Effect of Acetazolamide Vs Placebo On Duration of Invasive Mechanical Ventilation Among Patients With Chronic Obstructive Pulmonary Disease

Research
Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT
Effect of Acetazolamide vs Placebo on Duration

of Invasive Mechanical Ventilation Among Patients
With Chronic Obstructive Pulmonary Disease
A Randomized Clinical Trial
Christophe Faisy, MD, PhD; Ferhat Meziani, MD, PhD; Benjamin Planquette, MD; Marc Clavel, MD; Arnaud Gacouin, MD; Caroline Bornstain, MD;
Francis Schneider, MD, PhD; Alexandre Duguet, MD, PhD; Sbastien Gibot, MD, PhD; Nicolas Lerolle, MD, PhD; Jean-Damien Ricard, MD, PhD;
Olivier Sanchez, MD, PhD; Michel Djibre, MD; Jean-Louis Ricome, MD; Antoine Rabbat, MD; Nicholas Heming, MD; Sak Urien, MD, PhD;
Maxime Esvan, MSc; Sandrine Katsahian, MD, PhD; for the DIABOLO Investigators
IMPORTANCE Acetazolamide has been used for decades as a respiratory stimulant for
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patients with chronic obstructive pulmonary disease (COPD) and metabolic alkalosis, but no
large randomized placebo-controlled trial is available to confirm this approach.
OBJECTIVE To determine whether acetazolamide reduces mechanical ventilation duration in
critically ill patients with COPD and metabolic alkalosis.

DESIGN, SETTING, AND PARTICIPANTS The DIABOLO study, a randomized, double-blind,
multicenter trial, was conducted from October 2011 through July 2014 in 15 intensive care
units (ICUs) in France. A total of 382 patients with COPD who were expected to receive
mechanical ventilation for more 24 hours were randomized to the acetazolamide or placebo
group and 380 were included in an intention-to treat analysis.
INTERVENTIONS Acetazolamide (500-1000 mg, twice daily) vs placebo administered
intravenously in cases of pure or mixed metabolic alkalosis, initiated within 48 hours of ICU
admission and continued during the ICU stay for a maximum of 28 days.
MAIN OUTCOMES AND MEASURES The primary outcome was the duration of invasive mechanical
ventilation via endotracheal intubation or tracheotomy. Secondary outcomes included changes in
arterial blood gas and respiratory parameters, weaning duration, adverse events, use of noninvasive
ventilation after extubation, successful weaning, the duration of ICU stay, and in-ICU mortality.
RESULTS Among 382 randomized patients, 380 (mean age, 69 years; 272 men [71.6%]; 379
[99.7%] with endotracheal intubation) completed the study. For the acetazolamide group
(n = 187), compared with the placebo group (n = 193), no significant between-group differences
were found for median duration of mechanical ventilation (16.0 hours; 95% CI, 36.5 to
4.0 hours; P = .17), duration of weaning off mechanical ventilation (0.9 hours; 95% CI, 4.3 to
1.3 hours; P = .36), daily changes of minute-ventilation (0.0 L/min; 95% CI, 0.2 to 0.2 L/min;
P = .72), or partial carbon-dioxide pressure in arterial blood (0.3 mm Hg; 95% CI, 0.8 to
0.2 mm Hg; P = .25), although daily changes of serum bicarbonate (between-group difference,
0.8 mEq/L; 95% CI, 1.2 to 0.5 mEq/L; P < .001) and number of days with metabolic alkalosis
(between-group difference, 1; 95% CI, 2 to 1 days; P < .001) decreased significantly more in the
acetazolamide group. Other secondary outcomes also did not differ significantly between groups.
CONCLUSIONS AND RELEVANCE Among patients with COPD receiving invasive mechanical
ventilation, the use of acetazolamide, compared with placebo, did not result in a statistically
significant reduction in the duration of invasive mechanical ventilation. However, the
magnitude of the difference was clinically important, and it is possible that the study was
underpowered to establish statistical significance.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01627639
JAMA. 2016;315(5):480-488. doi:10.1001/jama.2016.0019
480
Author Affiliations: Author

affiliations are listed at the end of this
article.
Group Information: A complete list
of the DIABOLO Trial Investigators
are listed in the Supplement file.
Corresponding Author: Christophe
Faisy, MD, PhD, Medical Intensive
Care Unit, European Georges
Pompidou Hospital, 20 rue Leblanc,
Paris, France 75015
(christophe.faisy@egp.aphp.fr).
Section Editor: Derek C. Angus, MD,
MPH, Associate Editor, JAMA
(angusdc@upmc.edu).
(Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Acetazolamide and Duration of Invasive Mechanical Ventilation
hronic obstructive pulmonary disease (COPD) is a frequent cause of intensive care unit (ICU) admission.1
Noninvasive mechanical ventilation has altered the outcomes of patients with acute COPD exacerbation by reducing
the need for intubation.2,3 Nevertheless, patients with COPD
may still require invasive mechanical ventilation when noninvasive ventilation fails or for an unrelated pathology.
Respiratory acidosis and metabolic alkalosis are the principal acid-base disturbances in patients with COPD receiving
mechanical ventilation. Metabolic alkalosis can be caused by
many conditions encountered during ICU stays, including diuretic or glucocorticoid use, vomiting or nasogastric suctioning, and permissive hypercapnia induced by lung-protective
strategies.4 Furthermore, the acid-base disorders most frequently observed while weaning patients with COPD off mechanical ventilation are mixed (ie, chronic respiratory acidosis and metabolic alkalosis).5 Metabolic alkalosis may inhibit
the activity of the central nervous respiratory command center and cardiac output or alter oxyhemoglobin dissociation and
favors the development of hypokalemia and hypophosphatemia, thereby prolonging the weaning period and mechanical
ventilation duration for critically ill patients.6-10
Acetazolamide, a carbonic anhydrase inhibitor, has been
used for decades as a respiratory stimulant in patients with
COPD and metabolic alkalosis.11 The classic mechanism of
acetazolamides action as a respiratory stimulant is based on
the inhibition of the renal carbonic anhydrase enzyme, which
in turn decreases serum bicarbonate and arterial pH, leading
to increased minute ventilation via stimulation of peripheral
and central chemoreceptors. However, data from uncontrolled clinical studies yielded inconsistent effects when
acetazolamide was administered at usual doses (250 to
500 mg once or twice daily).12 Recent pharmacodynamics
models indicated that patients with COPD breathing with the
aid of mechanical ventilation might benefit from its respiratory stimulant effect after administration of higher doses.13,14
In designing the DIABOLO trial, we hypothesized that higher
acetazolamide doses (1000 mg/d) would shorten the
mechanical ventilation duration in critically ill patients with
COPD (trial protocol in Supplement 1).
Methods
2014. Patients were enrolled (day 0) at 15 adult ICUs in France.

Written informed consent was obtained from all patients or
from their next of kin for patients unconscious at inclusion.
Definitive post hoc written consent was ultimately obtained
from patients who survived but were initially unable to provide informed consent.
Participants
Patients older than 18 years with a history of COPD according
to the American Thoracic Society criteria15 (smoking, other environmental risk factors, chronic cough, acute chest illnesses, dyspnea, physical examination, and laboratory investigations such as chest radiography, lung function tests, or
arterial blood gases) were enrolled if they required invasive ventilation via an intubation or tracheotomy tube and were evaluated within 24 hours after its onset. Exclusion criteria were judicial guardianship, no affiliation with the French health care
system, pregnancy, cystic fibrosis or diffuse bronchiectasis, previous allergy to acetazolamide or sulfonamides, permanent acetazolamide contraindication, recent participation in another interventional study with mechanical ventilation
duration as the primary end point, or investigators decision
not to resuscitate.
Randomization and Allocation

Within 24 hours of starting invasive ventilation, patients
were randomized via a computer-generated assignment
sequence in a centralized, blinded fashion (Figure 1). The randomization sequence was programmed in advance and generated by a statistician independent of the study. One-forone randomization was carried out, with stratification for
centers, respiratory status of the patients before hospitalization (no respiratory assistance at home vs respiratory assistance at home, whatever its nature [oxygen supplementation,
noninvasive ventilation, tracheotomy + ventilation]), and
disease severity at inclusion assessed with Simplified Acute
Physiology Score (SAPS) II less than 50 or 50 or higher. The
list was balanced by blocks of different sizes alternated in a
random manner. Physicians assigned the treatment after randomization, which was accessible through dedicated webbased software. Investigators, patients, and research staff
were masked to the randomization list.
Intervention
Study Design
This multicenter, double-blind (participants, caregivers, investigators, and outcome assessors), parallel-group, randomized clinical trial was approved for all centers by the Comit
de Protection des Personnes ParisIle-de-France VI (ethics committee: No. 2011-000492-14). The French National Committee for Health Research funded the study and convened a trial
steering committee and independent data monitoring committee. A safety monitoring committee was not considered necessary because the acetazolamide doses had adhered to the
marketing authorization and the study design included daily
patient evaluation for adverse events or temporary contraindications. The European Georges Pompidou Hospital Clinical
Research Center managed the study, from October 2011 to July
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Original Investigation Research
After inclusion, patients were assigned to receive either 500 mg

or 1000 mg (when loop diuretics were coprescribed) of acetazolamide twice daily or placebo (10 mL of saline) in case of
pure or mixed metabolic alkalosis (serum bicarbonate
>26 mEql/L and arterial pH 7.35), monitored according to arterial blood gases determined on mechanical ventilation between 7 AM and 8 AM from day 1 to the day invasive ventilation ended (eFigure 1 in Supplement 2). Physicians in charge
were different from the investigators who monitored and prescribed the tested treatment. Tested treatment was prepared
and blinded in each local pharmacy. Acetazolamide was supplied as a freeze-dried powder. The product was reconstituted with saline and then administered immediately in the
ICU, as a slow intravenous injection. The placebo was sup(Reprinted) JAMA February 2, 2016 Volume 315, Number 5
481
Research Original Investigation
plied in the form of a solvent (saline) and was administered in

the same manner. If a contraindication for the test treatment
arose (for details, see Supplement 2), it was temporarily suspended until the contraindication had resolved. Patients with
pure or mixed metabolic alkalosis received acetazolamide or
placebo intravenously twice daily for a maximum of 28 days.
Treatment doses were based on recent pharmacodynamics
models predicting that 500 mg twice daily (or double-dose
when loop diuretics were coprescribed) were required to significantly lower serum bicarbonate and raise minute ventilation in patients with COPD breathing with the aid of a ventilator, regardless of the ventilation mode (volume-assisted or
pressure-support ventilation) used.13,14 Other treatments were
left to the discretion of the treating physicians and had to be
in accordance with classic guidelines.1 Investigators were aware
of the need to correct hypokalemia.
Readiness to wean was defined according to the criteria
of the Sixth International Consensus Conference on Intensive Care Medicine held in 2005.16 The weaning strategy consisted of the progressive decrease of pressure-support or
volume-assisted ventilation with progressively longer times
on a T-piece and was tailored by treating physicians, according to the difficulty of the weaning process.17 External positive end-expiratory pressure was applied to counterbalance intrinsic positive end-expiratory pressure, typically 4 to 6 cm of
H2O. Criteria for extubation and reintubation were standardized in a written protocol (for details, see Supplement 1). Patients enrolled were extubated when they tolerated, for at least
1 hour, a spontaneous breathing trial via a T-piece oxygenated with the same inspiratory oxygen fraction (FIO2) used during mechanical ventilation. Patients satisfying spontaneous
breathing-trial criteria were extubated in the presence of a
physiotherapist and received supplemental oxygen to achieve
arterial oxygen saturation of 90% or more. Prophylactic use
of noninvasive ventilation after extubation was permitted.
Weaning was considered successful when reintroduction of
invasive ventilation was not required within 48 hours after its
termination.17 Tracheotomy indication and modalities for patients with prolonged weaning failure were left to the discretion of the treating physicians. Group assignments for patients who died before being weaned off mechanical ventilation
or those who received no test treatment during the study period were not modified, and data analysis was conducted on
an intention-to-treat basis.
Study Outcomes
The primary end point was the duration of invasive ventilation. Secondary outcomes were the changes of serum bicarbonate, partial pressure of carbon dioxide in arterial blood
(Pa CO 2 ), pH, partial pressure of oxygen in arterial blood
(PaO2):FIO2 ratio and respiratory parameters (tidal volume,
respiratory rate, and minute ventilation), weaning duration,
the numbers of spontaneous breathing trials, unplanned
extubations and ventilator-associated pneumonia episodes,
use of noninvasive ventilation after extubation, successful
weaning, the duration of ICU stay, and in-ICU mortality.
Adverse events were monitored for 28 days. All outcomes are
defined in Supplement 2.
482
Statistics
The sample size was calculated a priori based on the following assumptions: placebo group with an estimated mean (SD)
duration of mechanical ventilation of 12 (5) days based of one
of our preliminary studies,5 and because we expected to include the most severely ill patients with COPD (ie, requiring
invasive mechanical ventilation); acetazolamide-group patients, compared with those in the placebo group, would have
a potential 15% relative risk reduction for the primary end
point5 to be clinically relevant. Based on those estimates, we
calculated that 380 patients had to be enrolled to achieve 80%
power to detect that difference for the acetazolamide group
with a 2-sided level of .05.
The analyses were performed on the intention-to-treat
population, which was defined as all patients who had undergone randomization, excluding those erroneously included.
Analyses were then confirmed on per-protocol population,
which is defined as the set of patients, who did not perform
any protocol violation that may interfere with primary criteria evaluation (ie, patients receiving the allocated treatment;
patients with all the inclusion criteria met). Missing data were
only imputed for the end of invasive mechanical ventilation.
We used the mean hour of the end of invasive mechanical
ventilation of the center because planned extubations were performed around the same time. To take censored data into account (patients who died before extubation), the KaplanMeier method was used to calculate the probabilities of being
successfully weaned off invasive ventilation during the 28day observation period. The generated Kaplan-Meier curves
were compared with the log-rank test. Quantitative variables
are expressed as means and standard deviation or medians and
interquartile ranges (IQRs), when appropriate. Data were compared with t tests, when the sample size of each group was 30
or more, or Wilcoxon rank-sum tests, when one groups sample
size was less than 30. All tests were 2-sided. Either 2 or Fischer
exact tests, as appropriate, were used to compare qualitative
variables, expressed as percentages. All comparisons included the entire sample stratification (as prespecified). Hazard ratios were calculated using a Cox model and the centers
were taken into account as a random effect using gamma frailty
model.18 Tests of proportionality were performed including
time-dependent covariates in the Cox model. Post hoc subgroups were defined according to the presence or absence
(yes/no) of acute prolonged mechanical ventilation (96
hours),19 the preferential use (>50% of the time) of pressuresupport ventilation or not during the weaning period, the prescription or not of loop diuretics or glucocorticoids, and the
presence or absence (yes/no) of pure metabolic alkalosis
(pH>7.42 and serum bicarbonate >26 mEq/L) at baseline.
P < .05 defined statistical significance. All analyses were computed using SAS software, version 9.4 (SAS Institute Inc).
Results
Patients
Among the 694 patients screened in the 15 participating French
ICUs, 382 were enrolled, including 2 patients who subse-
JAMA February 2, 2016 Volume 315, Number 5 (Reprinted)
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Figure 1. Study Flow of Patients in the DIABOLO Trial

694 Patients assessed for eligibility
312 Excluded
105 Did not meet inclusion criteria
53 Intubation lasted >24 h
52 Declined to participate or no available
next of kin
154 Met exclusion criteria
70 Close to death
40 Had contraindication to acetazolamide
26 Under judicial guardianship
15 Enrolled in another study
2 Not affiliated with health care system
1 Allergic to sulfonamides
53 Other reasons
41 Overlooked by investigator
12 Intubation planned in <24 h
382 Randomized
188 Randomized to receive acetazolamide

134 Received acetazolamide
as randomized
1 Incorrectly included in
randomization (at the wrong center)
53 Did not receive acetazolamide as
randomized (no metabolic alkalosis
or temporary contraindication)
194 Randomized to receive placebo

150 Received placebo as randomized
1 Incorrectly included in
randomization (detainee
wearing an electronic bracelet)
43 Did not receive placebo as
randomized (no metabolic alkalosis
or temporary contraindication)
2 Forgotten administrations
1 Dosage error
1 Dosage error
187 Included in the primary analysis

1 Excluded (at the wrong center)
131 Included in per-protocol population
193 Included in the primary analysis

1 Excluded (detainee wearing an
electronic bracelet)
Patients who did not receive the

assigned test treatment did not have
metabolic alkalosis or had at least 1
temporary contraindication to that
treatment during the study period.
149 Included in per-protocol population
quently withdrew from the study, resulting in an intentionto-treat population of 380 patients: 187 randomized to the acetazolamide group and 193 to receive the placebo (Figure 1).
Baseline characteristics of the patients in the 2 study groups
were comparable (Table 1). All 187 patients had endotracheal
intubation (100%) in the acetazolamide group vs 192 (99.5%)
with endotracheal intubation and 1 (0.5%) with tracheotomy
in the placebo group.
Primary and Secondary Outcomes

The total durations of invasive ventilation was a median of 136.5
hours (IQR, 68.7 to 234.7 hours) in the acetazolamide group vs
163.0 hours (IQR, 86.2 to 242.9 hours) in the placebo group, for
a between-group difference of 16.0 hours (95% CI, 36.5 to
4.0 hours), which did not differ significantly (Table 2 and
Figure 2). Acetazolamide lowered the median daily change of
serum bicarbonate (0.3 mEq/L; IQR, 1 to 0.4 mEq/L vs
0.3 mEq/L; IQR, 0.2 to 1.3 mEq/L), for a between-group difference of 0.8 mEq/L (95% CI, 1.2 to 0.05 mEq/L) and increased the median daily PaO2:FIO2 ratio (7.8 mm Hg; IQR,
1.5 to 20.5 mm Hg vs 3.5 mm Hg; IQR, 5.2 to 13.9 mm Hg),
for a between-group difference of 4.6 mm Hg (95% CI,
0.6-8.6 mm Hg) more than the placebo, but had no respiratory
stimulant effect on the median changes of respiratory rate 0.1
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cycles/min (IQR, 0.8 to 1.0 cycles/min) vs 0.3 cycles/min (IQR,

0.3 to 1.4 cycles/min), for a between-group difference of 0.3
cycles/min (95% CI, 0.7 to 0.0 cycles/min); a tidal volume of
4.1 mL (IQR, 7.1 to 28.0 mL) vs 3.8 mL (IQR, 8.6 to 19.4 mL),
for a between-group difference of 1.3 mL (95% CI, 4.2 to 7.5 mL);
or median minute ventilation change of 0.2 L/min (IQR, 0.2
to 0.8 L/min ) vs 0.2 L/min (IQR, 0.1 to 0.6 L/min), for a
between-group difference of 0.0 L/min (95% CI, 0.2 to
0.2 L/min) (eTable 1 and eFigures 2 and 3 in Supplement 2).
Moreover, other secondary outcomes also did not differ
significantly: durations of weaning off invasive ventilation,
numbers of spontaneous breathing trials, use of tracheotomy
or noninvasive ventilation after extubation, successful weaning
rates, unplanned extubations, ventilator-associated pneumonia episodes, other laboratory-parameter values, ICU stays
or in-ICU mortality rates (eTable 2 in Supplement 2). Perprotocol analysis yielded results similar to those of the
intention-to-treat analysis with respect to significant findings (eTables 1 and 3 in Supplement 2).
Metabolic Alkalosis and Treatment Administration

As expected, the numbers of days with metabolic alkalosis and
treatment doses were significantly lower for the acetazolamide than for the placebo group (Table 2). A total of 53
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483
Table 1. Characteristics of the Patients at Baseline
Table 1. Characteristics of the Patients at Baseline (continued)
Study Group, Mean (SD)

Characteristic
Age, y
Men, No. (%)
SAPS II scorea
SOFA scoreb
Acetazolamide
(n = 187)
Study Group, Mean (SD)
Placebo
(n = 193)
Characteristic
69 (10)
69 (11)
Hematocrit, %
131 (70)
141 (73.1)
49.4 (13.9)
White blood cells/L

Blood platelets, 103/L
50 (15.1)
37.3 (8)
13700 (7200)
Placebo
(n = 193)
37.6 (8.4)
13900 (8200)
251.5 (116.6)
245.6 (118.5)
73.7 (21.6)
75.9 (22.1)
7.2 (3.1)
7.1 (3.2)
27.2 (8.0)
26.7 (9.1)
Oxygen
49 (26.2)
52 (26.9)
Unilateral alveolar opacities
57 (30.5)
53 (27.5)
Noninvasive ventilation
19 (10.1)
21 (10.9)
Bilateral alveolar opacities
84 (44.9)
93 (48.2)
BMI
Prothrombin ratio, %
Chest radiography, No. (%)
Home treatment, No. (%)
Tracheotomy mechanical
ventilation
Smoker or ex-smoker, No. (%)
Smoking history, pack-years
FEV1, mLc
FEV1/FVCc
Distension of the lungs
0
170 (90.9)
48.3 (24.7)
1232 (609)
0.51 (0.15)
1 (0.5)
179 (92.7)
50.4 (22.1)
1124 (586)
0.53 (0.15)
>8 Weeks, No. (%)

Systemic glucocorticoids
32 (17.1)
39 (20.2)
Loop diuretics
51 (27.3)
67 (34.7)
2-Agonists
96 (51.3)
95 (49.2)
4 (2.1)
3 (1.6)
1 (0-1)
1 (0-1)
Acetazolamide
ICU stay before randomization,
median (IQR), dd
Causes of invasive mechanical
ventilation, No. (%)e
Community-acquired pneumonia
83 (44.3)
83 (43.0)
Bronchitis
37 (19.8)
33 (17.1)
Left ventricular insufficiency
43 (23.0)
32 (16.6)
Surgery
12 (6.4)
13 (6.7)
Use of sedative
4 (2.1)
17 (8.8)
Pulmonary embolism
2 (1.1)
1 (0.5)
Stroke
3 (1.6)
2 (1.0)
Others
52 (27.8)
44 (22.8)
Unknown
10 (5.3)
9 (4.7)
Endotracheal intubation/
tracheotomy at inclusion, No.
187/0
192/1
Laboratory measurements
at inclusion
pH
7.32 (0.11)
7.30 (0.12)
PaO2, mm Hg
150.5 (108)
143.6 (90)
PaCO2, mm Hg
52.5 (16)
55.6 (17)
26.9 (6.9)
27.4 (6.6)
4.2 (0.7)
4.2 (0.7)
Serum
Bicarbonate, mEq/L
Potassium, mEq/L
147 (78.6)
148 (76.7)
Abbreviations: BMI, body mass index, calculated as weight in kilograms

divided by height in meters squared; FEV1, forced expiratory volume in the
first second of expiration; FVC, forced vital capacity; ICU, intensive care unit;
IQR, interquartile range; PaCO2, partial carbon-dioxide pressure in arterial blood;
PaO2, partial oxygen pressure in arterial blood; SAPS, Simplified Acute
Physiology score; SOFA, Sequential Organ Failure Assessment.
SI conversion factor: To convert aspartate aminotransferase from U/L to Kat/L,
multiply by 0.0167; bilirubin from mg/dL to mol/L, multiply by 17.104;
creatinine from mg/dL to mol/L, multiply by 88.4; glucose from mg/dL to
mmol/L, multiply by 0.0555; PaO2 and PaCO2 from mm Hg to kPA, multiply by
0.133; uric acid from mg/dL to mol/L, multiply by 59.485.
a
The SAPS II is based on 17 variables; scores range from 0 to 163, with higher
scores indicating more severe disease.
The SOFA score includes subscores ranging from 0 to 4 for each of

the 5 components (circulation, lung, liver, kidneys, and coagulation).
Aggregate scores range from 0 to 20, with higher scores indicating more
severe organ failure.
Data were available from 71 patients in the acetazolamide group and from 82
patients in the placebo group.
Seventy-eight patients in the acetazolamide group and 91 patients in the

placebo group were hospitalized in ICU prior to randomization.
Several situations requiring invasive ventilation are possible; hence, the total
can exceed 100%.
acetazolamide-group patients (28.3%) and 43 placebo-group

patients (22.2%) never received the assigned treatment (P = .17)
because of no metabolic alkalosis or temporary contraindication. Cotreatments with loop diuretics, glucocorticoids,
2-agonists or catecholamines, the mechanical ventilation
mode used, and the left ventricular ejection fraction at weaning were comparable for the 2 groups.
Adverse Events
Sodium, mEq/L
138 (5.8)
139 (4.9)
Chloride, mEq/L
100.9 (8.4)
100.6 (6.8)
No significant between-group differences were observed for

the overall incidence of serious adverse events (Table 2; eTable
1 in Supplement 2).
Protein, g/dL
5.9 (0.9)
5.9 (0.8)
Post Hoc Subgroup Analyses
Creatinine, mg/dL
1.3 (0.9)
1.2 (0.8)
31.4 (25.8)
29.7 (23.2)
No significant interactions were identified between study

groups and any post hoc subgroup with respect to the total durations of invasive ventilation or weaning (Figure 3 and eFigure
4A-B in Supplement 2).
Urea, mg/dL
Glucose, mg/dL
165.8 (133.3)
165.8 (79.3)
Aspartate aminotransferase, U/L
105.2 (290.6)
115.1 (448.6)
Bilirubin, mg/dL
0.8 (0.6)
0.8 (0.9)
Uric acid, mg/dL
6.3 (2.7)
5.9 (3.1)
Thyroid-stimulating hormone,
mIU/L
2.5 (8)
2.2 (5.7)
1.2 (0.2)
1.2 (0.2)
Hemoglobin, g/dL
(continued)
484
Acetazolamide
(n = 187)
Discussion
This multicenter, randomized, double-blind trial was designed to compare the respiratory effects of acetazolamide vs
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Table 2. Clinical Outcomes and Serious Adverse Eventsa

Group, Median (Interquartile Range)
Variable
Acetazolamide
(n = 187)
Placebo
(n = 193)
Between-Group Difference
(95% CI)
136.5 (68.7 to 234.7)
163 (86.2 to 242.9)
16.0 (36.5 to 4.0)
.17
0.8 (1.2 to 0.5)
<.001
0.3 (0.8 to 0.2)
.25
P Value
Primary Outcome
Duration of invasive ventilation, h
Secondary Outcomesb
Daily
Serum bicarbonate change, mEq/L
0.3 (1.0 to 0.4)
PaCO2 change, mm Hg
0.5 (2.0 to 0.8)
0.3 (0.2 to 1.3)

0.2 (1.4 to 1)
pH change
0 (0.01 to 0.02)
0.01 (0 to 0.02)
0.01 (0.01 to 0.0)
PaO2:FIO2-ratio change, mm Hg
7.8 (1.5 to 20.5)
3.5 (5.2 to 13.9)
4.6 (0.6 to 8.6)
.008
.009
Respiratory rate change, cycle/min
0.1 (0.8 to 1.0)
0.3 (0.3 to 1.4)
0.3 (0.7 to 0.0)
.10
Tidal volume change, mL
4.1 (7.1 to 28.0)
3.8 (8.6 to 19.4)
1.3 (4.2 to 7.5)
.72
Volume-minute change, L/min
0.2 (0.2 to 0.8)
Weaning duration, h
18.7 (3.0 to 46.5)
0.2 (0.1 to 0.6)

22.0 (3.0 to 44.3)
0.0 (0.2 to 0.2)
.72
0.9 (4.3 to 1.3)
.36
Spontaneous breathing trials, d
1 (1 to 2)
1 (1 to 2)
0 (0 to 0)
.42
Tracheotomy, median (range), d
0 (0 to 21)
0 (0 to 9)
0 (0 to 0)
.67
Endotracheal intubation, No. (%)

Use of noninvasive ventilation after
extubation, No. (%)
Successful weaning, No. (%)c
Unplanned extubation, median (range), d
187 (100)
192 (99.5)
62 (33.1)
72 (37.3)
4.2 (13.8 to 5.5)
.39
118 (74.7)
127 (78.4)
3.7 (13.1 to 5.6)
.43
0 (0 to 2)
0 (0 to 1)
0.05 (0.05 to 1.5)
0 (0 to 0)
.99
.65
VAP episodes, No. (%)
23 (12.3)
33 (17.1)
4.8 (12.0 to 2.4)
.18
Duration of ICU stay, d
10 (6 to 17)
10 (7 to 18)
2.1 (6.1 to 1.9)
.30
In-ICU mortality, No. (%)
22 (11.7)
26 (13.4)
6 (0.03)
7 (0.04)
Loop diuretics
1 (0 to 4)
1 (0 to 4)
0 (0 to 0)
Systemic glucocorticoids
0 (0 to 3)
0 (0 to 4)
0 (0 to 0)
.29
2-Agonists
0 (0 to 4)
1 (0 to 6)
0 (0 to 0)
.07
Catecholamines
1 (0 to 3)
1 (0 to 3)
Test-treatment doses
2 (0 to 5)
6 (1 to 13)
2 (4 to 1)
<.001
Metabolic alkalosis, de
2 (1 to 4)
4 (2 to 8)
1 (2 to 1)
<.001
Temporary contraindication to test

treatment, median (range), d
0 (0 to 10)
0 (0 to 7)
0 (0 to 0)
Serious adverse events, No. (%)d
1 (2 to 0)
0.4 (4.1 to 3.2)
.61
.82
Days receiving treatment
0 (0 to 0)
.55
.98
.16
Pressure-support ventilation, d
2 (1 to 5)
2 (1 to 5)
0 (1 to 0)
.22
Volume-assisted ventilation, d
3 (1 to 5)
3 (1 to 6)
0 (1 to 0)
.52
55 (40 to 60)
50 (42 to 60)
0 (5 to 5)
.86
Left ventricular ejection fraction

at weaning, %f
Abbreviations: FIO2, fraction of inspired oxygen; ICU, intensive care unit;

PaCO2, partial carbon-dioxide pressure in arterial blood; PaO2 partial oxygen
pressure in arterial blood; and VAP, ventilator-associated pneumonia
(diagnostic criteria are provided in Supplement 2).
Weaning was considered successful when invasive ventilation reintroduction

was not required within 48 hours after its termination. Criteria for extubation
and reintubation are detailed in Supplement 2. Weaning-failure causes are
given in eTable 2 in Supplement 2.
SI conversion factor: To convert PaCO2 and PaO2 from mm Hg to kPA,

multiply by 0.133.
Adverse events were considered serious when they required intensive care
procedures (use of vasopressors, hemodialysis, central venous
catheterization, cardiac pacing, or tube thoracostomy) or surgery, and those
events prolonged hospitalization or resulted in persistent or major disability or
incapacity.
Metabolic alkalosis was defined as serum bicarbonate of more than 26 mEql/L

and arterial pH of 7.35 or more.
Left ventricular ejection fraction was assessed by transthoracic

echocardiography during the weaning period.
Range was preferred over IQR because several of the latter were (0-0).
Between-group differences for quantitative variables are expressed as
medians with the 95% CI around the median difference.
Median daily changes of arterial blood gases or respiratory parameters

corresponded to the differences between 2 consecutive days from day 1 to the
end of invasive ventilation. Arterial blood gases and respiratory parameters on
mechanical ventilation were measured between 7 AM and 8 AM Other
laboratory-parameter changes are given in eTable 2 in Supplement 2.
placebo in mechanically ventilated patients with COPD and

pure or mixed metabolic alkalosis. Acetazolamide had no significant effect on durations of mechanical ventilation or weaning, respiratory parameter-values (respiratory frequency, tidal
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volume, and minute ventilation) despite achieving larger decreases in serum bicarbonate and fewer days with metabolic
alkalosis. In addition, the acetazolamide groups PaO2:FIO2
ratio was significantly increased, possibly via the drugs
485
Figure 2. Kaplan-Meier Curves for the Cumulative Probabilities of Being Weaned Off Invasive Ventilation
100
HR, 1.14 (95% CI, 0.91-1.42); Log-rank P = .24
Cumulative Ventilated, %
80
60
Placebo
40
Data for the analysis, conducted on

the intention-to-treat population,
were censored for patients who died
before extubation or were still
breathing with the aid of mechanical
ventilation on day 28. Successful
weaning rates on day 28 (672 hours)
did not differ significantly for the
acetazolamide and placebo groups
(P = .24, log-rank test on day 28).
HR indicates hazard ratio.
Acetazolamide
20
0
0
48
96
144 192 240 288 336 384 432 480 528 576 624 672
Total Length of Invasive Mechanical Ventilation, h

No. at risk
Acetazolamide 187 168 119 89 60
Placebo
193 174 137 108 73
44
51
28
39
19
33
14
20
13
16
11
13
7
9
7
8
6
5
5
4
Figure 3. Subgroup Analyses of the Effect of Acetazolamide on the Duration of Invasive Ventilation
or Weaning
A Duration of ventilation
Acetazolamide
Group, No.
Subgroup
Events a Patients
Acute prolonged invasive ventilation, 96 h
Placebo
Group, No.
Events a Patients
Hazard Ratio
(95% CI)
Yes
102
119
121
137
1.06 (0.811.38)
No
57
68
45
56
0.91 (0.611.37)
Favors
Placebo
Favors
Acetazolamide
Pressure support ventilation >50% of the weaning period

Yes
62
66
83
87
1.20 (0.861.68)
No
93
117
82
103
1.15 (0.851.55)
Loop diuretics or corticosteroids

Yes
121
141
128
143
1.11 (0.861.42)
No
34
42
37
47
1.37 (0.842.23)
Pure metabolic alkalosis at baseline

Yes
55
59
48
50
1.36 (0.912.03)
No
104
128
118
143
1.11 (0.851.44)
Overall
166
187
159
193
1.16 (0.931.44)
0.5
1.0
3.0
Hazard Ratio (95% CI)

B
Duration of weaning
Acetazolamide
Group, No.
Subgroup
Events a Patients
Acute prolonged invasive ventilation, 96 h
Placebo
Group, No.
Events a Patients
Hazard Ratio
(95% CI)
Yes
93
99
111
112
0.98 (0.741.30)
No
50
51
42
43
0.91 (0.591.41)
Favors
Placebo
Favors
Acetazolamide
Pressure support ventilation >50% of the weaning period

Yes
59
62
82
83
1.00 (0.711.40)
No
80
84
70
71
1.12 (0.811.56)
The duration of weaning was the time

between its onset (criteria are
detailed in Supplement 2) and its
termination. In the case of temporary
interruption of the weaning
procedure, the total duration
corresponded to the number of hours
of attempted withdrawal until
successful weaning minus
discontinued hours.
Loop diuretics or corticosteroids

Yes
108
113
118
120
1.00 (0.771.31)
No
31
33
34
34
1.13 (0.691.86)
1.09 (0.721.64)
Pure metabolic alkalosis at baseline

Yes
51
53
45
45
No
92
97
108
110
1.02 (0.771.36)
Overall
143
150
153
155
1.04 (0.831.31)
0.5
1.0
3.0
486
An event corresponds to the

termination of invasive mechanical
ventilation.
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diuretic effect 5,20 or the increased oxygen saturation of

hemoglobin.8,11 Taken together, these findings indicated that
the inhibition of the renal carbonic anhydrase enzyme and the
resulting serum bicarbonate reduction did not trigger a sufficient respiratory-stimulating effect to effect outcomes of critically ill patients with COPD. Nevertheless, this overall conclusion must be considered with prudence. Indeed, the study may
have identified a clinically important benefit of acetazolamide for the primary end point that did not demonstrate statistical significance because of a possible lack of power.
The between-group difference in median durations of invasive mechanical ventilation was clinically substantial
(16 hours) although it did not the reach statistical significance. Our trial was prospectively powered to detect a 15% difference in the invasive ventilation duration, considered clinically relevant in light of the usual duration of intubation in
these patients.5,21-23 However, the observed median durations of invasive mechanical ventilation in the placebo and acetazolamide groups were lower than anticipated for statistical power, complicating the study interpretation. This means
that the 10% reduction of invasive mechanical ventilation by
acetazolamide could have reached statistical significance if the
study was designed to detect such a difference. Similar proportions of patients in the 2 groups did not develop metabolic alkalosis or have transient treatment contraindications,
and intention-to-treat and per-protocol analyses findings converged. Moreover, the decision to consider weaning duration
a secondary outcome was based on the fact that weaning may
be discontinuous, making it difficult to measure its total time
accurately. For the same reason, the test treatment was administered from day 1 in case of metabolic alkalosis.
Pharmacological factors could contribute to the absence
of a stronger acetazolamide respiratory effect. First, inadequate dosing could limit the drugs effect on respiratory
parameters: the serum bicarbonate decline that would cause
a clinically relevant respiratory effect (ie, PaCO2 decrease
>5 mm Hg) should be at least 5 mEq/L.12,14 A recent casecontrol study showed that the use of insufficient acetazolamide dosage (500 mg/d) had no significant effect on the
duration of mechanical ventilation in critically ill patients
with COPD requiring invasive mechanical ventilation. 24
Herein, we administered a dose that lowered serum bicarbonate but the corresponding respiratory effect was not
observed. Tissue compartmentalization of carbonic anhydrase isozymes and low acetazolamide selectivity might
explain why this drug had no benefit in terms of improving
ARTICLE INFORMATION
Author Affiliations: European Georges Pompidou
Hospital, Assistance PubliqueHpitaux de Paris,
Paris, France (Faisy, Sanchez, Heming, Esvan,
Katsahian); Nouvel Hpital Civil, Medical Intensive
Care Unit, Hpitaux Universitaires de Strasbourg
and EA 7293, Fdration de Mdecine
Translationnelle de Strasbourg, Strasbourg
University, Strasbourg, France (Meziani); Andr
Mignot Hospital, Medico-Surgical Intensive Care
Unit, Le Chesnay, France (Planquette); Limoges
University Hospital, Medical Intensive Care Unit,
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minute ventilation and PaCO2 in patients with COPD receiving

respiratory support. Indeed, only the inhibition of carbonic
anhydrase isozymes II, IV, and XIII should induce a
respiratory-stimulating effect by increasing the respiratory
rate and tidal volume, whereas blockage of isozymes I and II
can modulate erythrocyte functions.12,25,26 Hence, our findings might support further investigations of more selective
molecules targeting isozymes I, II, IV and XII, rather than
relying on the traditional concept of renal isozyme inhibition.
It cannot be excluded that higher acetazolamide doses could
have a double-sided effect on respiratory parameters by
increasing the respiratory muscle workload and causing
respiratory muscle fatigue. Pertinently, we observed that, out
to approximately 360 hours, the acetazolamide group performed worse than the placebo group. However, post hoc
analysis did not show significant difference between patients
with or without acute prolonged mechanical ventilation.
A limitation of this study is the presence of mixed metabolic alkalosis in most patients. Indeed, the lack of acetazolamide respiratory effect may be because so many of the
patients had a degree of metabolic alkalosis too mild for the
intervention. But previous models used to evaluate the acetazolamide effect on respiratory parameters in the present
study were based on patients with COPD patients and with
mixed metabolic alkalosis.13,14 Moreover, our post hoc analysis did not show that patients with COPD and pure metabolic
alkalosis at baseline responded better than others. Another
possible limitation could be the presence of factors more
strongly influencing the discontinuation of mechanical ventilation or ICU outcomes (eg, age, severely limited airflow,
long-term glucocorticoid use or diaphragm atrophy).13,27-29
However, our study groups had similar overall characteristics
and cotreatments, and acetazolamide did not seem to have
greater effect on patients with COPD mechanically ventilated
for fewer than 96 hours.
Conclusions
Among mechanically ventilated patients with COPD and pure
or mixed metabolic alkalosis, the use of effective acetazolamide doses, compared with placebo, did not result in a statistically significant reduction in the duration of invasive mechanical ventilation. However, the magnitude of the difference
(16 hours) was clinically important, and it is possible that the
study was underpowered to establish statistical significance.
Limoges, France (Clavel); Rennes University

Hospital, Medical Intensive Care Unit, Rennes,
France (Gacouin); Le Raincy-Montfermeil Hospital,
Medical Intensive Care Unit, Montfermeil, France
(Bornstain); Hautepierre Hospital, Strasbourg,
Medical Intensive Care Unit, France (Schneider);
Piti-Salptrire Hospital, Department of
Respiratory and Intensive Care Medicine, Paris,
France (Duguet); Nancy University Hospital,
Medical Intensive Care Unit, Nancy, France (Gibot);
Angers University Hospital, Medical Intensive Care
Unit, Angers, France (Lerolle); Louis-Mourier
Hospital, Medico-Surgical Intensive Care Unit,
Colombes, France (Ricard); Tenon Hospital,

Medico-Surgical Intensive Care Unit, Paris, France
(Djibre); Poissy-Saint Germain Hospital, Medical
Intensive Care Unit, Poissy, France (Ricome); Cochin
Hospital, Medical Intensive Care Unit, Paris, France
(Rabbat, Urien); .
Author Contributions: Dr Faisy had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Faisy, Heming,
Katsahian.
487
Acquisition, analysis, or interpretation of data: Faisy,

Meziani, Planquette, Clavel, Gacouin, Bornstain,
Schneider, Duguet, Gibot, Lerolle, Ricard, Sanchez,
Djibre, Ricome, Rabbat, Urien, Esvan, Katsahian.
Drafting of the manuscript: Faisy, Duguet, Urien,
Esvan, Katsahian.
Critical revision of the manuscript for important
intellectual content: Faisy, Meziani, Planquette,
Clavel, Gacouin, Bornstain, Schneider, Gibot,
Lerolle, Ricard, Sanchez, Djibre, Ricome, Rabbat,
Heming, Urien, Katsahian.
Statistical analysis: Urien, Esvan, Katsahian.
Obtained funding: Faisy, Clavel, Katsahian.
Administrative, technical, or material support:
Gacouin, Bornstain, Duguet, Heming, Katsahian.
Study supervision: Faisy, Schneider, Katsahian.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest.
Dr Ricard reported receiving travel expenses from
Fisher and Paykel. Dr Sanchez reported receiving
grants from Bayer, Daiichi Sankyo, Boehringer
Ingelheim, and Actelion; personal fees from Bayer,
Daiichi Sankyo, Bristol-Myers Squibb, Boehringer
Ingelheim, Chiesi, and Actelion; and nonfinancial
support from Bayer, Chiesi, GlaxoSmithKline, and
Actelion. No other disclosures were reported.
Funding/Support: The work was supported by the
French Ministry of Health and sanofi-aventis
France.
Role of the Funder/Sponsor: sanofi-aventis France
supplied the active treatment (acetazolamide) free
of charge. The sponsors had no role in the design
and conduct of the study; collection, management,
analysis, and interpretation of the data;
preparation, review, or approval of the manuscript;
and decision to submit the manuscript for
publication.
Previous Presentation: Presented, in part, at the
annual meeting of Socit de Ranimation de
Langue Franaise, Paris, January 21-23, 2015.
Additional Contributions: We thank the patients
who participated in this study and the ICU
personnel. We thank Abel Grine, MSc, Delphine
Hourton, PhD, Ralf Niarra, MSc, Erik Figuier, MSc,
Jihene Duflos, MSc, Juliette Djadi-Prat, MD, PhD,
and Gilles Chatellier, MD, PhD, for study
coordination and data management, for which they
received no compensation beyond their regular
salaries. We also thank Janet Jacobson, biomedical
translator, for editorial assistance. Ms Jacobson
received financial compensation for her work.
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488
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R2:342:aFkcdqnqa"xgtukqp"4"fw"4412814233"
"
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SIGNATURE of a biomedical research PROTOCOL

By the COORDINATING INVESTIGATOR and a representative of the PROMOTER
R2:342:
Biomedical research study no.
Title: Randomized trial of the efficacy of acetazolamide in patients with COPD developing metabolic alkalosis
during invasive mechanical ventilation
Version no. 2 dated 06 / 22 / 2011

Coordinating investigator:
Fqevqt"Ejtkuvqrjg"Hcku{"
Ugtxkeg"fg"Tcpkocvkqp"ofkecng"
Jrkvcn"Gwtqrgp"Igqtigu"Rqorkfqw
Date : //..
Signature :
Promoter:
Ot"Ejtkuvqrjg"OKUUG"
Assistance publique hpitaux de Paris
Date : //..
Dlgation Intergionale la Recherche Clinique

Hpital Saint Louis
Signature :
75010 PARIS
NB: This version corresponds to the text of the protocol and appendices sent to the IRB and the competent
authority, respectively, for expert opinion and to request authorization.
If a new version is subsequently produced following modifications, signatures must be obtained again, to ensure
that the active protocol is always updated.
R2:342:aFkcdqnqa"xgtukqp"4"fw"4412814233"
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50504"
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38182" "
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rtqvqeqn"*Crrgpfkz"8+0"Vjg"itkf"hqt"encuukh{kpi"ugtkqwu"cpf"pqp/ugtkqwu"cfxgtug"gxgpvu"ku"cnuq"
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qt" tgurktcvqt{" ukipu" *dtqpejqurcuo+." vjgug" ukipu" dgkpi" rqvgpvkcnn{" qh" xctkqwu" fgitggu" qh"
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wpgzrgevgfpguu"qh"vjg"UCG"qdugtxgf0"
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53182" "
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54182" "
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57182" "
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59182" "
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rtqoqvgt."dghqtg"vjg"uvctv"qh"vjg"uvwf{0""
"
3505" Oqfkhkecvkqpu"
Vjg"FTEF"owuv"dg"kphqtogf."d{"vjg"Eqqtfkpcvkpi"Kpxguvkicvqt."qh"cnn"rncppgf"ejcpigu"
vq"vjg"rtqvqeqn0"
Vjg"oqfkhkecvkqpu"owuv"dg"encuukhkgf"cu"uwduvcpvkcn"qt"pqv"uwduvcpvkcn0"
C"uwduvcpvkcn"oqfkhkecvkqp"ku"cp{"ejcpig"nkmgn{."kp"cp{"yc{."vq"oqfkh{"vjg"iwctcpvggu"
rtqxkfgf" vq" vjg" rctvkekrcpvu" kp" vjg" tgugctej" uvwf{" *ejcpigu" vq" vjg" kpenwukqp" etkvgtkc."
rtqnqpicvkqp"qh"vjg"kpenwukqp"rgtkqf."rctvkekrcvkqp"qh"pgy"egpvgtu."gve0+0"
Qpeg" vjg" uvwf{" jcu" dgiwp." cp{" uwduvcpvkcn" oqfkhkecvkqp" cv" vjg" rtqoqvgtu" kpkvkcvkxg"
owuv."dghqtg"kvu"korngogpvcvkqp."dg"crrtqxgf"d{"vjg"gvjkeu"eqookvvgg"cpf"cwvjqtk|gf"d{"vjg"
eqorgvgpv" cwvjqtkv{0" Kp" vjku" ecug." kh" pgeguuct{." vjg" eqookvvgg" yknn" gpuwtg" vjcv" kphqtogf"
eqpugpv"ku"eqnngevgf"cickp"htqo"vjg"rctvkekrcpvu"kp"vjg"uvwf{0"
Cp{" gzvgpukqp" qh" vjg" uvwf{" *rtqhqwpf" oqfkhkecvkqp" qh" vjg" vtgcvogpv" rncp" qt" qh" vjg"
rqrwncvkqpu"kpenwfgf."rtqnqpicvkqp"qh"vtgcvogpvu"cpf1qt"vjgtcrgwvke"cevu"pqv"kpkvkcnn{"kpenwfgf"
kp"vjg"rtqvqeqn+"ujqwnf"dg"eqpukfgtgf"cu"c"pgy"uvwf{0"
Cnn"uwduvcpvkcn"oqfkhkecvkqpu"ujqwnf"dg"vjg"qdlgev"qh"c"tgswguv"hqt"cwvjqtk|cvkqp"htqo"
CHUUCRU"cpf1qt"c"tgswguv"hqt"gvjkeu"eqookvvgg"crrtqxcn"uwdokvvgf"d{"vjg"rtqoqvgt0"
"
3506" EPKN"fgenctcvkqp"""
Vjg"ncy"tgswktgu"c"fgenctcvkqp"qh"vjg"eqorwvgtk|gf"hkng"qh"rgtuqpcn"fcvc"eqnngevgf"hqt"
vjg"uvwf{"dghqtg"vjg"uvwf{"dgikpu0"
C" tghgtgpeg" ogvjqfqnqi{" urgekhke" vq" vjg" vtgcvogpv" qh" rgtuqpcn" fcvc" kp" vjg"
htcogyqtm" qh" dkqogfkecn" tgugctej." fghkpgf" d{" ncy" 4226/:28" qh" Cwiwuv" ;" 4226" crrnkgu"
wpfgt"ctvkengu"N03343/3"cpf"ceeqtfkpi"vq"vjg"Htgpej"Rwdnke"Jgcnvj"Eqfg0"Vjku"ogvjqfqnqi{"
ycu"guvcdnkujgf"d{"vjg"EPKN"kp"Lcpwct{"42280"
"
5;182" "
"
Vjku"ogvjqfqnqi{"cnnqyu"c"ukornkhkgf"fgenctcvkqp"rtqegfwtg"yjgp"vjg"pcvwtg"qh"vjg"
fcvc"eqnngevgf"kp"vjg"uvwf{"ku"eqorcvkdng"ykvj"vjg"nkuv"rtqxkfgf"d{"vjg"EPKN"kp"kvu"tghgtgpeg"
fqewogpv0"
Yjgp" vjg" rtqvqeqn" ku" uwdlgev" vq" fcvc" swcnkv{" eqpvtqn" d{" c" enkpkecn" tgugctej" cuukuvcpv"
tgrtgugpvkpi"vjg"rtqoqvgt"cpf"hcnnu"kpvq"vjg"hkgnf"qh"crrnkecvkqp"qh"vjg"ukornkhkgf"rtqegfwtg"qh"
vjg"EPKN."vjg"FTEF."cu"vjg"rtqoqvgt."yknn"cum"vjg"rgtuqp"tgurqpukdng"hqt"vjg"eqorwvgt"hkng"vq"
rtqxkfg"c"ytkvvgp"eqookvogpv"vq"tgurgev"vjg"OT223"ukornkhkgf"tghgtgpeg"ogvjqfqnqi{0"
"
3507" Kphqtocvkqp"cpf"kphqtogf"eqpugpv"hqtou"
Kpfkxkfwcnu" cfokvvgf" vq" kpvgpukxg" ectg" hqt" tgurktcvqt{" kpuwhhkekgpe{." kpenwfkpi"
rquvqrgtcvkxg" tgurktcvqt{" kpuwhhkekgpe{." yknn" dg" kpenwfgf" kp" vjku" dkqogfkecn" tgugctej" uvwf{0"
Vjg" rcvkgpvu" yknn" pqv" kpkvkcnn{" dg" cdng" vq" ikxg" eqpugpv" vjgougnxgu0" Eqpugpv" yknn" vjgtghqtg" dg"
tgswguvgf" htqo" hcokn{" ogodgtu" qt" enqug" htkgpfu." kh" rtgugpv." kp" ceeqtfcpeg" ykvj" ctvkeng" N0"
3344/3/4"qh"vjg"Htgpej"Rwdnke"Jgcnvj"Eqfg0""
Vjg" rcvkgpv" yknn" dg" kphqtogf" cu" uqqp" cu" rquukdng" cpf." chvgt" c" uwkvcdng" rgtkqf" qh"
tghngevkqp." yknn" dg" cumgf" hqt" jku" qt" jgt" eqpugpv" vq" eqpvkpwg" rctvkekrcvkqp" kp" vjg" uvwf{0" Vjg"
rcvkgpv"oc{."cv"cp{"vkog."qrrqug"vjg"wug"qh"jku"qt"jgt"fcvc"kp"vjg"htcogyqtm"qh"vjku"uvwf{0"
Vjku"uvwf{"yknn"pqv"kpenwfg"kpfkxkfwcnu"eqxgtgf"d{"ctvkengu"N0"3343/7"vq"N0"3343/:"qh"
vjg"Htgpej"Rwdnke"Jgcnvj"Eqfg<"rtgipcpv"yqogp."rtkuqpgtu"cpf"kpuvkvwvkqpcnk|gf"uwdlgevu."cpf"
cfwnvu"uwdlgev"vq"ngicn"rtqvgevkqp0"
"
3508" Hkpcn"tgrqtv"
Vjg"hkpcn"uvwf{"tgrqtv"yknn"dg"lqkpvn{"ytkvvgp"d{"vjg"Eqqtfkpcvqt"cpf"vjg"Dkquvcvkuvkekcp"hqt"
vjku" uvwf{0" Vjku" tgrqtv" yknn" dg" uwdokvvgf" vq" gcej" qh" vjg" kpxguvkicvqtu" hqt" crrtqxcn0" Qpeg" c"
eqpugpuwu"jcu"dggp"tgcejgf."vjg"hkpcn"xgtukqp"yknn"dg"gpfqtugf"d{"vjg"ukipcvwtg"qh"gcej"qh"vjg"
kpxguvkicvqtu"cpf"ugpv"vq"vjg"rtqoqvgt."cu"uqqp"cu"rquukdng"chvgt"vjg"ghhgevkxg"gpf"qh"vjg"uvwf{0"
C" tgrqtv" ytkvvgp" ceeqtfkpi" vq" vjg" tghgtgpeg" rncp" qh" vjg" eqorgvgpv" cwvjqtkv{" owuv" dg" ugpv" vq"
vjku"cwvjqtkv{"cpf"vq"vjg"gvjkeu"eqookvvgg"ykvjkp"qpg"{gct"qh"vjg"gpf"qh"vjg"uvwf{."fghkpgf"cu"
vjg" ncuv" hqnnqy/wr" xkukv" qh" vjg" ncuv" uwdlgev" kpenwfgf0" Vjku" vkog" nkokv" yknn" dg" fgetgcugf" vq" ;2"
fc{u"kh"vjg"uvwf{"gpfu"gctn{0"
/"Hktuv"cwvjqt<"Rtkpekrcn"Kpxguvkicvqt."Ft"Ejtkuvqrjg"Hcku{"
/"Ugeqpf"cwvjqt<"Kpvgpukxg"ectg"fqevqt"
"
62182" "
"
/"Vjktf"cwvjqt<"tgrtgugpvcvkxg"qh"vjg"Enkpkecn"Tgugctej"Wpkv"qh"JGIR"
/"Hqwtvj."hkhvj"cpf"ukzvj"cwvjqtu<"Kpvgpukxg"ectg"fqevqtu""
/"Rgpwnvkocvg"cwvjqt<"Kpvgpukxg"ectg"fqevqt"
/"Ncuv"cwvjqt<"Uekgpvkhke"Fktgevqt.""Rtqh0"Lgcp/[xgu"Hciqp"
Vjg"tcpmkpi"qh"vjg"cwvjqtu"yknn"dg"fgvgtokpgf"d{"vjg"pwodgt"qh"kpenwukqpu"cv"gcej"egpvgt0"
"
36"FCVC" RTQEGUUKPI" CPF" UVQTCIG" QH" FCVC" CPF"

FQEWOGPVU"TGNCVKPI"VQ"VJKU"UVWF["
Chvgt"oqpkvqtkpi."vjg"fcvc"yknn"dg"gpvgtgf"kpvq"cp"OU/Ceeguu"fcvcdcug"fgxgnqrgf"d{"
vjg"Enkpkecn"Tgugctej"Wpkv"qh"JGIR0"C"fcvc/ocpcigogpv"rncp"eqpukuvgpv"ykvj"vjg"oqpkvqtkpi"
rncp"cpf"fgxgnqrgf"lqkpvn{"d{"vjg"fcvc"ocpcigt."vjg"enkpkecn"tgugctej"cuukuvcpv"cuukipgf"vq"vjg"
uvwf{."vjg"RK"cpf"vjg"uvcvkuvkekcp"yknn"dg"rtqfwegf0"Chvgt"vjg"eqttgevkqp"qh"cp{"gttqtu"tgxgcngf"
d{"vjku"rncp."vjg"fcvcdcug"yknn"dg"hkzgf"hqt"uvcvkuvkecn"cpcn{uku0"Rtqh0"Iknngu"Ejcvgnnkgt"yknn"dg"
tgurqpukdng"hqt"vjg"rtqeguukpi"qh"cnn"vjg"fcvc"igpgtcvgf"d{"vjku"uvwf{0""
Vjg"uvwf{"fqewogpvu"eqxgtgf"d{"vjg"ncy"qp"dkqogfkecn"tgugctej"yknn"dg"ctejkxgf"d{"
cnn"vjg"rctvkgu"hqt"c"rgtkqf"qh"37"{gctu"chvgt"vjg"gpf"qh"vjg"uvwf{0"
(See GCP, chapter 8: Essential documents)
"Vjg"kpfgzgf"ctejkxg"yknn"kpenwfg<"
" Eqrkgu"qh"vjg"ngvvgtu"qh"cwvjqtk|cvkqp"htqo"CHUUCRU"cpf"vjg"gvjkeu"eqookvvgg"
" Vjg"uweeguukxg"xgtukqpu"qh"vjg"rtqvqeqn"*kfgpvkhkgf"d{"xgtukqp"pwodgt"cpf"fcvg+."
" Cnn"ytkvvgp"eqttgurqpfgpeg"ykvj"vjg"rtqoqvgt."
" Vjg"ukipgf"kphqtogf"eqpugpv"hqtou"qh"vjg"uwdlgevu."kp"ugcngf"gpxgnqrgu."ykvj"vjg"
eqttgurqpfkpi"kpenwukqp"nkuv"qt"tgikuvgt."
Vjg"eqorngvgf"cpf"xcnkfcvgf"qdugtxcvkqp"pqvgdqqm"hqt"gcej"uwdlgev"kpenwfgf.""
" Cnn"vjg"crrgpfkegu"urgekhke"vq"vjg"uvwf{."
" Vjg"hkpcn"tgrqtv"hqt"vjg"uvwf{."kpenwfkpi"vjg"uvcvkuvkecn"cpcn{uku"cpf"swcnkv{"eqpvtqn"
hkpfkpiu"*c"eqr{"qh"yjkej"owuv"dg"ugpv"vq"vjg"rtqoqvgt+0"
" Vjg"egtvkhkecvgu"eqttgurqpfkpi"vq"cp{"cwfkvu"ecttkgf"qwv"fwtkpi"vjg"uvwf{0"
Vjg"fcvcdcug"wugf"hqt"vjg"uvcvkuvkecn"cpcn{uku"owuv"cnuq"dg"ctejkxgf"d{"vjg"rgtuqp"
tgurqpukdng"hqt"vjg"cpcn{uku"*gkvjgt"qp"rcrgt"qt"c"eqorwvgtk|gf"xgtukqp+0"
"
63182" "
"
"
37"KPUWTCPEG"CPF"UEKGPVKHKE"EQOOKVOGPV
3703" Kpuwtcpeg"
Assistance Publique-Hpitaux de Paris" ku" vjg" rtqoqvgt" qh" vjku" uvwf{0" Kp" ceeqtfcpeg"
ykvj"dkqogfkecn"tgugctej"ncy."CR/JR"jcu"vcmgp"qwv"cp"kpuwtcpeg"rqnke{"ykvj"JFQ"IGTNKPI"
hqt"vjg"gpvktg"fwtcvkqp"qh"vjku"uvwf{."eqxgtkpi"kvu"qyp"ekxkn"tgurqpukdknkvkgu"cpf"vjqug"qh"cp{qpg"
kpxqnxgf" kp"vjg" uvwf{" *fqevqtu" cpf" uvchh" ogodgtu" ectt{kpi" qwv" vjg" uvwf{=" ncy" pq0" 4226/:28."
Ctv"N03343/32"qh"vjg"Htgpej"Rwdnke"Jgcnvj"Eqfg+0"
Assistance Publique-Hpitaux de Paris" tgugtxgu" vjg" tkijv" vq" uvqr" vjg" uvwf{" cv" cp{"
oqogpv." hqt" ogfkecn" qt" cfokpkuvtcvkxg" tgcuqpu0" Ujqwnf" vjku" qeewt." vjg" kpxguvkicvqt" yknn" dg"
pqvkhkgf0"
"
3704" Uekgpvkhke"eqookvogpv"
Gcej"kpxguvkicvqt"yknn"citgg"vq"tgurgev"ngicn"qdnkicvkqpu"cpf"vq"ectt{"qwv"vjg"uvwf{"kp"
ceeqtfcpeg" ykvj" IER" cpf" vjg" vgtou" qh" vjg" Jgnukpmk" Fgenctcvkqp" kp" hqteg0" C" eqr{" qh" vjg"
uekgpvkhke"eqookvogpv"*FTEF/v{rg"fqewogpv+."fcvgf"cpf"ukipgf"d{"gcej"kpxguvkicvqt"cv"
gcej"qh"vjg"rctvkekrcvkpi"egpvgtu"yknn"dg"uwrrnkgf"vq"tgrtgugpvcvkxg"qh"vjg"rtqoqvgt"vq"gpuwtg"
vjku0"
"
38"RWDNKECVKQP"TWNGU"
CR/JR"qypu"vjg"fcvc."yjkej"owuv"pqv"dg"wugf"qt"vtcpuokvvgf"vq"c"vjktf"rctv{"ykvjqwv"vjg"
rtkqt"citggogpv"qh"vjg"CR/JR0"
Vjg" hktuv" cwvjqtu" qp" rwdnkecvkqpu" yknn" dg" vjg" kpfkxkfwcnu" yjq" tgcnn{" rctvkekrcvgf" kp" vjg"
fgxgnqrogpv"cpf"twppkpi"qh"vjg"rtqvqeqn."cpf"kp"vjg"igpgtcvkqp"cpf"ytkvkpi"qh"tguwnvu0"
Assistance Publique-Hpitaux de Paris"owuv"dg"ekvgf"cu"vjg"rtqoqvgt"qh"vjg"tgugctej"cpf"
cu"vjg"uqwteg"qh"hwpfkpi."cu"crrtqrtkcvg0"Vjg"vgtou"Assistance Publique-Hpitaux de Paris"
owuv"crrgct"kp"vjg"cfftguugu"qh"vjg"cwvjqtu0"
"
64182" "
"
"
39"TGHGTGPEGU""
3/" Tcekpgwz" LE." Xkfcn" LH." Ogunkgt" P0" Ngu" ocncfkgu" tgurktcvqktgu" ejtqpkswgu" nkgu" cw"
vcdcikuog0"Tgx"Rtcv"3;;5=37"<354/363"
4/" Oqtcp" L." Itggp" LX." Jqocp" UF<" Cewvg" gzcegtdcvkqpu" qh" ejtqpke" qduvtwevkxg" rwnoqpct{"
fkugcug"cpf"ogejcpkecn"xgpvkncvkqp<"C"tggxcnwcvkqp0"Etkv"Ectg"Ogf"3;;:=48<93/"9:"
5/"Ugpghh"OI."Ycigpgt"FR."Ycigpgt"TR<"Jqurkvcn"cpf"3"{gct"uwtxkxcn"qh"rcvkgpvu"cfokvvgf"
vq" kpvgpukxg" ectg" wpkvu" ykvj" cewvg" gzcegtdcvkqpu" qh" ejtqpke" qduvtwevkxg" nwpi" fkugcug0" LCOC"
3;;7=496<3:74/3:79"
6/" Xkgik" I." Ueqipcokinkq" C." Dcnfceeku" U" cpf" cn0" Grkfgokqnqi{" qh" ejtqpke" qduvtwevkxg"
rwnoqpct{"fkugcug"*EQRF+0"Tgurktcvkqp"4223=8:<6/3;"
7/"Hwuq"N."Kpecn|k"TC."Rkuvgnnk"T"gv"cn0"Rtgfkevkpi"oqtvcnkv{"qh"rcvkgpvu"jqurkvcnk|gf"hqt"cewvgn{"
gzcegtdcvgf"ejtqpke"qduvtwevkxg"rwnoqpct{"fkugcug0"Co"L"Ogf"3;;7=;:<494/499"
8/" Mpcwu" YC0" Rtqipquku" ykvj" ogejcpkecn" xgpvkncvkqp<" vjg" kphnwgpeg" qh" fkugcug." ugxgtkv{" qh"
fkugcug." cig" cpf" ejtqpke" uvcvwu" qp" uwtxkxcn" htqo" cp" cewvg" knnpguu0" Co" Tgx" Tgur" Fku"
3;:;=362<U:/U35"
9/"Iwn"Iwtugn0"Fgvgtokpcpvu"qh"vjg"ngpivj"qh"ogejcpkecn"xgpvkncvkqp"kp"rcvkgpvu"ykvj"EQRF"kp"
vjg"kpvgpukxg"ectg"wpkv0"Tgurktcvqt{"Ogfkekpg"4227=94<83/89"
:/"Pgxkpu"ON."Gruvgkp"UM0"Rtgfkevqtu"qh"qwveqog"hqt"rcvkgpvu"ykvj"EQRF"tgswktkpi"kpvgpukxg"
ogejcpkecn"xgpvkncvkqp0"Ejguv"4223=33;<3:62/3:6;"
;/"Ogp|kgu"T."Ikddqpu"Y."Iqnfdgti"R0"Fgvgtokpcpvu"qh"ygcpkpi"cpf"uwtxkxcn"coqpi"rcvkgpvu"
ykvj" EQRF" yjq" tgswktg" ogejcpkecn" xgpvkncvkqp" hqt" cewvg" tgurktcvqt{" hcknwtg0" Ejguv"
3;:;=;7<5;:/627"
32/" Ygduvgt" PT." Mwnmctpk" X0" Ogvcdqnke" cnmcnquku" kp" vjg" etkvkecnn{" knn0" Etkv" Tgx" Ncd" uek"
3;;;=58"*7+<6;9/732"
33/" Icnncigt" VL0" Ogvcdqnke" cnmcnquku" eqornkecvkpi" ygcpkpi" htqo" ogejcpkecn" xgpvkncvkqp0"
Uqwvj"Ogf"L"3;9;=94<9:8"
34/"Ejgxtqngv"LE0"Rgtvwtdcvkqpu"fg"nswknkdtg"cekfg/dcug0"Gpe{enqrfkg"Ofkeq/ejktwtikecng"
Rpgwoq."8/222/C/97"
35/" Tqug" D0" Tgurktcvqt{" cekfquku0Kp" Tqug" D" gf0" Enkpkecn" rj{ukqnqi{" qh" cekf/dcug" cpf"
gngevtqn{vgu"fkuqtfgtu0"Pgy"[qtm<"OeItcy/Jknn.3;:6<662/683"
36/"Mjcppc"C."Mwtv|ocp"C0"Ogvcdqnke"cnmcnquku0"Tgurkt"Ectg"4223=68<576/587"
"
65182" "
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37/" Yknuqp" 3" TH." Ikduqp" F." Rgtekpgn" CM." " Cnk" OC." Dcmgt" I." NgDncpe" R." Nwecu" E0" Ugxgtg"
cnmcnquku"kp"etkvkecnn{"knn"uwtikecn"rcvkgpvu0"Ctej"Uwti"3;94=327<3;9/425"
38/" Jqfimkp" LG." Uqgrtqpq" HH." Ejcp" FO0" Kpekfgpeg" qh" ogvcdqnke" cnmcngokc" kp" jqurkvcnkugf"
rcvkgpvu0"Etkv"Ectg"Ogf"3;:2=34<947/94:"
39/" Mtkpvgn" LL." Jczjqnfv" QU." Dgtvjgnugp" R." Dtqempgt" L0" Ectdqp" fqzkfg" gnkokpcvkqp" chvgt"
cegvc|qncokfg"kp"rcvkgpvu"ykvj"ejtqpke"qduvtwevkxg"rwnoqpct{"fkugcug"cpf"ogvcdqnke"cnmcnquku0"
Cevc"Cpguvjgukqn"Uecpf"3;:5=49<474/476"
3:/" Dgtvjgnugp" R0" Ectfkqxcuewnct" rgthqtocpeg" cpf" qz{jgoqinqdkp" fkuuqekcvkqp" chvgt"
cegvc|qncokfg"kp"ogvcdqnke"cnmcnquku0"Kpvgpukxg"Ectg"Ogf"3;:4=:<48;/496"
3;/" Cppg" G." Jqnncpf." Lqjp" Y" Yknuqp0" Ogvcdqnke" cnmcnquku" eqpvtkdwvg" vq" cewvg" j{rgtecrpke"
tgurktcvqt{"hcknwtg"kp"cfwnv"e{uvke"hkdtquku0"Ejguv"4225=346<6;2/6;5"
42/" Tqug" D." Rquv" V0Enkpkecn" rj{ukqnqi{" qh" cekf/dcug" cpf" gngevtqn{vgu" fkuqtfgtu0" Pgy" [qtm<"
OeItcy/Jknn"4223"
43/" Dgtvjgnugp" R." Iqvjigp" K." Jwuwo" D" gv" cn0" Qz{igp" wrvcmg" cpf" EQ4" gnkokpcvkqp" chvgt"
cegvc|qncokfg"kp"etkvkecnn{"knn0"Kpvgpukxg"Ectg"Ogf"3;:7=33<48/4;"
44/" Dtkokqwnng" U." Dgttg" L." Fwhc{g" R" gv" cn0" J{ftqejnqtke" cekf" kphwukqp" hqt" vtgcvogpv" qh"
ogvcdqnke"cnmcnquku"cuuqekcvgf"ykvj"tgurktcvqt{"cekfquku0"Etkv"Ectg"Ogf"3;:;=39<454"
45/" Uygpuqp" GT0" Ectdqpke" cpj{ftcug" kpjkdkvqtu" cpf" xgpvkncvkqp<" c" eqorngz" kpvgtrnc{" qh"
uvkowncvkqp"cpf"uwrrtguukqp0"Gwt"Tgurkt"L"3;;:"=34"<3464/3469"
46/" Tkejcngv" LR." Nctokipcv" R." Tcvjcv" E0" Rqwoqp" gv" cnvkvwfg0" Gpe{enqrfkg" Ofkeq/
ejktwtikecng"Rpgwoqnqikg."8/285/C/32"
47/" Uygpuqp" GT." Octgp" VJ0" C" swcpvkvcvkxg" cpcn{uku" qh" EQ4" vtcpurqtv" cv" tguv" cpf" oczkocn"
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Supplementary Online Content
Faisy C, Meziani F, Planquette, et al, DIABOLO Investigators. Effect of

acetazolamide vs placebo on duration of invasive mechanical ventilation among
patients with chronic obstructive pulmonary disease:
a randomized clinical trial. JAMA. doi:10.1001/jama.2016.0019.
eFigure 1. Trial Course for an Individual Patient

eFigure 2. Intention-to-Treat Analysis: Daily Arterial Blood Gases and
Respiratory Parameters
eFigure 3. Per-protocol analysis: Daily Arterial Blood Gases and Respiratory
Parameters
eFigure 4. Per-Protocol Analysis: Subgroup Analyses of the Acetazolamide
Effect on Duration of Invasive
eTable 1. Per-Protocol Analysis: Clinical Outcomes and Serious Adverse
Eventsa
eTable 2. Intention-to-Treat Analysis: Study Laboratory Parametersa and
Causes of Weaning Failure
eTable 3. Per-protocol analysis: Study laboratory parametersa and causes of
weaning failure
This supplementary material has been provided by the authors to give readers
additional information about their work.
2016 American Medical Association. All rights reserved.
On-line-Only Supplement
Effect of Acetazolamide versus Placebo on Duration of Invasive Mechanical
Ventilation among Patients with Chronic Obstructive Pulmonary Disease: A
Randomized Clinical Trial
Investigators in the DIABOLO Trial
Iris Pelieu, Brice Lortat-Jacob, Marion Venot, Antoine Roux, Marine Gosset (European Georges Pompidou
Hospital, Paris); Olivier Martinet, Hassene Rahmani, Christine Kummerlen, David Schnell, Anca Raluga Neagu,
Xavier Delabranche, Julie Boisram-Helms (Nouvel Hpital Civil and EA 7293, Fdration de Mdecine
Translationnelle de Strasbourg, Strasbourg University, Strasbourg); Benjamin Zuber, Gilles Troch, Stphane
Legriel, Fabrice Brunel, Pierre Guezennec, Virginie Laurent, Julia Hilly-Ginoux, Mathieu Henry-Lagarrigue
(Andr Mignot Hospital, Le Chesnay); Philippe Vignon, Nicolas Pichon, Bruno Franois, Anthony Dugard,
Jean-Bernard Amiel, Emmanuelle Beguot, Remy Bellier (Limoges University Hospital, Limoges); Jean-Michel
Coulaud, Laurence Donetti, Jean Barchasz (Le Raincy-Montfermeil Hospital, Montfermeil); Marie-Line Harley,
Vincent Castelain, Philippe Lutun, Jean-Etienne Herbrecht, Ralf Janssen-Langestein, Maleka Schenck, Max
Guillot, Antoine Poidevin (Hautepierre Hospital, Strasbourg); Hlne Prodanovic, Mathieu Schmidt, Julien
Mayaux, Julie Delemazure, Romain Persichini (Piti-Salptrire University Hospital, Paris); Marie Conrad,
Damien Barraud, Alexandre Lai, Jrmie Lemarie, Lionel Nace, Aurlie Cravoisy-Popovic (Nancy University
Hospital, Nancy); Alain Mercat, Pierre Asfar, Achille Kouatchet, Marc Pierrot, Vincent Souday, Pierre
Bourgoin, Carole Fleury, Annelise Foucher-Lezla, Guillaume Bouvier, Tarek Abouzahr, Jacques-Armel
Giquello, Satar Mortaza (Angers University Hospital, Angers); Cdric Rafat, Clment Leclaire, Jonathan
Messika, Nicolas Dufour, Sylvain Jean-Baptiste, Romain Miguel Montanes, Stphane Gaudry (Louis-Mourier
University Hospital, Colombes); Muriel Fartoukh, Vincent Labbe, Antoine Parrot (Tenon University Hospital,
Paris); Pascal Fangio, Herv Outin, Christophe Barbier, Bernard De Jonghe, Jan Hayon, Yann Loubieres
(Poissy-Saint Germain Hospital, Poissy); Aurlie Lefebvre, Antoine Tesnieres (Cochin Hospital, Paris).
Criteria for Temporary or Definitive Suspension of Assigned Treatment

Temporary contraindications to assigned test treatment were screened every day:
Liver insufficiency defined as any 2 of the following: serum bilirubin > 8.77 mg/dL (150 mol/L) and serum
aspartate aminotransferase >500 U/L, prothrombin ratio <50%, and clinical signs and symptoms of hepatic
coma;
Renal insufficiency with serum creatinine >2.83 mg/dL (250 mol/L) or patient on dialysis;
Uncorrected adrenal insufficiency;
Uncorrected hypothyroidism;
Concomitant prescription of quinidine-like drugs or carbamazepine.
Test treatment was withdrawn definitively when anaphylactic shock or an anaphylactoid reaction occurred
during or following its administration.
Criteria Defining Weaning from Invasive Mechanical Ventilation

The situation requiring invasive ventilation resolved (if identified);
No sedation and Coma Glasgow Score >12;
No excessive bronchial secretions or effective cough reflex;
Body temperature <38.5C;
Hemodynamic stability (no vasoconstrictors, heart rate <120/minute, systolic arterial blood pressure 90160 mm
Hg);
No major dyskalemia of dysnatremia;
Hemoglobin >0.8 g/dL (8 g/dL);
Respiratory frequency 35 cycles/minute;
External positive end-expiratory pressure (PEEP) 8 cm H2O;
Inspiratory oxygen fraction (FiO2) 50% and partial oxygen pressure in arterial blood
(PaO2)/FiO2 ratio 150 mm Hg.
Criteria for Extubation and Reintubation

Patients were extubated when they tolerated, for at least 1 hour, a spontaneous breathing trial via a T-piece
oxygenated with the same FiO2 used during mechanical ventilation. Arterial blood gases were analyzed at the
end of the trial. Criteria for passing a spontaneous breathing trial included: respiratory frequency 35
breaths/min; arterial oxygen saturation decreased <5% or PaO2/FiO2 150 mm Hg; PaCO2 increased <10 mm Hg
and pH decreased <0.10; hemodynamic stability (increased heart rate or systolic blood pressure <20%); stable
mental status; no need for frequent suctioning of airway secretions. Criteria for considering reintubation or
noninvasive ventilation were: agitation or depressed mental status; tachypnea >35 breaths/min; tachycardia,
hypertension, hypotension or arrhythmia; inability to clear pulmonary secretions or an upper airway obstruction;
PaCO2 increased 10 mm Hg and pH decreased 0.10; PaO2 <60 mm Hg or arterial oxygen saturation <90%
while receiving FiO2 >50%.
Data Collected
Data collected at inclusion included age, sex, smoking history, use of long-term (>8 weeks) systemic
glucocorticoids, diuretics, acetazolamide or inhaled
2-agonists,
home oxygen therapy or noninvasive
ventilation, tracheotomy, prior pulmonary function tests obtained with patient in stable condition when available,
body mass index, arterial blood gases measured on invasive ventilation, serum sodium, serum potassium, serum
chloride, serum proteins, serum glucose, serum calcium, serum creatinine, serum urea, plasma uric acid,
complete blood count, liver-function (enzyme) tests, prothrombin ratio, serum thyroid-stimulating hormone
(TSH) level, chest radiography, and calculation of Sequential Organ Failure Assessment (SOFA) score and
Simplified Acute Physiology Score (SAPS) II.
Day 0 was the day of inclusion. Data collected every day from day 1 to termination of invasive mechanical
ventilation were serum bicarbonate, PaCO2, pH, PaO2/FiO2 ratio, and respiratory parameters (tidal volume,
respiratory rate and minute ventilation), external PEEP level, type of mechanical ventilation (pressure-support or
volume-assisted ventilation), glucocorticoids prescribed, loop diuretics prescribed, catecholamines prescribed,
2-agonists
prescribed, side effects of the assigned test treatment (Yes/No), metabolic alkalosis (Yes/No), criteria
defining weaning (see above) (Yes/No), successful or failed spontaneous breathing trial, unplanned extubation,
use of noninvasive ventilation after planned extubation, reintubation required, need for tracheotomy, ventilatorassociated pneumonia. Serum calcium, white blood cell count, liver-function (enzyme) test results and
prothrombin ratio were also determined at least every 5 days from day 1 until the termination of invasive
ventilation or were collected every day, when available. Plasma uric acid or serum TSH determination was
required in the case of signs of renal lithiasis, gout attack or thyroid dysfunction. Left ventricular ejection
fraction assessed by echocardiography was required only during the weaning period.
Definition of Outcome
The duration of invasive ventilation was the time between its start and termination (via an intubation tube or a
tracheotomy). The duration of weaning was the time between its onset (see criteria above) and its termination. In
the case of temporary interruption(s) of the weaning procedure, the total duration corresponded to the number of
hours of attempted withdrawal until successful weaning minus discontinued hours. Weaning was considered
successful when invasive ventilation reintroduction was not required within 48 hours after its termination.
Changes of serum bicarbonate, PaCO2, pH, PaO2/FiO2 ratio and respiratory parameters (tidal volume, respiratory
rate and minute ventilation) corresponded to the means of the differences between 2 consecutive days from day 1
to termination of invasive ventilation. Ventilator-associated pneumonia was diagnosed based on the following
criteria: systemic signs of infection (fever, tachycardia, and/or leukocytosis), new or worsening infiltrates seen
on the chest roentgenogram, and bacteriologic evidence of pulmonary parenchymal infection (protected
specimen brush with >103 or bronchoalveolar lavage with >104 colony-forming units/mL or tracheal secretions
with 106 colony-forming units/mL, leukocytes 25/field and/or epithelial cells 25/field). Serious adverse events
were considered the need for intensive care procedures (mechanical ventilation, use of vasopressors,
haemodialysis, central venous catheterization, cardiac pacing and/or tube thoracostomy) and/or surgery, and
those events prolonged hospitalization or resulted in persistent or major disability/incapacity.
Online-Only Figure Legends

eFigure 1. Trial Course for an Individual Patient
eFigure 2. Intention-to-Treat Analysis: Daily Arterial Blood Gases and Respiratory Parameters
From day 1 to the end of invasive ventilation: serum bicarbonate (Panel A); pH (Panel B), PaCO2 (Panel C),
PaO2/FiO2 ratio (Panel D), respiratory frequency (Panel E), tidal volume (Panel F), volume minute (Panel G),
and external positive end-expiratory pressure (PEEP) (Panel H). Values are means, 95% confidence intervals
(vertical T-bars).
eFigure 3. Per-protocol analysis: Daily Arterial Blood Gases and Respiratory Parameters
From day 1 to the end of invasive ventilation: serum bicarbonate (Panel A); pH (Panel B), PaCO2 (panel C),
PaO2/FiO2 ratio (Panel D), respiratory frequency (Panel E), tidal volume (Panel F), volume minute (Panel G),
and external positive end-expiratory pressure (PEEP) (Panel H). Values are means, 95% confidence intervals
(vertical T-bars).
eFigure 4. Per-Protocol Analysis: Subgroup Analyses of the Acetazolamide Effect on Duration of Invasive
Mechanical Ventilation (A) or Weaning (B)
The duration of weaning was the time between its onset (see criteria above) and its termination. In the case of
temporary interruption(s) of the weaning procedure, the total duration corresponded to the number of hours of
attempted withdrawal until successful weaning minus discontinued hours. Horizontal bars are 95% confidence
intervals for hazard ratios.
An event corresponds to the termination of invasive mechanical ventilation.
eTable 1. Per-Protocol Analysis: Clinical Outcomes and Serious Adverse Eventsa

Acetazolamide Group
Placebo Group
Between-Group Difference
(n = 131)
(n = 149)
(95% CI)
166.5 (92.7-258.2)
183.7 (108.1-279.5)
15.8 (48.6-8.5)
.36
0. (.3-0.)
0.3 (0.2-1.1)
1.0 (1.3- 0.7)
<.0001
Daily PaCO2 change, median (IQR), mm Hg
0. (2-0.8)
0. (1-0.5)
0.2 (0.7-0.3)
.29
Daily pH change, median (IQR)
0 (0.01-0.02)
0.01 (0-0.02)
0.01 (0.01- 0.01)
.0003
Daily PaO2/FiO2-ratio change, median (IQR), mm Hg
8.1 (0-18.5)
4 (2.3-12.2)
4.6 (0.9-8.3)
.005
Daily respiratory rate change, median (IQR), cycles/min
0.2 (0.7-1)
0.3 (0.3-1.2)
0.2 (0.6-0.1)
.14
4 (6-27)
3.8 (8-18.2)
1.9 (3.5-8.8)
.34
Daily volume-minute change, median (IQR), L/min
0.2 (0.1-0.8)
0.2 (0.1-0.6)
0.0 (0.1-0.2)
.44
Duration of weaning, median (IQR), h
22.5 (3.3-49.5)
24 (4-45.5)
0.5 (5.5-3.0)
.68
No. of spontaneous breathing trials, median (IQR)
1 (1-3)
1 (1-3)
0 (0-0)
.61
Days with tracheotomy, median (range)
0 (0-21)
0 (0-9)
0 (0-0)
.63
Use of noninvasive ventilation after extubation, No. (%)
52 (39.6)
63 (42.8)
2.6 (14.6-9.1)
.66
Variable
Primary outcome: duration of invasive ventilation, median (IQR), h
P Value
Secondary outcomesb
Daily serum bicarbonate change, median (IQR), mEq/L
Daily tidal volume change, median (IQR), mL
Successful weaningc, No. (%)
81 (61.8)
103 (69.1)
7.0 (18.0-4.0)
.20
Days with unplanned extubation, median (range)
0 (0-2)
0 (0-1)
0 (0-0)
.71
VAP episodes, No. (%)
21 (16)
27 (18.1)
2.1 (11.0-6.8)
.64
11 (7-17)
12 (8-21)
-1 (-3-0)
.50
In-ICU mortality, No. (%)
9 (6.9)
11 (7.4)
0.5 (6.5-5.5)
.86
Serious adverse eventsd, No. (%)
4 (3.1)
5 (3.4)
0.3 (4.4-3.82)
.91
No. of days on loop diuretics, median (IQR)
2 (0-4)
2 (0-5)
0 (0-0)
.71
No. of days on systemic glucocorticoids, median (IQR)
1 (0-4)
1 (0-5)
0 (0-0)
.49
No. of days on 2-agonists, median (IQR)
2 (0-5)
2 (0-7)
0 (-1-0)
.16
No. of days on catecholamines, median (IQR)
1 (0-3)
1 (0-3)
0 (0-0)
.36
No. of assigned test-treatment doses, median (IQR)
4 (2-8)
8 (4-14)
3 (5- 2)
<.0001
No. of days with metabolic alkalosise, median (IQR)
3 (2-5)
5 (3-8)
2 (3- 1)
<.0001
No. of days with transient contraindication to test treatment,
0 (0-5)
0 (0-2)
0 (0-0)
.07
No. of days on pressure-support ventilation, median (IQR)
3 (1-5)
3 (1-5)
0 (1-0)
.44
No. of days on volume-assisted ventilation, median (IQR)
3 (1-6)
3 (1-6)
0 (1-1)
.63
Duration of ICU stay, median (IQR), d
median (range)
Left ventricular ejection fraction at weaningf, median (IQR), %
50 (39-60)
50 (42-60)
0 (5-5)
.49
Abbreviations: CI, confidence interval; FiO2, fraction of inspired oxygen; ICU, intensive care unit; IQR, interquartile range; PaO2 and PaCO2, partial oxygen or
carbon-dioxide pressure in arterial blood, respectively; and VAP, ventilator-associated pneumonia.
aRange
was preferred over IQR because several of the latter were (00). Between-group differences for quantitative variables are expressed as medians with the
95% CI around the median difference.

bMedian
daily changes of arterial blood gases or respiratory parameters corresponded to the differences between 2 consecutive days from day 1 to the end of
invasive ventilation. Arterial blood gases and respiratory parameters on mechanical ventilation were measured between 7 a.m. and 8 a.m. Other laboratoryparameter changes are given in eTable 3.
cWeaning
was considered successful when invasive ventilation reintroduction was not required within 48 hours after its termination. Criteria for extubation and
reintubation are detailed in Supplement. Weaning-failure causes are given in eTable 3.

dAdverse
events were considered serious when they required intensive care procedures (use of vasopressors, hemodialysis, central venous catheterization,
cardiac pacing and/or tube thoracostomy) and/or surgery, and those events prolonged hospitalization or resulted in persistent or major disability/incapacity.
eMetabolic
fLeft
alkalosis was defined as serum bicarbonate >26 mEql/L and arterial pH 7.35.
ventricular ejection fraction was assessed by transthoracic echocardiography during the weaning period.
eTable 2. Intention-to-Treat Analysis: Study Laboratory Parametersa and Causes of Weaning Failure
Acetazolamide Group
Placebo Group
Between-Group Differenceb
(n = 187)
(n = 193)
(95% CI)
Serum calcium change, median (IQR), mg/dL
0.04 (0.04-0.20)
0.04 (0.04.0.16)
0.0 (0.0-0.0)
.96
White blood cell change, median (IQR), /L
130 (830-900)
80 (850-530)
0.0 (300-400)
.71
Prothrombin-ratio change, median (IQR), %
2.0 (1.7-7.3)
2.0 (0.6-5.5)
0.3 (1.5-2.1)
.65
Serum ASAT change, median (IQR), U/L
0.7 (7.0-5.5)
0 (9.8-6.1)
0.5 (5.0-4.2)
.77
Pneumonia
5 (2.7)
1 (0.5)
2.2 (0.4-4.7)
.09
8 (4.3)
6 (3.1)
1.2 (2.6-5.0)
.41
Hypercapnic encephalopathy
14 (7.5)
16 (8.3)
0.8 (6.2-4.6)
.98
Postextubation laryngeal oedema
2 (1.1)
3 (1.6)
0.5 (2.8-1.8)
.99
Cardiorespiratory arrest
2 (1.1)
1 (0.5)
0.6 (1.2-2.3)
.60
Unspecified
9 (4.8)
8 (4.1)
0.7 (3.5-4.8)
.81
Variable
P Value
Causes of weaning failure, No. (%)
Abbreviations: ASAT, aspartate aminotransferase; CI, confidence interval; and IQR, interquartile range.
aLaboratory
parameter values were determined at least every 5 days from day 1 until the end of invasive ventilation or collected every day, when available.
9
bBetween-group
differences for quantitative variables are expressed as medians with the 95% CI around the median difference.
10
eTable 3: Per-protocol analysis: Study laboratory parametersa and causes of weaning failure
Acetazolamide Group
Placebo Group
Between-Group Differenceb
(n = 131)
(n = 149)
(95% CI)
Serum calcium change, median (IQR), mg/dL
0.04 (0.04-0.20)
0.04 (0.04-0.16)
0.0 (0.0-0.0)
.56
White blood cell change, median (IQR), /L
100 (730-830)
80 (850-510)
0.0 (0.3-0.4)
.53
Prothrombin-ratio change, median (IQR), %
2 (1-8)
2 (0.6-5.7)
0.8 (1.2-2.9)
.34
0.3 (6.5-5.5)
0 (7-6)
0.5 (4.6-3.8)
.78
Pneumonia
5 (3.8)
1 (0.7)
3.1 (0.4-6.7)
.09
6 (4.6)
3 (2)
2.6 (1.7-6.8)
.29
Hypercapnic encephalopathy
13 (9.9)
16 (10.7)
0.8 (8.0-6.3)
.93
Postextubation laryngeal oedema
2 (1.5)
3 (2)
0.5 (3.6-2.6)
.99
Cardiorespiratory arrest
2 (1.5)
1 (0.7)
0.9 (1.6-3.3)
.59
Unspecified
6 (4.6)
6 (4)
0.6 (4.2-5.3)
.81
Variable
Serum ASAT change, median (IQR), U/L
P Value
Causes of weaning failure, No. (%)
Abbreviations: ASAT, aspartate aminotransferase; CI, confidence interval; and IQR, interquartile range.
aLaboratory
parameter values were determined at least every 5 days from day 1 until the end of invasive ventilation or collected every day, when available.
11
bBetween-group
differences for quantitative variables are expressed as medians with the 95% CI around the median difference.
12
eFigure 1
COPD (with or without respiratory assistance at home)

Invasive ventilation (by intubation or with a tracheotomy cannula)
needed <24 hours before ICU admission or during an ICU stay
Randomization
Acetazolamide
Placebo
D0
(Before 24 hours of invasive ventilation)
Daily evaluation from randomization onwards:

Serum bicarbonate >26 mmol/liter
Arterial blood pH 7.35 ?
YES
Temporary acetazolamide
contraindication?
NO
YES
NO
Temporary
withdrawal
Acetazolamide
or placebo
NO
Successful weaning test?

Resumption of usual
ventilation method for patients
YES
Possible tracheotomy
during weaning off
invasive ventilation
NO
Invasive
ventilation >28
days?
YES
End of
protocol
D1 to D28
Daily evaluation of weaning criteria, as of randomization

Test of weaning suitability if weaning criteria present:
eFigure 2
Panel A: Bicarbonate
60
7.6
50
7.5
mEq/L
40
30
7.4
7.3
20
7.2
10
7.1
Placebo
Acetazolamide
Panel B: pH
7.7
7.0
1
10
15
20
25
187
182
115
104
49
44
26
16
13
11
8
6
Days
Placebo
Acetazolamide
Panel C: PaCO2
120
10
15
20
25
188
182
115
104
49
44
26
16
13
11
8
6
Days
Panel D: PaO2/FiO2 Ratio
800
100
600
60
mm Hg
mm Hg
80
400
40
200
20
0
Placebo
Acetazolamide
0
1
10
15
20
25
188
182
115
104
49
44
26
16
13
11
8
5
Days
Placebo
Acetazolamide
Panel E: Respiratory Frequency
60
10
15
20
25
188
181
112
102
49
43
26
16
13
11
8
6
Panel F: Tidal Volume
1000
50
Days
800
600
30
20
mL
Cycle/min
40
10
15
20
25
190
182
114
106
49
44
26
16
13
10
8
6
Days
Placebo
Acetazolamide
Panel G: Volume Minute
10
15
20
25
188
182
114
106
49
44
26
16
13
10
7
6
Days
Panel H: Positive End Expiratory Pressure
20
20
L/min
cm H2O
15
15
10
Placebo
Acetazolamide
25
10
200
10
Placebo
Acetazolamide
400
0
1
10
15
20
25
188
180
114
106
48
44
26
15
13
10
7
6
Days
Placebo
Acetazolamide
Placebo
10
15
20
25
189
181
116
105
50
44
26
16
13
11
7
6
Acetazolamide
Days
eFigure 3
Panel A: Bicarbonate
60
7.6
50
7.5
mEq/L
40
30
7.4
7.3
20
7.2
10
7.1
Placebo
Acetazolamide
Panel B: pH
7.7
7.0
1
10
15
20
25
148
130
104
86
44
38
24
16
13
11
8
6
Days
Placebo
Acetazolamide
Panel C: PaCO2
120
10
15
20
25
149
130
104
86
44
38
24
16
13
11
8
6
Days
Panel D: PaO2/FiO2 Ratio
800
100
600
60
mm Hg
mm Hg
80
400
40
200
20
0
Placebo
Acetazolamide
0
1
10
15
20
25
149
130
104
86
44
38
24
16
13
11
8
5
Days
Placebo
Acetazolamide
Panel E: Respiratory Frequency
60
10
15
20
25
149
129
101
84
44
37
24
16
13
11
8
6
Panel F: Tidal Volume
1000
50
Days
800
600
30
20
mL
Cycle/min
40
0
1
10
15
20
25
149
130
102
87
44
38
24
16
13
10
8
6
Days
Placebo
Acetazolamide
Panel G: Volume Minute
10
15
20
25
147
130
102
87
44
38
24
16
13
10
7
6
Days
Panel H: Positive End Expiratory Pressure
20
20
L/min
cm H2O
15
15
10
Placebo
Acetazolamide
25
10
200
10
Placebo
Acetazolamide
400
0
1
10
15
20
25
148
129
102
87
43
38
24
15
13
10
7
6
Days
Placebo
Acetazolamide
Placebo
10
15
20
25
148
130
104
87
45
38
24
16
13
11
7
6
Acetazolamide
Days
eFigure 4A
Subgroup
Overall
Acetazolamide Group
Placebo Group
Eventsa, n Patients, n
117
131
137
149
1.09 (0.851.40)
Yes
84
95
112
123
0.98 (0.741.30)
No
33
36
25
26
0.66 (0.381.14)
Yes
50
53
64
67
1.27 (0.871.85)
No
67
78
73
82
1.01 (0.721.41)
Yes
101
113
111
122
1.14 (0.871.49)
No
16
18
26
27
1.04 (0.532.10)
Yes
51
52
43
44
1.59 (1.042.42)
No
66
79
94
105
0.91 (0.661.24)
Acute Prolonged Invasive Ventilation ( 96 hours)
Pressure Support Ventilation >50% the Weaning Period
Loops Diuretics and/or Corticosteroids
Pure Metabolic Alkalosis at Baseline
0.5
1.0
Placebo
better
1.5
2.0 2.5
Acetazolamide
better
eFigure 4B
Subgroup
Overall
Acetazolamide Group
Placebo Group
105
110
127
129
0.98 (0.751.27)
Yes
76
81
103
104
0.90 (0.661.21)
No
29
29
24
25
0.77 (0.431.39)
Yes
47
49
63
64
1.02 (0.701.50)
No
58
61
64
65
1.01 (0.701.45)
Yes
90
94
103
105
1.01 (0.761.34)
No
15
16
24
24
0.87 (0.451.66)
Yes
47
47
40
40
1.21 (0.791.85)
No
58
63
87
89
0.84 (0601.19)
Acute Prolonged Invasive Ventilation ( 96 hours)
Pressure Support Ventilation >50% the Weaning Period
Loops Diuretics and/or Corticosteroids
Pure Metabolic Alkalosis at Baseline
0.5
1.0
Placebo
better
1.5
2.0
Acetazolamide
better
2.5

Effect of Acetazolamide Vs Placebo On Duration of Invasive Mechanical Ventilation Among Patients With Chronic Obstructive Pulmonary Disease

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Effect of Acetazolamide Vs Placebo On Duration of Invasive Mechanical Ventilation Among Patients With Chronic Obstructive Pulmonary Disease

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Research

Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT

Effect of Acetazolamide vs Placebo on Duration

critically ill patients with COPD and metabolic alkalosis.

Author Affiliations: Author

Copyright 2016 American Medical Association. All rights reserved.

Acetazolamide and Duration of Invasive Mechanical Ventilation

2014. Patients were enrolled (day 0) at 15 adult ICUs in France.

Randomization and Allocation

Original Investigation Research

After inclusion, patients were assigned to receive either 500 mg

Copyright 2016 American Medical Association. All rights reserved.

Research Original Investigation

Acetazolamide and Duration of Invasive Mechanical Ventilation

plied in the form of a solvent (saline) and was administered in

JAMA February 2, 2016 Volume 315, Number 5 (Reprinted)

Copyright 2016 American Medical Association. All rights reserved.

Acetazolamide and Duration of Invasive Mechanical Ventilation

Original Investigation Research

Figure 1. Study Flow of Patients in the DIABOLO Trial

188 Randomized to receive acetazolamide

194 Randomized to receive placebo

187 Included in the primary analysis

193 Included in the primary analysis

Patients who did not receive the

149 Included in per-protocol population

Primary and Secondary Outcomes

cycles/min (IQR, 0.8 to 1.0 cycles/min) vs 0.3 cycles/min (IQR,

Metabolic Alkalosis and Treatment Administration

Copyright 2016 American Medical Association. All rights reserved.

Research Original Investigation

Acetazolamide and Duration of Invasive Mechanical Ventilation

Table 1. Characteristics of the Patients at Baseline

Table 1. Characteristics of the Patients at Baseline (continued)

Study Group, Mean (SD)

Study Group, Mean (SD)

White blood cells/L

Unilateral alveolar opacities

Bilateral alveolar opacities

Home treatment, No. (%)

Distension of the lungs

>8 Weeks, No. (%)

Left ventricular insufficiency

Abbreviations: BMI, body mass index, calculated as weight in kilograms

The SOFA score includes subscores ranging from 0 to 4 for each of

Seventy-eight patients in the acetazolamide group and 91 patients in the

acetazolamide-group patients (28.3%) and 43 placebo-group

No significant between-group differences were observed for

Post Hoc Subgroup Analyses

No significant interactions were identified between study

Aspartate aminotransferase, U/L

Uric acid, mg/dL

JAMA February 2, 2016 Volume 315, Number 5 (Reprinted)

Copyright 2016 American Medical Association. All rights reserved.

Acetazolamide and Duration of Invasive Mechanical Ventilation

Original Investigation Research

Table 2. Clinical Outcomes and Serious Adverse Eventsa

136.5 (68.7 to 234.7)

163 (86.2 to 242.9)

16.0 (36.5 to 4.0)

0.8 (1.2 to 0.5)

0.3 (0.8 to 0.2)

0.3 (1.0 to 0.4)