measurement with echocardiography Doppler (in centers routinely using transpulmonary thermodilution). Quality of left ventricular contraction	Hour 6, Day 1, Day 2 AND Day 3
Secondary	RV volume measurement	Ratio between systolic and diastolic right ventricular volume / routinely using with echocardiography	Hour 6, Day 1, Day 2 AND Day 3
Secondary	RV ejection fraction measurement	Cardiac output measurement with echocardiography Doppler (in centers routinely using transpulmonary thermodilution). Quality of right ventricular contraction	Hour 6, Day 1, Day 2 AND Day 3
Secondary	Transpulmonary thermodilution measurement	In selected centers routinely using continuous monitoring of cardiac output using transpulmonary thermodilution: agreement of cardiac output measurement with echocardiography Doppler.	Hour 6, Day 1, Day 2 AND Day 3