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    Clinical Trial Results:
    Study Comparing the Efficacy and Tolerability of Epinephrine and Norepinephrine in Cardiogenic Shock. OPTIMA CC. (French full title : Optimisation du traitement vasopresseur du choc cardiogénique postinfarctus du myocarde reperfusé. Etude comparant l'efficacité et la tolérance de l'adrénaline et la noradrénaline (Optima CC))

    Summary
    EudraCT number
    		 2009-017081-23
    Trial protocol
    		 FR  
    Global end of trial date
    10 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2022
    First version publication date
    28 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CPRC2009/OPTIMA CC-LEVY/NK
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01367743
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CHRU de NANCY
    Sponsor organisation address
    29 Avenue du Maréchal de Lattre de Tassigny, NANCY, France, 54035
    Public contact
    El Mehdi SIAGHY, CHRU de NANCY, 0033 383155286, dripromoteur@chru-nancy.fr
    Scientific contact
    El Mehdi SIAGHY, CHRU de NANCY, 0033 383155286, dripromoteur@chru-nancy.fr
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Compare the efficiency and the tolerability of norepinephrine and epinephrine in cardiogenic shock after reperfused myocardial infarction.
    Protection of trial subjects
    Patients was included in emergency situation. For all patients included, all diagnostic, therapeutic and weaning procedures have be done according to the current standard of care at the discretion of the investigator. There was no foreseeable risks associated with this study; the drugs was used in the usual therapeutic setting. The doses were adapted according to the therapeutic objectives. The administration scheme was identical for both molecules, and corresponds to current practices in intensive care.
    Background therapy
    		 For all patients included, all therapeutic and weaning procedures have be done according to the current standard of care at the discretion of the investigator.
    Evidence for comparator
    		 Norepinephrine and epinephrine are currently the most commonly used vasopressor agents in clinical practice (PMID: 19781431 ; 28131429 ; 22920912). Studies comparing epinephrine and norepinephrine in patients with septic shock found no significant differences in outcome (PMID: 24686400). Nevertheless, these drugs may have certain specific effects in patients with cardiogenic shock (CS) that could influence outcome. Norepinephrine is likely less thermogenic than epinephrine and therefore may have a more desirable effect on myocardial oxygen consumption (PMID : 22920912). During acute ischemic CS, norepinephrine induces favorable effects on myocardial function (PMID: 26849625, PMID: 24509521). Conversely, epinephrine may induce a higher cardiac index and deliver available nutrients very rapidly to the heart through lactate production (PMID: 17242933). Two retrospective studies further suggested that epinephrine may have deleterious effects associated with greater circulating cardiovascular biomarkers in patients with CS (PMID: 27374027, PMID: 12458064). Moreover, despite these potential negative warnings, epinephrine is still used to treat the most severe forms of CS after myocardial infarction. However, none of these findings has been assessed prospectively in this specific clinical setting. The recent scientific statement from the American Heart Association recommends performing RCTs to identify the optimal vasopressor regimen in these patients (PMID: 28923988).
    Actual start date of recruitment
    06 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 57
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    22
    From 65 to 84 years
    31
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multicenter study was conducted between 6 Sept 2011 (first inclusion) and 10 Feb 2016 (last patient last visit) in 9 French intensive care units (ICUs). The cardiogenic shock patients admitted in ICUs was included in emergency situation with inclusion/exclusion criteria verification.

    Pre-assignment
    Screening details
    		 Nb of subjects screened for inclusion : 163.Reasons for excluding subjects: Moribund (34);Poor neurologic prognosis (30);Immediate ECLS(22);Declined to participate(7);No medical insurance(5); Other reasons(8).Nb of patients included:58 (57 patients with written informed consent (27 EPI vs 30 NOREPI). No written consent obtained for one patient).

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Randomization was computer generated, based on random blocks of 4, and stratified according to participating ICU. Treatment assignments and patient reference number were placed in sealed, opaque envelopes, which were opened by an independent pharmacist in charge of the preparation of the study drugs. Norepinephrine or epinephrine syringes were prepared extemporaneously by the pharmacist. Each syringe was subsequently labeled with the patient’s number only and was indistinguishable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Epinephrine
    Arm description
    		 continuous infusion of commercial epinephrine prepared in syringes in order to obtain a MAP of 65-70 mmHg
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Epinephrine
    Investigational medicinal product code
    ATC code : C01CA24
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IMP doses are expressed in micrograms per kilogram per minute. The dosages of epinephrine or norepinephrine will be the same (whatever the drug) as those used in same as those used in standard practice for the management of cardiogenic shock, with dosages ranging from 0.1 to 3 μg/kg/min being the usual dosages used in this in this pathology. The administration will be administrated with a syringe pump in continuous infusion. Doses were increased by 0.02 mg/kg/min (or higher in emergency cases). The targeted MAP was 65 to 70 mm Hg. A patient was considered to be weaned from vasopressor therapy after 24 h of hemodynamic stability without vasopressor support.

    Arm title
    		 Norepinephrine
    Arm description
    		 continuous infusion of commercial norepinephrine prepared in syringes in order to obtain a MAP of 65-70 mmHg
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Norepinephrine
    Investigational medicinal product code
    code ATC : C01CA03
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IMP doses are expressed in micrograms per kilogram per minute. The dosages of epinephrine or norepinephrine will be the same (whatever the drug) as those used in same as those used in standard practice for the management of cardiogenic shock, with dosages ranging from 0.1 to 3 μg/kg/min being the usual dosages used in this in this pathology. The administration will be administrated with a syringe pump in coninuous infusion. Doses were increased by 0.02 mg/kg/min (or higher in emergency cases). The targeted MAP was 65 to 70 mm Hg. A patient was considered to be weaned from vasopressor therapy after 24 h of hemodynamic stability without vasopressor support.

    Number of subjects in period 1
    		Epinephrine Norepinephrine
    Started
    27
    30
    Completed
    27
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Epinephrine
    Reporting group description
    		 continuous infusion of commercial epinephrine prepared in syringes in order to obtain a MAP of 65-70 mmHg

    Reporting group title
    Norepinephrine
    Reporting group description
    		 continuous infusion of commercial norepinephrine prepared in syringes in order to obtain a MAP of 65-70 mmHg

    Reporting group values
    		 Epinephrine Norepinephrine Total
    Number of subjects
    		 27 30 57
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 13 22
        From 65-84 years
    		 15 16 31
        85 years and over
    		 3 1 4
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 68 (55 to 79) 66 (55 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 13 6 19
        Male
    		 14 24 38

    End points

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    End points reporting groups
    Reporting group title
    Epinephrine
    Reporting group description
    		 continuous infusion of commercial epinephrine prepared in syringes in order to obtain a MAP of 65-70 mmHg

    Reporting group title
    Norepinephrine
    Reporting group description
    		 continuous infusion of commercial norepinephrine prepared in syringes in order to obtain a MAP of 65-70 mmHg

    Primary: Change in cardiac index between H0 and H72

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    End point title
    		 Change in cardiac index between H0 and H72
    End point description
    Baseline cardiac index was described in each group as median (Q1 - Q3).
    End point type
    Primary
    End point timeframe
    Cardiac index was measured at randomization (H0) and at H2, H4, H6, H12, H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    30
    Units: L/min/m2
        median (inter-quartile range (Q1-Q3))
    1.8 (1.6 to 2.7)
    2.1 (1.8 to 2.5)
    Attachments
    		 FIg
    Statistical analysis title
    		 Primary endpoint
    Statistical analysis description
    The evolution of cardiac index between H0 and H72 was compared in the 2 groups by using repeated-measures ANOVA based on the ranks of the values with the rank of baseline value as adjustment covariate. Because the post-baseline values were constrained by the clinical events observed during the follow-up, each value was ranked from lowest to highest at each time point, with the worst rank attributed for deceased patients and the second worst rank for patients who underwent ECLS.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.43 [1]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [1] - Cardiac index evolution did not significantly differ between the epinephrine and norepinephrine groups.

    Secondary: Change in heart rate between H0 and H72

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    End point title
    		 Change in heart rate between H0 and H72
    End point description
    Baseline heart rate was described in each group as median (Q1 - Q3).
    End point type
    Secondary
    End point timeframe
    Heart rate was measured at randomization (H0) and at H2, H4, H6, H12, H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    30
    Units: bpm
        median (inter-quartile range (Q1-Q3))
    96 (85 to 116)
    97 (78 to 111)
    Attachments
    		 Change in heart rate
    Statistical analysis title
    		 Change in heart rate between H0 and H72
    Statistical analysis description
    The evolution of heart rate between H0 and H72 was compared in the 2 groups by using repeated-measures ANOVA based on the ranks of the values with the rank of baseline value as adjustment covariate. Because the post-baseline values were constrained by the clinical events observed during the follow-up, each value was ranked from lowest to highest at each time point, with the worst rank attributed for deceased patients and the second worst rank for patients who underwent ECLS.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031 [2]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [2] - Mean heart rate increased significantly in the epinephrine group, whereas it did not change significantly in the norepinephrine group.

    Secondary: Change in mean arterial pressure

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    End point title
    		 Change in mean arterial pressure
    End point description
    Baseline mean arterial pressure was described in each group as median (Q1 - Q3).
    End point type
    Secondary
    End point timeframe
    Mean arterial pressure was measured at randomization (H0) and at H2, H4, H6, H12, H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    30
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    72 (69 to 79)
    71 (66 to 83)
    Attachments
    		 Change in MAP
    Statistical analysis title
    		 Change in MAP between H0 and H72
    Statistical analysis description
    The evolution of MAP between H0 and H72 was compared in the 2 groups by using repeated-measures ANOVA based on the ranks of the values with the rank of baseline value as adjustment covariate. Because the post-baseline values were constrained by the clinical events observed during the follow-up, each value was ranked from lowest to highest at each time point, with the worst rank attributed for deceased patients and the second worst rank for patients who underwent ECLS.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25 [3]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [3] - The evolution of MAP during the first 3 days of the study was similar between groups.

    Secondary: Change in stroke volume index between H0 and H72

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    End point title
    		 Change in stroke volume index between H0 and H72
    End point description
    Baseline stroke volume index was described in each group as median (Q1 - Q3).
    End point type
    Secondary
    End point timeframe
    Stroke volume index was measured at randomization (H0) and at H2, H4, H6, H12, H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    30
    Units: mL/beat/m²
        median (inter-quartile range (Q1-Q3))
    20.2 (15.2 to 29.8)
    21.5 (17.5 to 27.6)
    Attachments
    		 Change in SVi
    Statistical analysis title
    		 Change in SVi between H0 and H72
    Statistical analysis description
    The evolution of SVi between H0 and H72 was compared in the 2 groups by using repeated-measures ANOVA based on the ranks of the values with the rank of baseline value as adjustment covariate. Because the post-baseline values were constrained by the clinical events observed during the follow-up, each value was ranked from lowest to highest at each time point, with the worst rank attributed for deceased patients and the second worst rank for patients who underwent ECLS.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25 [4]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [4] - The evolution of SVi was similar between groups.

    Secondary: Change in cardiac double product between H0 and H72

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    End point title
    		 Change in cardiac double product between H0 and H72
    End point description
    Baseline cardiac double product was described in each group as median (Q1 - Q3).
    End point type
    Secondary
    End point timeframe
    Cardiac double product was measured at randomization (H0) and at H2, H4, H6, H12, H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    30
    Units: mmHg.bpm
        median (inter-quartile range (Q1-Q3))
    10300 (8755 to 12549)
    9672 (8040 to 11858)
    Attachments
    		 Change in CDP
    Statistical analysis title
    		 Change in CDP between H0 and H72
    Statistical analysis description
    The evolution of CDP between H0 and H72 was compared in the 2 groups by using repeated-measures ANOVA based on the ranks of the values with the rank of baseline value as adjustment covariate. Because the post-baseline values were constrained by the clinical events observed during the follow-up, each value was ranked from lowest to highest at each time point, with the worst rank attributed for deceased patients and the second worst rank for patients who underwent ECLS.
    Comparison groups
    Norepinephrine v Epinephrine
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [5] - Cardiac double product, a surrogate of myocardial oxygen consumption, increased in the epinephrine group, whereas it did not change in the norepinephrine group.

    Secondary: Change in cardiac power index between H0 and H72

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    End point title
    		 Change in cardiac power index between H0 and H72
    End point description
    Baseline cardiac power index was described in each group as median (Q1 - Q3).
    End point type
    Secondary
    End point timeframe
    Cardiac power index was measured at randomization (H0) and at H2, H4, H6, H12, H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    30
    Units: W/m²
        median (inter-quartile range (Q1-Q3))
    0.29 (0.24 to 0.43)
    0.33 (0.26 to 0.41)
    Attachments
    		 Change in CPI
    Statistical analysis title
    		 Change in cardiac power index between H0 and H72
    Statistical analysis description
    The evolution of cardiac power index between H0 and H72 was compared in the 2 groups by using repeated-measures ANOVA based on the ranks of the values with the rank of baseline value as adjustment covariate. Because the post-baseline values were constrained by the clinical events observed during the follow-up, each value was ranked from lowest to highest at each time point, with the worst rank attributed for deceased patients and the second worst rank for patients who underwent ECLS.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44 [6]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [6] - The evolution of cardiac power index was similar between groups.

    Secondary: Change in SvO2 between H0 and H72

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    End point title
    		 Change in SvO2 between H0 and H72
    End point description
    Baseline SvO2 was described in each group as median (Q1 - Q3).
    End point type
    Secondary
    End point timeframe
    SvO2 was measured at randomization (H0) and at H2, H4, H6, H12, H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    29
    Units: pct
        median (inter-quartile range (Q1-Q3))
    72 (59 to 79)
    71 (65 to 78)
    Attachments
    		 Change in SvO2
    Statistical analysis title
    		 Change in SvO2 between H0 and H72
    Statistical analysis description
    The evolution of SvO2 between H0 and H72 was compared in the 2 groups by using repeated-measures ANOVA based on the ranks of the values with the rank of baseline value as adjustment covariate. Because the post-baseline values were constrained by the clinical events observed during the follow-up, each value was ranked from lowest to highest at each time point, with the worst rank attributed for deceased patients and the second worst rank for patients who underwent ECLS.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18 [7]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [7] - The evolution of SvO2 during the study period was similar between the 2 groups.

    Secondary: Change in arterial lactate between H0 and H72

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    End point title
    		 Change in arterial lactate between H0 and H72
    End point description
    Baseline arterial lactate was described in each group as median (Q1 - Q3).
    End point type
    Secondary
    End point timeframe
    Arterial lactate was measured at randomization (H0) and at H2, H4, H6, H12, H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    30
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    5.0 (2.7 to 6.1)
    2.9 (1.9 to 4.8)
    Attachments
    		 Change in arterial lactate
    Statistical analysis title
    		 Change in arterial lactate between H0 and H72
    Statistical analysis description
    The evolution of arterial lactate between H0 and H72 was compared in the 2 groups by using repeated-measures ANOVA based on the ranks of the values with the rank of baseline value as adjustment covariate. Because the post-baseline values were constrained by the clinical events observed during the follow-up, each value was ranked from lowest to highest at each time point, with the worst rank attributed for deceased patients and the second worst rank for patients who underwent ECLS.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [8] - Regarding metabolic changes, during the first 24 h, epinephrine use was associated with increased lactate level, whereas lactate level decreased in the norepinephrine group.

    Secondary: Change in SOFA score between H0 and H72

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    End point title
    		 Change in SOFA score between H0 and H72
    End point description
    Baseline SOFA score was described in each group as median (Q1 - Q3).
    End point type
    Secondary
    End point timeframe
    SOFA score was calculated at randomization (H0) and at H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    30
    Units: pts
        median (inter-quartile range (Q1-Q3))
    10 (9 to 12)
    9 (8 to 12)
    Statistical analysis title
    		 Change in SOFA score between H0 and H72
    Statistical analysis description
    The evolution of SOFA score was compared in the 2 groups by using repeated measures ANOVA with baseline value as the adjustment covariate.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    57
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.44 [9]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [9] - Regarding organ dysfunction, the SOFA score and its components did not differ between the 2 groups, either at inclusion or during patient course.

    Other pre-specified: Refractory cardiogenic shock (primary safety endpoint)

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    End point title
    		 Refractory cardiogenic shock (primary safety endpoint)
    End point description
    Refractory CS was defined as CS with major cardiac dysfunction assessed according to echocardiography, elevated lactate level, and acute deterioration of organ function (e.g., oliguria, liver failure) despite the use of >1 mg/kg/min of epinephrine/norepinephrine or dobutamine >10 mg/kg/min and/or intra-aortic balloon support and sustained hypotension (SAP <90 mm Hg or MAP <65 mm Hg) despite adequate intravascular volume. This event was defined by the independent safety monitoring board at the first meeting (September 2015) while reviewing adverse events.
    End point type
    Other pre-specified
    End point timeframe
    Refractory cardiogenic shock were observed during study follow-up.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    30
    Units: no unit
        No refractory shock
    17
    28
        Refractory shock
    10
    2
    Statistical analysis title
    		 Incidence of refractory cardiogenic shock
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    8.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.61
         upper limit
    		 42.18
    Notes
    [10] - Epinephrine was associated with a higher incidence of refractory cardiogenic shock.

    Post-hoc: Change in use of inotropes between H0 and H72

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    End point title
    		 Change in use of inotropes between H0 and H72
    End point description
    Baseline dobutamine dose was described in each group as median (Q1 - Q3).
    End point type
    Post-hoc
    End point timeframe
    Dobutamine dose was measured at randomization (H0) and at H2, H4, H6, H12, H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    18
    20
    Units: µg/min/kg
        median (inter-quartile range (Q1-Q3))
    6.1 (0.5 to 11.7)
    4.8 (0.0 to 8.0)
    Statistical analysis title
    		 Change in dobutamine dose between H0 and H72
    Statistical analysis description
    The evolution of dobutamine dose was compared in the 2 groups by using repeated measures ANOVA with baseline value as the adjustment covariate.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.78 [11]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [11] - There was no statistically significant difference in dobutamine at the different time points.

    Post-hoc: Change in NT-proBNP between H0 and H72

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    End point title
    		 Change in NT-proBNP between H0 and H72
    End point description
    Baseline NT-proBNP was described in each group as median (Q1 - Q3).
    End point type
    Post-hoc
    End point timeframe
    NT-proBNP was measured at randomization (H0) and at H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    29
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    4499 (541 to 11668)
    1739 (702 to 5956)
    Statistical analysis title
    		 Change in NT-proBNP between H0 and H72
    Statistical analysis description
    The evolution of NT-proBNP was compared in the 2 groups by using repeated measures ANOVA with baseline value as the adjustment covariate.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    56
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.2 [12]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [12] - No statistically significant difference was observed in levels of NT-proBNP during the first 72 h.

    Post-hoc: Change in Troponin T between H0 and H72

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    End point title
    		 Change in Troponin T between H0 and H72
    End point description
    Baseline Troponin T was described in each group as median (Q1 - Q3).
    End point type
    Post-hoc
    End point timeframe
    Troponin T was measured at randomization (H0) and at H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    29
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    9.9 (3.1 to 33.0)
    6.1 (2.1 to 19.7)
    Statistical analysis title
    		 Change in Troponin T between H0 and H72
    Statistical analysis description
    The evolution of Troponin T was compared in the 2 groups by using repeated measures ANOVA with baseline value as the adjustment covariate
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    56
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.21 [13]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [13] - No statistically significant difference was observed in levels of Troponin T during the first 72 h.

    Post-hoc: Change in GDF-15 between H0 and H72

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    End point title
    		 Change in GDF-15 between H0 and H72
    End point description
    Baseline GDF-15 was described in each group as median (Q1 - Q3).
    End point type
    Post-hoc
    End point timeframe
    GDF-15 was measured at randomization (H0) and at H24, H48, and H72.
    End point values
    		 Epinephrine Norepinephrine
    Number of subjects analysed
    27
    29
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    11182 (5108 to 22892)
    17748 (9938 to 23586)
    Attachments
    		 Change in GDF-15
    Statistical analysis title
    		 Change in GDF-15 between H0 and H72
    Statistical analysis description
    The evolution of GDF-15 was compared in the 2 groups by using repeated measures ANOVA with baseline value as the adjustment covariate.
    Comparison groups
    Epinephrine v Norepinephrine
    Number of subjects included in analysis
    56
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [14]
    Method
    		 Repeated-measures ANOVA
    Confidence interval
    Notes
    [14] - Levels of GDF-15 were markedly higher in the epinephrine versus norepinephrine group from H24 to H72.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The AE and SAE were collected and transmitted within 48 hours to sponsor from the enrollment until the end of hospital stay. After discharge, serious adverse events and deaths were collected until the end of study participation (6 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    norepinephrine
    Reporting group description
    		 -

    Reporting group title
    epinephrine
    Reporting group description
    		 -

    Serious adverse events
    		 norepinephrine epinephrine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 30 (60.00%)
    20 / 27 (74.07%)
         number of deaths (all causes)
    11
    14
         number of deaths resulting from adverse events
    1
    5
    Vascular disorders
    Shock
         subjects affected / exposed
    3 / 30 (10.00%)
    7 / 27 (25.93%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 7
    haemorrhagic shock
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hypoperfusion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Peripheral ischaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac disorders
    Ventricular fibrillation
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Ventricular tachycardia
         subjects affected / exposed
    4 / 30 (13.33%)
    4 / 27 (14.81%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 2
    1 / 4
    Pericardial effusion
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    4 / 30 (13.33%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac failure chronic
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Atrial tachycardia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Ventricular failure
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Implantable defibrillator insertion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary revascularisation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoxic-ischaemic encephalopathy
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Coma
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain hypoxia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Effusion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune heparin-induced thrombocytopenia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    pneumopathy
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Haemophilus infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Serratia bacteraemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    septicemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 norepinephrine epinephrine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 30 (66.67%)
    16 / 27 (59.26%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 27 (7.41%)
         occurrences all number
    2
    2
    Hypertension
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 27 (11.11%)
         occurrences all number
    1
    4
    Deep vein thrombosis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    hematoma
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Acute respiratory distress
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Hyperthermia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    Catheter site haematoma
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    medical site device haematoma
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    4
    Vascular stent stenosis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    Pneumothorax
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    pneumopathy
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    Pulmonary oedema
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    Haemothorax
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 27 (11.11%)
         occurrences all number
    2
    3
    Anxiety
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Atrial fibrillation
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 27 (11.11%)
         occurrences all number
    4
    4
    Tachyarrhythmia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Cardiogenic shock
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Conduction disorder
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Ventricular tachycardia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Nervous system disorders
    neurological status deterioration
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Polyneuropathy
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 27 (11.11%)
         occurrences all number
    6
    3
    Thrombocytopenia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 27 (7.41%)
         occurrences all number
    2
    2
    Nausea
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Intestinal dilatation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    redness
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 27 (7.41%)
         occurrences all number
    2
    2
    Renal failure
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 27 (11.11%)
         occurrences all number
    1
    3
    Acute kidney injury
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Pneumonia aspiration
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    Influenza
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    4 / 30 (13.33%)
    4 / 27 (14.81%)
         occurrences all number
    4
    4
    Respiratory tract infection
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    urinary infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    5 / 27 (18.52%)
         occurrences all number
    1
    5
    Hyperglycaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 27 (14.81%)
         occurrences all number
    1
    4
    Hyperkalaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2011
    Increase in the number of participating centers to increase the number of patients included; Increase in the number of patients after statistical re-evaluation; Simplification: some parameters that are complicated to obtain in all centers have been removed (gastric tonometry and indirect calorimetry).
    02 Dec 2011
    Different specialties of Adrenalin, with or without sulfites, and Noradrenalin can be used, according to the practice of each hospital. Suppression of near IR spectroscopy Modification of certain data to be collected Modification of the volume of the SST tube for biobanking from 7 to 5 ml Modification of the inclusion criteria, no need for the patient to be already intubated and ventilated, 8 hours instead of 6 Clarification of the discontinuation of vasopressors and the use of the Swan Ganz probe for the measurement of the cardiac index Added assessment of rhythm disturbances at each time interval Added the possibility to prepare a syringe at a concentration of 0.5mg/ml for weaning Clarification of the weaning day Clarification on the treatments to be reported in the CRF Addition of appendices with the echocardiography protocol and the use of the probe Addition of expected side effects
    04 Oct 2012
    Modification of the principal investigator of the Strasbourg center; Modification of the address of the Metz center (relocation of the service); Addition of a new center (Marseille); Clarification of concomitant treatments to be collected in the observation booklet; Collection of observational data concerning the anesthetic induction technique (if available) and the synacthen test (if available); Modification of the safety section (addition of an AR classification grid)
    10 Jan 2014
    Extension of the enrolment period by 2 years, clarifications regarding the administration of investigational drugs, addition of a new investigator center (CHU Toulouse)

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The main limitation is that our study lasted 4 years and included only 57 patients during this period.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29976291
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