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    Clinical Trial Results:
    Dexamethasone twice for pain treatment of total knee arthroplasty (DEX-2-TKA) A randomized blinded placebo-controlled clinical trial

    Summary
    EudraCT number
    		 2018-001099-39
    Trial protocol
    		 DK  
    Global end of trial date
    07 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2022
    First version publication date
    01 Mar 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SM1-KAKG-2018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03506789
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Anaesthesiology
    Sponsor organisation address
    Ringstedgade 61, Næstved, Denmark, 4700
    Public contact
    Daniel Hägi-Pedersen, Department of Anaesthesiology, Naestved Hospital, 0045 56514002, anaestesisekretariat@regionsjaelland.dk
    Scientific contact
    Daniel Hägi-Pedersen, Department of Anaesthesiology, Naestved Hospital, 0045 56514002, anaestesisekretariat@regionsjaelland.dk
    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
    27 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this trial is to investigate the analgesic efficacy and safety of one or two doses of dexamethasone after total knee arthroplasty
    Protection of trial subjects
    Subjects received a Patient Controlled Analgesia Pump with morphine, where they could steer their own pain treatment. Thus reducing patients discomfort in trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Oct 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 485
    Worldwide total number of subjects
    485
    EEA total number of subjects
    485
    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)
    179
    From 65 to 84 years
    296
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All participants scheduled for primary, unilateral total knee arthroplasty were screened for enrolment. 1599 patients were assessed for eleigibility.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DEX1
    Arm description
    		 24 mg dexamethasone i.v. perioperatively and placebo (isotonic saline) i.v. on the first postoperative day
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    24 milligramme intravenous after start of anaesthesia.

    Investigational medicinal product name
    NaCl (Sodium Chloride)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo (isotonic saline) i.v. on the first postoperative day 6 ml. 24 hours after last suture.

    Arm title
    		 DEX2
    Arm description
    		 24 mg dexamethasone i.v. perioperatively and 24 mg dexamethasone i.v. on the first postoperative day
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    24 mg dexamethasone i.v. perioperatively and 24 mg dexamethasone i.v. on the first postoperative day, 24 hours after last suture.

    Arm title
    		 Placebo
    Arm description
    		 Placebo (isotonic saline) i.v. perioperatively and placebo (isotonic saline) i.v. on the first postoperative day
    Arm type
    		 Placebo

    Investigational medicinal product name
    NaCl (Sodium Chloride)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo (isotonic saline) i.v. perioperatively 6 ml and placebo (isotonic saline) i.v. on the first postoperative day 6 ml, 24 hours after last suture.

    Number of subjects in period 1
    		DEX1 DEX2 Placebo
    Started
    161
    162
    162
    Completed
    161
    162
    162

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DEX1
    Reporting group description
    		 24 mg dexamethasone i.v. perioperatively and placebo (isotonic saline) i.v. on the first postoperative day

    Reporting group title
    DEX2
    Reporting group description
    		 24 mg dexamethasone i.v. perioperatively and 24 mg dexamethasone i.v. on the first postoperative day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (isotonic saline) i.v. perioperatively and placebo (isotonic saline) i.v. on the first postoperative day

    Reporting group values
    		 DEX1 DEX2 Placebo Total
    Number of subjects
    		 161 162 162 485
    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
    Age in years
    Units: years
        arithmetic mean (standard deviation)
    		 69 ± 9 67 ± 9 68 ± 9 -
    Gender categorical
    Sex
    Units: Subjects
        Female
    		 81 87 88 256
        Male
    		 80 75 74 229
    American Society of Anesthesiologists physical status
    American Society of Anesthesiologists physical status
    Units: Subjects
        Healthy
    		 28 28 19 75
        Mild systemic disease
    		 102 114 120 336
        Severe systemic disease
    		 31 20 23 74
    Type 2 diabetes
    Type 2 diabetes
    Units: Subjects
        No
    		 145 146 145 436
        Yes
    		 16 16 17 49
    Type of Anaesthesia
    Units: Subjects
        Spinal
    		 128 131 132 391
        General
    		 30 28 26 84
        Conversion of spinal to general
    		 3 3 4 10
    Use of PONV prophylaxis
    Administration of 4 mg ondansetron PONV prophylaxis
    Units: Subjects
        Yes
    		 140 146 151 437
        No
    		 21 16 11 48
    Local infiltration analgesia
    Administration of local infiltration analgesia
    Units: Subjects
        Yes
    		 157 162 161 480
        No
    		 4 0 1 5
    Type of knee arthroplasty
    Type of knee arthroplasty
    Units: Subjects
        Cemented
    		 97 96 94 287
        Cement less
    		 5 2 4 11
        Hybrid
    		 59 64 64 187
    Height
    Height in cm
    Units: centimetre
        arithmetic mean (standard deviation)
    		 173 ± 10 172 ± 9 172 ± 10 -
    Weight
    Weight in kg
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 86 ± 17 88 ± 15 89 ± 16 -
    BMI
    Body mass index
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 29 ± 5 30 ± 4 30 ± 4 -
    Median use of sufentanil under GA
    Mean (SD) amount of sufentanil used if general anaesthesia (μg)
    Units: microgram(s)
        arithmetic mean (standard deviation)
    		 26.6 ± 6.1 26.2 ± 4.7 27.8 ± 8.7 -
    Median amonut bupivacaine in spinal
    Median (IQR) amount of bupivacaine in spinal anaesthesia (mg)
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    		 11 (10 to 11.5) 11 (10 to 12) 11 (10 to 12) -
    Intraoperative bloodloss
    Median (IQR) intraoperative blood loss (mL). Intraoperative blood loss was registered at the end of surgery, comprising blood in the suction bottle and gauze
    Units: millilitre(s)
        median (inter-quartile range (Q1-Q3))
    		 150 (50 to 250) 150 (100 to 200) 150 (56 to 250) -
    Duration of surgery
    Median (IQR) duration of surgery (min)
    Units: minute'
        median (inter-quartile range (Q1-Q3))
    		 61 (55 to 71) 62 (53 to 73) 63 (54 to 71) -
    Median use of morphine
    Previous median (IQR) amount of opioid used (mg).
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    		 12.5 (11.3 to 13.8) 15 (10 to 20) 20 (20 to 20) -

    End points

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    End points reporting groups
    Reporting group title
    DEX1
    Reporting group description
    		 24 mg dexamethasone i.v. perioperatively and placebo (isotonic saline) i.v. on the first postoperative day

    Reporting group title
    DEX2
    Reporting group description
    		 24 mg dexamethasone i.v. perioperatively and 24 mg dexamethasone i.v. on the first postoperative day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (isotonic saline) i.v. perioperatively and placebo (isotonic saline) i.v. on the first postoperative day

    Primary: Median morphine consumption at 0-48 h

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    End point title
    		 Median morphine consumption at 0-48 h
    End point description
    End point type
    Primary
    End point timeframe
    Morphine consumption from last suture of operation to 48 hours after last suture.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: milligram(s)
        median (confidence interval 98.3%)
    37.9 (20.7 to 56.7)
    35.0 (20.6 to 52.0)
    43 (28.7 to 64.0)
    Statistical analysis title
    		 Median diffrence between DEX2 and DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.3 [2]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -2.7
    Confidence interval
         level
    		 98.3%
         sides
    2-sided
         lower limit
    		 -9.3
         upper limit
    		 3.7
    Notes
    [1] - Hodges-Lehman median diffrence
    [2] - Because three intervention groups were included, we used an α of 0.0167 (Bonferroni correction; two sided)
    Statistical analysis title
    		 Median diffrence between DEX2 and DEX1
    Comparison groups
    Placebo v DEX1
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.008 [4]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    7.8
    Confidence interval
         level
    		 98.3%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 14.7
    Notes
    [3] - Hodges-Lehman median diffrence
    [4] - Because three intervention groups were included, we used an α of 0.0167 (Bonferroni correction; two sided)
    Statistical analysis title
    		 Median diffrence between DEX2 and placebo group
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001 [6]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10.7
    Confidence interval
         level
    		 98.3%
         sides
    2-sided
         lower limit
    		 4
         upper limit
    		 17.3
    Notes
    [5] - Hodges-Lehman median diffrence
    [6] - Because three intervention groups were included, we used an α of 0.0167 (Bonferroni correction; two sided)

    Secondary: Pain intensity level; knee flexion

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    End point title
    		 Pain intensity level; knee flexion
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours postoperatively
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    50 (32 to 69.5)
    50 (35 to 68)
    60 (44 to 80)
    Statistical analysis title
    		 Pain int level; knee flex at 24 h, DEX2 vs DEX1
    Statistical analysis description
    Pain intensity level; knee flexion at 24 h (mm)
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.91 [7]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 5
    Notes
    [7] - Significance level 0.05.
    Statistical analysis title
    		 Pain int level; knee flex at 24 h, Plac and DEX1
    Statistical analysis description
    Pain intensity level; knee flexion at 24 h (mm)
    Comparison groups
    Placebo v DEX1
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [8]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4
         upper limit
    		 15
    Notes
    [8] - Significance level 0.05.
    Statistical analysis title
    		 Pain int level; knee flex at 24 h, Plac and DEX2
    Statistical analysis description
    Pain intensity level; knee flexion at 24 h (mm)
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [9]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 15
    Notes
    [9] - Significance level 0.05.

    Secondary: Pain intensity level at rest 24 h

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    End point title
    		 Pain intensity level at rest 24 h
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours postoperatively
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    20 (8 to 31)
    20 (10 to 35)
    24.5 (14 to 45)
    Statistical analysis title
    		 Median diff pain rest, DEX2 vs DEX1
    Statistical analysis description
    Pain intensity level at rest
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25 [10]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 6
    Notes
    [10] - Significance level 0.05
    Statistical analysis title
    		 Median diff pain rest, Plac vs DEX1
    Statistical analysis description
    Pain intensity level at rest
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [11]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3
         upper limit
    		 11
    Notes
    [11] - Significance level 0.05
    Statistical analysis title
    		 Median diff pain rest, Plac vs DEX2
    Statistical analysis description
    Pain intensity level at rest
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031 [12]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 10
    Notes
    [12] - Significance level 0.05

    Secondary: Level of highest pain 0-24h

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    End point title
    		 Level of highest pain 0-24h
    End point description
    End point type
    Secondary
    End point timeframe
    From last suture to 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    70 (50 to 85)
    69 (50 to 82)
    80 (66 to 90)
    Statistical analysis title
    		 Median diff highest pain, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.81 [13]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 5
    Notes
    [13] - Significance level 0.05.
    Statistical analysis title
    		 Median diff highest pain, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [14]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 15
    Notes
    [14] - Significance level 0.05.
    Statistical analysis title
    		 Median diff highest pain, Plac vs DEX2
    Comparison groups
    DEX2 v Placebo
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [15]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 15
    Notes
    [15] - Significance level 0.05.

    Secondary: Pain Intensity level, knee flexion 48 h

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    End point title
    		 Pain Intensity level, knee flexion 48 h
    End point description
    End point type
    Secondary
    End point timeframe
    48 hours postoperatively
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    55 (40 to 70)
    40 (30 to 50)
    50 (35 to 63.5)
    Statistical analysis title
    		 Medeian difference pain, knee flex, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [16]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20
         upper limit
    		 -10
    Notes
    [16] - Significance level 0.05
    Statistical analysis title
    		 Medeian difference pain, knee flex, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011 [17]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10
         upper limit
    		 0
    Notes
    [17] - Significance level 0.05
    Statistical analysis title
    		 Medeian difference pain, knee flex, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003 [18]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3
         upper limit
    		 11
    Notes
    [18] - Significance level 0.05

    Secondary: Pain Intensity level at rest at 48h

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    End point title
    		 Pain Intensity level at rest at 48h
    End point description
    End point type
    Secondary
    End point timeframe
    48 hours postoperatively
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    30 (10 to 40)
    15 (9 to 30)
    20 (10 to 35)
    Statistical analysis title
    		 Median diff pain, rest DEX2 vs DEX1
    Statistical analysis description
    Median diffrence of pain intensity level at rest 48 hours postoperatively
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [19]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 -5
    Notes
    [19] - Significance level 0.05
    Statistical analysis title
    		 Median diff pain, rest Plac vs DEX1
    Statistical analysis description
    Median diffrence of pain intensity level at rest 48 hours postoperatively
    Comparison groups
    Placebo v DEX1
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [20]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10
         upper limit
    		 0
    Notes
    [20] - Significance level 0.05
    Statistical analysis title
    		 Median diff pain, rest Plac vs DEX2
    Statistical analysis description
    Median diffrence of pain intensity level at rest 48 hours postoperatively
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003 [21]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 10
    Notes
    [21] - Significance level 0.05

    Secondary: Level for highest pain intensity 24–48 h

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    End point title
    		 Level for highest pain intensity 24–48 h
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours to 48 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    70 (50 to 84)
    60 (40 to 71)
    70 (52 to 80)
    Statistical analysis title
    		 Median diff highest pain, DEX2 vs DEX1
    Statistical analysis description
    Median diffrence of the level for highest pain intensity between 24–48 hours postoperatively
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [22]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20
         upper limit
    		 -10
    Notes
    [22] - Significance level 0.05
    Statistical analysis title
    		 Median diff highest pain, Plac vs DEX1
    Statistical analysis description
    Median diffrence of the level for highest pain intensity between 24–48 hours postoperatively
    Comparison groups
    Placebo v DEX1
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.89 [23]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 5
    Notes
    [23] - Significance level 0.05
    Statistical analysis title
    		 Median diff highest pain, Plac vs DEX2
    Statistical analysis description
    Median diffrence of the level for highest pain intensity between 24–48 hours postoperatively
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [24]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10
         upper limit
    		 20
    Notes
    [24] - Significance level 0.05

    Secondary: Adverse Events 0- 48 hours postoperatively

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    End point title
    		 Adverse Events 0- 48 hours postoperatively
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse events from last suture of operation to 48 hours after last suture.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: Events
    7
    4
    10
    Statistical analysis title
    		 Odds ratio, AE, DEX2 vs DEX1
    Statistical analysis description
    Adverse events 0- 48 hours postoperatively, odds ratio.
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35 [25]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 1.92
    Notes
    [25] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio, AE, Plac vs DEX1
    Statistical analysis description
    Adverse events 0- 48 hours postoperatively, odds ratio.
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45 [26]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 4.09
    Notes
    [26] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio, AE, Plac vs DEX2
    Statistical analysis description
    Adverse events 0- 48 hours postoperatively, odds ratio.
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1 [27]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 9.25
    Notes
    [27] - Significance level 0.05.

    Other pre-specified: Serious adverse events within 90 days

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    End point title
    		 Serious adverse events within 90 days
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From the day of surgery until 90 days postoperatively
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: Events
    21
    9
    18
    Statistical analysis title
    		 Odds ratio, SAE 90 days, DEX2 vs DEX1
    Comparison groups
    DEX2 v DEX1
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023 [28]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.88
    Notes
    [28] - Significance level 0.05
    Statistical analysis title
    		 Odds ratio, SAE 90 days, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06 [29]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.64
    Notes
    [29] - Significance level 0.05
    Statistical analysis title
    		 Odds ratio, SAE 90 days, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.075 [30]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 4.9
    Notes
    [30] - Significance level 0.05

    Other pre-specified: Nausea 24 hours

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    End point title
    		 Nausea 24 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Nausea at 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    57
    76
    108
    Statistical analysis title
    		 Odds ratio nausea 24h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.035
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 2.56
    Statistical analysis title
    		 Odds ratio nausea 24h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.57
         upper limit
    		 6.7
    Statistical analysis title
    		 Odds ratio nausea 24h, Plac vs DEX2
    Comparison groups
    DEX2 v Placebo
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.54
         upper limit
    		 3.85

    Other pre-specified: Nausea 48 hours

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    End point title
    		 Nausea 48 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Nausea at 48 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    63
    46
    72
    Statistical analysis title
    		 Odds ratio nausea 48 h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05 [31]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1
    Notes
    [31] - Significance level 0.05
    Statistical analysis title
    		 Odds ratio nausea 48 h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24 [32]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 2.06
    Notes
    [32] - Significance level 0.05
    Statistical analysis title
    		 Odds ratio nausea 48 h, Plac vs DEX2
    Comparison groups
    DEX2 v Placebo
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [33]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.31
         upper limit
    		 3.38
    Notes
    [33] - Significance level 0.05

    Other pre-specified: Sedation 24 hours

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    End point title
    		 Sedation 24 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Sedation at 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    49
    74
    93
    Statistical analysis title
    		 Odds ratio sedation 24 h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [34]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.25
         upper limit
    		 3.13
    Notes
    [34] - Significane level 0.05.
    Statistical analysis title
    		 Odds ratio sedation 24 h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [35]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.08
         upper limit
    		 5.28
    Notes
    [35] - Significane level 0.05.
    Statistical analysis title
    		 Odds ratio sedation 24 h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027 [36]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 2.59
    Notes
    [36] - Significane level 0.05.

    Other pre-specified: Sedation 48 hours

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    End point title
    		 Sedation 48 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Sedation at 48 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    59
    53
    75
    Statistical analysis title
    		 Odds ratio sedation 48h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.43 [37]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.33
    Notes
    [37] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio sedation 48h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.047 [38]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.5
    Notes
    [38] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio sedation 48h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007 [39]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 3
    Notes
    [39] - Significance level 0.05.

    Other pre-specified: Dizziness 24 hours

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    End point title
    		 Dizziness 24 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Dizziness at 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    60
    71
    104
    Statistical analysis title
    		 Odds ratio dizziness 24h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21 [40]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 2.08
    Notes
    [40] - Significance level 0.05
    Statistical analysis title
    		 Odds ratio dizziness 24h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [41]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.06
         upper limit
    		 5.21
    Notes
    [41] - Significance level 0.05
    Statistical analysis title
    		 Copy of Odds ratio dizziness 24h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [42]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.54
         upper limit
    		 3.8
    Notes
    [42] - Significance level 0.05

    Other pre-specified: Dizziness 48 hours

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    End point title
    		 Dizziness 48 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Dizziness at 48 hours postoperatively
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    47
    40
    54
    Statistical analysis title
    		 Odds ratio dizziness 48 h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38 [43]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.32
    Notes
    [43] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio dizziness 48 h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34 [44]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 2.04
    Notes
    [44] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio dizziness 48 h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.068 [45]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 2.58
    Notes
    [45] - Significance level 0.05.

    Other pre-specified: Vomiting episodes 0-24 h

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    End point title
    		 Vomiting episodes 0-24 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Vomiting episodes between 0 hours and 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: episodes
    31
    35
    66
    Statistical analysis title
    		 Odds ratio vomiting 0-24h, DEX2 vs DEX1
    Comparison groups
    DEX2 v DEX1
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65 [46]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.96
    Notes
    [46] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio vomiting 0-24h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [47]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.89
         upper limit
    		 5.34
    Notes
    [47] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio vomiting 0-24h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [48]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 4.29
    Notes
    [48] - Significance level 0.05.

    Other pre-specified: Vomiting episodes 24-48 hours

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    End point title
    		 Vomiting episodes 24-48 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Vomiting episodes between 24 hours and 48 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: episodes
    17
    11
    28
    Statistical analysis title
    		 Odds ratio vomiting 24-48h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24 [49]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 1.37
    Notes
    [49] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio vomiting 24-48h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.065 [50]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 3.54
    Notes
    [50] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio vomiting 24-48h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [51]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.41
         upper limit
    		 6.17
    Notes
    [51] - Significance level 0.05.

    Other pre-specified: Ondansetron used 0-24 h

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    End point title
    		 Ondansetron used 0-24 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Ondansetron used i milligrams between 0 hours until 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 1)
    0 (0 to 2)
    Statistical analysis title
    		 Median diff ondansetron 0-24h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.066
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Statistical analysis title
    		 Median diff ondansetron 0-24h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Statistical analysis title
    		 Median diff ondansetron 0-24h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0

    Other pre-specified: Ondansetron used 24-48 hours

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    End point title
    		 Ondansetron used 24-48 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Ondansetron used between 24 hours until 48 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Odds ratio ondansetron 24-48h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86 [52]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [52] - Significance level 0.05
    Statistical analysis title
    		 Odds ratio ondansetron 24-48h, Plac vs DEX1
    Comparison groups
    Placebo v DEX1
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [53]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [53] - Significance level 0.05
    Statistical analysis title
    		 Odds ratio ondansetron 24-48h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007 [54]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [54] - Significance level 0.05

    Other pre-specified: Droperidol used 0-24 hours

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    End point title
    		 Droperidol used 0-24 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Droperidol used between 0 hours and 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Odds ratio droperidol 0-24 h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36 [55]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [55] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio droperidol 0-24 h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [56]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [56] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio droperidol 0-24 h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031 [57]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [57] - Significance level 0.05.

    Other pre-specified: Droperidol used 24-48 h

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    End point title
    		 Droperidol used 24-48 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Droperidol used between 0 hours and 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Odds ratio droperidol 24-48 h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66 [58]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [58] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio droperidol 24-48 h,Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12 [59]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [59] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio droperidol 24-48 h,Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.054 [60]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [60] - Significance level 0.05.

    Other pre-specified: Morphine consumption 0-24 hours

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    End point title
    		 Morphine consumption 0-24 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Morphine consumption between 0 hours and 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    28 (17.0 to 42.0)
    28 (16.0 to 42.0)
    36.3 (22.0 to 52.0)
    Statistical analysis title
    		 Median diff morphine 0-24 h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.646
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 4
    Statistical analysis title
    		 Median diff morphine 0-24 h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 12
    Statistical analysis title
    		 Median diff morphine 0-24 h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.7
         upper limit
    		 12

    Other pre-specified: Morphine consumption 24-48 hours

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    End point title
    		 Morphine consumption 24-48 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Morphine consumption between 24 hours and 48 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    6.7 (3.3 to 13.3)
    6.7 (0.0 to 10.0)
    6.7 (3.3 to 13.3)
    Statistical analysis title
    		 Median diff morphine 24-48h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012 [61]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 0
    Notes
    [61] - Significance level 0.05.
    Statistical analysis title
    		 Median diff morphine 24-48h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.258 [62]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 3.3
    Notes
    [62] - Significance level 0.05.
    Statistical analysis title
    		 Median diff morphine 24-48h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [63]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 3.3
    Notes
    [63] - Significance level 0.05.

    Other pre-specified: Pain intensity llevel, knee flexion at 6 h

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    End point title
    		 Pain intensity llevel, knee flexion at 6 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Pain intensitiy level with knee flexion at 6 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    50 (30 to 66)
    45 (25 to 64.5)
    59 (39 to 75)
    Statistical analysis title
    		 Median diff pain int flex 6h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.538 [64]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8
         upper limit
    		 5
    Notes
    [64] - Significance level 0.05.
    Statistical analysis title
    		 Median diff pain int flex 6h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [65]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 16
    Notes
    [65] - Significance level 0.05.
    Statistical analysis title
    		 Median diff pain int flex 6h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [66]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 19
    Notes
    [66] - Significance level 0.05.

    Other pre-specified: Pain intensitiy level at rest at 6 h

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    End point title
    		 Pain intensitiy level at rest at 6 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Pain intensitiy level at rest at 6 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    23 (10 to 42)
    24 (11 to 39)
    34 (20 to 50)
    Statistical analysis title
    		 Median diff pain intens rest 6h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.658 [67]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 4
    Notes
    [67] - Significance level 0.05.
    Statistical analysis title
    		 Median diff pain intens rest 6h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [68]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4
         upper limit
    		 15
    Notes
    [68] - Significance level 0.05.
    Statistical analysis title
    		 Median diff pain intens rest 6h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [69]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 15
    Notes
    [69] - Significance level 0.05.

    Other pre-specified: Nausea 6 h

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    End point title
    		 Nausea 6 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Nausea at 6 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    11
    22
    45
    Statistical analysis title
    		 Odds ratio nausea 6h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.054 [70]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 4.56
    Notes
    [70] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio nausea 6h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [71]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.73
         upper limit
    		 11.32
    Notes
    [71] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio nausea 6h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [72]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.44
         upper limit
    		 4.51
    Notes
    [72] - Significance level 0.05.

    Other pre-specified: Sedation 6 h

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    End point title
    		 Sedation 6 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Sedation at 6 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: Patients
    43
    49
    61
    Statistical analysis title
    		 Median diff sedation 6h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.538
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.91
    Statistical analysis title
    		 Median diff sedation 6h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 2.82
    Statistical analysis title
    		 Median diff sedation 6h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.098
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 2.39

    Other pre-specified: Dizziness at 6 h

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    End point title
    		 Dizziness at 6 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Dizziness at 6 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    22
    28
    44
    Statistical analysis title
    		 Median diff dizziness 6h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41 [73]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 2.41
    Notes
    [73] - Significance level 0.05.
    Statistical analysis title
    		 Median diff dizziness 6h, Plac vs DEX1
    Comparison groups
    Placebo v DEX1
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003 [74]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.36
         upper limit
    		 4.28
    Notes
    [74] - Significance level 0.05.
    Statistical analysis title
    		 Median diff dizziness 6h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025 [75]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 3.2
    Notes
    [75] - Significance level 0.05.

    Other pre-specified: Level for average pain intensity 0-24 h

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    End point title
    		 Level for average pain intensity 0-24 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Level for average pain intensity between 0 hours until 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    37 (25 to 48)
    39 (30 to 50)
    48 (39 to 57)
    Statistical analysis title
    		 Med diff pain average 0-24h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.268
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 6
    Statistical analysis title
    		 Med diff pain average 0-24h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7
         upper limit
    		 15
    Statistical analysis title
    		 Med diff pain average 0-24h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 12

    Other pre-specified: Level for average pain intensity between 24-48 h

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    End point title
    		 Level for average pain intensity between 24-48 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Level for average pain intensity between 24 hours until 48 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    45 (30 to 52)
    30 (20 to 50)
    40 (30 to 50)
    Statistical analysis title
    		 Median diff pain average 24-48h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [76]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15
         upper limit
    		 -5
    Notes
    [76] - Significance level 0.05
    Statistical analysis title
    		 Median diff pain average 24-48h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.431 [77]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 0
    Notes
    [77] - Significance level 0.05
    Statistical analysis title
    		 Median diff pain average 24-48h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [78]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 12
    Notes
    [78] - Significance level 0.05

    Other pre-specified: Quality of sleep 24 h

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    End point title
    		 Quality of sleep 24 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Quality of sleep at 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    70
    73
    87
    Statistical analysis title
    		 Odds ratio sleep 24h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.819
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.64
    Statistical analysis title
    		 Odds ratio sleep 24h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.044
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.46
    Statistical analysis title
    		 Odds ratio sleep 24h, Plac vs DEX2
    Comparison groups
    DEX2 v Placebo
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.073
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 2.33

    Other pre-specified: Quality of sleep at 24 h

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    End point title
    		 Quality of sleep at 24 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Quality of sleep at 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: Patients
    44
    26
    35
    Statistical analysis title
    		 Odds ratio sleep 48 h, DEX2 vs DEX1
    Comparison groups
    DEX2 v DEX1
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015 [79]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.88
    Notes
    [79] - Significance level 0.05.
    Statistical analysis title
    		 Odds ratio sleep 48 h,Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.283 [80]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 1.26
    Notes
    [80] - Significance level 0.05.
    Statistical analysis title
    		 Copy of Odds ratio sleep 48 h,Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.187 [81]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 2.59
    Notes
    [81] - Significance level 0.05.

    Other pre-specified: Fatigue at 24 h

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    End point title
    		 Fatigue at 24 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Fatigue at 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    70
    81
    120
    Statistical analysis title
    		 Odds ratio fatigue 24 h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.222
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 2.05
    Statistical analysis title
    		 Odds ratio fatigue 24 h, Plac vs DEX1
    Comparison groups
    Placebo v DEX1
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.54
         upper limit
    		 6.66
    Statistical analysis title
    		 Odds ratio fatigue 24 h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.92
         upper limit
    		 5.02

    Other pre-specified: Fatigue at 48 h

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    End point title
    		 Fatigue at 48 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Fatigue at 48 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    133
    116
    135
    Statistical analysis title
    		 Odds ratio fatigue 48 h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.92
    Statistical analysis title
    		 Odds ratio fatigue 48 h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.289
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 2.79
    Statistical analysis title
    		 Odds ratio fatigue 48 h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.47
         upper limit
    		 5.08

    Other pre-specified: Failure to fulfill timed up and go test 24 h

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    End point title
    		 Failure to fulfill timed up and go test 24 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Timed up and go test at 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    158
    156
    158
    Units: patients
    46
    48
    62
    No statistical analyses for this end point

    Other pre-specified: Time for completion of timed up and go test 24 h

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    End point title
    		 Time for completion of timed up and go test 24 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Time for completion of timed up and go test 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    112
    108
    96
    Units: second
        median (inter-quartile range (Q1-Q3))
    30.5 (22 to 44)
    31 (20 to 41)
    40 (26.5 to 54.5)
    Statistical analysis title
    		 Median diff TUG time 24h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.413 [82]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 2
    Notes
    [82] - Significance level 0.05.
    Statistical analysis title
    		 Median diff TUG time 24h, Plac vs DEX1
    Comparison groups
    DEX1 v Placebo
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.058 [83]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 12
    Notes
    [83] - Significance level 0.05.
    Statistical analysis title
    		 Median diff TUG time 24h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [84]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4
         upper limit
    		 14
    Notes
    [84] - Significance level 0.05.

    Other pre-specified: Level for highest pain intensitiy during TUG 24 h

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    End point title
    		 Level for highest pain intensitiy during TUG 24 h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Level for highest pain intensitiy during timed up and go test at 24 hours postoperatively.
    End point values
    		 DEX1 DEX2 Placebo
    Number of subjects analysed
    112
    108
    96
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    49 (30 to 60)
    42 (25 to 58)
    48 (34.5 to 61.5)
    Statistical analysis title
    		 Med diff highest pain TUG 24 h, DEX2 vs DEX1
    Comparison groups
    DEX1 v DEX2
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.164 [85]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    -5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 1
    Notes
    [85] - Significance level 0.05.
    Statistical analysis title
    		 Med diff highest pain TUG 24 h, Plac vs DEX1
    Comparison groups
    Placebo v DEX1
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.466 [86]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 9
    Notes
    [86] - Significance level 0.05.
    Statistical analysis title
    		 Med diff highest pain TUG 24 h, Plac vs DEX2
    Comparison groups
    Placebo v DEX2
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026 [87]
    Method
    		 Van Elteren test
    Parameter type
    		 Hodges-Lehmann
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 13
    Notes
    [87] - Significance level 0.05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the intervention is given to 48 hours postoperatively. SAE were followed up to 90 days.
    Adverse event reporting additional description
    SAE were followed by patient charts until 90 days postoperatively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICH-GCP
    Dictionary version
    Revision 2
    Reporting groups
    Reporting group title
    DEX1
    Reporting group description
    		 24 mg dexamethasone i.v. perioperatively and placebo (isotonic saline) i.v. on the first postoperative day

    Reporting group title
    DEX2
    Reporting group description
    		 24 mg dexamethasone i.v. perioperatively and 24 mg dexamethasone i.v. on the first postoperative day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (isotonic saline) i.v. perioperatively and placebo (isotonic saline) i.v. on the first postoperative day

    Serious adverse events
    		 DEX1 DEX2 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 161 (13.04%)
    9 / 162 (5.56%)
    18 / 162 (11.11%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis/lung embolism
         subjects affected / exposed
    1 / 161 (0.62%)
    3 / 162 (1.85%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Infection
    Additional description: Surgical site infection
         subjects affected / exposed
    2 / 161 (1.24%)
    1 / 162 (0.62%)
    5 / 162 (3.09%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound related problems
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical problems with prosthesis
         subjects affected / exposed
    6 / 161 (3.73%)
    1 / 162 (0.62%)
    7 / 162 (4.32%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 1
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Morphine side effects
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hospital admittance longer than 4 days
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 162 (0.00%)
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Unknown
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    1 / 161 (0.62%)
    2 / 162 (1.23%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral disorder
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Low haemoglobin
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 162 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 162 (0.62%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture, not anatomically related
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 162 (0.62%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection not anatomically related
         subjects affected / exposed
    3 / 161 (1.86%)
    1 / 162 (0.62%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DEX1 DEX2 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 161 (4.35%)
    4 / 162 (2.47%)
    10 / 162 (6.17%)
    Cardiac disorders
    Hypotension
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 162 (0.62%)
    0 / 162 (0.00%)
         occurrences all number
    1
    1
    0
    Syncope during mobilisation
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 162 (0.00%)
    1 / 162 (0.62%)
         occurrences all number
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 162 (0.00%)
    1 / 162 (0.62%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Confusion
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 162 (0.00%)
    2 / 162 (1.23%)
         occurrences all number
    2
    0
    2
    Headache
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 162 (0.00%)
    1 / 162 (0.62%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences all number
    1
    0
    0
    Stomach ache
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 162 (0.00%)
    1 / 162 (0.62%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Itching
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 162 (0.62%)
    1 / 162 (0.62%)
         occurrences all number
    1
    1
    1
    Renal and urinary disorders
    Elevated creatinine
         subjects affected / exposed
    1 / 161 (0.62%)
    2 / 162 (1.23%)
    3 / 162 (1.85%)
         occurrences all number
    1
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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/34983775
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