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    Clinical Trial Results:
    Multicenter study on the effect of the treatment of metabolic alkalosis with acetazolamide on the duration of mechanical ventilation in patients with chronic obstructive pulmonary disease or obesity-hypoventilation syndrome.

    Summary
    EudraCT number
    		 2010-022901-16
    Trial protocol
    		 ES  
    Global end of trial date
    25 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2020
    First version publication date
    25 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TRAMA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hospital Universitario Son Llàtzer. Conselleria de Salut i Consum del Govern de les Illes Balears
    Sponsor organisation address
    Ctra. Manacor, km 4, PALMA, Spain, 07198
    Public contact
    Gemma Rialp Cervera. Intensive Care Department. Hospital Son Llàtzer. grialp@hsll.es, Gemma Rialp Cervera. Intensive Care Department. Hospital Son Llàtzer. grialp@hsll.es, grialp@hsll.es
    Scientific contact
    Gemma Rialp Cervera. Intensive Care Department. Hospital Son Llàtzer. grialp@hsll.es, Gemma Rialp Cervera. Intensive Care Department. Hospital Son Llàtzer. grialp@hsll.es, grialp@hsll.es
    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
    01 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of treatment of metabolic alkalosis with acetazolamide on the evolution of patients with COPD or with SOH connected to invasive MV due to acute respiratory failure.
    Protection of trial subjects
    The study was approved by the Ethics Committee (CEIC-IB 1411/10PI) and was conducted in accordance with the amended Declaration of Helsinki. Patients or patients' next of kin provided written informed consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 47
    Worldwide total number of subjects
    47
    EEA total number of subjects
    47
    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)
    47
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 104 patients were enrolled between November 2011 and February 2014 in seven intensive care units in Spain. 47 patients were included in the study.

    Pre-assignment
    Screening details
    		 57 patients were excluded before assignment. 47 patients were allocated randomly on a 1:1 basis to Placebo and Acetazolamide.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    500 mg of placebo by nasogastric tube

    Arm title
    		 Acetazolamide
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    ACETAZOLAMIDA
    Investigational medicinal product code
    59-66-5
    Other name
    ACETAZOLAMIDE
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    capsules of 500 mg of acetazolamide by nasogastric tube.

    Number of subjects in period 1
    		Placebo Acetazolamide
    Started
    23
    24
    Completed
    23
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Acetazolamide
    Reporting group description
    		 -

    Reporting group values
    		 Placebo Acetazolamide Total
    Number of subjects
    		 23 24 47
    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
    Units: years
        arithmetic mean (standard deviation)
    		 67 ( 11 ) 67 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 8 11
        Male
    		 20 16 36
    Systemic corticosteroids "Home treatment"
    Units: Subjects
        YES
    		 1 3 4
        NO
    		 22 21 43
    COPD (Chronic obstructive pulmonary disease)
    Units: Subjects
        YES
    		 20 22 42
        NO
    		 3 2 5
    Obesity hypoventilation syndrome
    Units: Subjects
        YES
    		 5 6 11
        NO
    		 18 18 36
    Heart failure
    Units: Subjects
        YES
    		 3 3 6
        NO
    		 20 21 41
    NYHA functional classification >/= III
    Units: Subjects
        YES
    		 2 0 2
        NO
    		 21 24 45
    Home oxygenotherapy "Home treatment"
    Units: Subjects
        YES
    		 7 11 18
        NO
    		 16 13 29
    Home NIV (non-invasive ventilation)
    Units: Subjects
        YES
    		 2 5 7
        NO
    		 21 19 40
    Home diuretic treatment
    Units: Subjects
        YES
    		 5 13 18
        NO
    		 18 11 29
    BMI >/= 30 kg/m2
    Units: Subjects
        YES
    		 10 10 20
        NO
    		 13 14 27
    Failure of NIV before inclusion
    Failure of noninvasive mechanical ventilation
    Units: Subjects
        YES
    		 17 15 32
        NO
    		 6 9 15
    Reason of IMV
    Reason of invasive mechanical ventilation
    Units: Subjects
        COPD exacerbation
    		 13 13 26
        Hypercapnic encephalopaty
    		 3 1 4
        Heart failure
    		 1 4 5
        Pneumonia
    		 6 5 11
        Cardiac arrest
    		 0 1 1
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 83 ( 22 ) 82 ( 25 ) -
    Height
    Units: centimeter
        arithmetic mean (standard deviation)
    		 167 ( 8 ) 166 ( 9 ) -
    Simplified Acute Phisiology Score at ICU admission
    Units: number
        arithmetic mean (standard deviation)
    		 51 ( 16 ) 59 ( 16 ) -
    BMI
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 29.6 ( 6.7 ) 30.7 ( 9.7 ) -
    FEV1 (Forced expired volume at 1s)
    Units: percent
        arithmetic mean (standard deviation)
    		 39 ( 12 ) 44 ( 20 ) -
    FVC (Forced vital capacity)
    Units: percent
        arithmetic mean (standard deviation)
    		 60 ( 13 ) 64 ( 20 ) -
    FEV1/FVC
    Units: percent
        arithmetic mean (standard deviation)
    		 50.4 ( 17.9 ) 50.1 ( 17.9 ) -
    Previous baseline PaCO2
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 53 ( 8 ) 49 ( 8 ) -
    Previous baseline creatinine
    Units: milligram/dL
        arithmetic mean (standard deviation)
    		 0.90 ( 0.31 ) 0.75 ( 0.29 ) -
    SOFA score at inclusion
    Sepsis-related Organ Failure Assessment score
    Units: points
        arithmetic mean (standard deviation)
    		 5.5 ( 2.6 ) 5.4 ( 2.4 ) -
    Arterial lactate
    Serum laboratory tests at inclusion
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    		 1.4 ( 0.6 ) 1.5 ( 0.6 ) -
    Leukocyte count
    Serum laboratory tests at inclusion
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 11.9 ( 5.3 ) 14.0 ( 7.7 ) -
    Hemoglobin
    Serum laboratory tests at inclusion.
    Units: g/dL
        arithmetic mean (standard deviation)
    		 13.9 ( 3.0 ) 14.1 ( 2.6 ) -
    Albumin
    Serum laboratory tests at inclusion.
    Units: g/dL
        arithmetic mean (standard deviation)
    		 3.15 ( 0.47 ) 2.78 ( 0.47 ) -
    Prothrombin activity
    Serum laboratory tests at inclusion.
    Units: percent
        arithmetic mean (standard deviation)
    		 80 ( 16 ) 74 ( 22 ) -
    pH
    Blood gas analysis at inclusion.
    Units: points
        arithmetic mean (standard deviation)
    		 7.42 ( 0.04 ) 7.43 ( 0.06 ) -
    PaCO2
    Blood gas analysis at inclusion
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 52 ( 6 ) 52 ( 7 ) -
    Bicarbonate
    Blood gas analysis at inclusion
    Units: millimole(s)/litre
        arithmetic mean (standard deviation)
    		 33 ( 2 ) 34 ( 4 ) -
    PaO2/FiO2
    Blood gas analysis at inclusion
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 228 ( 93 ) 202 ( 69 ) -
    Minute ventilation
    Units: L/min
        arithmetic mean (standard deviation)
    		 9.1 ( 2.0 ) 9.0 ( 2.6 ) -
    Respiratory rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 18 ( 3 ) 19 ( 5 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Acetazolamide
    Reporting group description
    		 -

    Primary: Bicarbonate concentration

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    End point title
    		 Bicarbonate concentration
    End point description
    End point type
    Primary
    End point timeframe
    day 3
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: mmol/L
        median (full range (min-max))
    34 (32 to 35)
    30 (29 to 31)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Primary: Carbon dioxide partial pressure (PaCO2)

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    End point title
    		 Carbon dioxide partial pressure (PaCO2)
    End point description
    End point type
    Primary
    End point timeframe
    day 3
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: mmHg
        median (full range (min-max))
    54 (51 to 57)
    50 (48 to 52)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Acetazolamide v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.02 [2]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Primary: PaO2/FiO2

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    End point title
    		 PaO2/FiO2
    End point description
    End point type
    Primary
    End point timeframe
    day 3
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: mm Hg
        median (full range (min-max))
    230 (198 to 262)
    234 (199 to 271)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.84 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Primary: pH

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    End point title
    		 pH
    End point description
    End point type
    Primary
    End point timeframe
    day 3
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: number
        median (full range (min-max))
    7.41 (7.39 to 7.42)
    7.40 (7.38 to 7.41)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Primary: Minute volume

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    End point title
    		 Minute volume
    End point description
    End point type
    Primary
    End point timeframe
    day 3
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: L/min
        median (full range (min-max))
    9.3 (8.6 to 10.0)
    9.7 (8.7 to 10.7)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.53 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Primary: Respiratory rate

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    End point title
    		 Respiratory rate
    End point description
    End point type
    Primary
    End point timeframe
    day 3
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    23
    Units: bpm
        median (full range (min-max))
    19 (17 to 20)
    20 (19 to 22)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.13 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Primary: Daily volume intake

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    End point title
    		 Daily volume intake
    End point description
    End point type
    Primary
    End point timeframe
    day 3
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: mL
        median (full range (min-max))
    2853 (2570 to 3136)
    2553 (2169 to 2937)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.22 [7]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Primary: Daily diuresis

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    End point title
    		 Daily diuresis
    End point description
    End point type
    Primary
    End point timeframe
    day 3
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    23
    Units: millilitre(s)
        median (full range (min-max))
    2193 (1958 to 2428)
    2065 (1825 to 2305)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Acetazolamide v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.46 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Duration of invasive mechanical ventilation (IMV)

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    End point title
    		 Duration of invasive mechanical ventilation (IMV)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: Day
        arithmetic mean (standard deviation)
    8.2 ( 5.6 )
    6.8 ( 6.0 )
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.44 [9]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [9] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Weaning duration

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    End point title
    		 Weaning duration
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: day
        arithmetic mean (standard deviation)
    2.2 ( 2.6 )
    1.9 ( 1.9 )
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Acetazolamide v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.72 [10]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [10] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Carbon dioxide partial pressure (PaCO2)

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    End point title
    		 Carbon dioxide partial pressure (PaCO2)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: mm Hg
        median (full range (min-max))
    55 (51 to 59)
    48 (47 to 50)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002 [11]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Bicarbonate concentration

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    End point title
    		 Bicarbonate concentration
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: mmol/L
        median (full range (min-max))
    34 (32 to 35)
    29 (28 to 30)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [12]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [12] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: PaO2/FiO2

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    End point title
    		 PaO2/FiO2
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: mm Hg
        median (full range (min-max))
    207 (174 to 239)
    223 (190 to 258)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Acetazolamide v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.47 [13]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [13] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: pH

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    End point title
    		 pH
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: number
        median (full range (min-max))
    7.41 (7.39 to 7.42)
    7.40 (7.39 to 7.41)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Acetazolamide v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.31 [14]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [14] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Minute volume

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    End point title
    		 Minute volume
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: L/min
        median (full range (min-max))
    9.7 (8.9 to 10.4)
    10.6 (9.2 to 12.0)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.26 [15]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Respiratory rate

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    End point title
    		 Respiratory rate
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: bpm
        median (full range (min-max))
    20 (19 to 22)
    21 (19 to 22)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.67 [16]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [16] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Daily volume intake

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    End point title
    		 Daily volume intake
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: millilitre(s)
        median (full range (min-max))
    2735 (2558 to 2913)
    2600 (2285 to 2916)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.46 [17]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [17] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Daily diuresis

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    End point title
    		 Daily diuresis
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: millilitre(s)
        median (full range (min-max))
    2546 (2244 to 2849)
    2311 (1954 to 2670)
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.33 [18]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [18] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Length of ICU stay

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    End point title
    		 Length of ICU stay
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: day
        arithmetic mean (standard deviation)
    14.8 ( 13.8 )
    11.8 ( 10.6 )
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4 [19]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [19] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Length of hospital stay

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    End point title
    		 Length of hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: day
        arithmetic mean (standard deviation)
    25.6 ( 16.7 )
    21.5 ( 14.9 )
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.22 [20]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [20] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Hospital mortality

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    End point title
    		 Hospital mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: number
    2
    4
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.41 [21]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [21] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Vasoactive drugs administration

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    End point title
    		 Vasoactive drugs administration
    End point description
    Treatment and techniques applied during mechanical ventilation period.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: number
    8
    12
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.09 [22]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [22] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Antibiotic administration

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    End point title
    		 Antibiotic administration
    End point description
    Treatment and tehcniques applied during mechanical ventilation period.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: number
    21
    23
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.53 [23]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [23] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Furosemide

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    End point title
    		 Furosemide
    End point description
    Treatment and tehcniques applied during mechanical ventilation period.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: number
    16
    17
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Acetazolamide v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [24]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [24] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Furosemide, total doses

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    End point title
    		 Furosemide, total doses
    End point description
    Treatment and tehcniques applied during mechanical ventilation period.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: milligram(s)
        arithmetic mean (standard deviation)
    139 ( 194 )
    179 ( 270 )
    Statistical analysis title
    		 Experimental (Acetazolamide) vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.88 [25]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [25] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Prednisone, total doses

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    End point title
    		 Prednisone, total doses
    End point description
    Treatment and tehcniques applied during mechanical ventilation period.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: milligram(s)
        arithmetic mean (standard deviation)
    1026 ( 869 )
    610 ( 800 )
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1 [26]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [26] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Tracheostomy

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    End point title
    		 Tracheostomy
    End point description
    Treatment and tehcniques applied during mechanical ventilation period.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: number
    5
    3
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.46 [27]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [27] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Postextubation NIV

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    End point title
    		 Postextubation NIV
    End point description
    Treatment and tehcniques applied during mechanical ventilation period.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: number
    6
    8
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Acetazolamide v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.59 [28]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [28] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Secondary: Reintubation in 48 h

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    End point title
    		 Reintubation in 48 h
    End point description
    Treatment and tehcniques applied during mechanical ventilation period.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Placebo Acetazolamide
    Number of subjects analysed
    23
    24
    Units: number
    4
    2
    Statistical analysis title
    		 Acetazolamide vs Placebo
    Comparison groups
    Placebo v Acetazolamide
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.66 [29]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [29] - All analyses were two-tailed and p < 0.05 was considered of statistical significance.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    PATIENTS WERE MONITORED DURING THE WHOLE STUDY PERIOD.
    Adverse event reporting additional description
    the presence of: bicarbonate concentration < 23 mmol/L, serum potassium < 3.5 mEq/L serum sodium < 135 mEq/L paresthesia in extremities or mild rashes Creatinine > 2.5 g/dL bilirubin > 3.5 mg/dL prothrombin activity < 40 % leukocyte count < 4.0x109/L platelets < 150x109/L appearance of seizures or severe allergic reaction.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Acetazolamide
    Reporting group description
    		 -

    Serious adverse events
    		 Acetazolamide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
         number of deaths (all causes)
    4
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Acetazolamide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 24 (25.00%)
    General disorders and administration site conditions
    Somnolence
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    supraventricular tachycardia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Bicarbonate concentration <23 mmol/L
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2

    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.
    1. Sample size. 2. Lack of measurement of central drive performance due to the multicentre study and the different equipment among hospitals. 3. No measurement of asynchrony episodes, respiratory muscles workload or duration of respiratory cycle

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28286047
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