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    Clinical Trial Results:
    Pain relief for chest drain removal in children after cardiac surgery: Sevoflurane versus Ketamine.

    Summary
    EudraCT number
    		 2011-003786-14
    Trial protocol
    		 BE  
    Global end of trial date
    30 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Sep 2022
    First version publication date
    25 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AGO/2011/006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ghent University Hospital
    Sponsor organisation address
    C. Heymanslaan 10, Gent, Belgium, 9000
    Public contact
    HIRUZ CTU, Ghent University Hospital, 32 93320500, hiruz.ctu@uzgent.be
    Scientific contact
    HIRUZ CTU, Ghent University Hospital, 32 93320500, hiruz.ctu@uzgent.be
    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
    28 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Investigate whether the administration of ketamine or sevoflurane in extubated children, in addition to the standard analgesics, can provide greater comfort during the removal of surgical thoracic drains.
    Protection of trial subjects
    Ethics review and approval, informed consent, supportive care and routine monitoring.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2011
    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
    Belgium: 51
    Worldwide total number of subjects
    51
    EEA total number of subjects
    51
    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)
    51
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 51 patients were recruited between 28-02-2012 and 17-03-2014. End of trial notification was dated 17-03-2014 (last patient last visit) and submitted to EC and CA on 01-02-2017. There were no dropouts.

    Pre-assignment
    Screening details
    		 Age < 14 years, post cardiac surgery, presence of surgical thoracic drains, written informed consent of the legal representative (+ oral consent of the patient if older than 12 years), sober (> eight hours ago solid food, > four hours ago milk, > two hours ago clear fluid).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard of Care
    Arm description
    		 Standard analgesia (paracetamol ± ibuprofen and possibly an infusion of morphine).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paracetamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg paracetamol per administration. The administration is repeated every six hours.

    Investigational medicinal product name
    Nurofen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Enteral use
    Dosage and administration details
    The dosage is 7.5 mg/kg per os. The administration is repeated every six hours.

    Investigational medicinal product name
    Morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Morphine is administered via continuous infusion at doses ranging from 10 to 40 µg/kg/hour depending on the pain score measured by the Comfort-B scale.

    Arm title
    		 Sevoflurane
    Arm description
    		 Standard analgesia + Sevoflurane
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paracetamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg paracetamol per administration. The administration is repeated every six hours.

    Investigational medicinal product name
    Nurofen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Enteral use
    Dosage and administration details
    The dosage is 7.5 mg/kg per os. The administration is repeated every six hours.

    Investigational medicinal product name
    Morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Morphine is administered via continuous infusion at doses ranging from 10 to 40 µg/kg/hour depending on the pain score measured by the Comfort-B scale.

    Investigational medicinal product name
    Sevoflurane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Sevoflurane is administered in the form of an inhalation gas. A combination of x L oxygen/minute (x = 2 times the normal minute volume by weight) and 6% sevoflurane is started.

    Arm title
    		 Ketamine
    Arm description
    		 Standard analgesia + Ketamine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paracetamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg paracetamol per administration. The administration is repeated every six hours.

    Investigational medicinal product name
    Nurofen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Enteral use
    Dosage and administration details
    The dosage is 7.5 mg/kg per os. The administration is repeated every six hours.

    Investigational medicinal product name
    Morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Morphine is administered via continuous infusion at doses ranging from 10 to 40 µg/kg/hour depending on the pain score measured by the Comfort-B scale.

    Investigational medicinal product name
    Ketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of ketamine is a single intravenous administration of 1mg/kg body weight over a time span of at least one minute.

    Number of subjects in period 1
    		Standard of Care Sevoflurane Ketamine
    Started
    17
    17
    17
    Completed
    17
    17
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 51 51
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 2.2 (0.5 to 4.6) -
    Gender categorical
    Units: Subjects
        Female
    		 19 19
        Male
    		 32 32
    Drains
    Units: Subjects
        1 drain
    		 8 8
        2 drains
    		 23 23
        3 drains
    		 12 12
        4 drains
    		 8 8
    RACHS-1 score
    Units: Subjects
        Score 1
    		 12 12
        Score 2
    		 18 18
        Score 3
    		 20 20
        Score 4
    		 1 1
    Length
    Units: cm
        median (inter-quartile range (Q1-Q3))
    		 82 (66 to 102) -
    Weight
    Units: kg
        median (inter-quartile range (Q1-Q3))
    		 11 (6 to 16) -
    Subject analysis sets

    Subject analysis set title
    Pain and comfort
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All groups started and ended with an average Comfort-B score between comfort limits of 12 to 16. When removing the dressing, the standard group peaked at an average value of about 21. In the ketamine group, there was a slight decrease in the average score. The sevoflurane group peaked at an average value of about eight. This trend persisted throughout the entire procedure.

    Subject analysis sets values
    		 Pain and comfort
    Number of subjects
    51
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    2.2 (0.5 to 4.6)
    Gender categorical
    Units: Subjects
        Female
        Male
    Drains
    Units: Subjects
        1 drain
        2 drains
        3 drains
        4 drains
    RACHS-1 score
    Units: Subjects
        Score 1
        Score 2
        Score 3
        Score 4
    Length
    Units: cm
        median (inter-quartile range (Q1-Q3))
    Weight
    Units: kg
        median (inter-quartile range (Q1-Q3))

    End points

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    End points reporting groups
    Reporting group title
    Standard of Care
    Reporting group description
    		 Standard analgesia (paracetamol ± ibuprofen and possibly an infusion of morphine).

    Reporting group title
    Sevoflurane
    Reporting group description
    		 Standard analgesia + Sevoflurane

    Reporting group title
    Ketamine
    Reporting group description
    		 Standard analgesia + Ketamine

    Subject analysis set title
    Pain and comfort
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All groups started and ended with an average Comfort-B score between comfort limits of 12 to 16. When removing the dressing, the standard group peaked at an average value of about 21. In the ketamine group, there was a slight decrease in the average score. The sevoflurane group peaked at an average value of about eight. This trend persisted throughout the entire procedure.

    Primary: Comfort Behavior

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    End point title
    		 Comfort Behavior
    End point description
    End point type
    Primary
    End point timeframe
    Comfort B-score measured during all phases of the procedure: pre-measurement, removal bandage, removal drains, bandage, post-measurement.
    End point values
    		 Standard of Care Sevoflurane Ketamine
    Number of subjects analysed
    17
    17
    17
    Units: Score
    number (not applicable)
        pre-measurement
    13
    13
    15
        removal bandage
    21
    8
    12
        removal drains
    22
    8
    13
        bandage
    20
    8
    14
        post-measurement
    14
    14
    13
    Statistical analysis title
    		 Pain and comfort evolution
    Statistical analysis description
    It was tested whether the visual differences are also statistically significant. Before the procedure and one hour after the procedure, the respective categorized Comfort-B scores between the three groups were not significantly different from each other, but during the removal of the dressing, the drains and the re-establishment of the dressing, the difference of the respective categorized Comfort-B scores between the three groups was significant.
    Comparison groups
    Standard of Care v Sevoflurane v Ketamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Impact on arterial blood pressure - RRs0 and RRs2

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    End point title
    		 Impact on arterial blood pressure - RRs0 and RRs2
    End point description
    RRs0 (mmHg) = systolic blood pressure before the start of the procedure RRs2 (mmHg) = systolic blood pressure when removing drains Mean = RRs0 - RRs2
    End point type
    Secondary
    End point timeframe
    Before administration of anesthesia, 3x during procedure (removal of thoracic drains) and 60 minutes after end of procedure.
    End point values
    		 Standard of Care Sevoflurane Ketamine
    Number of subjects analysed
    17
    17
    17
    Units: difference between RRs0 and RRs2 (mmHg)
        arithmetic mean (standard deviation)
    -27.250 ± 19.443
    16.182 ± 9.998
    -12.167 ± 17.440
    Statistical analysis title
    		 Standard Care
    Comparison groups
    Standard of Care v Sevoflurane v Ketamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [1]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - A paired t-test (P < 0.05) was used to determine statistically significance. When p < 0.05, it can be concluded that the blood pressure (systolic/mean) before the start significantly differ from that during the removal of the drains.
    Statistical analysis title
    		 Sevoflurane
    Comparison groups
    Sevoflurane v Standard of Care v Ketamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0 [2]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - A paired t-test (P < 0.05) was used to determine statistically significance. When p < 0.05, it can be concluded that the blood pressure (systolic/mean) before the start significantly differ from that during the removal of the drains.
    Statistical analysis title
    		 Ketamine
    Comparison groups
    Ketamine v Standard of Care v Sevoflurane
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034 [3]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [3] - A paired t-test (P < 0.05) was used to determine statistically significance. When p < 0.05, it can be concluded that the blood pressure (systolic/mean) before the start significantly differ from that during the removal of the drains.

    Secondary: Impact on arterial blood pressure - RRm0 and RRm2

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    End point title
    		 Impact on arterial blood pressure - RRm0 and RRm2
    End point description
    RRm0 (mmHg) = meanblood pressure before the start of the procedure RRm2 (mmHg) = mean blood pressure when removing drains Mean = RRm0 - RRm2
    End point type
    Secondary
    End point timeframe
    Before administration of anesthesia, 3x during procedure (removal of thoracic drains) and 60 minutes after end of procedure.
    End point values
    		 Standard of Care Sevoflurane Ketamine
    Number of subjects analysed
    17
    17
    17
    Units: difference between RRm0 and RRm2 (mmHg)
        arithmetic mean (standard deviation)
    -21.000 ± 14.924
    13.364 ± 8.441
    -9.750 ± 12.913
    Statistical analysis title
    		 Standard Care
    Comparison groups
    Standard of Care v Sevoflurane v Ketamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0 [4]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [4] - A paired t-test (P < 0.05) was used to determine statistically significance. When p < 0.05, it can be concluded that the blood pressure (systolic/mean) before the start significantly differ from that during the removal of the drains.
    Statistical analysis title
    		 Sevoflurane
    Comparison groups
    Sevoflurane v Standard of Care v Ketamine
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0 [5]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [5] - A paired t-test (P < 0.05) was used to determine statistically significance. When p < 0.05, it can be concluded that the blood pressure (systolic/mean) before the start significantly differ from that during the removal of the drains.
    Statistical analysis title
    		 Ketamine
    Comparison groups
    Ketamine v Standard of Care v Sevoflurane
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024 [6]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [6] - A paired t-test (P < 0.05) was used to determine statistically significance. When p < 0.05, it can be concluded that the blood pressure (systolic/mean) before the start significantly differ from that during the removal of the drains.

    Secondary: Impact on hartrate

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    End point title
    		 Impact on hartrate
    End point description
    HF0-HF2)
    End point type
    Secondary
    End point timeframe
    Start of procedure (O) until drain removal (2)
    End point values
    		 Standard of Care Sevoflurane Ketamine
    Number of subjects analysed
    17
    17
    17
    Units: BPM
        number (not applicable)
    -3.061
    -1.734
    -2.228
    No statistical analyses for this end point

    Secondary: impact on arterial oxygen saturation

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    End point title
    		 impact on arterial oxygen saturation
    End point description
    Sat0 (start of procedure)-Sat2 (drain removal
    End point type
    Secondary
    End point timeframe
    From start of procedure until drain removal
    End point values
    		 Standard of Care Sevoflurane Ketamine
    Number of subjects analysed
    17
    17
    17
    Units: SpO2%
        number (not applicable)
    -1.409
    -1.577
    -0.216
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events will be reported between the first dose administration of trial medication and the last trial related activity
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: All Serious Adverse Events and Serious Adverse Reactions were reported according to the applicable regulatory requirements. None of them occurred.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jul 2012
    Adjustment of the dose of paracetamol according to the latest scientific guidelines. Adjustment of the amount of oxygen in the sevoflurane group: adjustment of the amount of oxygen administered for a particular patient group because in this patient group the administration of extra oxygen is also done according to these proportions in other circumstances (e.g. giving aerosol). Supplementing the exclusion criteria in order to avoid the creation of further subgroups.

    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
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