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    Clinical Trial Results:
    A single-centre randomised controlled trial of propofol cardioplegia on blood and myocardial biomarkers of stress and injury in patients having isolated coronary artery bypass grafting (CABG) or aortic valve replacement (AVR) using cardiopulmonary bypass (CPB)

    Summary
    EudraCT number
    2009-015779-28
    Trial protocol
    GB  
    Global end of trial date
    31 Dec 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Sep 2018
    First version publication date
    01 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CS/2008/3029
    Additional study identifiers
    ISRCTN number
    ISRCTN84968882
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University Hospitals Bristol NHS Foundation Trust
    Sponsor organisation address
    Research & Innovation Dept, Level 3, UH Bristol Education Centre, Upper Maudlin Street, Bristol , United Kingdom, BS2 8AE
    Public contact
    Research and Development Department, University Hospitals Bristol NHS Foundation Trust, 0117 342 0233, R&DSponsorship@UHBristol.nhs.uk
    Scientific contact
    Clinical Trials Evaluation Unit, University of Bristol, 0117 342 3151, btc-mailbox@bristol.ac.uk
    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
    05 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the cardioprotective effect of a general anaesthetic, Propofol, when added to the cardioplegia (heart-stopping) solution used for patients undergoing isolated coronary artery bypass grafting (CABG) or aortic valve replacement (AVR) surgery using a heart-lung machine.
    Protection of trial subjects
    All potential participants were sent or given an invitation letter and patient information sheet (PIS) (approved by the local Research Ethics Committee,(REC)) describing the study. The patient had time to read the PIS and to discuss their participation with others outside the research team (e.g. relatives or friends) if they wished. Most patients had at least 24 hours to consider whether to participate. Full informed consent was obtained for every trial participant. The patient's GP was informed of their participation in the trial. All members of the direct healthcare team are contractually bound to abide by standard NHS conditions of confidentiality and the need to access medical records will be explained to each patient during the process of obtaining consent.
    Background therapy
    There is extensive evidence that propofol is able to protect the heart muscle from the damage that occurs when the blood supply is allowed to return to the heart after a period of low oxygen (ischaemia). Propofol has been shown to have an ability to scavenge the harmful molecules that are thought to be one of the main causes of damage and in addition, block other damaging processes. Recent research conducted within our institute using an animal model has shown propofol used at a clinically relevant dose can indeed be cardioprotective. We therefore plan to investigate the cardioprotective action of propofol when added to the cardioplegia (heart-stopping) solution, in humans undergoing isolated coronary artery bypass grafting (CABG) or aortic valve replacement surgery (AVR) using a heart-lung machine.
    Evidence for comparator
    Potential benefits to participants include the possibility of improved cardioprotection for the propofol supplementation group, which we hypothesise will lead to less injury to the heart and possibly fewer post-operative complications. Conversely, the participants randomised to the intralipid placebo group may be receiving an inferior treatment (a possible harm of participating in any trial) though this would be the same for non-trial patients receiving standard care. Patients will be randomised in a 1:1 ratio so that all will have an equal chance of being placed in either group.
    Actual start date of recruitment
    08 Mar 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 101
    Worldwide total number of subjects
    101
    EEA total number of subjects
    101
    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)
    32
    From 65 to 84 years
    69
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    All potential participants received an information leaflet. Of the 159 eligible patients screened, full informed consent was taken from 101 patients who agreed to take part in the study.

    Pre-assignment
    Screening details
    Between March 2010 and July 2012, 203 patients were screened for inclusion in the trial, 44 of whom were ineligible.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Randomization was carried out using a secure internet-based system (www.sealedenvelope.com) by staff not involved in data collection or patient care. The perfusionist was handed a sealed opaque envelope that contained the intervention, then prepared the cardioplegia solution (the two interventions were visually indistinguishable). All other staff remained blinded to the treatment allocation for the duration of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Propofol
    Arm description
    Cardioplegia supplementation with propofol at a concentration of 6μg/ml. A propofol concentration of 6μg/ml does not exceed the level routinely observed in the circulation during induction or maintenance of anesthesia for cardiac surgery. The stock propofol (Fresenius propoven 1% emulsion: 10,000ug/ml) was diluted as recommended by the manufacturer to achieve a working solution of 2000μg/ml.
    Arm type
    Experimental

    Investigational medicinal product name
    Fresenius Propoven 1% emulsion
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection/infusion
    Routes of administration
    Intracardiac use
    Dosage and administration details
    Fresenius Propoven 1% emulsion was diluted to achieve a working solution of 2000 mg/mL. Administration via cardioplegia solution.

    Arm title
    Intralipid
    Arm description
    Cardioplegia supplementation with intralipid. The intralipid emulsion (Fresenius 10%), was diluted in the same manner as the propofol.
    Arm type
    Placebo

    Investigational medicinal product name
    Intralipid 10%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for infusion
    Routes of administration
    Intracardiac use
    Dosage and administration details
    Intralipid emulsion (Fresenius 10%) diluted to a working solution (equivalent to 2000 mg/mL of Fresenius Propoven 1%). administered via cardioplegia solution.

    Number of subjects in period 1
    Propofol Intralipid
    Started
    51
    50
    Completed
    51
    50

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Propofol
    Reporting group description
    Cardioplegia supplementation with propofol at a concentration of 6μg/ml. A propofol concentration of 6μg/ml does not exceed the level routinely observed in the circulation during induction or maintenance of anesthesia for cardiac surgery. The stock propofol (Fresenius propoven 1% emulsion: 10,000ug/ml) was diluted as recommended by the manufacturer to achieve a working solution of 2000μg/ml.

    Reporting group title
    Intralipid
    Reporting group description
    Cardioplegia supplementation with intralipid. The intralipid emulsion (Fresenius 10%), was diluted in the same manner as the propofol.

    Reporting group values
    Propofol Intralipid Total
    Number of subjects
    51 50 101
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    The median age of participants was 67.9 years (IQR, 63.9- 73.7 years)
    Units: years
        median (inter-quartile range (Q1-Q3))
    66.5 (62.5 to 72.1) 70.6 (65 to 76.4) -
    Gender categorical
    Units: Subjects
        Female
    10 14 24
        Male
    41 36 77
    Operation
    Units: Subjects
        CABG
    31 30 61
        AVR
    20 20 40
    Diabetic
    Units: Subjects
        Diabetic
    11 10 21
        Non-diabetic
    40 40 80
    Number of diseased vessels
    One participant in the intralipid group had AVR and CABG (planned AVR surgery, decision to perform CABG made intra-operatively), therefore only 19 patients with no diseased vessels.
    Units: Subjects
        None
    20 19 39
        Single
    1 2 3
        Double
    6 12 18
        Triple
    24 17 41
    >50% disease in left main stem
    Units: Subjects
        Yes
    9 5 14
        No
    42 45 87
    Smoking status
    Units: Subjects
        Smoker
    5 5 10
        Non-smoker
    17 24 41
        Ex-smoker >1 month
    29 21 50
    Family history
    Units: Subjects
        Yes
    24 31 55
        No
    27 19 46
    Previous stroke (CVA) or transient ischemic attack (TIA)
    Units: Subjects
        Yes
    2 4 6
        No
    49 46 95
    Operative priority
    Units: Subjects
        Elective
    47 46 93
        Urgent
    4 4 8
    Number of grafts (intra-operative, CABG patients only)
    Number of grafts (therefore post-intervention but not a study end point).
    Units: Subjects
        1 graft
    1 0 1
        2 grafts
    8 7 15
        3 grafts
    16 18 34
        4 grafts
    6 5 11
        AVR participants
    20 20 40
    NYHA class
    Units: Subjects
        I/Asymptomatic
    14 10 24
        II
    20 26 46
        III
    16 14 30
        IV
    1 0 1
    CCS class
    Units: Subjects
        Asymptomatic
    11 16 27
        I.
    8 6 14
        II
    20 17 37
        III
    11 8 19
        IV
    1 3 4
    Previous myocardial infarction
    Units: Subjects
        Yes
    10 13 23
        No
    41 37 78
    Hypercholesterolaemia
    Units: Subjects
        Yes
    37 39 76
        No
    14 11 25
    Hypothyroidism
    Units: Subjects
        Yes
    4 5 9
        No
    47 45 92
    Pre-operative aspirin
    Units: Subjects
        Yes
    35 35 70
        No
    16 15 31
    Pre-operative clopidogrel
    Units: Subjects
        Yes
    16 11 27
        No
    35 39 74
    Pre-operative warfarin
    Units: Subjects
        Yes
    4 3 7
        No
    47 47 94
    Pre-operative heparin/clexane
    Units: Subjects
        Yes
    1 2 3
        No
    50 48 98
    Pre-operative beta blockers
    Units: Subjects
        Yes
    28 24 52
        No
    23 26 49
    Pre-operative calcium antagonists
    Units: Subjects
        Yes
    16 11 27
        No
    35 39 74
    Pre-operative oral nitrates
    Units: Subjects
        Yes
    7 9 16
        No
    44 41 85
    Pre-operative other lipid lowering agents
    Units: Subjects
        Yes
    2 2 4
        No
    49 48 97
    Pre-operative statins
    Units: Subjects
        Yes
    41 39 80
        No
    10 11 21
    Pre-operative ACE inhibitors
    Units: Subjects
        Yes
    27 22 49
        No
    24 28 52
    Pre-operative angiotensin 2 blockers
    Units: Subjects
        Yes
    5 1 6
        No
    46 49 95
    Pre-operative diuretics
    Units: Subjects
        Yes
    12 8 20
        No
    39 42 81
    Pre-operative digoxin
    Units: Subjects
        Yes
    3 3 6
        No
    48 47 95
    Pre-operative anti-arrhythmic drugs
    Units: Subjects
        Yes
    1 1 2
        No
    50 49 99
    Hypertension requiring treatment
    Units: Subjects
        Yes
    44 35 79
        No
    7 15 22
    Myocardial infarction within the last 90 days of randomisation
    Units: Subjects
        Yes
    3 7 10
        No
    47 42 89
        Missing
    1 1 2
    Heart rhythm
    Units: Subjects
        Sinus
    44 47 91
        Atrial fibrillation/flutter
    6 3 9
        Missing
    1 0 1
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    29.3 ± 5.6 27.1 ± 3.8 -
    estimated glomerular filtration rate
    Units: mL/min/1.73 m2
        arithmetic mean (standard deviation)
    69.9 ± 20 72.2 ± 14.8 -
    EuroSCORE (additive)
    Units: N/A
        median (inter-quartile range (Q1-Q3))
    4 (2 to 5) 5 (3 to 6) -
    Operation length (intra-operative)
    Length of operation (therefore post-intervention but not a study end point)
    Units: Minutes
        arithmetic mean (standard deviation)
    191 ± 32.2 190.1 ± 29.7 -
    Cumulative cross-clamp time (intra-operative)
    Amount of time participant on cross-clamp (therefore post-intervention but not a study end point). One participant in propofol arm with cross-clamp time missing because surgery performed off-pump.
    Units: Minutes
        arithmetic mean (standard deviation)
    54 ± 19.7 53.4 ± 16.2 -
    Total bypass time (intra-operative)
    Amount of time on cardiopulmonary bypass (therefore post-intervention but not a study end point). One participant in propofol arm with cross-clamp time missing because surgery performed off-pump.
    Units: Minutes
        arithmetic mean (standard deviation)
    88.2 ± 22 88.8 ± 19 -
    Concentration of propofol in cardioplegia (intra-operative)
    Total concentration of propofol in cardioplegia (therefore post-intervention but not a study end point). Six participants with systemic propofol concentration missing, as they did not receive any intervention.
    Units: μg/ml
        arithmetic mean (standard deviation)
    9.92 ± 1.38 4.46 ± 1.8 -
    Concentration of systemic (arterial line) plasma propofol pre-cross-clamp (intra-operative)
    Concentration of systemic (arterial line) plasma propofol (therefore post-intervention but not a study end point). Six participants with systemic propofol concentration missing, as they did not receive any intervention.
    Units: μg/ml
        arithmetic mean (standard deviation)
    3.92 ± 1.38 4.34 ± 1.36 -
    Concentration of systemic (arterial line) plasma propofol during cross-clamp (intra-operative)
    Concentration of systemic (arterial line) plasma propofol (therefore post-intervention but not a study end point). Six participants with systemic propofol concentration missing, as they did not receive any intervention.
    Units: μg/ml
        arithmetic mean (standard deviation)
    4.16 ± 1.2 4.36 ± 1.23 -
    Concentration of systemic (arterial line) plasma propofol 10mins post-cross-clamp release (intra-op)
    Concentration of systemic (arterial line) plasma propofol (therefore post-intervention but not a study end point). Six participants with systemic propofol concentration missing, as they did not receive any intervention.
    Units: μg/ml
        arithmetic mean (standard deviation)
    4.07 ± 1.1 4.51 ± 1.18 -
    Estimated volume of cardioplegia given (intra-operative, CABG participants only)
    Estimated volume of cardioplegia given in CABG participants (therefore post-intervention but not a study end point)
    Units: ml
        arithmetic mean (standard deviation)
    1207 ± 355 1197 ± 333 -
    Total volume of cold blood cardioplegia (intra-operative, AVR participants only)
    Total volume of cold blood cardioplegia in AVR participants (therefore post-intervention but not a study end point).
    Units: ml
        arithmetic mean (standard deviation)
    1790.2 ± 322 1782.4 ± 264.1 -
    Haemoglobin
    Units: g/L
        arithmetic mean (standard deviation)
    13.7 ± 1.7 13.5 ± 1.7 -
    Platelets
    Units: 10^9 /L
        arithmetic mean (standard deviation)
    221.2 ± 53.6 232.1 ± 63.9 -

    End points

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    End points reporting groups
    Reporting group title
    Propofol
    Reporting group description
    Cardioplegia supplementation with propofol at a concentration of 6μg/ml. A propofol concentration of 6μg/ml does not exceed the level routinely observed in the circulation during induction or maintenance of anesthesia for cardiac surgery. The stock propofol (Fresenius propoven 1% emulsion: 10,000ug/ml) was diluted as recommended by the manufacturer to achieve a working solution of 2000μg/ml.

    Reporting group title
    Intralipid
    Reporting group description
    Cardioplegia supplementation with intralipid. The intralipid emulsion (Fresenius 10%), was diluted in the same manner as the propofol.

    Subject analysis set title
    CABG patients - propofol
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    CABG patients, propofol arm

    Subject analysis set title
    CABG patients - intralipid
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    CABG patients, intralipid arm

    Subject analysis set title
    AVR patients - propofol
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    AVR patients, propofol arm

    Subject analysis set title
    AVR patients - intralipid
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    AVR patients, intralipid arm

    Subject analysis set title
    Patients for biopsy analysis - propofol
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup of patients with biopsy samples analysed - propofol group

    Subject analysis set title
    Patients for biopsy analysis - intralipid
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup of patients with biopsy samples analysed - intralipid group

    Subject analysis set title
    CABG patients for biopsy analysis - propofol
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup of CABG patients with biopsy samples analysed - propofol group

    Subject analysis set title
    CABG patients for biopsy analysis – intralipid
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup of CABG patients with biopsy samples analysed - intralipid group

    Subject analysis set title
    AVR patients for biopsy analysis – propofol
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup of AVR patients with biopsy samples analysed - propofol group

    Subject analysis set title
    AVR patients for biopsy analysis – intralipid
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subgroup of AVR patients with biopsy samples analysed - intralipid group

    Primary: Troponin T

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    End point title
    Troponin T
    End point description
    End point type
    Primary
    End point timeframe
    Measured at baseline, and then at 1, 6, 12, 24 and 48 hours post chest closure
    End point values
    Propofol Intralipid
    Number of subjects analysed
    51
    50
    Units: ng/L
    median (inter-quartile range (Q1-Q3))
        Pre-operative (number <14ng/L)
    30 (30 to 30)
    34 (34 to 34)
        Pre-operative (number >=14ng/L)
    20 (20 to 20)
    15 (15 to 15)
        Pre-operative (>=14ng/L only)
    21 (15 to 24)
    20 (15 to 29)
        1hr post-chest closure
    393 (298 to 597)
    486 (360 to 571)
        6hr post-chest closure
    552 (396 to 827)
    616.5 (492.5 to 704)
        12hr post-chest closure
    434 (350.5 to 651.5)
    497 (419 to 607)
        24hr post-chest closure
    385 (263 to 448)
    395 (300 to 507.3)
        48hr post-chest closure
    302.7 (211 to 378)
    280.5 (222 to 367)
    Statistical analysis title
    Troponin T geometric mean ratio (95% CI)
    Comparison groups
    Intralipid v Propofol
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.051
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    1.01

    Secondary: Lactate

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    End point title
    Lactate
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baseline, and then at 1, 6, 12, 24 and 48 hours post chest closure
    End point values
    Propofol Intralipid
    Number of subjects analysed
    51
    50
    Units: mmol/L
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    0.8 (0.5 to 1.1)
    0.8 (0.6 to 1)
        1hr post-chest closure
    1.2 (0.9 to 1.4)
    1 (0.7 to 1.1)
        6hr post-chest closure
    1.1 (0.9 to 1.6)
    1.1 (0.8 to 1.4)
        12hr post-chest closure
    1.5 (1 to 1.7)
    1.2 (1 to 1.5)
        24hr post-chest closure
    1.3 (1.1 to 1.8)
    1.2 (1 to 1.6)
        48hr post-chest closure
    1.2 (0.9 to 1.5)
    1.2 (1 to 1.6)
    Statistical analysis title
    Lactate geometric mean ratio
    Comparison groups
    Propofol v Intralipid
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.18

    Secondary: pH

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    End point title
    pH
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baseline, and then at 1, 6, 12, 24 and 48 hours post chest closure
    End point values
    Propofol Intralipid
    Number of subjects analysed
    51
    50
    Units: pH units
    arithmetic mean (standard deviation)
        Pre-operative
    7.416 ± 0.031
    7.426 ± 0.039
        1hr post-chest closure
    7.373 ± 0.047
    7.369 ± 0.058
        6hr post-chest closure
    7.339 ± 0.046
    7.347 ± 0.054
        12hr post-chest closure
    7.339 ± 0.047
    7.351 ± 0.055
        24hr post-chest closure
    7.336 ± 0.044
    7.351 ± 0.048
        48hr post-chest closure
    7.356 ± 0.041
    7.367 ± 0.06
    Statistical analysis title
    pH mean difference
    Comparison groups
    Propofol v Intralipid
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.17
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.018
         upper limit
    0.003

    Secondary: Creatinine

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    End point title
    Creatinine
    End point description
    The effect of propofol supplementation on post-operative renal function differed between CABG and AVR participants - p=0.069.
    End point type
    Secondary
    End point timeframe
    Measured at baseline, and then at 1, 6, 12, 24 and 48 hours post chest closure
    End point values
    CABG patients - propofol CABG patients - intralipid AVR patients - propofol AVR patients - intralipid
    Number of subjects analysed
    31
    30
    20
    20
    Units: µmol/L
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    88 (74 to 105)
    88 (78 to 92)
    88.5 (81.5 to 106.5)
    83.5 (72 to 95.5)
        1hr post-chest closure
    91 (77 to 98)
    84 (78 to 96)
    95 (85.5 to 111.5)
    83.5 (67 to 91)
        6hr post-chest closure
    96 (81 to 113)
    90.5 (82 to 100)
    101 (94 to 119)
    90.5 (78 to 96)
        12hr post-chest closure
    98 (85 to 112)
    94 (85 to 102)
    115 (97 to 127)
    94 (82 to 109)
        24hr post-chest closure
    110 (90 to 147)
    97 (90.5 to 118)
    129 (107 to 157)
    92.5 (77 to 110)
        48hr post-chest closure
    112 (87 to 165)
    97 (81 to 114.5)
    119 (104 to 145)
    88.5 (80 to 115.5)
    Statistical analysis title
    Creatinine geometric mean ratio - CABG patients
    Statistical analysis description
    Geometric mean ratio for propofol vs. intralipid in isolated CABG patients.
    Comparison groups
    CABG patients - propofol v CABG patients - intralipid
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.62
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    1.051
    Statistical analysis title
    Creatinine geometric mean ratio - AVR patients
    Statistical analysis description
    Geometric mean ratio for propofol vs. intralipid in isolated AVR patients
    Comparison groups
    AVR patients - propofol v AVR patients - intralipid
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.007
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    1.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.019
         upper limit
    1.125

    Secondary: Length of ICU stay

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    End point title
    Length of ICU stay
    End point description
    The effect of propofol supplementation on length of ICU stay differed between CABG and AVR participants - p=0.068.
    End point type
    Secondary
    End point timeframe
    Length of stay in intensive care unit
    End point values
    CABG patients - propofol CABG patients - intralipid AVR patients - propofol AVR patients - intralipid
    Number of subjects analysed
    31
    30
    20
    20
    Units: hours
        median (inter-quartile range (Q1-Q3))
    69.3 (47.8 to 113)
    87.3 (68 to 114)
    89.5 (46.9 to 120.5)
    47 (43 to 89.5)
    Statistical analysis title
    Time in ICU hazard ratio - CABG patients
    Statistical analysis description
    Hazard ratio for time in intensive care unit in propofol group compared to intralipid group in isolated CABG patients
    Comparison groups
    CABG patients - propofol v CABG patients - intralipid
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    2.09
    Statistical analysis title
    Time in ICU hazard ratio - AVR patients
    Statistical analysis description
    Hazard ratio for time in intensive care unit in propofol group compared to intralipid group in isolated AVR patients
    Comparison groups
    AVR patients - propofol v AVR patients - intralipid
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.09
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.31
         upper limit
    1.09

    Secondary: EQ5D visual analogue score

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    End point title
    EQ5D visual analogue score
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    Propofol Intralipid
    Number of subjects analysed
    51
    50
    Units: Scale of 0 to 100
    arithmetic mean (standard deviation)
        Pre-operative
    68 ± 21
    66 ± 20.8
        3 months post-operative
    77 ± 19.2
    80 ± 12.4
    Statistical analysis title
    EQ5D VAS score mean difference
    Comparison groups
    Propofol v Intralipid
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.39
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.21
         upper limit
    2.87

    Secondary: EQ5D utility score

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    End point title
    EQ5D utility score
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    CABG patients - propofol CABG patients - intralipid AVR patients - propofol AVR patients - intralipid
    Number of subjects analysed
    31
    30
    20
    20
    Units: Possible range from -0.11 to 1.00
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    0.796 (0.689 to 1)
    0.727 (0.62 to 0.85)
    0.867 (0.638 to 1)
    0.76 (0.62 to 1)
        3 months post-operative
    0.814 (0.727 to 1)
    0.796 (0.689 to 1)
    0.788 (0.586 to 0.925)
    1 (0.691 to 1)
    No statistical analyses for this end point

    Secondary: EQ5D utility score (binary)

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    End point title
    EQ5D utility score (binary)
    End point description
    EQ5D scores dichotomised into perfect health (score of 1) vs. less than perfect health (score <1.000) for statistical analysis. The effect of propofol supplementation on post-operative EQ5D utility score differed between CABG and AVR participants - test for interaction p=0.067.
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    CABG patients - propofol CABG patients - intralipid AVR patients - propofol AVR patients - intralipid
    Number of subjects analysed
    30 [1]
    29 [2]
    20
    19 [3]
    Units: patients
        3 months post-operatively
    12
    9
    5
    10
    Notes
    [1] - 1 patient with 3 month EQ5D utility score missing
    [2] - 1 patient with 3 month EQ5D utility score missing
    [3] - 1 patient with 3 month EQ5D utility score missing
    Statistical analysis title
    EQ5D utility score 1 vs. <1 - CABG patients
    Statistical analysis description
    Odds ratio for proportion of patients with EQ5D utility score 1 vs. <1 for propofol compared to intralipid groups in CABG patients.
    Comparison groups
    CABG patients - propofol v CABG patients - intralipid
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.61
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    3.62
    Statistical analysis title
    EQ5D utility score 1 vs. <1 - AVR patients
    Statistical analysis description
    Odds ratio for proportion of patients with EQ5D utility score 1 vs. <1 for propofol compared to intralipid groups in AVR patients.
    Comparison groups
    AVR patients - intralipid v AVR patients - propofol
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.058
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    1.05

    Secondary: CROQ core score (CABG patients only)

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    End point title
    CROQ core score (CABG patients only)
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    CABG patients - propofol CABG patients - intralipid
    Number of subjects analysed
    31
    30
    Units: N/A
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    50 (44.3 to 54.8)
    52.1 (44.9 to 57.7)
        3 months post-operative
    51.6 (45.9 to 55.6)
    52.9 (48.1 to 55)
    Statistical analysis title
    CROQ core score mean difference
    Comparison groups
    CABG patients - propofol v CABG patients - intralipid
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.37
         upper limit
    2.69

    Secondary: MLHFQ overall score (AVR patients only)

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    End point title
    MLHFQ overall score (AVR patients only)
    End point description
    Overall score from Minnisota Living with Heart Failure Questionnaire
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    AVR patients - propofol AVR patients - intralipid
    Number of subjects analysed
    20
    20
    Units: N/A
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    28.5 (11 to 54)
    27 (11 to 35.5)
        3 months post-operative
    15 (5 to 32)
    12.5 (3 to 29)
    Statistical analysis title
    MLHFQ overall score mean difference
    Comparison groups
    AVR patients - propofol v AVR patients - intralipid
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.72
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.07
         upper limit
    7.84

    Secondary: CROQ symptoms score (CABG patients only)

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    End point title
    CROQ symptoms score (CABG patients only)
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    CABG patients - propofol CABG patients - intralipid
    Number of subjects analysed
    31
    30
    Units: N/A
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    67.9 (54.7 to 85.7)
    78.6 (50 to 89.9)
        3 months post-operative
    94.7 (82.1 to 100)
    96.4 (91.7 to 100)
    No statistical analyses for this end point

    Secondary: CROQ physical functioning score (CABG patients only)

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    End point title
    CROQ physical functioning score (CABG patients only)
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    CABG patients - propofol CABG patients - intralipid
    Number of subjects analysed
    31
    30
    Units: N/A
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    75 (50 to 87.5)
    68.8 (40.7 to 96.9)
        3 months post-operative
    81.3 (68.8 to 100)
    87.5 (75 to 100)
    No statistical analyses for this end point

    Secondary: CROQ cognitive functioning score (CABG patients only)

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    End point title
    CROQ cognitive functioning score (CABG patients only)
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    CABG patients - propofol CABG patients - intralipid
    Number of subjects analysed
    31
    30
    Units: N/A
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    80 (60 to 93.3)
    86.7 (66.7 to 93.3)
        3 months post-operative
    90 (66.7 to 100)
    86.7 (73.3 to 100)
    No statistical analyses for this end point

    Secondary: CROQ psychosocial functioning score (CABG patients only)

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    End point title
    CROQ psychosocial functioning score (CABG patients only)
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    CABG patients - propofol CABG patients - intralipid
    Number of subjects analysed
    31
    30
    Units: N/A
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    65.9 (51.8 to 85.7)
    73.2 (53.6 to 91.1)
        3 months post-operative
    86.6 (67.9 to 96.4)
    87.5 (75 to 94.6)
    No statistical analyses for this end point

    Secondary: CROQ satisfaction score (CABG patients only)

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    End point title
    CROQ satisfaction score (CABG patients only)
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at 3 months post-operatively
    End point values
    CABG patients - propofol CABG patients - intralipid
    Number of subjects analysed
    31
    30
    Units: N/A
        median (inter-quartile range (Q1-Q3))
    84.7 (72.2 to 95.8)
    83.3 (72.2 to 95.8)
    No statistical analyses for this end point

    Secondary: CROQ adverse events score (CABG patients only)

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    End point title
    CROQ adverse events score (CABG patients only)
    End point description
    End point type
    Secondary
    End point timeframe
    Collected 3 months post-operatively
    End point values
    CABG patients - propofol CABG patients - intralipid
    Number of subjects analysed
    31
    30
    Units: N/A
        median (inter-quartile range (Q1-Q3))
    89.8 (70.5 to 95.5)
    87.5 (79.5 to 95.5)
    No statistical analyses for this end point

    Secondary: MLHFQ physical dimension score (AVR patients only)

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    End point title
    MLHFQ physical dimension score (AVR patients only)
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    AVR patients - propofol AVR patients - intralipid
    Number of subjects analysed
    20
    20
    Units: N/A
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    15.5 (5.5 to 24)
    16 (8.5 to 21)
        3 months post-operative
    8 (3 to 16)
    6 (1 to 15)
    No statistical analyses for this end point

    Secondary: MLHFQ emotional dimension score (AVR patients only)

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    End point title
    MLHFQ emotional dimension score (AVR patients only)
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline and 3 months post-operatively
    End point values
    AVR patients - propofol AVR patients - intralipid
    Number of subjects analysed
    20
    20
    Units: N/A
    median (inter-quartile range (Q1-Q3))
        Pre-operative
    4.5 (1.5 to 12.5)
    4 (1.5 to 8)
        3 months post-operative
    3 (0 to 8)
    4 (0 to 7)
    No statistical analyses for this end point

    Secondary: ATP in left ventricle

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    End point title
    ATP in left ventricle
    End point description
    Adenosine triphosphate in the left ventricle
    End point type
    Secondary
    End point timeframe
    Measured prior to cross-clamp and 10 minutes post cross-clamp release.
    End point values
    Patients for biopsy analysis - propofol Patients for biopsy analysis - intralipid
    Number of subjects analysed
    39
    39
    Units: nmol/mg
    median (inter-quartile range (Q1-Q3))
        Prior to cross-clamp
    2.74 (2.12 to 3.55)
    3.44 (2.37 to 4.16)
        10 minutes post cross-clamp release
    2.46 (1.58 to 3.67)
    2.77 (2.11 to 3.98)
    Statistical analysis title
    ATP in left ventricle geometric mean ratio
    Statistical analysis description
    Geometric mean ratio for comparison of ATP in left ventricle
    Comparison groups
    Patients for biopsy analysis - propofol v Patients for biopsy analysis - intralipid
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.71
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1.3

    Secondary: ATP in right ventricle

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    End point title
    ATP in right ventricle
    End point description
    Adenosine triphosphate in the right ventricle
    End point type
    Secondary
    End point timeframe
    Measured prior to cross-clamp and 10 minutes post cross-clamp release.
    End point values
    Patients for biopsy analysis - propofol Patients for biopsy analysis - intralipid
    Number of subjects analysed
    39
    39
    Units: nmol/mg
    median (inter-quartile range (Q1-Q3))
        Prior to cross-clamp
    3.13 (2.18 to 3.86)
    3.29 (2.33 to 3.79)
        10 minutes post cross-clamp release
    2.87 (1.87 to 3.62)
    3.25 (1.89 to 4.17)
    Statistical analysis title
    ATP in right ventricle geometric mean ratio
    Statistical analysis description
    Geometric mean ratio for comparison of ATP in left ventricle
    Comparison groups
    Patients for biopsy analysis - propofol v Patients for biopsy analysis - intralipid
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.21
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.08

    Secondary: ADP in the left ventricle

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    End point title
    ADP in the left ventricle
    End point description
    Adenosine diphosphate in the left ventricle. P-value for test for interaction between treatment group and operation type = 0.049
    End point type
    Secondary
    End point timeframe
    Measured prior to cross-clamp and 10 minutes post cross-clamp release.
    End point values
    CABG patients for biopsy analysis - propofol CABG patients for biopsy analysis – intralipid AVR patients for biopsy analysis – propofol AVR patients for biopsy analysis – intralipid
    Number of subjects analysed
    24
    25
    15
    14
    Units: nmol/mg
    median (inter-quartile range (Q1-Q3))
        Prior to cross-clamp
    2.28 (1.63 to 2.67)
    2.42 (1.72 to 2.86)
    2.42 (2.01 to 2.62)
    2.15 (2.02 to 2.4)
        10 minutes post cross-clamp release
    1.8 (1.45 to 2.15)
    2.31 (1.71 to 2.94)
    1.93 (1.49 to 2.93)
    1.75 (1.65 to 2.24)
    Statistical analysis title
    ADP in left ventricle geometric mean ratio - CABG
    Statistical analysis description
    Geometric mean ratio for comparison of ADP in left ventricle between propofol and intralipid groups in CABG patients only
    Comparison groups
    CABG patients for biopsy analysis - propofol v CABG patients for biopsy analysis – intralipid
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.013
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    0.95
    Statistical analysis title
    ADP in left ventricle geometric mean ratio - AVR
    Statistical analysis description
    Geometric mean ratio for comparison of ADP in left ventricle between propofol and intralipid groups in AVR patients only
    Comparison groups
    AVR patients for biopsy analysis – intralipid v AVR patients for biopsy analysis – propofol
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.55
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.4

    Secondary: AMP in the left ventricle

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    End point title
    AMP in the left ventricle
    End point description
    Adenosine monophosphate in the left ventricle. P-value for test for interaction between treatment group and operation type = 0.027
    End point type
    Secondary
    End point timeframe
    Measured prior to cross-clamp and 10 minutes post cross-clamp release.
    End point values
    CABG patients for biopsy analysis - propofol CABG patients for biopsy analysis – intralipid AVR patients for biopsy analysis – propofol AVR patients for biopsy analysis – intralipid
    Number of subjects analysed
    24
    25
    15
    14
    Units: nmol/mg
    median (inter-quartile range (Q1-Q3))
        Prior to cross-clamp
    1.11 (0.71 to 1.44)
    0.98 (0.73 to 2)
    1.13 (0.94 to 1.37)
    0.97 (0.77 to 1.04)
        10 minutes post cross-clamp release
    0.84 (0.56 to 1.17)
    1.04 (0.77 to 1.65)
    1.22 (0.67 to 1.58)
    0.68 (0.5 to 1.07)
    Statistical analysis title
    AMP in left ventricle geometric mean ratio - CABG
    Statistical analysis description
    Geometric mean ratio for comparison of AMP in left ventricle between propofol and intralipid groups in CABG patients only
    Comparison groups
    CABG patients for biopsy analysis - propofol v CABG patients for biopsy analysis – intralipid
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.061
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.02
    Statistical analysis title
    AMP in left ventricle geometric mean ratio - AVR
    Statistical analysis description
    Geometric mean ratio for comparison of AMP in left ventricle between propofol and intralipid groups in AVR patients only
    Comparison groups
    AVR patients for biopsy analysis – propofol v AVR patients for biopsy analysis – intralipid
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.16
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    1.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    2

    Secondary: AMP in the right ventricle

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    End point title
    AMP in the right ventricle
    End point description
    Adenosine monophosphate in the right ventricle
    End point type
    Secondary
    End point timeframe
    Measured prior to cross-clamp and 10 minutes post cross-clamp release.
    End point values
    Patients for biopsy analysis - propofol Patients for biopsy analysis - intralipid
    Number of subjects analysed
    39
    39
    Units: nmol/mg
    median (inter-quartile range (Q1-Q3))
        Prior to cross-clamp
    0.85 (0.6 to 1.24)
    0.95 (0.63 to 1.41)
        10 minutes post cross-clamp release
    0.92 (0.66 to 1.26)
    0.83 (0.52 to 1.22)
    Statistical analysis title
    AMP in right ventricle geometric mean ratio
    Statistical analysis description
    Geometric mean ratio for comparison of AMP in right ventricle
    Comparison groups
    Patients for biopsy analysis - propofol v Patients for biopsy analysis - intralipid
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.56
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.4

    Secondary: ATP/AMP ratio in the left ventricle

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    End point title
    ATP/AMP ratio in the left ventricle
    End point description
    Ratio of ATP/AMP in the left ventricle
    End point type
    Secondary
    End point timeframe
    Measured prior to cross-clamp and 10 minutes post cross-clamp release.
    End point values
    Patients for biopsy analysis - propofol Patients for biopsy analysis - intralipid
    Number of subjects analysed
    39
    39
    Units: ratio
    median (inter-quartile range (Q1-Q3))
        Prior to cross-clamp
    2.75 (1.78 to 3.47)
    3.38 (2.36 to 4.56)
        10 minutes post cross-clamp release
    2.75 (1.43 to 4.48)
    3.09 (1.91 to 4.85)
    Statistical analysis title
    ATP/AMP ratio in left ventricle GMR
    Statistical analysis description
    Geometric mean ratio for comparison of ATP/AMP ratio in left ventricle
    Comparison groups
    Patients for biopsy analysis - propofol v Patients for biopsy analysis - intralipid
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.68
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.43

    Secondary: ATP/AMP ratio in the right ventricle

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    End point title
    ATP/AMP ratio in the right ventricle
    End point description
    Ratio of ATP/AMP in the right ventricle
    End point type
    Secondary
    End point timeframe
    Measured prior to cross-clamp and 10 minutes post cross-clamp release.
    End point values
    Patients for biopsy analysis - propofol Patients for biopsy analysis - intralipid
    Number of subjects analysed
    39
    39
    Units: ratio
    median (inter-quartile range (Q1-Q3))
        Prior to cross-clamp
    3.6 (2.55 to 6.36)
    3.34 (1.92 to 4.98)
        10 minutes post cross-clamp release
    3.39 (1.89 to 5.47)
    3.33 (2.2 to 5.89)
    Statistical analysis title
    ATP/AMP ratio in right ventricle GMR
    Statistical analysis description
    Geometric mean ratio for comparison of ATP/AMP ratio in right ventricle
    Comparison groups
    Patients for biopsy analysis - propofol v Patients for biopsy analysis - intralipid
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.46
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    1.22

    Secondary: ATP/ADP ratio in the left ventricle

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    End point title
    ATP/ADP ratio in the left ventricle
    End point description
    Ratio of ATP/ADP in the left ventricle
    End point type
    Secondary
    End point timeframe
    Measured prior to cross-clamp and 10 minutes post cross-clamp release.
    End point values
    Patients for biopsy analysis - propofol Patients for biopsy analysis - intralipid
    Number of subjects analysed
    39
    39
    Units: ratio
    arithmetic mean (standard deviation)
        Prior to cross-clamp
    1.272 ± 0.436
    1.459 ± 0.545
        10 minutes post cross-clamp release
    1.309 ± 0.563
    1.34 ± 0.484
    Statistical analysis title
    ATP/ADP ratio in left ventricle mean difference
    Statistical analysis description
    Mean difference for comparison of ATP/ADP ratio in left ventricle
    Comparison groups
    Patients for biopsy analysis - propofol v Patients for biopsy analysis - intralipid
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.83
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.024
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.192
         upper limit
    0.239

    Secondary: ATP/ADP ratio in the right ventricle

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    End point title
    ATP/ADP ratio in the right ventricle
    End point description
    Ratio of ATP/ADP in the right ventricle. P-value for test for interaction between treatment group and operation type = 0.062.
    End point type
    Secondary
    End point timeframe
    Measured prior to cross-clamp and 10 minutes post cross-clamp release.
    End point values
    CABG patients for biopsy analysis - propofol CABG patients for biopsy analysis – intralipid AVR patients for biopsy analysis – propofol AVR patients for biopsy analysis – intralipid
    Number of subjects analysed
    24
    25
    15
    14
    Units: ratio
    arithmetic mean (standard deviation)
        Prior to cross-clamp
    1.58 ± 0.66
    1.545 ± 0.583
    1.654 ± 0.804
    1.443 ± 0.822
        10 minutes post cross-clamp release
    1.588 ± 0.701
    1.545 ± 0.602
    1.347 ± 0.526
    1.719 ± 0.866
    Statistical analysis title
    ATP/ADP ratio in right ventricle MD - CABG
    Statistical analysis description
    Mean difference for comparison of ATP/ADP ratio in right ventricle between propofol and intralipid groups in CABG patients only
    Comparison groups
    CABG patients for biopsy analysis - propofol v CABG patients for biopsy analysis – intralipid
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.88
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.024
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.301
         upper limit
    0.35
    Statistical analysis title
    ATP/ADP ratio in right ventricle MD - AVR
    Statistical analysis description
    Mean difference for comparison of ATP/ADP ratio in right ventricle between propofol and intralipid groups in AVR patients only
    Comparison groups
    AVR patients for biopsy analysis – propofol v AVR patients for biopsy analysis – intralipid
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.025
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.487
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.913
         upper limit
    -0.06

    Other pre-specified: Total ventilation time

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    End point title
    Total ventilation time
    End point description
    End point type
    Other pre-specified
    End point timeframe
    In-hospital
    End point values
    Propofol Intralipid
    Number of subjects analysed
    51
    50
    Units: Hours
        median (inter-quartile range (Q1-Q3))
    6.8 (4.9 to 8.8)
    7.2 (5.6 to 10.5)
    No statistical analyses for this end point

    Other pre-specified: Time on ward pre-discharge

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    End point title
    Time on ward pre-discharge
    End point description
    End point type
    Other pre-specified
    End point timeframe
    In-hospital
    End point values
    Propofol Intralipid
    Number of subjects analysed
    51
    47 [4]
    Units: Hours
        median (inter-quartile range (Q1-Q3))
    73.5 (43.2 to 115)
    92.8 (51 to 139)
    Notes
    [4] - Three participants not admitted to ward from intensive care unit
    No statistical analyses for this end point

    Other pre-specified: Length of hospital stay

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    End point title
    Length of hospital stay
    End point description
    End point type
    Other pre-specified
    End point timeframe
    In-hospital
    End point values
    Propofol Intralipid
    Number of subjects analysed
    51
    50
    Units: Days
        median (inter-quartile range (Q1-Q3))
    7 (6 to 8)
    6 (5 to 9)
    No statistical analyses for this end point

    Other pre-specified: ADP in the right ventricle

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    End point title
    ADP in the right ventricle
    End point description
    Adenosine diphosphate in the right ventricle
    End point type
    Other pre-specified
    End point timeframe
    Measured prior to cross-clamp and 10 minutes post cross-clamp release.
    End point values
    Patients for biopsy analysis - propofol Patients for biopsy analysis - intralipid
    Number of subjects analysed
    39
    39
    Units: nmol/mg
    median (inter-quartile range (Q1-Q3))
        Prior to cross-clamp
    2.02 (1.8 to 2.54)
    2.13 (1.68 to 2.61)
        10 minutes post cross-clamp release
    1.87 (1.63 to 2.52)
    2.2 (1.68 to 2.56)
    Statistical analysis title
    ADP in right ventricle geometric mean ratio
    Statistical analysis description
    Geometric mean ratio for comparison of ADP in right ventricle
    Comparison groups
    Patients for biopsy analysis - propofol v Patients for biopsy analysis - intralipid
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6
    Method
    Mixed models analysis
    Parameter type
    Geometric mean ratio
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.13

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    In-hospital and up to 3 months post-operatively
    Adverse event reporting additional description
    All expected adverse events reported as event names (not put through medical dictionary). Unexpected adverse events reported using MedDRA dictionary. For all events, 'non-serious adverse events' includes ALL events (serious and non-serious). This is consistent with the trial publication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    Not used
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    Propofol
    Reporting group description
    -

    Reporting group title
    Intralipid
    Reporting group description
    -

    Serious adverse events
    Propofol Intralipid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 51 (21.57%)
    11 / 50 (22.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Reintubation/ventilation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence requiring reoperation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Inotropes used post-operatively
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-aortic balloon pump used
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    New haemofiltration/dialysis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystectomy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia/atrial fibrillation requiring treatment
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    New post-operative pacing
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Permanent pacing
    Additional description: Collected as the need for permanent post-operative pacing.
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Low cardiac output
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pnuemothorax or pleural effusion requiring drainage
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Permanent stroke
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Maculopathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Peptic ulcer/GI bleed/perforation
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other GI complications
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective complication
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Propofol Intralipid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 51 (82.35%)
    43 / 50 (86.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Peripheral ischaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Reintubation/ventilation
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Wound dehiscence requiring reoperation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Chest reopened due to bleeding
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Post procedural haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Inotropes used post-operatively
         subjects affected / exposed
    16 / 51 (31.37%)
    18 / 50 (36.00%)
         occurrences all number
    15
    17
    Intra-aortic balloon pump used
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Vasodilator used
         subjects affected / exposed
    12 / 51 (23.53%)
    13 / 50 (26.00%)
         occurrences all number
    12
    13
    Tracheostomy
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Continuous Positive Airway Pressure Mask
         subjects affected / exposed
    7 / 51 (13.73%)
    4 / 50 (8.00%)
         occurrences all number
    7
    5
    New haemofiltration/dialysis
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Cholecystectomy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    Supraventricular tachycardia/atrial fibrillation requiring treatment
    Additional description: Collected in data collection forms as supraventricular tachycardia/atrial fibrillation requiring treatment.
         subjects affected / exposed
    21 / 51 (41.18%)
    24 / 50 (48.00%)
         occurrences all number
    25
    24
    Ventricular fibrillation/ventricular tachycardia requiring intervention
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Myocardial infarction
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    New post-operative pacing
         subjects affected / exposed
    5 / 51 (9.80%)
    8 / 50 (16.00%)
         occurrences all number
    5
    8
    Permanent pacing
    Additional description: Collected as the need for permanent post-operative pacing.
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Low cardiac output
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Bradycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Cardiac failure congestive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax or pleural effusion requiring drainage
         subjects affected / exposed
    1 / 51 (1.96%)
    7 / 50 (14.00%)
         occurrences all number
    1
    8
    Pulmonary embolism
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Permanent stroke
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Paraesthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Eye disorders
    Maculopathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Peptic ulcer/GI bleed/perforation
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Other GI complications
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 50 (4.00%)
         occurrences all number
    3
    2
    Diverticulum
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Renal failure acute
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Infective complication
         subjects affected / exposed
    9 / 51 (17.65%)
    18 / 50 (36.00%)
         occurrences all number
    11
    21
    Sepsis
         subjects affected / exposed
    4 / 51 (7.84%)
    11 / 50 (22.00%)
         occurrences all number
    5
    13
    Respiratory infection
         subjects affected / exposed
    5 / 51 (9.80%)
    10 / 50 (20.00%)
         occurrences all number
    5
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jan 2010
    Amendment 1: Microparticle testing removal
    15 Jun 2010
    Amendment 2: IL-6, IL-8, IL-10, C3a, C5a, TNFα, NGAL, 8-Isoprostane testing removed. Addition of a 3 month follow up questionnaire cover letter.
    04 Oct 2011
    Amendment 3: Approaching patients in pre-assessment, Jehovah’s witness to exclusion criteria chest pain as expected event, update members of CRB) PIS (v3.0) update of PALS contact details
    29 Mar 2012
    Amendment 4: Submitted to the MHRA to retract amendment 3 as REC did not approve amendment 3
    29 Oct 2012
    Amendment 5: Changed end of trial definition and end date to 30/09/2013. REC details updated in CT form

    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.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26256300
    The status of studies in GB is no longer updated from 1.1.2021
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