ADAPT: Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Control 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 |
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.
|
| Experimental: Experimental 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 |
Drug: 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.
|
Outcome Measures
Primary Outcome Measures
- 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
- 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
- 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)
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age > 18 years hospitalized in ICU
-
Septic shock (Sepsis-3 definition):
-
Clinically suspected or documented acute infection
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Responsible for organ dysfunction(s): change in SOFA ≥ 2 points
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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)
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Requiring vasopressor support (Norepinephrine) to maintain steady mean arterial pressure ≥ 65 mmHg
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And lactate > 2 mmol/L
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Septic cardiomyopathy: echocardiographically measured LV ejection fraction (EF) ≤ 40% and LV outflow tract velocity-time integral < 14 cm
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Informed consent
Exclusion Criteria:
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Pregnancy or breast feeding
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Hypersensitivity to Dobutamine, 5% Dextrose, or to the excipients
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Ventricular rate > 130 bpm (sinus rhythm or not)
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Severe ventricular arrhythmia
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Obstructive cardiomyopathy with pressure gradient at rest ≥ 50 mmHg unrelated to uncorrected hypovolemia
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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)
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Acute coronary syndrome
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Decision to limit care or moribund status (life expectancy < 24 h)
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Absence of affiliation to Social Security
-
Subjects under juridical protection.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Hospital | Amiens | France | 80000 | |
| 2 | Angouleme Hospital | Angoulême | France | 16959 | |
| 3 | Argenteuil Hospital | Argenteuil | France | 95107 | |
| 4 | University Hospital | Brest | France | 29200 | |
| 5 | Aphp - Henri Mondor | Créteil | France | 94010 | |
| 6 | Dijon university hospital | Dijon | France | 21033 | |
| 7 | Le Mans Hospital | Le Mans | France | 72000 | |
| 8 | Lille University Hospital | Lille | France | 59045 | |
| 9 | Limoges University Hospital | Limoges | France | 87042 | |
| 10 | Montpellier University Hospital | Montpellier | France | 34295 | |
| 11 | CHU de Nancy | Nancy | France | 54511 | |
| 12 | Nice University Hospital | Nice | France | 06202 | |
| 13 | CHU Orléans - service de Réanimation | Orleans | France | 47067 | |
| 14 | Aphp - Ambroise Paré | Paris | France | 75010 | |
| 15 | Hôpital Cochin - service de Réanimation | Paris | France | 75014 | |
| 16 | Poitiers University Hospital | Poitiers | France | 86000 | |
| 17 | CHU Strasbourg - service de Réanimation | Strasbourg | France | 67000 | |
| 18 | CHU Tours - Service de Réanimation | Tours | France | 37044 |
Sponsors and Collaborators
- University Hospital, Limoges
- Centre d'Investigation Clinique 1415
Investigators
- Principal Investigator: VIGNON Philippe, MD, University Hospital, Limoges
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 87RI18_0012 (ADAPT)