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Transcript of 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
Section Editor:Derek C. Angus, MD,
MPH, Associate Editor, JAMA
Research
Original Investigation | CARING FORTHE CRITICALLY ILL PATIENT
480 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Copyright 2016 American Medical Association. All rights reserved.
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
Copyright 2016 American Medical Association. All rights reserved.
Copyright 2016 American Medical Association. All rights reserved.
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
Copyright 2016 American Medical Association. All rights reserved.
Copyright 2016 American Medical Association. All rights reserved.
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 and Duration of Invasive Mechanical Ventilation Original Investigation Research
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Copyright 2016 American Medical Association. All rights reserved.
Copyright 2016 American Medical Association. All rights reserved.
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)
Acetazolamide(n = 187)
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%.
Research Original Investigation Acetazolamide and Duration of Invasive Mechanical Ventilation
484 JAMA February 2, 2016 Volume 315, Number 5 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Copyright 2016 American Medical Association. All rights reserved.
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
Acetazolamide(n = 187)
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.
Acetazolamide and Duration of Invasive Mechanical Ventilation Original Investigation Research
jama.com (Reprinted) JAMA February 2, 2016 Volume 315, Number 5 485
Copyright 2016 American Medical Association. All rights reserved.
Copyright 2016 American Medical Association. All rights reserved.
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.
Research Original Investigation Acetazolamide and Duration of Invasive Mechanical Ventilation
486 JAMA February 2, 2016 Volume 315, Number 5 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Copyright 2016 American Medical Association. All rights reserved.
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.
Acetazolamide and Duration of Invasive Mechanical Ventilation Original Investigation Research
jama.com (Reprinted) JAMA February 2, 2016 Volume 315, Number 5 487
Copyright 2016 American Medical Association. All rights reserved.
Copyright 2016 American Medical Association. All rights reserved.
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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Research Original Investigation Acetazolamide and Duration of Invasive Mechanical Ventilation
488 JAMA February 2, 2016 Volume 315, Number 5 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
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
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:
Fqevqt"Ejtkuvqrjg"Hcku{"
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.
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 5182" " "
EQPVGPVU"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 6182" " "
:070" Wpdnkpfkpi"rtqegfwtg"000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000"55";" EQOOKVVGGU"URGEKHKE"VQ"VJKU"UVWF["00000000000000000000000000000000000000000000000000000000000000000000000000000000000000"55"32" UVCVKUVKEU"000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000"57"3203" Fguetkrvkqp"qh"vjg"uvcvkuvkecn"ogvjqfu"vq"dg"wugf."kpenwfkpi"c"vkogvcdng"hqt"vjg"uejgfwngf"kpvgtogfkcvg"cpcn{ugu00"00000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000"57"3204" Pwodgt"qh"rctvkekrcpvu"vq"dg"kpenwfgf"kp"vjg"uvwf{"cpf"rncppgf"fgitgg"qh"uvcvkuvkecn"ukipkhkecpeg"000"57"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 7182" " "
NKUV"QH"CDDTGXKCVKQPU"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 8182" " "
UWOOCT["
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vjg" uvwfkgu" qh" Uygpuqp" ]45_" cpf" Vgrrgoc" ]4:_" ujqygf" vjcv" cegvc¦qncokfg" kpetgcugf"
tgurktcvqt{" okpwvg" xgpvkncvkqp" d{" fgetgcukpi" vjg" dcug" gzeguu0" Jqygxgt." kv" jcu" cnuq" dggp"
tgrqtvgf" vjcv" rcvkgpvu" pqv" tgurqpfkpi" vq" cegvc¦qncokfg" vtgcvogpv" *fgetgcug" kp" RcEQ4" >" 209"
mRc+" fkurnc{" oqtg" ugxgtg" dtqpejkcn" qduvtwevkqp" *HGX3" 46'" qh" vjg" rtgfkevgf" xcnwg+" vjcp"
rcvkgpvu"tgurqpfkpi"vq"vtgcvogpv"*HGX3"64"'"qh"vjg"rtgfkevgf"xcnwg+"]4;_."dwv"vjg"eqttgncvkqp"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 33182" " "
dgvyggp" HGX3" cpf" vjg" uvtgpivj" qh" vjg" tgurqpug" vq" cegvc¦qncokfg" jcu" pqv" dggp" engctn{"
guvcdnkujgf0"Qpg"tcpfqok¦gf"ownvkegpvgt"uvwf{"kpkvkcvgf"kp"4224"kp"Pqtyc{"ckogf"vq"gxcnwcvg"
vjg" dgpghkvu" qh" qtcnn{" cfokpkuvgtgf" cegvc¦qncokfg" fwtkpi" tgurktcvqt{" fgeqorgpucvkqp" kp"
EQRF" rcvkgpvu" tgswktkpi" jqurkvcnk¦cvkqp." dwv" vjg" tguwnvu" qh" vjku" uvwf{" *rctvkewnctn{" vjqug"
eqpegtpkpi" vjg" ghhgev" qh" cegvc¦qncokfg" qp" vjg" pggf" hqt" kpvwdcvkqp" cpf" kpxcukxg" tgurktcvqt{"
cuukuvcpeg+"ctg"pqv"{gv"cxckncdng"*jvvr<11enkpkecnvtkcnu0iqx1ev41ujqy1PEV22444756+0"
"
305" Fguetkrvkqp"cpf"lwuvkhkecvkqp"qh"vjg"tqwvg"qh"cfokpkuvtcvkqp."fqug."fqug"uejgfwng"cpf"fwtcvkqp"qh"vtgcvogpv"
Oc¦wt"et al." ]52_" gxcnwcvgf" vjg" ghhgevu" qh" vyq" fqug" uejgfwngu" hqt" cegvc¦qncokfg" *c"
ukping"fqug"qh"722"oi1fc{"xgtuwu"hqwt"fqugu"qh"472"oi1fc{+"qp"ejcpigu"kp"dkectdqpcvg"ngxgnu"
kp"5:"kpvwdcvgf"cpf"xgpvkncvgf"EQRF"rcvkgpvu"ykvj"ogvcdqnke"cnmcnquku"kp"kpvgpukxg"ectg."qxgt"
c"rgtkqf"qh"94"jqwtu0"C"uwuvckpgf."ukipkhkecpv"fgetgcug"kp"dkectdqpcvg"ngxgnu"ycu"tgrqtvgf"hqt"
dqvj" vjgug" cegvc¦qncokfg" tgikogpu0" Vjku" uwiiguvu" vjcv" vjg" fwtcvkqp" qh" vjg" rjctoceqnqikecn"
ghhgev" qh" cegvc¦qncokfg" gzeggfu" kvu" jcnh/nkhg" kp" vjg" rncuoc" *7" jqwtu+0" Kpfggf." fwtkpi"
cegvc¦qncokfg"cfokpkuvtcvkqp."52'"qh"vjg"hknvgtgf"dkectdqpcvgu"ctg"gnkokpcvgf"kp"vjg"wtkpg."cpf"
vjg"vtcpugrkvjgnkcn"vtcpurqtv"qh"dkectdqpcvgu"fgetgcugu"d{"92"vq"322'"]53."54_0"Cpqvjgt"uvwf{"
]55_." kp"uwtikecn" kpvgpukxg"ectg"wpkv."gxcnwcvgf" vjg"ghhgev"qh"cegvc¦qncokfg"cfokpkuvgtgf"cv"c"
fqug" qh" 722" oi1fc{" cpf" tgrqtvgf" ukoknct" tguwnvu0" Kp" c" tcpfqok¦gf." fqwdng/dnkpf" vtkcn."
cegvc¦qncokfg" cfokpkuvgtgf" vykeg" fckn{." cv" c" fqug" qh" 472"oi" *4"'" 472"oi1fc{+." kortqxgf"
RcQ4" kp"j{rqzgoke"EQRF"rcvkgpvu"ykvj"ogvcdqnke"cnmcnquku." kp" vjg"ujqtv" vgto"*dgvyggp"F5"
cpf"F8+"]56_0"Fgurkvg"vjg"htgswgpv"wug"qh"cegvc¦qncokfg"kp"ecugu"qh"ogvcdqnke"cnmcnquku"cpf"kp"
vjg"cdugpeg"qh"cuuqekcvgf"ogvcdqnke"rtqdngou."hgy"uvwfkgu"jcxg"eqpukfgtgf"vjg"tgeqoogpfgf"
fqug0"Uqog"]52."55_"tgeqoogpf"c"ukping"fqug"qh"472"vq"722"oi1fc{."yjgtgcu"qvjgtu"]43."57_"
tgeqoogpf"ownvkrng"fqugu"qh"472"vq"722"oi"cfokpkuvgtgf"cv"ukz/"vq"gkijv/jqwt"kpvgtxcnu0"Kp"
vjg" Gpinkuj/urgcmkpi" yqtnf" ]58." 59_." ownvkrng" fqugu" qh" cegvc¦qncokfg" ctg" igpgtcnn{"
tgeqoogpfgf" hqt" vjg" eqttgevkqp" qh" ogvcdqnke" cnmcnquku0" Yg" tgegpvn{" rwdnkujgf" c" uvwf{"
ujqykpi" vjcv" cegvc¦qncokfg" cfokpkuvgtgf" cv" c" fqug" qh" 722"oi1fc{" vq" EQRF" rcvkgpvu" ykvj"
ogvcdqnke"cnmcnquku"yjkng"vjg{"ygtg"dgkpi"ygcpgf"qhh"qh"ogejcpkecn"xgpvkncvkqp"ukipkhkecpvn{"
fgetgcugf" dkectdqpcvg" ngxgnu" cpf" kpetgcugf" vjg"RcQ41HkQ4" tcvkq"ykvjqwv" chhgevkpi"RcEQ4" qt"
tgurktcvqt{"rctcogvgtu"uwej"cu"tgurktcvqt{"okpwvg"xgpvkncvkqp"qt"tgurktcvqt{"tcvg"]5:_0"Yg"cnuq"
qdugtxgf"c"urqpvcpgqwu"fgetgcug"kp"dkectdqpcvg"ngxgnu"kp"vjg"eqpvtqn"itqwr."tguwnvkpi"kp"vjgtg"
dgkpi"pq"fkhhgtgpeg"kp"vgtou"qh"vjg"fgetgcug"kp"dkectdqpcvg"ngxgnu"dgvyggp"vjg"eqpvtqn"itqwr"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 34182" " "
cpf" vjg" itqwr" qh" rcvkgpvu" vtgcvgf" ykvj" 722" oi" cegvc¦qncokfg1fc{0" Vjku" hkpfkpi" tckugu"
swguvkqpu"cdqwv"vjg"ghhkece{"qh"722"oi1fc{"cegvc¦qncokfg"hqt"fgetgcukpi"dkectdqpcvg"ngxgnu"vq"
cp{"itgcv"gzvgpv" kp"rcvkgpvu0"Vjg" uvcvkuvkecnn{" ukipkhkecpv"dwv"enkpkecnn{" kttgngxcpv"fgetgcug" kp"
dkectdqpcvg"eqpegpvtcvkqp"*>"6"ooqn1N+"kp"vjg"vtgcvgf"rcvkgpvu"kp"vjku"uvwf{"oc{"ceeqwpv"hqt"
vjg" cdugpeg" qh" cp" ghhgev" qp" RcEQ4" cpf" tgurktcvqt{" rctcogvgtu0" Hwtvjgtoqtg." pq"
rjctoceqf{pcokeu"tguwnvu"ctg"cxckncdng"fguetkdkpi"vjg"ghhgev"qh"cegvc¦qncokfg"qp"dkectdqpcvg"
ngxgnu" kp" EQRF" rcvkgpvu" qp" ogejcpkecn" xgpvkncvkqp0" Yg" vjgtghqtg" ecttkgf" qwv" cpqvjgt"
rtgnkokpct{"uvwf{"dcugf"qp"vjg"cpcn{uku"qh"vjg"ogfkecn"fquukgtu"qh"728"EQRF"rcvkgpvu"vtgcvgf"
d{" kpxcukxg" xgpvkncvkqp"ogvjqfu."ykvj" vjg" cko" qh" kfgpvkh{kpi" hcevqtu" nkmgn{" vq" kphnwgpeg" vjg"
rjctoceqf{pcokeu"qh"cegvc¦qncokfg"kp"kpvwdcvgf"cpf"ogejcpkecnn{"xgpvkncvgf"EQRF"rcvkgpvu"
*Crrgpfkz" 4+0" Kp" vjku" ugeqpf" rtgnkokpct{" uvwf{." yg" oqfgngf" vjg" rjctoceqf{pcokeu" qh"cegvc¦qncokfg"kp"vjku"ukvwcvkqp<"vjg"rjctoceqf{pcokeu"oqfgn"kpfkecvgf"vjcv"kp"ecugu"qh"jkij"
ejnqtgokc" *@332" ooqn1N+." qtcn" eqtvkequvgtqkf" rtguetkrvkqp" cpf." rctvkewnctn{." hwtqugokfg"
eqrtguetkrvkqp" *ghhgev"qp" vjg"eqpuvcpv"qh" gnkokpcvkqp"mqwv" qh" vjg"oqfgn+." nctigt"wpkv"fqugu"qh"
cegvc¦qncokfg"ygtg" tgswktgf" vq"qdvckp" cp" ghhgevkxg"fgetgcug" kp"dkectdqpcvg" ngxgnu" kp"EQRF"
rcvkgpvu"ykvj"ogvcdqnke"cnmcnquku0"Vjg"cevkqp"qh"hwtqugokfg"*ghhgev"qp"mqwv+"ycu"vjg"hcevqt"ykvj"
vjg" uvtqpiguv" kphnwgpeg" qp" cegvc¦qncokfg" rjctoceqf{pcokeu0" Vjg" rtguetkrvkqp" qh" qtcn"
eqtvkequvgtqkfu" ku" tctg" kp" vjku" eqpvgzv" *cu" kpfggf" ku" ejnqtgokc" @332" ooqn1N+0" Qwt" hktuv"
rtgnkokpct{" uvwf{" ]5:_" cnuq" tgxgcngf" vjcv" oqtg" vjcp" 62'" qh" vjg" ogejcpkecnn{" xgpvkncvgf"
EQRF"rcvkgpvu"jcf"dggp"rtguetkdgf"hwtqugokfg."rctvkewnctn{"fwtkpi"vjg"rgtkqf"qh"ygcpkpi"qhh"
qh"ogejcpkecn"xgpvkncvkqp0"
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tqwvg" qh" cfokpkuvtcvkqp" iwctcpvggkpi" vjg" cfokpkuvtcvkqp" qh" 322'" qh" vjg" fqug" rtguetkdgf0"
Hwtvjgtoqtg."kpvwdcvgf"cpf"xgpvkncvgf"rcvkgpvu"kp"kpvgpukxg"ectg"fkurnc{"jkijn{"xctkcdng"ngxgnu"
qh" fkiguvkxg" cduqtrvkqp" cpf" vjg" qtcn" tqwvg" ku" pqv" cnyc{u" hgcukdng" kp" uwej" rcvkgpvu" *uvqocej"
gorv{kpi" cpf" kpvguvkpcn" vtcpukv" rtqdngou" ciitcxcvgf" d{" vjg" wug" qh" ugfcvkxgu" qt"
xcuqeqpuvtkevqtu+0"Vjg"fqug"uejgfwng"wugf"eqttgurqpfu"vq"vjcv"kp"vjg"COO"*vjg"cwvjqtk¦cvkqp"
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itqwr"]5:."Crrgpfkz"4_<"722"oi"vykeg"fckn{"qt."kp"ecugu"qh"eqrtguetkrvkqp"qh"hwtqugokfg"qt"c"
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4" QDLGEVKXGU"QH"VJG"UVWF["
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/" Vjg"pwodgt"qh"XCR0"
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hqt" cewvg" tgurktcvqt{" fgeqorgpucvkqp" cpf" cv" tkum" qh" rtqnqpigf" ogejcpkecn" xgpvkncvkqp" cpf"
fkhhkewnvkgu"dgkpi"ygcpgf"qhh"qh"tgurktcvqt{"cuukuvcpeg"*uwrgtkqtkv{"uvwf{+0"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 36182" " "
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" Vjg"uvwf{"rqrwncvkqp"eqpukuvu"qh"EQRF"rcvkgpvu<"
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" EQRF" rcvkgpvu" jcxg" c" ejtqpke" tgurktcvqt{" jcpfkecr." vjg" ugxgtkv{" qh" yjkej" fkhhgtu"
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" Oqtdkfkv{"cpf"oqtvcnkv{"kp"vjku"rqrwncvkqp"ctg"pqp/pginkikdng."fwg."kp"rctvkewnct."vq"vjg"
fwtcvkqp"qh"kpxcukxg"ogejcpkecn"xgpvkncvkqp"kp"kpvgpukxg"ectg"wpkv"*ogcp"qh"34"fc{u"kp"qwt"hktuv"
rtgnkokpct{" uvwf{" ]5:_" ecttkgf" qwv" cv" Igqtigu" Rqorkfqw" Gwtqrgcp" Jqurkvcn+" cpf" vjg"
eqornkecvkqpu" cuuqekcvgf" ykvj" uwej" rtqnqpigf" xgpvkncvkqp0" Vjg" gzrgevgf" dgpghkvu" qh"
cegvc¦qncokfg"vtgcvogpv"kp"vgtou"qh"vjg"fwtcvkqp"qh"kpxcukxg"xgpvkncvkqp"cpf1qt"ygcpkpi"qhh"qh"
tgurktcvqt{" cuukuvcpeg" cpf" vjg" tcvgu" qh" eqornkecvkqpu" cuuqekcvgf" ykvj" rtqnqpigf" kpxcukxg"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 37182" " "
/" EQRF." tgictfnguu" qh" tgurktcvqt{" uvcvwu" cv" jqog" *pq" tgurktcvqt{" cuukuvcpeg." Q4"
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fkcipquku"cpf"ectg"qh"rcvkgpvu"ykvj"EQRF0"Co"L"Tgurkt"Etkv"Ectg"Ogf"3;;7="374<U99/
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50504" Gzenwukqp"etkvgtkc"
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dkqogfkecn" tgugctej." tgictfnguu" qh" yjgvjgt" qt" pqv" vjg" ukip" eqpegtpgf" ku" nkpmgf" vq" vjg"
uvwf{"qt"vq"vjg"rtqfwev"uvwfkgf0"
‚" Cfxgtug"ghhgev"qh"cp"gzrgtkogpvcn"ftwi"Cnn" wpfguktcdng." vqzke" tgcevkqpu" vq" gzrgtkogpvcn" ftwiu." tgictfnguu" qh" vjg" fqug"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 4:182" " "
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"
Fcvc"vq"dg"tgeqtfgf" Ogejcpkecn"xgpvkncvkqp"
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Gzvwdcvkqp"qt"eguucvkqp"qh"kpxcukxg"
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" "
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 4;182" " "
:05" Rtqegfwtgu"korngogpvgf"hqt"vjg"tgeqtfkpi"cpf"pqvkhkecvkqp"qh"cfxgtug"gxgpvu"
:0503" Pqp/ugtkqwu"cfxgtug"gxgpvu"
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cdqxg" cpf" ctg" qdugtxgf" fwtkpi" vjg" uvwf{" cpf" vjg" rgtkqf" hqnnqykpi" vjg" uvwf{" ujqwnf" dg"
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o" Cu{orvqocvke"j{rgtwtkegokc0"
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o" Jgrcvke"fkuvwtdcpegu"*oqfgtcvg."cu{orvqocvke"e{vqn{uku"qt"ejqnguvcuku+0"
o" Icuvtqkpvguvkpcn"rtqdngou"*pcwugc."xqokvkpi."cdfqokpcn"rckp+0"
o" F{uguvjgukc"eqttgevcdng"d{"vjg"cffkvkqp"qh"c"rqvcuukwo"ucnv0"
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o" J{rgtugpukvkxkv{"tgcevkqpu."guugpvkcnn{"kp"vjg"hqto"qh"umkp"tcujgu"cpf"hgxgt0"
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nkpmgf"fkiguvkxg"u{uvgo"jgoqttjcig."vjtqodqgodqnke"fkugcug."kpvguvkpcn"kngwu+0"
/" Rqvgpvkcnn{" ugtkqwu" cfxgtug" ghhgevu" vjcv" ctg" ygnn" mpqyp." htgswgpv" cpf" ygnn"eqpvtqnngf."vjg"fgenctcvkqp"qh"yjkej"yqwnf"pqv"kpetgcug"rcvkgpv"uchgv{0"Gzcorngu"kpenwfg<""
/" Cfxgtug" gxgpvu" nkpmgf" vq" kpvgpukxg" ectg" rtqegfwtgu<" cnn" eqornkecvkqpu" nkpmgf" vq"
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ugtkqwu"cttj{vjokc"pqv"nkpmgf"vq"j{rqmcngokc."pquqeqokcn"rpgwoqpkc."uvtguu/nkpmgf"fkiguvkxg"
u{uvgo" jgoqttjcig." vjtqodqgodqnke" fkugcug." kpvguvkpcn" kngwu+" qt" eqornkecvkqpu" nkpmgf" vq"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 52182" " "
egpvtcn" xgpqwu" ecvjgvgtk¦cvkqp" *kphgevkqpu." rpgwoqvjqtcz." dnggfkpi" cv" vjg" ukvg" qh" ecvjgvgt"
kpugtvkqp+0"
:0504" Ugtkqwu"cfxgtug"gxgpvu"*UCG+"
Vjg" hqto" hqt" fgenctkpi" ugtkqwu" cfxgtug" gxgpvu." xcnkfcvgf" hqt" vjg" uvwf{." ku" kpenwfgf" kp" vjg"
rtqvqeqn"*Crrgpfkz"8+0"Vjg"itkf"hqt"encuukh{kpi"ugtkqwu"cpf"pqp/ugtkqwu"cfxgtug"gxgpvu"ku"cnuq"
rtqxkfgf"*Crrgpfkz"9+0"Vjku"itkf"ycu"fgxgnqrgf"vq"cuukuv" kpxguvkicvqtu"kp"vjgkt"ocpcigogpv"
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Eqqtfkpcvqt" qh" vjg" Enkpkecn" Tgugctej" cpf" Fgxgnqrogpv" Fgrctvogpv" cpf" vjg" Jgcf" qh"
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Vjg"gzrgevgf"ugtkqwu"cfxgtug"ghhgevu"*ceeqtfkpi"vq"vjg"URE+"ctg<""-" J{rgtwtkegokc"ykvj"cewvg"iqwv0"
-" U{orvqocvke"j{rqmcngokc"*cttj{vjokc+0"
-" Jgocvqnqikecn"kpekfgpvu"*vjtqodqe{vqrgpke"rwtrwtc."citcpwnqe{vquku."
ogfwnnct{"crncukc+."rtqdcdn{"fwg"vq"ugpukvk¦cvkqp"vq"uwnhcokfgu0"
-" Cpcrj{ncevke"ujqem0"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 53182" " "
iqwv."cpf"u{orvqocvke"j{rqmcngokc"ykvj"cttj{vjokc+"cpf"vjgkt"korwvcdknkv{"vq"vjg"vtgcvogpv"
yknn"dg"pqvgf"fwtkpi"hqnnqy/wr0"
Cpcrj{ncevke"ujqem"ku"fghkpgf"cu"vjg"uwffgp"crrgctcpeg."fwtkpi"vjg"okpwvgu"hqnnqykpi"
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vcej{ectfkc"qt"dtcf{ectfkc."ectfkce"cttguv+."ewvcpgqwu1owequcn"ukipu"*gt{vjgoc"qt"gpcpvjgoc+"
qt" tgurktcvqt{" ukipu" *dtqpejqurcuo+." vjgug" ukipu" dgkpi" rqvgpvkcnn{" qh" xctkqwu" fgitggu" qh"
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dgnqy" 92" oo" Ji" fgurkvg" xcuewnct" hknnkpi" ykvj" vyq" dqnwugu" qh" 472" oN" qh" ucnkpg" cpf" vjg"
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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""
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 54182" " "
Cnn" uwurgevgf"wpgzrgevgf"UCGu"yknn"dg"fgenctgf" vq" vjg"eqorgvgpv"cwvjqtkvkgu"d{" vjg"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 55182" " "
"
:070"Wpdnkpfkpi"rtqegfwtg"Cp" wpdnkpfkpi" rtqegfwtg" yknn" dg" korngogpvgf" kp" ecugu" qh" ugtkqwu" cfxgtug" gxgpvu"
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"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 57182" " "
32"UVCVKUVKEU"
3203" Fguetkrvkqp"qh"vjg"uvcvkuvkecn"ogvjqfu"vq"dg"wugf."kpenwfkpi"c"vkogvcdng"hqt"vjg"
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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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" Vjg"ugeqpfct{" lwfiogpv"etkvgtkc"yknn"dg"cuuguugf"hqt" vjg"gpvktg"uvwf{"rqrwncvkqp"cpf"
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pqtocnn{" fkuvtkdwvgf" xctkcdngu+" vq" eqorctg" swcpvkvcvkxg" xctkcdngu" dgvyggp" itqwru." qt" ぬ4" *qt"
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oqtvcnkv{" cpcn{uku"yknn" eqorctg" uwtxkxcn." dcugf"qp"Mcrncp/Ogkgt" ewtxgu" cpf" nqi/tcpm" vguvu."
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"
3204" Pwodgt"qh"rctvkekrcpvu"vq"dg"kpenwfgf"kp"vjg"uvwf{"cpf"rncppgf"fgitgg"qh"uvcvkuvkecn"ukipkhkecpeg"
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fwtcvkqp" qh" kpxcukxg" ogejcpkecn" xgpvkncvkqp" wpvkn" gzvwdcvkqp" qt" kvu" eqorngvg" eguucvkqp" kp"
vtcejgqvqok¦gf" rcvkgpvu0" Pq" uvwf{" jcu" dggp" rwdnkujgf" eqpegtpkpi" vjg" kphnwgpeg" qh"
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rcvkgpvu"kp"kpvgpukxg"ectg0"Jqygxgt."qwt"hktuv"rtgnkokpct{"uvwf{"qp"vjg"ghhgev"qh"cegvc¦qncokfg"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 58182" " "
cfokpkuvgtgf"cv"nqy"fqug"uqngn{"fwtkpi"vjg"ygcpkpi"qh"EQRF"rcvkgpvu"fgxgnqrkpi"ogvcdqnke"
cnmcnquku" ]5:_" kpfkecvgf" vjcv" vjg"ogcp" vqvcn"fwtcvkqp"qh" kpxcukxg"xgpvkncvkqp" kp" vjgug"rcvkgpvu"
ycu"34"‒"7"fc{u0"
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"
33"TKIJV" QH" CEEGUU" VQ" FCVC" CPF" UQWTEG"FQEWOGPVU"
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cwfkvqtu"cpf"cp{qpg"cumgf"vq"eqnncdqtcvg"kp"vjg"vtkcn+."yknn"vcmg"cnn"vjg"pgeguuct{"rtgecwvkqpu"vq"
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"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 59182" " "
34"SWCNKV["EQPVTQN"CPF"CUUWTCPEG"
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"
3403" Oqpkvqtkpi"rtqegfwtgu"
Gxcnwcvgf"tkum"ngxgn"qh"vjg"uvwf{<"E"
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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"
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tgugctej"uvwf{0"
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kpxguvkicvqtu"kpenwfkpi"qt"hqnnqykpi"wr"vjg"rcvkgpvu"rctvkekrcvkpi"kp"vjg"uvwf{"citgg"vq"tgiwnct"
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eqpukuvgpe{."kp"ceeqtfcpeg"ykvj"vjg"rtqegfwtgu"nckf"fqyp"d{"FTEF"twngu0"
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"
3404" Vtcpuetkrvkqp"qh"fcvc"kp"vjg"qdugtxcvkqp"pqvgdqqm""
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pqvgdqqm"cpf"vjg"kpxguvkicvqt"owuv"rtqxkfg"cp"gzrncpcvkqp"hqt"cp{"okuukpi"fcvc0""
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 5:182" " "
Vjg" fcvc" ujqwnf" dg" vtcpuhgttgf" vq" vjg" qdugtxcvkqp" pqvgdqqmu" cu" vjg{" ctg" qdvckpgf."
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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""
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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"
"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 5;182" " "
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"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 62182" " "
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"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 63182" " "
/"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"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 64182" " "
"
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"
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-Hôpitaux de Paris" tgugtxgu" vjg" tkijv" vq" uvqr" vjg" uvwf{" cv" cp{"
oqogpv." hqt" ogfkecn" qt" cfokpkuvtcvkxg" tgcuqpu0" Ujqwnf" vjku" qeewt." vjg" kpxguvkicvqt" yknn" dg"
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"
3704" Uekgpvkhke"eqookvogpv"
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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"
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"
38"RWDNKECVKQP"TWNGU"
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rtkqt"citggogpv"qh"vjg"CR/JR0"
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fgxgnqrogpv"cpf"twppkpi"qh"vjg"rtqvqeqn."cpf"kp"vjg"igpgtcvkqp"cpf"ytkvkpi"qh"tguwnvu0"
Assistance Publique-Hôpitaux de Paris"owuv"dg"ekvgf"cu"vjg"rtqoqvgt"qh"vjg"tgugctej"cpf"
cu"vjg"uqwteg"qh"hwpfkpi."cu"crrtqrtkcvg0"Vjg"vgtou"ÐAssistance Publique-Hôpitaux de ParisÑ"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 65182" " "
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39"TGHGTGPEGU""
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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"
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"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"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 66182" " "
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"
49/" Xqu" RLG." Hqnigtkpi" JVO." fg" Dqq" VO" gv" cn0" Ghhgevu" qh" ejnqtocfkpqpg" cefivcvg."
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"
4;/" Umcvtwf" LD." Fgoru{" LC0" Tgncvkxg" ghhgevkxgpguu" qh" cegvc¦qncokfg" xgtuwu"
ogftqz{rtqiguvgtqpg" cegvcvg" kp" eqttgevkqp" qh" ejtqpke" ectdqp" fkqzkfg" tgvgpvkqp0"Co" L"Tgur"
Tgur"Fku"3;:5=349<627/634"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 67182" " "
52/"Oc¦wt" LG." Fgxnkp" LY." Rgvgtu"OL." Lcpmqyumk"OC." Kcppw¦¦k"OE." ¥ctqykv¦" DL0" Ukping"
xgtuwu" ownvkrng" fqug" qh" cegvc¦qncokfg" hqt" ogvcdqnke" cnmcnquku" kp" etkvkecnn{" knn" rcvkgpvu<" c"
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"
55/"Octkm"RG."Mwuuocp"DF."Nkrocp"L."Mtcwu"R0"Cegvc¦qncokfg"kp"vjg"vtgcvogpv"qh"ogvcdqnke"
cnmcnquku"kp"etkvkecnn{"knn"rcvkgpvu0"Jgctv"nwpi"3;;3=42<677/67:"
56/"Jcemk"OC."Ycnfgem"I."Dtcpfnk"Q0"Cevc¦qncokfg"kp"j{rgtecrpke"ejtqpke"qduvtwevkxg"nwpi"
fkugcug/"/"c"tgpckuucpegA"Uejygk¦"Ogf"Yqejgpuejt03;:5=335"*5+<332/6"
57/" Fkemkpuqp" IG." O{gtu" ON." Iqnfdcej" O" gv" cn0" Cegvc¦qncokfg" kp" vjg" vtgcvogpv" qh"
xgpvkncvqt{"hcknwtg"eqornkecvkpi"cewvg"ogvcdqnke"cnmcnquku0"Cpguvj"Cpcn"3;:3=82<82:/832"
58/" Nkrrocp" DL0" Cekf/dcug" fkuqtfgtu0" Kp<" Vjg" ycujkpivqp" wpkxgtukv{" Ocpwcn" qh"
vjgtcrgwvkeu4:vj" " Gfkvkqp0" Gycnf"IC."Ogemgp¦kg" ET" *Gfu+0" Dquvqp." Nkvvng." Dtqyp" cpf"Eq."
3;;7."r"84"
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[qtm."Ejwtejknn"Nkxkpiuvqpg."3;;6."r98"
5:/"Hcku{"E."Oqmnkpg"C."Ucpejg¦"Q."Vcfkfi"LO."Hciqp"L[0"Ghhgevkxgpguu"qh"cegvc¦qncokfg"hqt"tgxgtucn" qh" ogvcdqnke" cnmcnquku" kp" ygcpkpi" EQRF" rcvkgpvu" htqo" ogejcpkecn" xgpvkncvkqp0"
Kpvgpukxg"Ectg"Ogf"4232="58<:7;/:85"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233" " 68182" " "
3:"NKUV"QH"CRRGPFKEGU"
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6030"Vjgtcrgwvke"kpfkecvkqpu"
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6040"Rquqnqi{"cpf"ogvjqf"qh"cfokpkuvtcvkqp"
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Combinations requiring precautions for use
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Pregnancy
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7030"Rjctoceqf{pcoke"rtqrgtvkgu"
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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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187 115 49 26 13 8182 104 44 16 11 6
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190 114 49 26 13 8182 106 44 16 10 6
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189 116 50 26 13 7181 105 44 16 11 6
Days
Acetazolamide
eFigure 2
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Panel A: Bicarbonate
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PlaceboAcetazolamide
148 104 44 24 13 8130 86 38 16 11 6
Days
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Panel B: pH
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Days
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Panel C: PaCO2
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PlaceboAcetazolamide
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Days
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Days
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PlaceboAcetazolamide
148 102 43 24 13 7129 87 38 15 10 6
Days
Placebo
● ● ● ● ● ●●
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2O
1 5 10 15 20 25
Panel H: Positive End Expiratory Pressure
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148 104 45 24 13 7130 87 38 16 11 6
Days
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