Effect of Acetazolamide vs Placebo on Duration of Invasive Mechanical Ventilation Among Patients...

Copyright 2016 American Medical Association. All rights reserved.

Effect of Acetazolamide vs Placebo on Duration

of InvasiveMechanical 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; Sébastien 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; Saïk 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

patients with chronic obstructive pulmonary disease (COPD) andmetabolic 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 andmetabolic alkalosis.

DESIGN, SETTING, AND PARTICIPANTS The DIABOLO study, a randomized, double-blind,

multicenter trial, was conducted fromOctober 2011 through July 2014 in 15 intensive care

units (ICUs) in France. A total of 382 patients with COPDwhowere expected to receive

mechanical ventilation for more 24 hours were randomized to the acetazolamide or placebo

group and 380were included in an intention-to treat analysis.

INTERVENTIONS Acetazolamide (500-1000mg, twice daily) vs placebo administered

intravenously in cases of pure or mixedmetabolic alkalosis, initiated within 48 hours of ICU

admission and continued during the ICU stay for a maximum of 28 days.

MAINOUTCOMESANDMEASURES Theprimaryoutcomewas thedurationof invasivemechanical

ventilation via endotracheal intubationor tracheotomy. Secondaryoutcomes included changes in

arterialbloodgasandrespiratoryparameters,weaningduration,adverseevents,useofnoninvasive

ventilation after extubation, successfulweaning, thedurationof ICU stay, and in-ICUmortality.

RESULTS Among382 randomizedpatients, 380 (meanage,69years; 272men [71.6%]; 379

[99.7%]with endotracheal intubation) completed the study. For the acetazolamidegroup

(n = 187), comparedwith theplacebogroup (n = 193), no significant between-groupdifferences

were found formediandurationofmechanical ventilation (−16.0hours; 95%CI, −36.5 to

4.0hours;P = .17), durationofweaningoffmechanical ventilation (−0.9hours; 95%CI, −4.3 to

1.3 hours;P = .36), daily changesofminute-ventilation (−0.0L/min; 95%CI, −0.2 to0.2 L/min;

P = .72), or partial carbon-dioxidepressure in arterial blood (−0.3mmHg;95%CI, −0.8 to

0.2mmHg;P = .25), althoughdaily changesof serumbicarbonate (between-groupdifference,

−0.8 mEq/L; 95% CI, −1.2 to −0.5 mEq/L; P < .001) and number of days with metabolic alkalosis

(between-groupdifference, −1;95%CI, −2 to−1days;P < .001)decreasedsignificantlymore in the

acetazolamidegroup.Other secondaryoutcomes alsodidnot differ significantly betweengroups.

CONCLUSIONS AND RELEVANCE Among patients with COPD receiving invasivemechanical

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

Supplemental content at

jama.com

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

([email protected]).

Section Editor:Derek C. Angus, MD,

MPH, Associate Editor, JAMA

([email protected]).

Research

Original Investigation | CARING FORTHE CRITICALLY ILL PATIENT

480 (Reprinted) jama.com


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Chronic obstructive pulmonary disease (COPD) is a fre-

quent cause of intensive care unit (ICU) admission.1

Noninvasivemechanicalventilationhasaltered theout-

comes 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 non-

invasive ventilation fails or for an unrelated pathology.

Respiratory acidosis andmetabolic alkalosis are the prin-

cipal acid-base disturbances in patients with COPD receiving

mechanical ventilation. Metabolic alkalosis can be caused by

many conditions encountered during ICU stays, including di-

uretic or glucocorticoid use, vomiting or nasogastric suction-

ing, and permissive hypercapnia induced by lung-protective

strategies.4 Furthermore, the acid-base disorders most fre-

quently observed while weaning patients with COPD off me-

chanical ventilation are mixed (ie, chronic respiratory acido-

sis and metabolic alkalosis).5 Metabolic alkalosis may inhibit

the activity of the central nervous respiratory command cen-

ter andcardiacoutputoralteroxyhemoglobindissociationand

favors thedevelopment of hypokalemia andhypophosphate-

mia, 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

acetazolamide’s 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 uncon-

trolled 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 respira-

tory 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

Study Design

This multicenter, double-blind (participants, caregivers, in-

vestigators, andoutcomeassessors), parallel-group, random-

ized clinical trial was approved for all centers by the Comité

deProtectiondesPersonnesParis–Ile-de-FranceVI (ethicscom-

mittee: No. 2011-000492-14). The French National Commit-

tee forHealthResearch funded the study and convened a trial

steering committee and independent data monitoring com-

mittee.Asafetymonitoringcommitteewasnotconsiderednec-

essary because the acetazolamide doses had adhered to the

marketing authorization and the study design included daily

patient evaluation for adverse events or temporary contrain-

dications. The EuropeanGeorges PompidouHospital Clinical

ResearchCentermanaged the study, fromOctober 2011 to July

2014. Patientswere enrolled (day0) at 15 adult ICUs inFrance.

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 pro-

vide informed consent.

Participants

Patients older than 18 years with a history of COPD according

to theAmericanThoracic Society criteria15 (smoking, other en-

vironmental risk factors, chronic cough, acute chest ill-

nesses, dyspnea, physical examination, and laboratory inves-

tigations such as chest radiography, lung function tests, or

arterialbloodgases)wereenrolled if theyrequired invasiveven-

tilationvia an intubationor tracheotomy tubeandwereevalu-

atedwithin24hours after its onset. Exclusion criteriawere ju-

dicial guardianship, no affiliationwith theFrenchhealth care

system,pregnancy,cystic fibrosisordiffusebronchiectasis,pre-

viousallergy toacetazolamideor sulfonamides,permanentac-

etazolamide contraindication, recent participation in an-

other interventional study with mechanical ventilation

duration as the primary end point, or investigator’s 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 ran-

domization sequence was programmed in advance and gen-

erated by a statistician independent of the study. One-for-

one randomization was carried out, with stratification for

centers, respiratory status of the patients before hospitaliza-

tion (no respiratory assistance at home vs respiratory assis-

tance 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

randommanner. Physicians assigned the treatment after ran-

domization, which was accessible through dedicated web-

based software. Investigators, patients, and research staff

were masked to the randomization list.

Intervention

After inclusion,patientswereassignedto receiveeither500mg

or 1000 mg (when loop diuretics were coprescribed) of acet-

azolamide twice daily or placebo (10 mL of saline) in case of

pure or mixed metabolic alkalosis (serum bicarbonate

>26mEql/L andarterial pH ≥ 7.35),monitoredaccording to ar-

terial blood gases determined on mechanical ventilation be-

tween 7 AM and 8 AM from day 1 to the day invasive ventila-

tion ended (eFigure 1 in Supplement 2). Physicians in charge

weredifferent from the investigatorswhomonitored andpre-

scribed the tested treatment. Tested treatment was prepared

and blinded in each local pharmacy. Acetazolamide was sup-

plied as a freeze-dried powder. The product was reconsti-

tuted with saline and then administered immediately in the

ICU, as a slow intravenous injection. The placebo was sup-

Acetazolamide and Duration of Invasive Mechanical Ventilation Original Investigation Research

jama.com (Reprinted) JAMA February 2, 2016 Volume 315, Number 5 481







plied in the formof a solvent (saline) andwas administered in

the samemanner. If a contraindication for the test treatment

arose (for details, see Supplement 2), it was temporarily sus-

pendeduntil the contraindicationhad resolved. Patientswith

pure or mixed metabolic alkalosis received acetazolamide or

placebo intravenously twice daily for amaximumof 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 sig-

nificantly lower serum bicarbonate and raise minute ventila-

tion in patients with COPD breathing with the aid of a venti-

lator, regardless of the ventilation mode (volume-assisted or

pressure-support ventilation)used.13,14Other treatmentswere

left to the discretion of the treating physicians and had to be

inaccordancewithclassicguidelines.1 Investigatorswereaware

of the need to correct hypokalemia.

Readiness to wean was defined according to the criteria

of the Sixth International Consensus Conference on Inten-

sive CareMedicine held in 2005.16Theweaning strategy con-

sisted 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, accord-

ing to the difficulty of the weaning process.17 External posi-

tiveend-expiratorypressurewasapplied tocounterbalance in-

trinsic positive end-expiratory pressure, typically 4 to6 cmof

H2O. Criteria for extubation and reintubation were standard-

ized in a written protocol (for details, see Supplement 1). Pa-

tients enrolledwereextubatedwhen they tolerated, for at least

1 hour, a spontaneous breathing trial via a T-piece oxygen-

atedwith thesame inspiratoryoxygen fraction (FIO2) useddur-

ing 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 ventilationwasnot requiredwithin48hours after its

termination.17Tracheotomy indication andmodalities for pa-

tients with prolonged weaning failure were left to the discre-

tion of the treating physicians. Group assignments for pa-

tientswhodiedbeforebeingweanedoffmechanicalventilation

or those who received no test treatment during the study pe-

riod 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 ventila-

tion. Secondary outcomes were the changes of serum bicar-

bonate, partial pressure of carbon dioxide in arterial blood

(PaCO2), 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.

Statistics

The sample size was calculated a priori based on the follow-

ing assumptions: placebo groupwith an estimatedmean (SD)

duration ofmechanical ventilation of 12 (5) days based of one

of our preliminary studies,5 and because we expected to in-

clude the most severely ill patients with COPD (ie, requiring

invasive mechanical ventilation); acetazolamide-group pa-

tients, comparedwith those in theplacebogroup,wouldhave

a potential 15% relative risk reduction for the primary end

point5 to be clinically relevant. Based on those estimates, we

calculated that 380patientshad tobeenrolled to achieve80%

power to detect that difference for the acetazolamide group

with a 2-sided α level of .05.

The analyses were performed on the intention-to-treat

population,whichwasdefined as all patientswhohadunder-

gone 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 crite-

ria evaluation (ie, patients receiving the allocated treatment;

patientswith all the inclusion criteriamet).Missingdatawere

only imputed for the end of invasive mechanical ventilation.

We used the mean hour of the end of invasive mechanical

ventilationof thecenterbecauseplannedextubationswereper-

formed around the same time. To take censored data into ac-

count (patients who died before extubation), the Kaplan-

Meiermethodwas used to calculate the probabilities of being

successfully weaned off invasive ventilation during the 28-

day observation period. The generated Kaplan-Meier curves

were comparedwith the log-rank test. Quantitative variables

areexpressedasmeansandstandarddeviationormediansand

interquartile ranges (IQRs),whenappropriate.Datawere com-

paredwith t tests, when the sample size of each groupwas 30

ormore,orWilcoxonrank-sumtests,whenonegroup’s sample

sizewas less than30.All testswere2-sided.Eitherχ2orFischer

exact tests, as appropriate, were used to compare qualitative

variables, expressed as percentages. All comparisons in-

cluded the entire sample stratification (as prespecified). Haz-

ard ratios were calculated using a Cox model and the centers

were taken intoaccountasa randomeffectusinggammafrailty

model.18 Tests of proportionality were performed including

time-dependent covariates in the Cox model. Post hoc sub-

groups 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 pressure-

support ventilationornot during theweaningperiod, thepre-

scription 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 < .05defined statistical significance.All analyseswere com-

puted using SAS software, version 9.4 (SAS Institute Inc).

Results

Patients

Amongthe694patients screened in the15participatingFrench

ICUs, 382 were enrolled, including 2 patients who subse-

Research Original Investigation Acetazolamide and Duration of Invasive Mechanical Ventilation

482 JAMA February 2, 2016 Volume 315, Number 5 (Reprinted) jama.com







quently withdrew from the study, resulting in an intention-

to-treat populationof 380patients: 187 randomized to the ac-

etazolamide 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

Thetotaldurationsof invasiveventilationwasamedianof 136.5

hours (IQR, 68.7 to 234.7 hours) in the acetazolamide group vs

163.0hours (IQR,86.2 to242.9hours) in theplacebogroup, 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 dif-

ference of −0.8 mEq/L (95% CI, −1.2 to −0.05 mEq/L) and in-

creased 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,

0.6-8.6mmHg)more than the placebo, but hadno respiratory

stimulant effect on themedian changes of respiratory rate 0.1

cycles/min (IQR,−0.8 to 1.0cycles/min)vs0.3 cycles/min (IQR,

−0.3 to 1.4 cycles/min), for a between-groupdifference 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 28.0mL) vs 3.8mL (IQR, −8.6 to 19.4mL),

forabetween-groupdifferenceof1.3mL(95%CI,−4.2to7.5mL);

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

ornoninvasiveventilationafterextubation, successfulweaning

rates, unplannedextubations, ventilator-associatedpneumo-

nia episodes, other laboratory-parameter values, ICU stays

or in-ICU mortality rates (eTable 2 in Supplement 2). Per-

protocol analysis yielded results similar to those of the

intention-to-treat analysis with respect to significant find-

ings (eTables 1 and 3 in Supplement 2).

Metabolic Alkalosis and Treatment Administration

Asexpected, thenumbersofdayswithmetabolic alkalosis and

treatment doses were significantly lower for the acetazol-

amide than for the placebo group (Table 2). A total of 53

Figure 1. Study Flow of Patients in the DIABOLO Trial

694 Patients assessed for eligibility

312 Excluded

105 Did not meet inclusion criteria

154 Met exclusion criteria

53 Other reasons

53 Intubation lasted >24 h

52 Declined to participate or no availablenext of kin

70 Close to death

40 Had ≥ contraindication to acetazolamide

26 Under judicial guardianship

15 Enrolled in another study

41 Overlooked by investigator

12 Intubation planned in <24 h

2 Not affiliated with health care system

1 Allergic to sulfonamides

382 Randomized

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 anelectronic bracelet)

149 Included in per-protocol population

188 Randomized to receive acetazolamide

134 Received acetazolamideas randomized

53 Did not receive acetazolamide asrandomized (no metabolic alkalosisor temporary contraindication)

1 Incorrectly included inrandomization (at the wrong center)

194 Randomized to receive placebo

150 Received placebo as randomized

43 Did not receive placebo asrandomized (no metabolic alkalosisor temporary contraindication)

1 Incorrectly included inrandomization (detaineewearing an electronic bracelet)

2 Forgotten administrations

1 Dosage error

1 Dosage error

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.









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

patients (22.2%)never receivedtheassignedtreatment (P = .17)

because of nometabolic alkalosis or temporary contraindica-

tion. Cotreatments with loop diuretics, glucocorticoids,

β2-agonists or catecholamines, the mechanical ventilation

modeused, and the left ventricular ejection fraction atwean-

ing were comparable for the 2 groups.

Adverse Events

No significant between-group differences were observed for

theoverall incidenceof seriousadverseevents (Table2; eTable

1 in Supplement 2).

Post Hoc Subgroup Analyses

No significant interactions were identified between study

groupsandanyposthoc subgroupwith respect to the total du-

rationsof invasiveventilationorweaning (Figure3andeFigure

4A-B in Supplement 2).

Discussion

This multicenter, randomized, double-blind trial was de-

signed to compare the respiratory effects of acetazolamide vs

Table 1. Characteristics of the Patients at Baseline

Characteristic

Study Group, Mean (SD)

Acetazolamide(n = 187)

Placebo(n = 193)

Age, y 69 (10) 69 (11)

Men, No. (%) 131 (70) 141 (73.1)

SAPS II scorea 49.4 (13.9) 50 (15.1)

SOFA scoreb 7.2 (3.1) 7.1 (3.2)

BMI 27.2 (8.0) 26.7 (9.1)

Home treatment, No. (%)

Oxygen 49 (26.2) 52 (26.9)

Noninvasive ventilation 19 (10.1) 21 (10.9)

Tracheotomy mechanicalventilation

0 1 (0.5)

Smoker or ex-smoker, No. (%) 170 (90.9) 179 (92.7)

Smoking history, pack-years 48.3 (24.7) 50.4 (22.1)

FEV1, mLc 1232 (609) 1124 (586)

FEV1/FVCc 0.51 (0.15) 0.53 (0.15)

>8 Weeks, No. (%)

Systemic glucocorticoids 32 (17.1) 39 (20.2)

Loop diuretics 51 (27.3) 67 (34.7)

β2-Agonists 96 (51.3) 95 (49.2)

Acetazolamide 4 (2.1) 3 (1.6)

ICU stay before randomization,median (IQR), dd

1 (0-1) 1 (0-1)

Causes of invasive mechanicalventilation, 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 measurementsat 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)

Serum

Bicarbonate, mEq/L 26.9 (6.9) 27.4 (6.6)

Potassium, mEq/L 4.2 (0.7) 4.2 (0.7)

Sodium, mEq/L 138 (5.8) 139 (4.9)

Chloride, mEq/L 100.9 (8.4) 100.6 (6.8)

Protein, g/dL 5.9 (0.9) 5.9 (0.8)

Creatinine, mg/dL 1.3 (0.9) 1.2 (0.8)

Urea, mg/dL 31.4 (25.8) 29.7 (23.2)

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)

Hemoglobin, g/dL 1.2 (0.2) 1.2 (0.2)

(continued)

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

Characteristic

Study Group, Mean (SD)


Placebo(n = 193)

Hematocrit, % 37.3 (8) 37.6 (8.4)

White blood cells/µL 13700 (7200) 13900 (8200)

Blood platelets, ×103/µL 251.5 (116.6) 245.6 (118.5)

Prothrombin ratio, % 73.7 (21.6) 75.9 (22.1)

Chest radiography, No. (%)

Distension of the lungs 147 (78.6) 148 (76.7)

Unilateral alveolar opacities 57 (30.5) 53 (27.5)

Bilateral alveolar opacities 84 (44.9) 93 (48.2)

Abbreviations: BMI, bodymass 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 fromU/L to μKat/L,

multiply by 0.0167; bilirubin frommg/dL to μmol/L, multiply by 17.104;

creatinine frommg/dL to μmol/L, multiply by 88.4; glucose frommg/dL to

mmol/L, multiply by 0.0555; PaO2 and PaCO2 frommmHg to kPA, multiply by

0.133; uric acid frommg/dL to μmol/L, multiply by 59.485.

a The SAPS II is based on 17 variables; scores range from0 to 163, with higher

scores indicating more severe disease.

bThe SOFA score includes subscores ranging from0 to 4 for each of

the 5 components (circulation, lung, liver, kidneys, and coagulation).

Aggregate scores range from0 to 20, with higher scores indicating more

severe organ failure.

c Data were available from 71 patients in the acetazolamide group and from 82

patients in the placebo group.

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

placebo group were hospitalized in ICU prior to randomization.

e Several situations requiring invasive ventilation are possible; hence, the total

can exceed 100%.








placebo in mechanically ventilated patients with COPD and

pure ormixedmetabolic alkalosis. Acetazolamide had no sig-

nificant effect ondurationsofmechanical ventilationorwean-

ing, respiratoryparameter-values (respiratory frequency, tidal

volume, andminute ventilation) despite achieving larger de-

creases in serum bicarbonate and fewer days with metabolic

alkalosis. In addition, the acetazolamide group’s PaO2:FIO2

ratio was significantly increased, possibly via the drug’s

Table 2. Clinical Outcomes and Serious Adverse Eventsa

Variable

Group, Median (Interquartile Range)

Between-Group Difference(95% CI) P Value


Placebo(n = 193)

Primary Outcome

Duration of invasive ventilation, h 136.5 (68.7 to 234.7) 163 (86.2 to 242.9) −16.0 (−36.5 to 4.0) .17

Secondary Outcomesb

Daily

Serum bicarbonate change, mEq/L −0.3 (−1.0 to 0.4) 0.3 (−0.2 to 1.3) −0.8 (−1.2 to −0.5) <.001

PaCO2 change, mm Hg −0.5 (−2.0 to 0.8) −0.2 (−1.4 to 1) −0.3 (−0.8 to 0.2) .25

pH change 0 (−0.01 to 0.02) 0.01 (0 to 0.02) −0.01 (−0.01 to −0.0) .008

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) .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) 0.2 (−0.1 to –0.6) 0.0 (−0.2 to 0.2) .72

Weaning duration, h 18.7 (3.0 to 46.5) 22.0 (3.0 to 44.3) −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. (%) 187 (100) 192 (99.5) 0.05 (−0.05 to 1.5) .99

Use of noninvasive ventilation afterextubation, No. (%)

62 (33.1) 72 (37.3) –4.2 (–13.8 to 5.5) .39

Successful weaning, No. (%)c 118 (74.7) 127 (78.4) –3.7 (–13.1 to 5.6) .43

Unplanned extubation, median (range), d 0 (0 to 2) 0 (0 to 1) 0 (0 to 0) .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) –1 (–2 to 0) .61

Serious adverse events, No. (%)d 6 (0.03) 7 (0.04) –0.4 (–4.1 to 3.2) .82

Days receiving treatment

Loop diuretics 1 (0 to 4) 1 (0 to 4) 0 (0 to 0) .55

Systemic glucocorticoids 0 (0 to 3) 0 (0 to 4) 0 (0 to 0) .29

β2-Agonists 0 (0 to 4) 1 (0 to 6) 0 (0 to 0) .07

Catecholamines 1 (0 to 3) 1 (0 to 3) 0 (0 to 0) .98

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 testtreatment, median (range), d

0 (0 to 10) 0 (0 to 7) 0 (0 to 0) .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

Left ventricular ejection fractionat weaning, %f

55 (40 to 60) 50 (42 to 60) 0 (–5 to 5) .86

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).

SI conversion factor: To convert PaCO2 and PaO2 frommmHg to kPA,

multiply by 0.133.

a 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 themedian 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 weremeasured between 7 AM and 8 AMOther

laboratory-parameter changes are given in eTable 2 in Supplement 2.

c 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.

dAdverse 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.

eMetabolic alkalosis was defined as serum bicarbonate of more than 26mEql/L

and arterial pH of 7.35 or more.

f Left ventricular ejection fraction was assessed by transthoracic

echocardiography during the weaning period.










Figure 3. Subgroup Analyses of the Effect of Acetazolamide on the Duration of Invasive Ventilation

or Weaning

Favors

Placebo

Favors

Acetazolamide

1.0 3.00.5

Hazard Ratio (95% CI)

Acetazolamide

Group, No.

Events aSubgroup

Acute prolonged invasive ventilation, ≥96 h

Hazard Ratio

(95% CI)Patients

Placebo

Group, No.

Events a Patients

102 119 121 137Yes 1.06 (0.81−1.38)

57 68 45 56No 0.91 (0.61−1.37)

Pressure support ventilation >50% of the weaning period

62 66 83 87Yes 1.20 (0.86−1.68)

93 117 82 103No 1.15 (0.85−1.55)

Loop diuretics or corticosteroids

121 141 128 143Yes 1.11 (0.86−1.42)

34 42 37 47No 1.37 (0.84−2.23)

Pure metabolic alkalosis at baseline

55 59 48 50Yes 1.36 (0.91−2.03)

104 128 118 143No 1.11 (0.85−1.44)

166 187 159 193Overall 1.16 (0.93−1.44)

Duration of ventilationA

Favors

Placebo

Favors

Acetazolamide

1.0 3.00.5

Hazard Ratio (95% CI)

Acetazolamide

Group, No.

Events aSubgroup

Acute prolonged invasive ventilation, ≥96 h

Hazard Ratio

(95% CI)Patients

Placebo

Group, No.

Events a Patients

93 99 111 112Yes 0.98 (0.74−1.30)

50 51 42 43No 0.91 (0.59−1.41)

Pressure support ventilation >50% of the weaning period

59 62 82 83Yes 1.00 (0.71−1.40)

80 84 70 71No 1.12 (0.81−1.56)

Loop diuretics or corticosteroids

108 113 118 120Yes 1.00 (0.77−1.31)

31 33 34 34No 1.13 (0.69−1.86)

Pure metabolic alkalosis at baseline

51 53 45 45Yes 1.09 (0.72−1.64)

92 97 108 110No 1.02 (0.77−1.36)

143 150 153 155Overall 1.04 (0.83−1.31)

Duration of weaningB

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 weaningminus

discontinued hours.

a An event corresponds to the

termination of invasive mechanical

ventilation.

Figure 2. Kaplan-Meier Curves for the Cumulative Probabilities of BeingWeanedOff Invasive Ventilation

100

80

60

40

20

00

187

193

48

168

174

96

119

137

144

89

108

192

60

73

240

44

51

288

28

39

336

19

33

384

14

20

432

13

16

480

11

13

528

7

9

576

7

8

624

6

5

672

5

4

Cu

mu

lati

ve

Ve

nti

late

d,

%

Total Length of Invasive Mechanical Ventilation, h

No. at risk

Acetazolamide

Acetazolamide

Placebo

Placebo

HR, 1.14 (95% CI, 0.91-1.42); Log-rank P = .24

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.







diuretic effect5,20 or the increased oxygen saturation of

hemoglobin.8,11Taken together, these findings indicated that

the inhibitionof the renal carbonic anhydrase enzymeand the

resulting serum bicarbonate reduction did not trigger a suffi-

cient respiratory-stimulating effect to effect outcomesof criti-

cally ill patientswithCOPD.Nevertheless, this overall conclu-

sionmustbeconsideredwithprudence. Indeed, thestudymay

have identified a clinically important benefit of acetazol-

amide for theprimary endpoint that didnot demonstrate sta-

tistical significance because of a possible lack of power.

The between-group difference inmedian durations of in-

vasive mechanical ventilation was clinically substantial

(16 hours) although it did not the reach statistical signifi-

cance.Our trialwasprospectivelypowered todetect a 15%dif-

ference in the invasive ventilation duration, considered clini-

cally relevant in light of the usual duration of intubation in

these patients.5,21-23 However, the observed median dura-

tionsof invasivemechanical ventilation in theplaceboandac-

etazolamide groups were lower than anticipated for statisti-

cal power, complicating the study interpretation. Thismeans

that the 10% reduction of invasivemechanical ventilation by

acetazolamidecouldhave reachedstatistical significance if the

study was designed to detect such a difference. Similar pro-

portions of patients in the 2 groups did not develop meta-

bolic alkalosis or have transient treatment contraindications,

and intention-to-treat andper-protocol analyses findings con-

verged.Moreover, the decision to consider weaning duration

a secondary outcomewas basedon the fact thatweaningmay

be discontinuous,making it difficult tomeasure its total time

accurately. For the same reason, the test treatment was ad-

ministered from day 1 in case of metabolic alkalosis.

Pharmacological factors could contribute to the absence

of a stronger acetazolamide respiratory effect. First, inad-

equate dosing could limit the drug’s 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 case-

control study showed that the use of insufficient acetazol-

amide 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 bicar-

bonate but the corresponding respiratory effect was not

observed. Tissue compartmentalization of carbonic anhy-

drase isozymes and low acetazolamide selectivity might

explain why this drug had no benefit in terms of improving

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 find-

ings 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 per-

formed 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 meta-

bolic alkalosis in most patients. Indeed, the lack of acetazol-

amide 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 acet-

azolamide 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 analy-

sis 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 venti-

lation 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

Amongmechanically ventilatedpatientswithCOPDandpure

or mixed metabolic alkalosis, the use of effective acetazol-

amide doses, compared with placebo, did not result in a sta-

tistically significant reduction in the duration of invasiveme-

chanical ventilation.However, themagnitudeof thedifference

(16 hours) was clinically important, and it is possible that the

studywas underpowered to establish statistical significance.

ARTICLE INFORMATION

Author Affiliations: European Georges Pompidou

Hospital, Assistance Publique–Hôpitaux de Paris,

Paris, France (Faisy, Sanchez, Heming, Esvan,

Katsahian); Nouvel Hôpital Civil, Medical Intensive

Care Unit, Hôpitaux Universitaires de Strasbourg

and EA 7293, Fédération deMédecine

Translationnelle de Strasbourg, Strasbourg

University, Strasbourg, France (Meziani); André

Mignot Hospital, Medico-Surgical Intensive Care

Unit, Le Chesnay, France (Planquette); Limoges

University Hospital, Medical Intensive Care Unit,

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);

Pitié-Salpêtrière 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.






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

FrenchMinistry 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 themanuscript;

and decision to submit themanuscript for

publication.

Previous Presentation: Presented, in part, at the

annual meeting of Société de Réanimation de

Langue Française, 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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http://www.ncbi.nlm.nih.gov/pubmed/17507545




















































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R2:342:aFkcdqnqa"xgtukqp"4"fw"4412814233" " " "

SIGNATURE of a biomedical research PROTOCOL

By the COORDINATING INVESTIGATOR and a representative of the PROMOTER

Biomedical research study no. R2:342:

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:

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Ugtxkeg"fg"Tficpkocvkqp"ofifkecng"

J»rkvcn"Gwtqrfigp"Igqtigu"Rqorkfqw

Date : ……………/………/………..

Signature :

Promoter:

Ot"Ejtkuvqrjg"OKUUG"

Assistance publique – hôpitaux de Paris

Délégation Interégionale à la Recherche Clinique

Date : ……………/………/………..

Hôpital 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.

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9" VTGCVOGPVU"CFOKPKUVGTGF"0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000"47"903" Pcog"cpf"fguetkrvkqp"qh"vjg"vtgcvogpvu"00000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000"47"

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Cnn"fgenctcvkqpu"ocfg"d{"kpxguvkicvqtu"ujqwnf"kfgpvkh{"vjg"uwdlgev"rctvkekrcvkpi"kp"vjg"

uvwf{"d{"ogcpu"qh"vjg"wpkswg"eqfg"pwodgt"cvvtkdwvgf"vq"vjg"rcvkgpv"eqpegtpgf0"Kp"ecugu"qh"vjg"pqvkhkecvkqp"qh"vjg"fgcvj"qh"c"uwdlgev"rctvkekrcvkpi" kp" vjg"uvwf{."vjg"

kpxguvkicvqt" yknn" ugpf" vjg" rtqoqvgt" cnn" vjg" cffkvkqpcn" kphqtocvkqp" tgswguvgf" *jqurkvcn"tgrqtvu."cwvqru{"tguwnvu"gve0+0"

Cnn" pgy" hkpfkpiu" ctkukpi" fwtkpi" vjg" uvwf{" qt" kp" vjg" eqpvgzv" qh" vjg" uvwf{." htqo"rwdnkujgf"fcvc"qt"htqo"uvwfkgu"wpfgtyc{."ujqwnf"dg"tgrqtvgf"vq"vjg"rtqoqvgt0"

/"Fgenctcvkqp"qh"ugtkqwu"cfxgtug"gxgpvu"vq"vjg"jgcnvj"cwvjqtkvkgu""

Vjku" fgenctcvkqp"yknn" dg"ocfg" d{" vjg" Rjctoceqxkikncpeg"Wpkv" qh" vjg"Fgrctvogpv" qh"

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ecwucn" nkpm" ykvj" vjg" gzrgtkogpvcn" ftwi" cpf" cp{" qvjgt" vtgcvogpvu" cfokpkuvgtgf" cpf" vjg"

wpgzrgevgfpguu"qh"vjg"UCG"qdugtxgf0"


Cnn" uwurgevgf"wpgzrgevgf"UCGu"yknn"dg"fgenctgf" vq" vjg"eqorgvgpv"cwvjqtkvkgu"d{" vjg"

rtqoqvgt."ykvjkp"vjg"ngicn"vkog"nkokv0"

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c+" Cp{" enkpkecnn{" ukipkhkecpv" kpetgcug" kp" vjg" htgswgpe{" qh" cp" gzrgevgf" ugtkqwu"

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tgrqtvu="

e+" Cp{"pgy"hkpfkpiu"eqpegtpkpi"vjg"yc{"kp"yjkej"vjg"enkpkecn"vtkcn"ku"ecttkgf"qwv"

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/" C" ugtkqwu" cfxgtug" gxgpv" nkmgn{" vq" dg" nkpmgf" vq" vjg" kpxguvkicvkqpu" cpf" fkcipquvke"

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ecttkgf"qwv."

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f+" Cp{" wpgzrgevgf" ugtkqwu" cfxgtug" ghhgev" tgrqtvgf" vq" vjg" rtqoqvgt" d{" cpqvjgt"

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"

:06" Oqfg"cpf"fwtcvkqp"qh"hqnnqy/wr"hqt"vjg"kpfkxkfwcnu"eqpegtpgf"hqnnqykpi"vjg"qeewttgpeg"qh"cfxgtug"gxgpvu"

Cnn"rcvkgpvu"rtgugpvkpi"cp"cfxgtug"gxgpv"ujqwnf"dg"hqnnqygf"wr"wpvkn"vjg"tguqnwvkqp"qt"

uvcdknk¦cvkqp"qh"vjg"gxgpv"eqpegtpgf0"

‚"Kh"vjg"gxgpv"ku"pqv"ugtkqwu."kvu"rtqitguukqp"yknn"dg"tgrqtvgf"qp"vjg"eqttgurqpfkpi"rcig"

qh"vjg"qdugtxcvkqp"pqvgdqqm."kp"vjg"crrtqrtkcvg"ugevkqp0"

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Enkpkecn"Tgugctej"cpf"Fgxgnqrogpv0"


"

:070"Wpdnkpfkpi"rtqegfwtg"Cp" wpdnkpfkpi" rtqegfwtg" yknn" dg" korngogpvgf" kp" ecugu" qh" ugtkqwu" cfxgtug" gxgpvu"

*cpcrj{ncevke"ujqem."ctvgtkcn"j{rqvgpukqp"qt"cttj{vjokc"tghtcevqt{"vq"wuwcn"vtgcvogpvu"fwtkpi"

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cttj{vjokc+0"

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korgtcvkxgn{" hqnnqy" vjg" rtqegfwtg" hqt" fgenctkpi" ugtkqwu" cfxgtug" gxgpvu" vq" vjg" rtqoqvgt0"

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230660:60390230"

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ukipgf" d{" vjg" kpxguvkicvqt."owuv" dg" ugpv" d{" hcz0" Kpxguvkicvqtu" ctg" cnuq" cumgf" vq" eqpvcev" vjg"

uvtwevwtg"vq"yjkej"vjg"hcz"ku"ugpv0"

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dwv" kh" vjg" vguv"rtqfwev"ycu"cfokpkuvgtgf." tgkplgevkqp"qh" vjg"rtqfwev"owuv"dg"rtgxgpvgf+0" Kh"c"

fgekukqp"owuv"dg" vcmgp"cu" vq"yjgvjgt"qt"pqv" vjg"rcvkgpv" ujqwnf"jcxg"cpqvjgt" kplgevkqp." vjgp"

wpdnkpfkpi"ujqwnf"dg"tgswguvgf."dwv"vjku"yqwnf"pqv"dg"cp"gogtigpe{"rtqegfwtg"*vjg"kpvgtxcn"

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vjg"wpdnkpfkpi"fwtkpi"qhhkeg"jqwtu+0"

"

;" EQOOKVVGGU"URGEKHKE"VQ"VJKU"UVWF["

Uvggtkpi"Eqookvvgg"

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Wpkv"cuukipgf"vq"vjku"rtqlgev<"

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*Rkvkfi."Rpgwoq"Ogf+0"


/" Fgnrjkpg" Jqwtvqp." Enkpkecn" Uvwf{" Eqqtfkpcvqt" qh" vjg" Enkpkecn" Tgugctej" Wpkv" qh"

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uvwf{."rctvkewnctn{"cu"eqpegtpu"cfxgtug"gxgpvu0"

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"


32"UVCVKUVKEU"

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" Vjg"rtkpekrcn"cpcn{uku"yknn"dg"cp"kpvgpvkqp/vq/vtgcv"cpcn{uku"hqt"vjg"gpvktg"tcpfqok¦gf"

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"

3204" Pwodgt"qh"rctvkekrcpvu"vq"dg"kpenwfgf"kp"vjg"uvwf{"cpf"rncppgf"fgitgg"qh"uvcvkuvkecn"ukipkhkecpeg"

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"

33"TKIJV" QH" CEEGUU" VQ" FCVC" CPF" UQWTEG"FQEWOGPVU"

Kpfkxkfwcnu"ykvj"fktgev"ceeguu."kp"ceeqtfcpeg"ykvj"vjg"ngicn"cpf"tgiwncvqt{"fkurqukvkqpu"

ewttgpvn{" kp" hqteg." kpenwfkpi"ctvkengu"N03343/5"cpf"T07343/35"qh" vjg"Rwdnke"Jgcnvj"Eqfg." kp"

rctvkewnct" *g0i0" kpxguvkicvqtu." swcnkv{" eqpvtqn" cigpvu." oqpkvqtu." enkpkecn" tgugctej" cuukuvcpvu."

cwfkvqtu"cpf"cp{qpg"cumgf"vq"eqnncdqtcvg"kp"vjg"vtkcn+."yknn"vcmg"cnn"vjg"pgeguuct{"rtgecwvkqpu"vq"

gpuwtg" vjg" eqphkfgpvkcnkv{" qh" kphqtocvkqp" tgncvkpi" vq" vjg" gzrgtkogpvcn" ftwiu." vjg" vtkcn." vjg"

rgqrng" vcmkpi" rctv" kp" vjg" uvwf{" *rctvkewnctn{" cu" eqpegtpu" vjgkt" kfgpvkv{+" cpf" vjg" tguwnvu"

qdvckpgf0" Vjg" fcvc" eqnngevgf" d{" vjgug" kpfkxkfwcnu" fwtkpi" swcnkv{" eqpvtqn" cpf" cwfkvu"yknn" dg"

tgpfgtgf"cpqp{oqwu0"

"


34"SWCNKV["EQPVTQN"CPF"CUUWTCPEG"

Vjg"uvwf{"yknn"dg"ecttkgf"qwv"kp"vjg"htcogyqtm"qh"vjg"uvcpfctf"qrgtcvkpi"rtqegfwtgu"qh"

vjg" rtqoqvgt0" Vjg" tgugctej" yknn" dg" ecttkgf" qwv" cpf" uwdlgevu" yknn" dg" ocpcigf." cv" vjg"

rctvkekrcvkpi"egpvgtu."kp"ceeqtfcpeg"ykvj"vjg"Jgnukpmk"Fgenctcvkqp"cpf"iqqf"enkpkecn"rtcevkeg0"

"

3403" Oqpkvqtkpi"rtqegfwtgu"

Gxcnwcvgf"tkum"ngxgn"qh"vjg"uvwf{<"E"

Vjg"enkpkecn" tgugctej"cuukuvcpvu"tgrtgugpvkpi" vjg"rtqoqvgt"yknn"xkukv" vjg" kpxguvkicvkpi"

egpvgtu"cv"vkogu"fgvgtokpgf"d{"vjg"uejgfwngf"hqnnqy/wr"qh"rcvkgpvu"kp"vjg"rtqvqeqn."kpenwukqpu"

cv"vjg"xctkqwu"egpvgtu"cpf"vjg"tkum"ngxgn"qh"E"cvvtkdwvgf"vq"vjku"uvwf{0"

/" Qrgpkpi" xkukv" hqt" gcej" egpvgt" *kpxguvkicvqt" cpf" rjctocekuv+<" dghqtg" kpenwukqp." hqt"

guvcdnkujogpv" qh" vjg" rtqvqeqn" cpf" vq" oggv" vjg" xctkqwu" rgqrng" kpxqnxgf" kp" vjg" dkqogfkecn"

tgugctej"uvwf{0"

/"Fwtkpi"uwdugswgpv"xkukvu."vjg"qdugtxcvkqp"pqvgdqqmu"yknn"dg"gzcokpgf"d{"vjg"enkpkecn"

tgugctej"cuukuvcpv."ykvj"vjg"rtqitguukqp"qh" vjg"tgugctej0"Vjg"RK"cv"gcej"egpvgt"cpf"vjg"qvjgt"

kpxguvkicvqtu"kpenwfkpi"qt"hqnnqykpi"wr"vjg"rcvkgpvu"rctvkekrcvkpi"kp"vjg"uvwf{"citgg"vq"tgiwnct"

xkukvu"htqo"vjg"enkpkecn"tgugctej"cuukuvcpv0"

Fwtkpi"vjgug"ukvg"xkukvu."vjg"hqnnqykpi"gngogpvu"yknn"dg"tgxkgygf."kp"ceeqtfcpeg"ykvj"

iqqf"enkpkecn"rtcevkeg<"

‚" Tgurgev"qh"vjg"rtqvqeqn"cpf"vjg"rtqegfwtgu"fghkpgf"hqt"vjg"uvwf{0"

‚" Kphqtogf"eqpugpv"htqo"vjg"rcvkgpvu0"

‚" Vjg"uqwteg"fqewogpvu."eqorctkpi"vjgo"ykvj"vjg"fcvc"tgrqtvgf"kp"vjg"qdugtxcvkqp"

pqvgdqqm." vq" xgtkh{" vjgkt" gzcevpguu" cpf" vq" ejgem" hqt" okuukpi" fcvc." cpf" fcvc"

eqpukuvgpe{."kp"ceeqtfcpeg"ykvj"vjg"rtqegfwtgu"nckf"fqyp"d{"FTEF"twngu0"

/"Enqukpi" xkukv<" tgeqxgt{" qh" vjg" qdugtxcvkqp" pqvgdqqmu." vjg" rjctoce{" gxcnwcvkqp" cpf"

dkqogfkecn"tgugctej"fqewogpvu."ctejkxkpi0"

"

3404" Vtcpuetkrvkqp"qh"fcvc"kp"vjg"qdugtxcvkqp"pqvgdqqm""

Cnn" vjg" kphqtocvkqp" tgswktgf" d{" vjg" rtqvqeqn" owuv" dg" rtqxkfgf" kp" vjg" qdugtxcvkqp"

pqvgdqqm"cpf"vjg"kpxguvkicvqt"owuv"rtqxkfg"cp"gzrncpcvkqp"hqt"cp{"okuukpi"fcvc0""


Vjg" fcvc" ujqwnf" dg" vtcpuhgttgf" vq" vjg" qdugtxcvkqp" pqvgdqqmu" cu" vjg{" ctg" qdvckpgf."

yjgvjgt" vjg{" ctg" enkpkecn" qt" rctcenkpkecn" kp" pcvwtg0" Vjg" fcvc" ujqwnf" dg" eqrkgf" kpvq" vjgug"

pqvgdqqmu"engctn{"cpf"ngikdn{."kp"dncem"kpm"*vq"hceknkvcvg"fwrnkecvkqp"cpf"eqorwvgt"gpvt{+0""

Cp{"gttqpgqwu"fcvc"kfgpvkhkgf"kp"vjg"qdugtxcvkqp"pqvgdqqmu"yknn"dg"engctn{"etquugf"qwv"

cpf"vjg"pgy"fcvc"yknn"dg"eqrkgf"kpvq"vjg"pqvgdqqm."ykvj"vjg"fcvg"qh"vjg"ejcpig"cpf"vjg"kpkvkcnu"

qh"vjg"ogodgt"qh"vjg"kpxguvkicvkpi"vgco"ocmkpi"vjg"eqttgevkqp0"

Vjg"cpqp{okv{"qh"vjg"uwdlgevu"kp"uvwf{"fqewogpvcvkqp"yknn"dg"gpuwtgf"d{"vjg"wug"qh"c"

eqfg" pwodgt" cpf" vjg" kpkvkcnu" qh" vjg" rgtuqp" vcmkpi" rctv" kp" vjg" uvwf{" octmgf" qp" cnn" vjg"

fqewogpvu"tgswktgf"hqt"vjg"uvwf{."ykvj"crrtqrtkcvg"ogcpu"wugf"vq"gtcug"pqokpcvkxg"fcvc"htqo"

eqrkgu"qh"vjg"uqwteg"fqewogpvu0"

"Eqorwvgtk¦gf" fcvc" yknn" dg" kpenwfgf" kp" c" hkng." yjkej" yknn" dg" fgenctgf" vq" vjg" EPKN"

ceeqtfkpi"vq"vjg"crrtqrtkcvg"rtqegfwtg0"

"

35"NGICN"CPF"GVJKECN"EQPUKFGTCVKQPU""

Vjg"rtqoqvgt"ku"fghkpgf"ceeqtfkpi"vq"ncy"4226/:28"htqo"Cwiwuv";"42260"Kp"vjku"uvwf{."

CR/JR"ku"vjg"rtqoqvgt"cpf"vjg"Fgrctvogpv"qh"Enkpkecn"Tgugctej"cpf"Fgxgnqrogpv"*FTET+"ku"

tgurqpukdng"hqt"tgiwncvqt{"chhcktu0"

Dghqtg" vjg" uvctv" qh" vjg" uvwf{." gcej" kpxguvkicvqt" yknn" rtqxkfg" vjg" rtqoqvgtÓu"

tgrtgugpvcvkxg" ykvj" c" fcvgf" cpf" ukipgf" rgtuqpcn" ewttkewnwo" xkvcg" dgctkpi" jku" qt" jgt"

tgikuvtcvkqp"pwodgt"ykvj"vjg"Htgpej"Ogfkecn"Eqnngig0"

"

3503" Tgswguv"hqt"cwvjqtk¦cvkqp"htqo"CHUUCRU"

CR/JR."cu" vjg"rtqoqvgt"qh" vjku"uvwf{."owuv"uwdokv"c"tgswguv" hqt" vjg"cwvjqtk¦cvkqp"qh"

vjku" uvwf{" vq" vjg" eqorgvgpv" cwvjqtkv{." CHUUCRU0" Vjg" eqorgvgpv" cwvjqtkv{." cu" fghkpgf" kp"

ctvkeng"N0"3345/34."yknn"kuuwg"kvu"qrkpkqp"eqpegtpkpi"vjg"uchgv{"qh"vjg"rgqrng"vcmkpi"rctv"kp"vjg"

dkqogfkecn" tgugctej" uvwf{." vcmkpi" kpvq" ceeqwpv." kp" rctvkewnct." vjg" uchgv{" cpf" swcnkv{" qh" vjg"

rtqfwevu" wugf" kp" vjg" uvwf{" kp" ceeqtfcpeg." cu" crrtqrtkcvg." ykvj" ewttgpv" iwkfgnkpgu." vjgkt"

eqpfkvkqpu"qh"wug"cpf"vjg"uchgv{"qh"vjg"rctvkekrcpvu"ykvj"tgurgev"vq"vjg"cevu"rtcevkegf"cpf"vjg"

ogvjqfu"wugf."vqigvjgt"ykvj"vjg"rncppgf"oqfg"qh"hqnnqy/wr"qh"vjg"rctvkekrcpvu0"

"


3504" Tgswguv"hqt"cwvjqtk¦cvkqp"htqo"vjg"gvjkeu"eqookvvgg"

Kp"ceeqtfcpeg"ykvj"ctvkeng"N03345/8"qh" vjg"Htgpej"Rwdnke"Jgcnvj"Eqfg." vjg"rtqoqvgt"

owuv"uwdokv"vjg"tgugctej"rtqvqeqn"vq"vjg"crrtqrtkcvg"gvjkeu"eqookvvgg"*Comité de Protection

des Personnes+0"Vjg"eqorgvgpv"cwvjqtkv{"ku"kphqtogf"qh"vjg"fgekukqp"qh"vjku"eqookvvgg"d{"vjg"

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" rtqoqvgtÓu" 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"


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"


/"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"


"

37"KPUWTCPEG"CPF"UEKGPVKHKE"EQOOKVOGPV

3703" Kpuwtcpeg"

Assistance Publique-Hôpitaux 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"

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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"

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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"

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32/" Ygduvgt" PT." Mwnmctpk" X0" Ogvcdqnke" cnmcnquku" kp" vjg" etkvkecnn{" knn0" Etkv" Tgx" Ncd" uek"

3;;;=58"*7+<6;9/732"

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Uqwvj"Ogf"L"3;9;=94<9:8"

34/"Ejgxtqngv"LE0"Rgtvwtdcvkqpu"fg"nÓfiswknkdtg"cekfg/dcug0"Gpe{enqrfifkg"Ofifkeq/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"


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{enqrfifkg" Ofifkeq/

ejktwtikecng"Rpgwoqnqikg."8/285/C/32"

47/"Uygpuqp"GT."Octgp"VJ0"C"swcpvkvcvkxg"cpcn{uku"qh"EQ4" vtcpurqtv" cv" tguv" cpf"oczkocn"

gzgtekug0"Tgur"Rj{ukqn"3;9:=57<34;/37;"

48/"Oqxkcv"O." Rkemmgtu" R" gv" cn0"Cegvc¦qncokfg/ogfkcvgf" fgetgcug" kp" uvtqpi" kqp" fkhhgtgpeg"

ceeqwpvu" hqt" vjg" eqttgevkqp" qh" ogvcdqnke" cnmcnquku" kp" etkvkecnn{" knn" rcvkgpvu0" Etkv" Ectg"

4228=32<3/8"

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cegvc¦qncokfg" cpf" qz{igp" kp" cycmg" cpf" cunggr" icu" gzejcpig" kp" rcvkgpvu" qh" ejtqpke"

qduvtwevkxg"rwnopct{"fkugcug"*EQRF+0"Gwt"Tgur"L"3;;6=9<:72/:77""

4:/"Vgrrgoc"N."Fcjcp"C0"Cegvc¦qncokfg"cpf"dtgcvjkpi0"Fqgu"c"enkpkecn"fqug"cnvgt"rgtkrjgtcn"cpf"egpvtcn"EQ4"ugpukvkxkv{A"Co"L"Tgur"Etkv"Ectg"Ogf"3;;;=382=37;4/37;9"

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Tgur"Fku"3;:5=349<627/634"


52/"Oc¦wt" LG." Fgxnkp" LY." Rgvgtu"OL." Lcpmqyumk"OC." Kcppw¦¦k"OE." ¥ctqykv¦" DL0" Ukping"

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tcpfqokugf"fqwpng/dnkpf"vtkcn0"Etkv"ectg"ogf"3;;;=49<3479/3483"

53/"Eqicp"OI."Ocffqz" FC."Yctpqem" FI" gv" cn0" Ghhgev" qh" cegvc¦qncokfg" qp" dkectdqpcvg"

tgcduqtrvkqp"kp"vjg"rtqzkocn"vwdwng"qh"vjg"tcv0"Co"L"Rj{ukqn"3;9;=459<H669/H676"

54/"Nweek"OU."Yctpqem"FI."Tgevqt"HI"Lt"gv"cn0"Ectdqpke"cpj{ftcug/fgrgpfcpv"dkectdqpcvg"

tgcduqtrvkqp"kp"vjg"tcv"rtqzkocn"vwdwng0"Co"L"Rj{ukqn"3;9;=458<H7:/H87"

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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.

1

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 Boisramé-Helms (Nouvel Hôpital Civil and EA 7293, Fédération de Médecine

Translationnelle de Strasbourg, Strasbourg University, Strasbourg); Benjamin Zuber, Gilles Troché, Stéphane

Legriel, Fabrice Brunel, Pierre Guezennec, Virginie Laurent, Julia Hilly-Ginoux, Mathieu Henry-Lagarrigue

(André Mignot Hospital, Le Chesnay); Philippe Vignon, Nicolas Pichon, Bruno François, 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); Hélène Prodanovic, Mathieu Schmidt, Julien

Mayaux, Julie Delemazure, Romain Persichini (Pitié-Salpêtrière University Hospital, Paris); Marie Conrad,

Damien Barraud, Alexandre Lai, Jérémie Lemarie, Lionel Nace, Aurélie 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); Cédric Rafat, Clément Leclaire, Jonathan

Messika, Nicolas Dufour, Sylvain Jean-Baptiste, Romain Miguel Montanes, Stéphane Gaudry (Louis-Mourier

University Hospital, Colombes); Muriel Fartoukh, Vincent Labbe, Antoine Parrot (Tenon University Hospital,

Paris); Pascal Fangio, Hervé Outin, Christophe Barbier, Bernard De Jonghe, Jan Hayon, Yann Loubieres

(Poissy-Saint Germain Hospital, Poissy); Aurélie 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 µmol/L) and serum

aspartate aminotransferase >500 U/L, prothrombin ratio <50%, and clinical signs and symptoms of hepatic

2

coma;

Renal insufficiency with serum creatinine >2.83 mg/dL (250 ȝmol/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 <38.5°C;

Hemodynamic stability (no vasoconstrictors, heart rate <120/minute, systolic arterial blood pressure 90–160 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%

3

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 く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,

く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, ventilator-

associated 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

4

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.

5

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.

aAn event corresponds to the termination of invasive mechanical ventilation.

6

eTable 1. Per-Protocol Analysis: Clinical Outcomes and Serious Adverse Eventsa

Variable

Acetazolamide Group

(n = 131)

Placebo Group

(n = 149)

Between-Group Difference

(95% CI)

P Value

Primary outcome: duration of invasive ventilation, median (IQR), h 166.5 (92.7-258.2) 183.7 (108.1-279.5) 15.8 (48.6-8.5) .36

Secondary outcomesb

Daily serum bicarbonate change, median (IQR), mEq/L �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

Daily tidal volume change, median (IQR), mL 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

7

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

Duration of ICU stay, median (IQR), d 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 く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,

median (range)

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

8

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 (0�0). 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 laboratory-

parameter 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 alkalosis was defined as serum bicarbonate >26 mEql/L and arterial pH ≥7.35.

fLeft ventricular ejection fraction was assessed by transthoracic echocardiography during the weaning period.

9

eTable 2. Intention-to-Treat Analysis: Study Laboratory Parametersa and Causes of Weaning Failure

Variable

Acetazolamide Group

(n = 187)

Placebo Group

(n = 193)

Between-Group Differenceb

(95% CI)

P Value

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), /µL �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

Causes of weaning failure, No. (%)

Pneumonia 5 (2.7) 1 (0.5) 2.2 (�0.4-4.7) .09

Left ventricular insufficiency 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

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.

10

bBetween-group differences for quantitative variables are expressed as medians with the 95% CI around the median difference.

11

eTable 3: Per-protocol analysis: Study laboratory parametersa and causes of weaning failure

Variable

Acetazolamide Group

(n = 131)

Placebo Group

(n = 149)

Between-Group Differenceb

(95% CI)

P Value

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), /µL �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

Serum ASAT change, median (IQR), U/L �0.3 (�6.5-5.5) 0 (�7-6) 0.5 (4.6-3.8) .78

Causes of weaning failure, No. (%)

Pneumonia 5 (3.8) 1 (0.7) 3.1 (�0.4-6.7) .09

Left ventricular insufficiency 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

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.

12

bBetween-group differences for quantitative variables are expressed as medians with the 95% CI around the median difference.

D1

to D

28

D0

Acetazolamide Placebo

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

(Before 24 hours of invasive ventilation)

Daily evaluation from randomization onwards: Serum bicarbonate >26 mmol/liter

Arterial blood pH ≥≥≥≥7.35 ?

Daily evaluation of weaning criteria, as of randomization Test of weaning suitability if weaning criteria present:

YES

YES Temporary acetazolamide contraindication?

NO

Acetazolamide or placebo

Temporary withdrawal

NO

NO

NO

Invasive ventilation >28

days?

YES

YES End of protocol

Successful weaning test? Resumption of usual

ventilation method for patients

Possible tracheotomy during weaning off invasive ventilation

eFigure 1

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eFigure 2

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148 102 43 24 13 7129 87 38 15 10 6

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148 104 45 24 13 7130 87 38 16 11 6

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Acetazolamide

eFigure 3

Subgroup

Overall

Acute Prolonged Invasive Ventilation hours)

Yes

No

Pressure Support Ventilation >50% the Weaning Period

Yes

No

Loops Diuretics and/or Corticosteroids

Yes

No

Pure Metabolic Alkalosis at Baseline

Yes

No

Eventsa, n

117

84

33

50

67

101

16

51

66

Patients, n

131

95

36

53

78

113

18

52

79

Eventsa, n

137

112

25

64

73

111

26

43

94

Patients, n

149

123

26

67

82

122

27

44

105

1.09 (0.85−1.40)

0.98 (0.74−1.30)

0.66 (0.38−1.14)

1.27 (0.87−1.85)

1.01 (0.72−1.41)

1.14 (0.87−1.49)

1.04 (0.53−2.10)

1.59 (1.04−2.42)

0.91 (0.66−1.24)

0.5 1.0 1.5 2.0 2.5

Placebo better

Acetazolamide better

Hazard Ratio (95% CI)Acetazolamide Group Placebo Group

( ≥ 96

eFigure 4A

Subgroup

Overall

Acute Prolonged Invasive Ventilation hours)

Yes

No

Pressure Support Ventilation >50% the Weaning Period

Yes

No

Loops Diuretics and/or Corticosteroids

Yes

No

Pure Metabolic Alkalosis at Baseline

Yes

No

Eventsa, n

105

76

29

47

58

90

15

47

58

Patients, n

110

81

29

49

61

94

16

47

63

Eventsa, n

127

103

24

63

64

103

24

40

87

Patients, n

129

104

25

64

65

105

24

40

89

0.98 (0.75−1.27)

0.90 (0.66−1.21)

0.77 (0.43−1.39)

1.02 (0.70−1.50)

1.01 (0.70−1.45)

1.01 (0.76−1.34)

0.87 (0.45−1.66)

1.21 (0.79−1.85)

0.84 (060−1.19)

0.5 1.0 1.5 2.0 2.5

Placebo better

Acetazolamide better

Hazard Ratio (95% CI)Acetazolamide Group Placebo Group

( ≥ 96

eFigure 4B

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