IMPORTANCE Acetazolamide has been used for decades as a respiratory stimulant for
Supplemental content at
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patients with chronic obstructive pulmonary disease (COPD) and metabolic alkalosis, but no
large randomized placebo-controlled trial is available to confirm this approach.
OBJECTIVE To determine whether acetazolamide reduces mechanical ventilation duration in
intravenously in cases of pure or mixed metabolic alkalosis, initiated within 48 hours of ICU
admission and continued during the ICU stay for a maximum of 28 days.
MAIN OUTCOMES AND MEASURES The primary outcome was the duration of invasive mechanical
ventilation via endotracheal intubation or tracheotomy. Secondary outcomes included changes in
arterial blood gas and respiratory parameters, weaning duration, adverse events, use of noninvasive
ventilation after extubation, successful weaning, the duration of ICU stay, and in-ICU mortality.
RESULTS Among 382 randomized patients, 380 (mean age, 69 years; 272 men [71.6%]; 379
[99.7%] with endotracheal intubation) completed the study. For the acetazolamide group
(n = 187), compared with the placebo group (n = 193), no significant between-group differences
were found for median duration of mechanical ventilation (16.0 hours; 95% CI, 36.5 to
4.0 hours; P = .17), duration of weaning off mechanical ventilation (0.9 hours; 95% CI, 4.3 to
1.3 hours; P = .36), daily changes of minute-ventilation (0.0 L/min; 95% CI, 0.2 to 0.2 L/min;
P = .72), or partial carbon-dioxide pressure in arterial blood (0.3 mm Hg; 95% CI, 0.8 to
0.2 mm Hg; P = .25), although daily changes of serum bicarbonate (between-group difference,
0.8 mEq/L; 95% CI, 1.2 to 0.5 mEq/L; P < .001) and number of days with metabolic alkalosis
(between-group difference, 1; 95% CI, 2 to 1 days; P < .001) decreased significantly more in the
acetazolamide group. Other secondary outcomes also did not differ significantly between groups.
CONCLUSIONS AND RELEVANCE Among patients with COPD receiving invasive mechanical
ventilation, the use of acetazolamide, compared with placebo, did not result in a statistically
significant reduction in the duration of invasive mechanical ventilation. However, the
magnitude of the difference was clinically important, and it is possible that the study was
underpowered to establish statistical significance.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01627639
JAMA. 2016;315(5):480-488. doi:10.1001/jama.2016.0019
480
hronic obstructive pulmonary disease (COPD) is a frequent cause of intensive care unit (ICU) admission.1
Noninvasive mechanical ventilation has altered the outcomes of patients with acute COPD exacerbation by reducing
the need for intubation.2,3 Nevertheless, patients with COPD
may still require invasive mechanical ventilation when noninvasive ventilation fails or for an unrelated pathology.
Respiratory acidosis and metabolic alkalosis are the principal acid-base disturbances in patients with COPD receiving
mechanical ventilation. Metabolic alkalosis can be caused by
many conditions encountered during ICU stays, including diuretic or glucocorticoid use, vomiting or nasogastric suctioning, and permissive hypercapnia induced by lung-protective
strategies.4 Furthermore, the acid-base disorders most frequently observed while weaning patients with COPD off mechanical ventilation are mixed (ie, chronic respiratory acidosis and metabolic alkalosis).5 Metabolic alkalosis may inhibit
the activity of the central nervous respiratory command center and cardiac output or alter oxyhemoglobin dissociation and
favors the development of hypokalemia and hypophosphatemia, thereby prolonging the weaning period and mechanical
ventilation duration for critically ill patients.6-10
Acetazolamide, a carbonic anhydrase inhibitor, has been
used for decades as a respiratory stimulant in patients with
COPD and metabolic alkalosis.11 The classic mechanism of
acetazolamides action as a respiratory stimulant is based on
the inhibition of the renal carbonic anhydrase enzyme, which
in turn decreases serum bicarbonate and arterial pH, leading
to increased minute ventilation via stimulation of peripheral
and central chemoreceptors. However, data from uncontrolled clinical studies yielded inconsistent effects when
acetazolamide was administered at usual doses (250 to
500 mg once or twice daily).12 Recent pharmacodynamics
models indicated that patients with COPD breathing with the
aid of mechanical ventilation might benefit from its respiratory stimulant effect after administration of higher doses.13,14
In designing the DIABOLO trial, we hypothesized that higher
acetazolamide doses (1000 mg/d) would shorten the
mechanical ventilation duration in critically ill patients with
COPD (trial protocol in Supplement 1).
Methods
Participants
Patients older than 18 years with a history of COPD according
to the American Thoracic Society criteria15 (smoking, other environmental risk factors, chronic cough, acute chest illnesses, dyspnea, physical examination, and laboratory investigations such as chest radiography, lung function tests, or
arterial blood gases) were enrolled if they required invasive ventilation via an intubation or tracheotomy tube and were evaluated within 24 hours after its onset. Exclusion criteria were judicial guardianship, no affiliation with the French health care
system, pregnancy, cystic fibrosis or diffuse bronchiectasis, previous allergy to acetazolamide or sulfonamides, permanent acetazolamide contraindication, recent participation in another interventional study with mechanical ventilation
duration as the primary end point, or investigators decision
not to resuscitate.
Intervention
Study Design
This multicenter, double-blind (participants, caregivers, investigators, and outcome assessors), parallel-group, randomized clinical trial was approved for all centers by the Comit
de Protection des Personnes ParisIle-de-France VI (ethics committee: No. 2011-000492-14). The French National Committee for Health Research funded the study and convened a trial
steering committee and independent data monitoring committee. A safety monitoring committee was not considered necessary because the acetazolamide doses had adhered to the
marketing authorization and the study design included daily
patient evaluation for adverse events or temporary contraindications. The European Georges Pompidou Hospital Clinical
Research Center managed the study, from October 2011 to July
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481
Study Outcomes
The primary end point was the duration of invasive ventilation. Secondary outcomes were the changes of serum bicarbonate, partial pressure of carbon dioxide in arterial blood
(Pa CO 2 ), pH, partial pressure of oxygen in arterial blood
(PaO2):FIO2 ratio and respiratory parameters (tidal volume,
respiratory rate, and minute ventilation), weaning duration,
the numbers of spontaneous breathing trials, unplanned
extubations and ventilator-associated pneumonia episodes,
use of noninvasive ventilation after extubation, successful
weaning, the duration of ICU stay, and in-ICU mortality.
Adverse events were monitored for 28 days. All outcomes are
defined in Supplement 2.
482
Statistics
The sample size was calculated a priori based on the following assumptions: placebo group with an estimated mean (SD)
duration of mechanical ventilation of 12 (5) days based of one
of our preliminary studies,5 and because we expected to include the most severely ill patients with COPD (ie, requiring
invasive mechanical ventilation); acetazolamide-group patients, compared with those in the placebo group, would have
a potential 15% relative risk reduction for the primary end
point5 to be clinically relevant. Based on those estimates, we
calculated that 380 patients had to be enrolled to achieve 80%
power to detect that difference for the acetazolamide group
with a 2-sided level of .05.
The analyses were performed on the intention-to-treat
population, which was defined as all patients who had undergone randomization, excluding those erroneously included.
Analyses were then confirmed on per-protocol population,
which is defined as the set of patients, who did not perform
any protocol violation that may interfere with primary criteria evaluation (ie, patients receiving the allocated treatment;
patients with all the inclusion criteria met). Missing data were
only imputed for the end of invasive mechanical ventilation.
We used the mean hour of the end of invasive mechanical
ventilation of the center because planned extubations were performed around the same time. To take censored data into account (patients who died before extubation), the KaplanMeier method was used to calculate the probabilities of being
successfully weaned off invasive ventilation during the 28day observation period. The generated Kaplan-Meier curves
were compared with the log-rank test. Quantitative variables
are expressed as means and standard deviation or medians and
interquartile ranges (IQRs), when appropriate. Data were compared with t tests, when the sample size of each group was 30
or more, or Wilcoxon rank-sum tests, when one groups sample
size was less than 30. All tests were 2-sided. Either 2 or Fischer
exact tests, as appropriate, were used to compare qualitative
variables, expressed as percentages. All comparisons included the entire sample stratification (as prespecified). Hazard ratios were calculated using a Cox model and the centers
were taken into account as a random effect using gamma frailty
model.18 Tests of proportionality were performed including
time-dependent covariates in the Cox model. Post hoc subgroups were defined according to the presence or absence
(yes/no) of acute prolonged mechanical ventilation (96
hours),19 the preferential use (>50% of the time) of pressuresupport ventilation or not during the weaning period, the prescription or not of loop diuretics or glucocorticoids, and the
presence or absence (yes/no) of pure metabolic alkalosis
(pH>7.42 and serum bicarbonate >26 mEq/L) at baseline.
P < .05 defined statistical significance. All analyses were computed using SAS software, version 9.4 (SAS Institute Inc).
Results
Patients
Among the 694 patients screened in the 15 participating French
ICUs, 382 were enrolled, including 2 patients who subse-
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312 Excluded
105 Did not meet inclusion criteria
53 Intubation lasted >24 h
52 Declined to participate or no available
next of kin
154 Met exclusion criteria
70 Close to death
40 Had contraindication to acetazolamide
26 Under judicial guardianship
15 Enrolled in another study
2 Not affiliated with health care system
1 Allergic to sulfonamides
53 Other reasons
41 Overlooked by investigator
12 Intubation planned in <24 h
382 Randomized
2 Forgotten administrations
1 Dosage error
1 Dosage error
quently withdrew from the study, resulting in an intentionto-treat population of 380 patients: 187 randomized to the acetazolamide group and 193 to receive the placebo (Figure 1).
Baseline characteristics of the patients in the 2 study groups
were comparable (Table 1). All 187 patients had endotracheal
intubation (100%) in the acetazolamide group vs 192 (99.5%)
with endotracheal intubation and 1 (0.5%) with tracheotomy
in the placebo group.
483
Acetazolamide
(n = 187)
Placebo
(n = 193)
Characteristic
69 (10)
69 (11)
Hematocrit, %
131 (70)
141 (73.1)
49.4 (13.9)
50 (15.1)
37.3 (8)
13700 (7200)
Placebo
(n = 193)
37.6 (8.4)
13900 (8200)
251.5 (116.6)
245.6 (118.5)
73.7 (21.6)
75.9 (22.1)
7.2 (3.1)
7.1 (3.2)
27.2 (8.0)
26.7 (9.1)
Oxygen
49 (26.2)
52 (26.9)
57 (30.5)
53 (27.5)
Noninvasive ventilation
19 (10.1)
21 (10.9)
84 (44.9)
93 (48.2)
BMI
Prothrombin ratio, %
Chest radiography, No. (%)
Tracheotomy mechanical
ventilation
Smoker or ex-smoker, No. (%)
Smoking history, pack-years
FEV1, mLc
FEV1/FVCc
0
170 (90.9)
48.3 (24.7)
1232 (609)
0.51 (0.15)
1 (0.5)
179 (92.7)
50.4 (22.1)
1124 (586)
0.53 (0.15)
32 (17.1)
39 (20.2)
Loop diuretics
51 (27.3)
67 (34.7)
2-Agonists
96 (51.3)
95 (49.2)
4 (2.1)
3 (1.6)
1 (0-1)
1 (0-1)
Acetazolamide
ICU stay before randomization,
median (IQR), dd
Causes of invasive mechanical
ventilation, No. (%)e
Community-acquired pneumonia
83 (44.3)
83 (43.0)
Bronchitis
37 (19.8)
33 (17.1)
43 (23.0)
32 (16.6)
Surgery
12 (6.4)
13 (6.7)
Use of sedative
4 (2.1)
17 (8.8)
Pulmonary embolism
2 (1.1)
1 (0.5)
Stroke
3 (1.6)
2 (1.0)
Others
52 (27.8)
44 (22.8)
Unknown
10 (5.3)
9 (4.7)
Endotracheal intubation/
tracheotomy at inclusion, No.
187/0
192/1
Laboratory measurements
at inclusion
pH
7.32 (0.11)
7.30 (0.12)
PaO2, mm Hg
150.5 (108)
143.6 (90)
PaCO2, mm Hg
52.5 (16)
55.6 (17)
26.9 (6.9)
27.4 (6.6)
4.2 (0.7)
4.2 (0.7)
Serum
Bicarbonate, mEq/L
Potassium, mEq/L
147 (78.6)
148 (76.7)
The SAPS II is based on 17 variables; scores range from 0 to 163, with higher
scores indicating more severe disease.
Data were available from 71 patients in the acetazolamide group and from 82
patients in the placebo group.
Several situations requiring invasive ventilation are possible; hence, the total
can exceed 100%.
Adverse Events
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)
31.4 (25.8)
29.7 (23.2)
Urea, mg/dL
Glucose, mg/dL
165.8 (133.3)
165.8 (79.3)
105.2 (290.6)
115.1 (448.6)
Bilirubin, mg/dL
0.8 (0.6)
0.8 (0.9)
6.3 (2.7)
5.9 (3.1)
Thyroid-stimulating hormone,
mIU/L
2.5 (8)
2.2 (5.7)
1.2 (0.2)
1.2 (0.2)
Hemoglobin, g/dL
(continued)
484
Acetazolamide
(n = 187)
Discussion
This multicenter, randomized, double-blind trial was designed to compare the respiratory effects of acetazolamide vs
jama.com
Acetazolamide
(n = 187)
Placebo
(n = 193)
Between-Group Difference
(95% CI)
.17
<.001
.25
P Value
Primary Outcome
Duration of invasive ventilation, h
Secondary Outcomesb
Daily
Serum bicarbonate change, mEq/L
PaCO2 change, mm Hg
pH change
0 (0.01 to 0.02)
0.01 (0 to 0.02)
PaO2:FIO2-ratio change, mm Hg
.008
.009
.10
.72
Weaning duration, h
.72
.36
1 (1 to 2)
1 (1 to 2)
0 (0 to 0)
.42
0 (0 to 21)
0 (0 to 9)
0 (0 to 0)
.67
187 (100)
192 (99.5)
62 (33.1)
72 (37.3)
.39
118 (74.7)
127 (78.4)
.43
0 (0 to 2)
0 (0 to 1)
0 (0 to 0)
.99
.65
23 (12.3)
33 (17.1)
.18
10 (6 to 17)
10 (7 to 18)
.30
22 (11.7)
26 (13.4)
6 (0.03)
7 (0.04)
Loop diuretics
1 (0 to 4)
1 (0 to 4)
0 (0 to 0)
Systemic glucocorticoids
0 (0 to 3)
0 (0 to 4)
0 (0 to 0)
.29
2-Agonists
0 (0 to 4)
1 (0 to 6)
0 (0 to 0)
.07
Catecholamines
1 (0 to 3)
1 (0 to 3)
Test-treatment doses
2 (0 to 5)
6 (1 to 13)
2 (4 to 1)
<.001
Metabolic alkalosis, de
2 (1 to 4)
4 (2 to 8)
1 (2 to 1)
<.001
0 (0 to 10)
0 (0 to 7)
0 (0 to 0)
1 (2 to 0)
0.4 (4.1 to 3.2)
.61
.82
0 (0 to 0)
.55
.98
.16
Pressure-support ventilation, d
2 (1 to 5)
2 (1 to 5)
0 (1 to 0)
.22
Volume-assisted ventilation, d
3 (1 to 5)
3 (1 to 6)
0 (1 to 0)
.52
55 (40 to 60)
50 (42 to 60)
0 (5 to 5)
.86
Adverse events were considered serious when they required intensive care
procedures (use of vasopressors, hemodialysis, central venous
catheterization, cardiac pacing, or tube thoracostomy) or surgery, and those
events prolonged hospitalization or resulted in persistent or major disability or
incapacity.
Range was preferred over IQR because several of the latter were (0-0).
Between-group differences for quantitative variables are expressed as
medians with the 95% CI around the median difference.
volume, and minute ventilation) despite achieving larger decreases in serum bicarbonate and fewer days with metabolic
alkalosis. In addition, the acetazolamide groups PaO2:FIO2
ratio was significantly increased, possibly via the drugs
(Reprinted) JAMA February 2, 2016 Volume 315, Number 5
485
Figure 2. Kaplan-Meier Curves for the Cumulative Probabilities of Being Weaned Off Invasive Ventilation
100
HR, 1.14 (95% CI, 0.91-1.42); Log-rank P = .24
Cumulative Ventilated, %
80
60
Placebo
40
Acetazolamide
20
0
0
48
96
144 192 240 288 336 384 432 480 528 576 624 672
44
51
28
39
19
33
14
20
13
16
11
13
7
9
7
8
6
5
5
4
Figure 3. Subgroup Analyses of the Effect of Acetazolamide on the Duration of Invasive Ventilation
or Weaning
A Duration of ventilation
Acetazolamide
Group, No.
Subgroup
Events a Patients
Acute prolonged invasive ventilation, 96 h
Placebo
Group, No.
Events a Patients
Hazard Ratio
(95% CI)
Yes
102
119
121
137
1.06 (0.811.38)
No
57
68
45
56
0.91 (0.611.37)
Favors
Placebo
Favors
Acetazolamide
62
66
83
87
1.20 (0.861.68)
No
93
117
82
103
1.15 (0.851.55)
121
141
128
143
1.11 (0.861.42)
No
34
42
37
47
1.37 (0.842.23)
55
59
48
50
1.36 (0.912.03)
No
104
128
118
143
1.11 (0.851.44)
Overall
166
187
159
193
1.16 (0.931.44)
0.5
1.0
3.0
Duration of weaning
Acetazolamide
Group, No.
Subgroup
Events a Patients
Acute prolonged invasive ventilation, 96 h
Placebo
Group, No.
Events a Patients
Hazard Ratio
(95% CI)
Yes
93
99
111
112
0.98 (0.741.30)
No
50
51
42
43
0.91 (0.591.41)
Favors
Placebo
Favors
Acetazolamide
59
62
82
83
1.00 (0.711.40)
No
80
84
70
71
1.12 (0.811.56)
108
113
118
120
1.00 (0.771.31)
No
31
33
34
34
1.13 (0.691.86)
1.09 (0.721.64)
51
53
45
45
No
92
97
108
110
1.02 (0.771.36)
Overall
143
150
153
155
1.04 (0.831.31)
0.5
1.0
3.0
486
ARTICLE INFORMATION
Author Affiliations: European Georges Pompidou
Hospital, Assistance PubliqueHpitaux de Paris,
Paris, France (Faisy, Sanchez, Heming, Esvan,
Katsahian); Nouvel Hpital Civil, Medical Intensive
Care Unit, Hpitaux Universitaires de Strasbourg
and EA 7293, Fdration de Mdecine
Translationnelle de Strasbourg, Strasbourg
University, Strasbourg, France (Meziani); Andr
Mignot Hospital, Medico-Surgical Intensive Care
Unit, Le Chesnay, France (Planquette); Limoges
University Hospital, Medical Intensive Care Unit,
jama.com
Conclusions
Among mechanically ventilated patients with COPD and pure
or mixed metabolic alkalosis, the use of effective acetazolamide doses, compared with placebo, did not result in a statistically significant reduction in the duration of invasive mechanical ventilation. However, the magnitude of the difference
(16 hours) was clinically important, and it is possible that the
study was underpowered to establish statistical significance.
487
488
jama.com
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R2:342:aFkcdqnqa"xgtukqp"4"fw"4412814233"
"
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R2:342:
Title: Randomized trial of the efficacy of acetazolamide in patients with COPD developing metabolic alkalosis
during invasive mechanical ventilation
Date : //..
Signature :
Promoter:
Ot"Ejtkuvqrjg"OKUUG"
Assistance publique hpitaux de Paris
Date : //..
Signature :
75010 PARIS
NB: This version corresponds to the text of the protocol and appendices sent to the IRB and the competent
authority, respectively, for expert opinion and to request authorization.
If a new version is subsequently produced following modifications, signatures must be obtained again, to ensure
that the active protocol is always updated.
R2:342:aFkcdqnqa"xgtukqp"4"fw"4412814233"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
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;182" "
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32182" "
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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"
"
33182" "
"
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"
hqt"octmgv"tgngcug"kp"Htcpeg+."vjg"tghgtgpegu"ekvgf"cdqxg"cpf"tgegpv"uvwfkgu"ecttkgf"qwv"d{"qwt"
itqwr"]5:."Crrgpfkz"4_<"722"oi"vykeg"fckn{"qt."kp"ecugu"qh"eqrtguetkrvkqp"qh"hwtqugokfg"qt"c"
nqqr" fkwtgvke." 3" i" vykeg" fckn{" *ugg" cdqxg+0" Vjg" cfokpkuvtcvkqp" uejgfwng" yknn" fgrgpf" qp"
yjgvjgt" vjg" rcvkgpv" jcu" rwtg" qt" okzgf" *dkectdqpcvgu" @48" ooqn1N+" cnmcnquku." yjkej" yknn" dg"
ejgemgf"fckn{"d{"dnqqf"icu"cpcn{ugu"yjkng"vjg"rcvkgpv"ku"qp"kpxcukxg"ogejcpkecn"xgpvkncvkqp0"
Vjg" vtgcvogpv" yknn" dg" cfokpkuvgtgf" vjtqwijqwv" vjg" fwtcvkqp" qh" kpxcukxg" ctvkhkekcn" xgpvkncvkqp"
*cegvc|qncokfg" vtgcvogpv" yknn" dg" uvqrrgf" qp" gzvwdcvkqp" qt" yjgp" ogejcpkecn" xgpvkncvkqp" ku"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
34182" "
"
uvqrrgf" kp" rcvkgpvu" ykvj" c" vtcejgqvqo{" qt" qp" vjg" tgvwtp" vq" wuwcn" xgpvkncvkqp" ogvjqfu" hqt"
rcvkgpvu"ykvj"vtcejgqvqokgu"tqwvkpgn{"xgpvkncvgf"cv"jqog+0"
"
4" QDLGEVKXGU"QH"VJG"UVWF["
403" Rtkpekrcn"qdlgevkxg"
Vjg"rtkpekrcn"qdlgevkxg"yknn"dg"vq"cuuguu"vjg"ghhgev"qh"cegvc|qncokfg"qp"vjg"fwtcvkqp"
qh" kpxcukxg" ogejcpkecn" xgpvkncvkqp" kp" kpvgpukxg" ectg" kp" kpvwdcvgf" qt" vtcejgqvqok|gf" EQRF"
rcvkgpvu0" Yg" gzrgev" vq" ugg" c" fgetgcug" qh" vjg" qtfgt" qh" 37'" kp" vjg" fwtcvkqp" qh" kpxcukxg"
ogejcpkecn" xgpvkncvkqp" *fwg" rctvkewnctn{" vq" c" fgetgcug" kp" vjg" fwtcvkqp" qh" ygcpkpi" qhh" qh"
kpxcukxg"ogejcpkecn"xgpvkncvkqp+."vqigvjgt"ykvj"c"fgetgcug"kp"vjg"htgswgpe{"qh"eqornkecvkqpu"
nkpmgf"vq"kpxcukxg"ogejcpkecn"xgpvkncvkqp0"
"
404" Ugeqpfct{"qdlgevkxgu"
"Vjg" ugeqpfct{" qdlgevkxgu" kpenwfg" cuuguukpi" vjg" uchgv{" qh" vtgcvogpv" cpf" gxcnwcvkpi"
vjg"ghhgev"qh"cegvc|qncokfg"qp<"
/" Vjg"fwtcvkqp"qh"ygcpkpi"qhh"qh"ogejcpkecn"xgpvkncvkqp0"
/" Ygcpkpi"uweeguu0"
/" Vjg"pwodgt"qh"wprncppgf"gzvwdcvkqpu0"
/" Vjg"pggf"hqt"pqpkpxcukxg"xgpvkncvkqp"*PKX+"chvgt"gzvwdcvkqp0"
/" Vjg"pwodgt"qh"XCR0"
/" Fwtcvkqp"qh"jqurkvcnk|cvkqpu"kp"kpvgpukxg"ectg"wpkv0"
/" Oqtvcnkv{"kp"kpvgpukxg"ectg"wpkv"wpkv0"
"
5" OGVJQFQNQI["
503" Gzrgtkogpvcn"rncp"
Yg" yknn" ectt{" qwv" c" tcpfqok|gf." rncegdq/eqpvtqnngf." fqwdng/dnkpf" ownvkegpvgt" uvwf{."
kpenwfkpi"vyq"rctcnngn"itqwru"qh"EQRF"rcvkgpvu"wpfgtiqkpi"kpxcukxg"ogejcpkecn"xgpvkncvkqp"
hqt" cewvg" tgurktcvqt{" fgeqorgpucvkqp" cpf" cv" tkum" qh" rtqnqpigf" ogejcpkecn" xgpvkncvkqp" cpf"
fkhhkewnvkgu"dgkpi"ygcpgf"qhh"qh"tgurktcvqt{"cuukuvcpeg"*uwrgtkqtkv{"uvwf{+0"
"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
35182" "
"
504" Uvwf{"rqrwncvkqp"
"
Vjg"uvwf{"rqrwncvkqp"eqpukuvu"qh"EQRF"rcvkgpvu<"
/" Tgswktkpi"kpxcukxg"ogejcpkecn"xgpvkncvkqp"kp"kpvgpukxg"ectg"wpkv"*xkc"kpvwdcvkqp"qt"
c" vtcejgqvqo{" ecppwnc+" hqt" cewvg" tgurktcvqt{" fgeqorgpucvkqp" *kpenwfkpi"
rquvqrgtcvkxg"fgeqorgpucvkqp+."
/" Cv"tkum"qh"fgxgnqrkpi"ogvcdqnke"cnmcnquku"fwtkpi"vjg"eqwtug"qh"kpxcukxg"ogejcpkecn"
xgpvkncvkqp" *c" htgswgpv" ukvwcvkqp" kp" kpvgpukxg" ectg" wpkv+." cpf" vjgtghqtg" cv" tkum" qh"
rtqnqpigf" ogejcpkecn" xgpvkncvkqp" cpf" fkhhkewnv" ygcpkpi" qhh" qh" tgurktcvqt{"
cuukuvcpeg0"
"
Ogvcdqnke" cnmcnquku" ku" gzvtgogn{" htgswgpv" kp" EQRF" rcvkgpvu" tgswktkpi" tgurktcvqt{"
cuukuvcpeg." fwg." kp" rctvkewnct." vq" vjg" tgxgpvkncvkqp" ghhgev." yjkej" tcrkfn{" nqygtu" j{rgtecrpke"
cekfquku0"Ogvcdqnke"cnmcnquku"ku"pqv"cp"kpenwukqp"etkvgtkqp."dwv"kv"ku"c"rctcogvgt"wugf"vq"oqpkvqt"
vtgcvogpv"cfokpkuvtcvkqp"*cegvc|qncokfg"qt"rncegdq+"kp"vjku"uvwf{0""
"
EQRF" rcvkgpvu" jcxg" c" ejtqpke" tgurktcvqt{" jcpfkecr." vjg" ugxgtkv{" qh" yjkej" fkhhgtu"
dgvyggp"rcvkgpvu0"Cv"jqog."vjgkt"tgurktcvkqp"oc{"tgswktg<"
/" Pq"cuukuvcpeg"
/" Qz{igp"uwrrngogpvcvkqp"
/" Pqpkpxcukxg"xgpvkncvkqp"*PKX+"
/" Vtcejgqvqo{"
/" Vtcejgqvqo{"cpf"tgurktcvqt{"cuukuvcpeg0"
"
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"
xgpvkncvkqp" ocmg" vjku" rqrwncvkqp" kfgcn" hqt" uvwfkgu" qh" vjg" ghhkece{" qh" cegvc|qncokfg" hqt" vjku"
kpfkecvkqp0"
"
505" Gnkikdknkv{"etkvgtkc"hqt"rctvkekrcvkqp"kp"vjku"uvwf{"
50503" Kpenwukqp"etkvgtkc"
Cnn"rcvkgpvu<"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
36182" "
"
/" EQRF." tgictfnguu" qh" tgurktcvqt{" uvcvwu" cv" jqog" *pq" tgurktcvqt{" cuukuvcpeg." Q4"
uwrrngogpvcvkqp." PKX." vtcejgqvqo{" qt" xgpvkncvkqp" -" vtcejgqvqo{+0" Vjg" etkvgtkc"
fghkpkpi"EQRF"ctg"vjqug"qh"vjg"CVU"*Cogtkecp"Vjqtceke"Uqekgv{0"Uvcpfctfu"hqt"vjg"
fkcipquku"cpf"ectg"qh"rcvkgpvu"ykvj"EQRF0"Co"L"Tgurkt"Etkv"Ectg"Ogf"3;;7="374<U99/
U342+0"
/" Cig" 3:"{gctu0"
/" Uqekcn"ugewtkv{"eqxgt0"
/" Jqurkvcnk|gf" kp" kpvgpukxg" ectg" hqt" tgurktcvqt{" kpuwhhkekgpe{" *kpenwfkpi" rquvqrgtcvkxg"
tgurktcvqt{"kpuwhhkekgpe{+0"
/" Kpxcukxg"xgpvkncvkqp"*d{"kpvwdcvkqp"qt"ykvj"c"vtcejgqvqo{"ecppwnc+>"46"jqwtu0"
/" Rtkqt"ogfkecn"gzcokpcvkqp"crrtqrtkcvg"hqt"vjg"uvwf{0"
/" Kphqtogf" eqpugpv" qdvckpgf" htqo" hcokn{" ogodgtu" qt" vtwuvgf" htkgpfu" kh" rtgugpv." cpf"
htqo"vjg"rcvkgpv"jkougnh1jgtugnh"cu"uqqp"cu"rquukdng0"
50504" Gzenwukqp"etkvgtkc"
/" Jkuvqt{"qh"cnngti{"vq"cegvc|qncokfg0"
/" Jkuvqt{"qh"cnngti{"vq"uwnhcokfgu0"
/" Eqpvtckpfkecvkqp"qh"cegvc|qncokfg<"jkuvqt{"qh"pgrjtkvke"eqnke."rtgipcpv."dtgcuv/hggfkpi."
jgrcvqegnnwnct"kpuwhhkekgpe{"*dknwtwdkp"eqpegpvtcvkqp"@372"oqn1N"cpf"CUCV"cevkxkv{"
@722" KW+" ykvj" c" RT" >72" '." cftgpcn" kpuwhhkekgpe{" ykvjqwv" qrqvjgtcr{" uwduvkvwvkqp."
ejtqpke"tgpcn"kpuwhhkekgpe{"ykvj"etgcvkpgokc"@472"oqn1N"cpf1qt"nqpi/vgto"gzvtctgpcn"
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/" E{uvke"hkdtquku"qt"dtqpejkcn"fkncvcvkqp0"
/" Oqtkdwpf"rcvkgpv"*nkhg"gzrgevcpe{">5"yggmu+0"
/" Rcvkgpv" cntgcf{" kpenwfgf" kp" cpqvjgt" kpvgtxgpvkqpcn" enkpkecn" vtkcn" rtqvqeqn." crctv" htqo"
gzegrvkqpu" cwvjqtk|gf" d{" vjg" eqqtfkpcvkpi" kpxguvkicvqt" tgrtgugpvkpi" vjg" uvggtkpi"
eqookvvgg0""
/" Rtgipcpv"qt"dtgcuvhggfkpi"yqogp0"
/" Rtkuqpgtu"cpf"kpuvkvwvkqpcnk|gf"rcvkgpvu0"
/" Ngicnn{"kpeqorgvgpv"cfwnvu0"
"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
37182" "
"
506" Fwtcvkqp"qh"vjg"uvwf{"cpf"qh"vjg"rctvkekrcvkqp"qh"kpfkxkfwcn"rcvkgpvu"
Vjg"vqvcn"fwtcvkqp"qh"vjg"uvwf{"ku"vjtgg"{gctu0"Vjg"fwtcvkqp"qh"vjg"kpenwukqp"rgtkqf"ku"
hkzgf" cv" 57" oqpvju0" Vjg" fwtcvkqp" qh" rctvkekrcvkqp" hqt" kpfkxkfwcn" rcvkgpvu" ku" nkokvgf" vq" vjg"
fwtcvkqp"qh"kpxcukxg"ogejcpkecn"xgpvkncvkqp"*yjkej"oc{"dg"kpkvkcvgf"dghqtg"cfokuukqp"vq"vjg"
kpvgpukxg"ectg"wpkv+"cpf"yknn"pqv"gzeggf"4:"eqpugewvkxg"fc{u"*Hkiwtg"3+0"Vjg"cfokpkuvtcvkqp"qh"
cegvc|qncokfg" qt" rncegdq" yknn" eqpvkpwg" wpvkn" gzvwdcvkqp" qt" vjg" eguucvkqp" qh" ogejcpkecn"
xgpvkncvkqp"kp"vtcejgqvqok|gf"rcvkgpvu"qt"wpvkn"vjg"tgvwtp"vq"wuwcn"xgpvkncvkqp"kp"vtcejgqvqok|gf"
rcvkgpvu"xgpvkncvgf"cv"jqog0"Vjg"oczkowo"fwtcvkqp"qh"rctvkekrcvkqp"ku"hkzgf"cv"4:"eqpugewvkxg"
fc{u"qh"kpxcukxg"ogejcpkecn"xgpvkncvkqp0"
"
6" LWFIOGPV"ETKVGTKC"
603" Rtkpekrcn"lwfiogpv"etkvgtkqp"
"
Vjg" rtkpekrcn" lwfiogpv" etkvgtkqp" ku" vjg" fwtcvkqp" *kp" jqwtu+" qh" kpxcukxg" ogejcpkecn"
xgpvkncvkqp0"
/" Hqt" rcvkgpvu" ykvjqwv" tgurktcvqt{" cuukuvcpeg" cv" jqog." qt" ykvj" qz{igp" uwrrngogpvcvkqp"
qt"PKX"cv"jqog."ogcuwtgogpv"yknn"dgikp"ykvj"kpvwdcvkqp"*pqv"pgeguuctkn{"kp"kpvgpukxg"
ectg+"cpf"yknn"gpf"cv"gzvwdcvkqp"kp"kpvgpukxg"ectg"wpkv0"
/" Hqt" rcvkgpvu" yjq" ygtg" cntgcf{" vtcejgqvqok|gf." ogcuwtgogpv" yknn" dgikp" ykvj" vjg"
kpkvkcvkqp" qh" kpxcukxg" xgpvkncvkqp" cpf" yknn" gpf" yjgp" vjku" kpxcukxg" xgpvkncvkqp" ku"
eqorngvgn{"uvqrrgf0"
/" Hqt" vtcejgqvqok|gf" rcvkgpvu" qp" tgurktcvqt{" cuukuvcpeg" cv" jqog." ogcuwtgogpv" yknn"
dgikp" cv" vjg" kpkvkcvkqp" qh" c" v{rg" qh" kpxcukxg" xgpvkncvkqp" fkhhgtgpv" htqo" vjcv" tqwvkpgn{"
wugf" cv" jqog" xkc" vjg" vtcejgqvqo{" ecppwnc" cpf" yknn" gpf" ykvj" vjg" tgvwtp" vq" wuwcn"
xgpvkncvkqp"ogvjqfu0"
"
604" Ugeqpfct{"lwfiogpv"etkvgtkc""
60403" Nkuv"qh"etkvgtkc"
Ugeqpfct{"lwfiogpv"etkvgtkc"tgncvkpi"vq"vjg"uchgv{"qh"cegvc|qncokfg"
/"
Vqngtcpeg"qh"cegvc|qncokfg"cpf"rquukdng"qeewttgpeg"qh"cfxgtug"ghhgevu0"
""""""""Ugeqpfct{"lwfiogpv"etkvgtkc"tgncvkpi"vq"vjg"ghhkece{"qh"cegvc|qncokfg"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
38182" "
"
/"
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:0503" Pqp/ugtkqwu"cfxgtug"gxgpvu"
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rpgwoqvjqtcz."ugtkqwu"cttj{vjokc"pqv"nkpmgf"vq"j{rqmcngokc."pquqeqokcn"rpgwoqpkc."uvtguu/
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"
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4;182" "
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kpugtvkqp+0"
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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"
qh" cfxgtug" gxgpvu" *k0g0" vq" jgnr" vjgo" vq" fkhhgtgpvkcvg" dgvyggp" gxgpvu" qh" fkhhgtgpv" fgitggu" qh"
itcxkv{+0"Vjku"itkf"ycu"fgxgnqrgf"cpf"xcnkfcvgf"d{"mg{"rnc{gtu"kp"vjku"uvwf{"*vjg"Jgcf"qh"vjg"
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Eqqtfkpcvqt" qh" vjg" Enkpkecn" Tgugctej" cpf" Fgxgnqrogpv" Fgrctvogpv" cpf" vjg" Jgcf" qh"
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qt"c"nkhg/vjtgcvgpkpi"gxgpv+0"
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qvjgt"rquukdng"vtgcvogpv0"
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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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tghtcevqt{" vq" wuwcn" vtgcvogpv" fwtkpi" rgthwukqp" qh" vjg" vguv" rtqfwev." j{rgtwtkegokc" ykvj" cewvg"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
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52182" "
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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"
vjg" kplgevkqp" qh" vjg" uvwf{" vtgcvogpv." qh" ectfkqxcuewnct" ukipu" *ugxgtg" ctvgtkcn" j{rqvgpukqp."
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"
ugxgtkv{0"
Tghtcevqt{"j{rqvgpukqp"ku"eqpukfgtgf"vq"eqttgurqpf"vq"c"ogcp"ctvgtkcn"dnqqf"rtguuwtg"
dgnqy" 92" oo" Ji" fgurkvg" xcuewnct" hknnkpi" ykvj" vyq" dqnwugu" qh" 472" oN" qh" ucnkpg" cpf" vjg"
kplgevkqp"qh"cv"ngcuv"qpg"xcuqeqpuvtkevqt"qt"kpqvtqrg0"Cttj{vjokc"ku"eqpukfgtgf"tghtcevqt{"kh"kv"
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uvwf{"d{"ogcpu"qh"vjg"wpkswg"eqfg"pwodgt"cvvtkdwvgf"vq"vjg"rcvkgpv"eqpegtpgf0"
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tgrqtvu."cwvqru{"tguwnvu"gve0+0"
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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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Enkpkecn"Tgugctej"cpf"Fgxgnqrogpv."chvgt"gxcnwcvkqp"qh"vjg"itcxkv{"qh"vjg"cfxgtug"gxgpv."vjg"
ecwucn" nkpm" ykvj" vjg" gzrgtkogpvcn" ftwi" cpf" cp{" qvjgt" vtgcvogpvu" cfokpkuvgtgf" cpf" vjg"
wpgzrgevgfpguu"qh"vjg"UCG"qdugtxgf0"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
53182" "
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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"
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54182" "
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:070"Wpdnkpfkpi"rtqegfwtg"
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*cpcrj{ncevke"ujqem."ctvgtkcn"j{rqvgpukqp"qt"cttj{vjokc"tghtcevqt{"vq"wuwcn"vtgcvogpvu"fwtkpi"
rgthwukqp"qh"vjg"vguv"rtqfwev."j{rgtwtkegokc"ykvj"cewvg"iqwv."u{orvqocvke"j{rqmcngokc"ykvj"
cttj{vjokc+0"
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korgtcvkxgn{" hqnnqy" vjg" rtqegfwtg" hqt" fgenctkpi" ugtkqwu" cfxgtug" gxgpvu" vq" vjg" rtqoqvgt0"
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*FTEF+." fwtkpi" qhhkeg" jqwtu<" Ocwf" Lcewdgtv" *Rtqlgev" Ngcfgt+" 23062049079049" 1" hcz"
230660:60390230"
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qpn{" lwuvkhkecvkqp" hqt" gogtigpe{" wpdnkpfkpi" ku" crrctgpv" cpcrj{ncevke" ujqem" qeewttkpi" chvgt"
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56182" "
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
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57182" "
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
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58182" "
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34"SWCNKV["EQPVTQN"CPF"CUUWTCPEG"
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59182" "
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Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
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3504" Tgswguv"hqt"cwvjqtk|cvkqp"htqo"vjg"gvjkeu"eqookvvgg"
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owuv"uwdokv"vjg"tgugctej"rtqvqeqn"vq"vjg"crrtqrtkcvg"gvjkeu"eqookvvgg"*Comit 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" rtqoqvgtu" kpkvkcvkxg"
owuv."dghqtg"kvu"korngogpvcvkqp."dg"crrtqxgf"d{"vjg"gvjkeu"eqookvvgg"cpf"cwvjqtk|gf"d{"vjg"
eqorgvgpv" cwvjqtkv{0" Kp" vjku" ecug." kh" pgeguuct{." vjg" eqookvvgg" yknn" gpuwtg" vjcv" kphqtogf"
eqpugpv"ku"eqnngevgf"cickp"htqo"vjg"rctvkekrcpvu"kp"vjg"uvwf{0"
Cp{" gzvgpukqp" qh" vjg" uvwf{" *rtqhqwpf" oqfkhkecvkqp" qh" vjg" vtgcvogpv" rncp" qt" qh" vjg"
rqrwncvkqpu"kpenwfgf."rtqnqpicvkqp"qh"vtgcvogpvu"cpf1qt"vjgtcrgwvke"cevu"pqv"kpkvkcnn{"kpenwfgf"
kp"vjg"rtqvqeqn+"ujqwnf"dg"eqpukfgtgf"cu"c"pgy"uvwf{0"
Cnn"uwduvcpvkcn"oqfkhkecvkqpu"ujqwnf"dg"vjg"qdlgev"qh"c"tgswguv"hqt"cwvjqtk|cvkqp"htqo"
CHUUCRU"cpf1qt"c"tgswguv"hqt"gvjkeu"eqookvvgg"crrtqxcn"uwdokvvgf"d{"vjg"rtqoqvgt0"
"
3506" EPKN"fgenctcvkqp"""
Vjg"ncy"tgswktgu"c"fgenctcvkqp"qh"vjg"eqorwvgtk|gf"hkng"qh"rgtuqpcn"fcvc"eqnngevgf"hqt"
vjg"uvwf{"dghqtg"vjg"uvwf{"dgikpu0"
C" tghgtgpeg" ogvjqfqnqi{" urgekhke" vq" vjg" vtgcvogpv" qh" rgtuqpcn" fcvc" kp" vjg"
htcogyqtm" qh" dkqogfkecn" tgugctej." fghkpgf" d{" ncy" 4226/:28" qh" Cwiwuv" ;" 4226" crrnkgu"
wpfgt"ctvkengu"N03343/3"cpf"ceeqtfkpi"vq"vjg"Htgpej"Rwdnke"Jgcnvj"Eqfg0"Vjku"ogvjqfqnqi{"
ycu"guvcdnkujgf"d{"vjg"EPKN"kp"Lcpwct{"42280"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
5;182" "
"
Vjku"ogvjqfqnqi{"cnnqyu"c"ukornkhkgf"fgenctcvkqp"rtqegfwtg"yjgp"vjg"pcvwtg"qh"vjg"
fcvc"eqnngevgf"kp"vjg"uvwf{"ku"eqorcvkdng"ykvj"vjg"nkuv"rtqxkfgf"d{"vjg"EPKN"kp"kvu"tghgtgpeg"
fqewogpv0"
Yjgp" vjg" rtqvqeqn" ku" uwdlgev" vq" fcvc" swcnkv{" eqpvtqn" d{" c" enkpkecn" tgugctej" cuukuvcpv"
tgrtgugpvkpi"vjg"rtqoqvgt"cpf"hcnnu"kpvq"vjg"hkgnf"qh"crrnkecvkqp"qh"vjg"ukornkhkgf"rtqegfwtg"qh"
vjg"EPKN."vjg"FTEF."cu"vjg"rtqoqvgt."yknn"cum"vjg"rgtuqp"tgurqpukdng"hqt"vjg"eqorwvgt"hkng"vq"
rtqxkfg"c"ytkvvgp"eqookvogpv"vq"tgurgev"vjg"OT223"ukornkhkgf"tghgtgpeg"ogvjqfqnqi{0"
"
3507" Kphqtocvkqp"cpf"kphqtogf"eqpugpv"hqtou"
Kpfkxkfwcnu" cfokvvgf" vq" kpvgpukxg" ectg" hqt" tgurktcvqt{" kpuwhhkekgpe{." kpenwfkpi"
rquvqrgtcvkxg" tgurktcvqt{" kpuwhhkekgpe{." yknn" dg" kpenwfgf" kp" vjku" dkqogfkecn" tgugctej" uvwf{0"
Vjg" rcvkgpvu" yknn" pqv" kpkvkcnn{" dg" cdng" vq" ikxg" eqpugpv" vjgougnxgu0" Eqpugpv" yknn" vjgtghqtg" dg"
tgswguvgf" htqo" hcokn{" ogodgtu" qt" enqug" htkgpfu." kh" rtgugpv." kp" ceeqtfcpeg" ykvj" ctvkeng" N0"
3344/3/4"qh"vjg"Htgpej"Rwdnke"Jgcnvj"Eqfg0""
Vjg" rcvkgpv" yknn" dg" kphqtogf" cu" uqqp" cu" rquukdng" cpf." chvgt" c" uwkvcdng" rgtkqf" qh"
tghngevkqp." yknn" dg" cumgf" hqt" jku" qt" jgt" eqpugpv" vq" eqpvkpwg" rctvkekrcvkqp" kp" vjg" uvwf{0" Vjg"
rcvkgpv"oc{."cv"cp{"vkog."qrrqug"vjg"wug"qh"jku"qt"jgt"fcvc"kp"vjg"htcogyqtm"qh"vjku"uvwf{0"
Vjku"uvwf{"yknn"pqv"kpenwfg"kpfkxkfwcnu"eqxgtgf"d{"ctvkengu"N0"3343/7"vq"N0"3343/:"qh"
vjg"Htgpej"Rwdnke"Jgcnvj"Eqfg<"rtgipcpv"yqogp."rtkuqpgtu"cpf"kpuvkvwvkqpcnk|gf"uwdlgevu."cpf"
cfwnvu"uwdlgev"vq"ngicn"rtqvgevkqp0"
"
3508" Hkpcn"tgrqtv"
Vjg"hkpcn"uvwf{"tgrqtv"yknn"dg"lqkpvn{"ytkvvgp"d{"vjg"Eqqtfkpcvqt"cpf"vjg"Dkquvcvkuvkekcp"hqt"
vjku" uvwf{0" Vjku" tgrqtv" yknn" dg" uwdokvvgf" vq" gcej" qh" vjg" kpxguvkicvqtu" hqt" crrtqxcn0" Qpeg" c"
eqpugpuwu"jcu"dggp"tgcejgf."vjg"hkpcn"xgtukqp"yknn"dg"gpfqtugf"d{"vjg"ukipcvwtg"qh"gcej"qh"vjg"
kpxguvkicvqtu"cpf"ugpv"vq"vjg"rtqoqvgt."cu"uqqp"cu"rquukdng"chvgt"vjg"ghhgevkxg"gpf"qh"vjg"uvwf{0"
C" tgrqtv" ytkvvgp" ceeqtfkpi" vq" vjg" tghgtgpeg" rncp" qh" vjg" eqorgvgpv" cwvjqtkv{" owuv" dg" ugpv" vq"
vjku"cwvjqtkv{"cpf"vq"vjg"gvjkeu"eqookvvgg"ykvjkp"qpg"{gct"qh"vjg"gpf"qh"vjg"uvwf{."fghkpgf"cu"
vjg" ncuv" hqnnqy/wr" xkukv" qh" vjg" ncuv" uwdlgev" kpenwfgf0" Vjku" vkog" nkokv" yknn" dg" fgetgcugf" vq" ;2"
fc{u"kh"vjg"uvwf{"gpfu"gctn{0"
/"Hktuv"cwvjqt<"Rtkpekrcn"Kpxguvkicvqt."Ft"Ejtkuvqrjg"Hcku{"
/"Ugeqpf"cwvjqt<"Kpvgpukxg"ectg"fqevqt"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
62182" "
"
/"Vjktf"cwvjqt<"tgrtgugpvcvkxg"qh"vjg"Enkpkecn"Tgugctej"Wpkv"qh"JGIR"
/"Hqwtvj."hkhvj"cpf"ukzvj"cwvjqtu<"Kpvgpukxg"ectg"fqevqtu""
/"Rgpwnvkocvg"cwvjqt<"Kpvgpukxg"ectg"fqevqt"
/"Ncuv"cwvjqt<"Uekgpvkhke"Fktgevqt.""Rtqh0"Lgcp/[xgu"Hciqp"
Vjg"tcpmkpi"qh"vjg"cwvjqtu"yknn"dg"fgvgtokpgf"d{"vjg"pwodgt"qh"kpenwukqpu"cv"gcej"egpvgt0"
"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
63182" "
"
"
37"KPUWTCPEG"CPF"UEKGPVKHKE"EQOOKVOGPV
3703" Kpuwtcpeg"
Assistance Publique-Hpitaux de Paris" ku" vjg" rtqoqvgt" qh" vjku" uvwf{0" Kp" ceeqtfcpeg"
ykvj"dkqogfkecn"tgugctej"ncy."CR/JR"jcu"vcmgp"qwv"cp"kpuwtcpeg"rqnke{"ykvj"JFQ"IGTNKPI"
hqt"vjg"gpvktg"fwtcvkqp"qh"vjku"uvwf{."eqxgtkpi"kvu"qyp"ekxkn"tgurqpukdknkvkgu"cpf"vjqug"qh"cp{qpg"
kpxqnxgf" kp"vjg" uvwf{" *fqevqtu" cpf" uvchh" ogodgtu" ectt{kpi" qwv" vjg" uvwf{=" ncy" pq0" 4226/:28."
Ctv"N03343/32"qh"vjg"Htgpej"Rwdnke"Jgcnvj"Eqfg+0"
Assistance Publique-Hpitaux de Paris" tgugtxgu" vjg" tkijv" vq" uvqr" vjg" uvwf{" cv" cp{"
oqogpv." hqt" ogfkecn" qt" cfokpkuvtcvkxg" tgcuqpu0" Ujqwnf" vjku" qeewt." vjg" kpxguvkicvqt" yknn" dg"
pqvkhkgf0"
"
3704" Uekgpvkhke"eqookvogpv"
Gcej"kpxguvkicvqt"yknn"citgg"vq"tgurgev"ngicn"qdnkicvkqpu"cpf"vq"ectt{"qwv"vjg"uvwf{"kp"
ceeqtfcpeg" ykvj" IER" cpf" vjg" vgtou" qh" vjg" Jgnukpmk" Fgenctcvkqp" kp" hqteg0" C" eqr{" qh" vjg"
uekgpvkhke"eqookvogpv"*FTEF/v{rg"fqewogpv+."fcvgf"cpf"ukipgf"d{"gcej"kpxguvkicvqt"cv"
gcej"qh"vjg"rctvkekrcvkpi"egpvgtu"yknn"dg"uwrrnkgf"vq"tgrtgugpvcvkxg"qh"vjg"rtqoqvgt"vq"gpuwtg"
vjku0"
"
38"RWDNKECVKQP"TWNGU"
CR/JR"qypu"vjg"fcvc."yjkej"owuv"pqv"dg"wugf"qt"vtcpuokvvgf"vq"c"vjktf"rctv{"ykvjqwv"vjg"
rtkqt"citggogpv"qh"vjg"CR/JR0"
Vjg" hktuv" cwvjqtu" qp" rwdnkecvkqpu" yknn" dg" vjg" kpfkxkfwcnu" yjq" tgcnn{" rctvkekrcvgf" kp" vjg"
fgxgnqrogpv"cpf"twppkpi"qh"vjg"rtqvqeqn."cpf"kp"vjg"igpgtcvkqp"cpf"ytkvkpi"qh"tguwnvu0"
Assistance Publique-Hpitaux de Paris"owuv"dg"ekvgf"cu"vjg"rtqoqvgt"qh"vjg"tgugctej"cpf"
cu"vjg"uqwteg"qh"hwpfkpi."cu"crrtqrtkcvg0"Vjg"vgtou"Assistance Publique-Hpitaux de Paris"
owuv"crrgct"kp"vjg"cfftguugu"qh"vjg"cwvjqtu0"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
64182" "
"
"
39"TGHGTGPEGU""
3/" Tcekpgwz" LE." Xkfcn" LH." Ogunkgt" P0" Ngu" ocncfkgu" tgurktcvqktgu" ejtqpkswgu" nkgu" cw"
vcdcikuog0"Tgx"Rtcv"3;;5=37"<354/363"
4/" Oqtcp" L." Itggp" LX." Jqocp" UF<" Cewvg" gzcegtdcvkqpu" qh" ejtqpke" qduvtwevkxg" rwnoqpct{"
fkugcug"cpf"ogejcpkecn"xgpvkncvkqp<"C"tggxcnwcvkqp0"Etkv"Ectg"Ogf"3;;:=48<93/"9:"
5/"Ugpghh"OI."Ycigpgt"FR."Ycigpgt"TR<"Jqurkvcn"cpf"3"{gct"uwtxkxcn"qh"rcvkgpvu"cfokvvgf"
vq" kpvgpukxg" ectg" wpkvu" ykvj" cewvg" gzcegtdcvkqpu" qh" ejtqpke" qduvtwevkxg" nwpi" fkugcug0" LCOC"
3;;7=496<3:74/3:79"
6/" Xkgik" I." Ueqipcokinkq" C." Dcnfceeku" U" cpf" cn0" Grkfgokqnqi{" qh" ejtqpke" qduvtwevkxg"
rwnoqpct{"fkugcug"*EQRF+0"Tgurktcvkqp"4223=8:<6/3;"
7/"Hwuq"N."Kpecn|k"TC."Rkuvgnnk"T"gv"cn0"Rtgfkevkpi"oqtvcnkv{"qh"rcvkgpvu"jqurkvcnk|gf"hqt"cewvgn{"
gzcegtdcvgf"ejtqpke"qduvtwevkxg"rwnoqpct{"fkugcug0"Co"L"Ogf"3;;7=;:<494/499"
8/" Mpcwu" YC0" Rtqipquku" ykvj" ogejcpkecn" xgpvkncvkqp<" vjg" kphnwgpeg" qh" fkugcug." ugxgtkv{" qh"
fkugcug." cig" cpf" ejtqpke" uvcvwu" qp" uwtxkxcn" htqo" cp" cewvg" knnpguu0" Co" Tgx" Tgur" Fku"
3;:;=362<U:/U35"
9/"Iwn"Iwtugn0"Fgvgtokpcpvu"qh"vjg"ngpivj"qh"ogejcpkecn"xgpvkncvkqp"kp"rcvkgpvu"ykvj"EQRF"kp"
vjg"kpvgpukxg"ectg"wpkv0"Tgurktcvqt{"Ogfkekpg"4227=94<83/89"
:/"Pgxkpu"ON."Gruvgkp"UM0"Rtgfkevqtu"qh"qwveqog"hqt"rcvkgpvu"ykvj"EQRF"tgswktkpi"kpvgpukxg"
ogejcpkecn"xgpvkncvkqp0"Ejguv"4223=33;<3:62/3:6;"
;/"Ogp|kgu"T."Ikddqpu"Y."Iqnfdgti"R0"Fgvgtokpcpvu"qh"ygcpkpi"cpf"uwtxkxcn"coqpi"rcvkgpvu"
ykvj" EQRF" yjq" tgswktg" ogejcpkecn" xgpvkncvkqp" hqt" cewvg" tgurktcvqt{" hcknwtg0" Ejguv"
3;:;=;7<5;:/627"
32/" Ygduvgt" PT." Mwnmctpk" X0" Ogvcdqnke" cnmcnquku" kp" vjg" etkvkecnn{" knn0" Etkv" Tgx" Ncd" uek"
3;;;=58"*7+<6;9/732"
33/" Icnncigt" VL0" Ogvcdqnke" cnmcnquku" eqornkecvkpi" ygcpkpi" htqo" ogejcpkecn" xgpvkncvkqp0"
Uqwvj"Ogf"L"3;9;=94<9:8"
34/"Ejgxtqngv"LE0"Rgtvwtdcvkqpu"fg"nswknkdtg"cekfg/dcug0"Gpe{enqrfkg"Ofkeq/ejktwtikecng"
Rpgwoq."8/222/C/97"
35/" Tqug" D0" Tgurktcvqt{" cekfquku0Kp" Tqug" D" gf0" Enkpkecn" rj{ukqnqi{" qh" cekf/dcug" cpf"
gngevtqn{vgu"fkuqtfgtu0"Pgy"[qtm<"OeItcy/Jknn.3;:6<662/683"
36/"Mjcppc"C."Mwtv|ocp"C0"Ogvcdqnke"cnmcnquku0"Tgurkt"Ectg"4223=68<576/587"
Rtqvqeqng"R2:342:a"xgtukqp"4"fw"4412814233"
"
65182" "
"
37/" Yknuqp" 3" TH." Ikduqp" F." Rgtekpgn" CM." " Cnk" OC." Dcmgt" I." NgDncpe" R." Nwecu" E0" Ugxgtg"
cnmcnquku"kp"etkvkecnn{"knn"uwtikecn"rcvkgpvu0"Ctej"Uwti"3;94=327<3;9/425"
38/" Jqfimkp" LG." Uqgrtqpq" HH." Ejcp" FO0" Kpekfgpeg" qh" ogvcdqnke" cnmcngokc" kp" jqurkvcnkugf"
rcvkgpvu0"Etkv"Ectg"Ogf"3;:2=34<947/94:"
39/" Mtkpvgn" LL." Jczjqnfv" QU." Dgtvjgnugp" R." Dtqempgt" L0" Ectdqp" fqzkfg" gnkokpcvkqp" chvgt"
cegvc|qncokfg"kp"rcvkgpvu"ykvj"ejtqpke"qduvtwevkxg"rwnoqpct{"fkugcug"cpf"ogvcdqnke"cnmcnquku0"
Cevc"Cpguvjgukqn"Uecpf"3;:5=49<474/476"
3:/" Dgtvjgnugp" R0" Ectfkqxcuewnct" rgthqtocpeg" cpf" qz{jgoqinqdkp" fkuuqekcvkqp" chvgt"
cegvc|qncokfg"kp"ogvcdqnke"cnmcnquku0"Kpvgpukxg"Ectg"Ogf"3;:4=:<48;/496"
3;/" Cppg" G." Jqnncpf." Lqjp" Y" Yknuqp0" Ogvcdqnke" cnmcnquku" eqpvtkdwvg" vq" cewvg" j{rgtecrpke"
tgurktcvqt{"hcknwtg"kp"cfwnv"e{uvke"hkdtquku0"Ejguv"4225=346<6;2/6;5"
42/" Tqug" D." Rquv" V0Enkpkecn" rj{ukqnqi{" qh" cekf/dcug" cpf" gngevtqn{vgu" fkuqtfgtu0" Pgy" [qtm<"
OeItcy/Jknn"4223"
43/" Dgtvjgnugp" R." Iqvjigp" K." Jwuwo" D" gv" cn0" Qz{igp" wrvcmg" cpf" EQ4" gnkokpcvkqp" chvgt"
cegvc|qncokfg"kp"etkvkecnn{"knn0"Kpvgpukxg"Ectg"Ogf"3;:7=33<48/4;"
44/" Dtkokqwnng" U." Dgttg" L." Fwhc{g" R" gv" cn0" J{ftqejnqtke" cekf" kphwukqp" hqt" vtgcvogpv" qh"
ogvcdqnke"cnmcnquku"cuuqekcvgf"ykvj"tgurktcvqt{"cekfquku0"Etkv"Ectg"Ogf"3;:;=39<454"
45/" Uygpuqp" GT0" Ectdqpke" cpj{ftcug" kpjkdkvqtu" cpf" xgpvkncvkqp<" c" eqorngz" kpvgtrnc{" qh"
uvkowncvkqp"cpf"uwrrtguukqp0"Gwt"Tgurkt"L"3;;:"=34"<3464/3469"
46/" Tkejcngv" LR." Nctokipcv" R." Tcvjcv" E0" Rqwoqp" gv" cnvkvwfg0" Gpe{enqrfkg" Ofkeq/
ejktwtikecng"Rpgwoqnqikg."8/285/C/32"
47/" Uygpuqp" GT." Octgp" VJ0" C" swcpvkvcvkxg" cpcn{uku" qh" EQ4" vtcpurqtv" cv" tguv" cpf" oczkocn"
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" cevcvg."
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"
"
66182" "
"
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"
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6080"Rtgipcpe{"cpf"ncevcvkqp"
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70"RJCTOCEQNQIKECN"RTQRGTVKGU"
7030"Rjctoceqf{pcoke"rtqrgtvkgu"
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This supplementary material has been provided by the authors to give readers
additional information about their work.
On-line-Only Supplement
Effect of Acetazolamide versus Placebo on Duration of Invasive Mechanical
Ventilation among Patients with Chronic Obstructive Pulmonary Disease: A
Randomized Clinical Trial
Investigators in the DIABOLO Trial
Iris Pelieu, Brice Lortat-Jacob, Marion Venot, Antoine Roux, Marine Gosset (European Georges Pompidou
Hospital, Paris); Olivier Martinet, Hassene Rahmani, Christine Kummerlen, David Schnell, Anca Raluga Neagu,
Xavier Delabranche, Julie Boisram-Helms (Nouvel Hpital Civil and EA 7293, Fdration de Mdecine
Translationnelle de Strasbourg, Strasbourg University, Strasbourg); Benjamin Zuber, Gilles Troch, Stphane
Legriel, Fabrice Brunel, Pierre Guezennec, Virginie Laurent, Julia Hilly-Ginoux, Mathieu Henry-Lagarrigue
(Andr Mignot Hospital, Le Chesnay); Philippe Vignon, Nicolas Pichon, Bruno Franois, Anthony Dugard,
Jean-Bernard Amiel, Emmanuelle Beguot, Remy Bellier (Limoges University Hospital, Limoges); Jean-Michel
Coulaud, Laurence Donetti, Jean Barchasz (Le Raincy-Montfermeil Hospital, Montfermeil); Marie-Line Harley,
Vincent Castelain, Philippe Lutun, Jean-Etienne Herbrecht, Ralf Janssen-Langestein, Maleka Schenck, Max
Guillot, Antoine Poidevin (Hautepierre Hospital, Strasbourg); Hlne Prodanovic, Mathieu Schmidt, Julien
Mayaux, Julie Delemazure, Romain Persichini (Piti-Salptrire University Hospital, Paris); Marie Conrad,
Damien Barraud, Alexandre Lai, Jrmie Lemarie, Lionel Nace, Aurlie Cravoisy-Popovic (Nancy University
Hospital, Nancy); Alain Mercat, Pierre Asfar, Achille Kouatchet, Marc Pierrot, Vincent Souday, Pierre
Bourgoin, Carole Fleury, Annelise Foucher-Lezla, Guillaume Bouvier, Tarek Abouzahr, Jacques-Armel
Giquello, Satar Mortaza (Angers University Hospital, Angers); Cdric Rafat, Clment Leclaire, Jonathan
Messika, Nicolas Dufour, Sylvain Jean-Baptiste, Romain Miguel Montanes, Stphane Gaudry (Louis-Mourier
University Hospital, Colombes); Muriel Fartoukh, Vincent Labbe, Antoine Parrot (Tenon University Hospital,
Paris); Pascal Fangio, Herv Outin, Christophe Barbier, Bernard De Jonghe, Jan Hayon, Yann Loubieres
(Poissy-Saint Germain Hospital, Poissy); Aurlie Lefebvre, Antoine Tesnieres (Cochin Hospital, Paris).
coma;
Renal insufficiency with serum creatinine >2.83 mg/dL (250 mol/L) or patient on dialysis;
Uncorrected adrenal insufficiency;
Uncorrected hypothyroidism;
Concomitant prescription of quinidine-like drugs or carbamazepine.
Test treatment was withdrawn definitively when anaphylactic shock or an anaphylactoid reaction occurred
during or following its administration.
Data Collected
Data collected at inclusion included age, sex, smoking history, use of long-term (>8 weeks) systemic
glucocorticoids, diuretics, acetazolamide or inhaled
2-agonists,
ventilation, tracheotomy, prior pulmonary function tests obtained with patient in stable condition when available,
body mass index, arterial blood gases measured on invasive ventilation, serum sodium, serum potassium, serum
chloride, serum proteins, serum glucose, serum calcium, serum creatinine, serum urea, plasma uric acid,
complete blood count, liver-function (enzyme) tests, prothrombin ratio, serum thyroid-stimulating hormone
(TSH) level, chest radiography, and calculation of Sequential Organ Failure Assessment (SOFA) score and
Simplified Acute Physiology Score (SAPS) II.
Day 0 was the day of inclusion. Data collected every day from day 1 to termination of invasive mechanical
ventilation were serum bicarbonate, PaCO2, pH, PaO2/FiO2 ratio, and respiratory parameters (tidal volume,
respiratory rate and minute ventilation), external PEEP level, type of mechanical ventilation (pressure-support or
volume-assisted ventilation), glucocorticoids prescribed, loop diuretics prescribed, catecholamines prescribed,
2-agonists
prescribed, side effects of the assigned test treatment (Yes/No), metabolic alkalosis (Yes/No), criteria
defining weaning (see above) (Yes/No), successful or failed spontaneous breathing trial, unplanned extubation,
use of noninvasive ventilation after planned extubation, reintubation required, need for tracheotomy, ventilatorassociated pneumonia. Serum calcium, white blood cell count, liver-function (enzyme) test results and
prothrombin ratio were also determined at least every 5 days from day 1 until the termination of invasive
ventilation or were collected every day, when available. Plasma uric acid or serum TSH determination was
required in the case of signs of renal lithiasis, gout attack or thyroid dysfunction. Left ventricular ejection
fraction assessed by echocardiography was required only during the weaning period.
Definition of Outcome
The duration of invasive ventilation was the time between its start and termination (via an intubation tube or a
tracheotomy). The duration of weaning was the time between its onset (see criteria above) and its termination. In
the case of temporary interruption(s) of the weaning procedure, the total duration corresponded to the number of
hours of attempted withdrawal until successful weaning minus discontinued hours. Weaning was considered
successful when invasive ventilation reintroduction was not required within 48 hours after its termination.
Changes of serum bicarbonate, PaCO2, pH, PaO2/FiO2 ratio and respiratory parameters (tidal volume, respiratory
rate and minute ventilation) corresponded to the means of the differences between 2 consecutive days from day 1
to termination of invasive ventilation. Ventilator-associated pneumonia was diagnosed based on the following
criteria: systemic signs of infection (fever, tachycardia, and/or leukocytosis), new or worsening infiltrates seen
on the chest roentgenogram, and bacteriologic evidence of pulmonary parenchymal infection (protected
specimen brush with >103 or bronchoalveolar lavage with >104 colony-forming units/mL or tracheal secretions
with 106 colony-forming units/mL, leukocytes 25/field and/or epithelial cells 25/field). Serious adverse events
were considered the need for intensive care procedures (mechanical ventilation, use of vasopressors,
haemodialysis, central venous catheterization, cardiac pacing and/or tube thoracostomy) and/or surgery, and
those events prolonged hospitalization or resulted in persistent or major disability/incapacity.
Placebo Group
Between-Group Difference
(n = 131)
(n = 149)
(95% CI)
166.5 (92.7-258.2)
183.7 (108.1-279.5)
15.8 (48.6-8.5)
.36
0. (.3-0.)
0.3 (0.2-1.1)
<.0001
0. (2-0.8)
0. (1-0.5)
0.2 (0.7-0.3)
.29
0 (0.01-0.02)
0.01 (0-0.02)
.0003
8.1 (0-18.5)
4 (2.3-12.2)
4.6 (0.9-8.3)
.005
0.2 (0.7-1)
0.3 (0.3-1.2)
0.2 (0.6-0.1)
.14
4 (6-27)
3.8 (8-18.2)
1.9 (3.5-8.8)
.34
0.2 (0.1-0.8)
0.2 (0.1-0.6)
0.0 (0.1-0.2)
.44
22.5 (3.3-49.5)
24 (4-45.5)
0.5 (5.5-3.0)
.68
1 (1-3)
1 (1-3)
0 (0-0)
.61
0 (0-21)
0 (0-9)
0 (0-0)
.63
52 (39.6)
63 (42.8)
2.6 (14.6-9.1)
.66
Variable
Primary outcome: duration of invasive ventilation, median (IQR), h
P Value
Secondary outcomesb
Daily serum bicarbonate change, median (IQR), mEq/L
81 (61.8)
103 (69.1)
7.0 (18.0-4.0)
.20
0 (0-2)
0 (0-1)
0 (0-0)
.71
21 (16)
27 (18.1)
2.1 (11.0-6.8)
.64
11 (7-17)
12 (8-21)
-1 (-3-0)
.50
9 (6.9)
11 (7.4)
0.5 (6.5-5.5)
.86
4 (3.1)
5 (3.4)
0.3 (4.4-3.82)
.91
2 (0-4)
2 (0-5)
0 (0-0)
.71
1 (0-4)
1 (0-5)
0 (0-0)
.49
2 (0-5)
2 (0-7)
0 (-1-0)
.16
1 (0-3)
1 (0-3)
0 (0-0)
.36
4 (2-8)
8 (4-14)
3 (5- 2)
<.0001
3 (2-5)
5 (3-8)
2 (3- 1)
<.0001
0 (0-5)
0 (0-2)
0 (0-0)
.07
3 (1-5)
3 (1-5)
0 (1-0)
.44
3 (1-6)
3 (1-6)
0 (1-1)
.63
median (range)
50 (39-60)
50 (42-60)
0 (5-5)
.49
Abbreviations: CI, confidence interval; FiO2, fraction of inspired oxygen; ICU, intensive care unit; IQR, interquartile range; PaO2 and PaCO2, partial oxygen or
carbon-dioxide pressure in arterial blood, respectively; and VAP, ventilator-associated pneumonia.
aRange
was preferred over IQR because several of the latter were (00). Between-group differences for quantitative variables are expressed as medians with the
daily changes of arterial blood gases or respiratory parameters corresponded to the differences between 2 consecutive days from day 1 to the end of
invasive ventilation. Arterial blood gases and respiratory parameters on mechanical ventilation were measured between 7 a.m. and 8 a.m. Other laboratoryparameter changes are given in eTable 3.
cWeaning
was considered successful when invasive ventilation reintroduction was not required within 48 hours after its termination. Criteria for extubation and
events were considered serious when they required intensive care procedures (use of vasopressors, hemodialysis, central venous catheterization,
cardiac pacing and/or tube thoracostomy) and/or surgery, and those events prolonged hospitalization or resulted in persistent or major disability/incapacity.
eMetabolic
fLeft
alkalosis was defined as serum bicarbonate >26 mEql/L and arterial pH 7.35.
ventricular ejection fraction was assessed by transthoracic echocardiography during the weaning period.
eTable 2. Intention-to-Treat Analysis: Study Laboratory Parametersa and Causes of Weaning Failure
Acetazolamide Group
Placebo Group
Between-Group Differenceb
(n = 187)
(n = 193)
(95% CI)
0.04 (0.04-0.20)
0.04 (0.04.0.16)
0.0 (0.0-0.0)
.96
130 (830-900)
80 (850-530)
0.0 (300-400)
.71
2.0 (1.7-7.3)
2.0 (0.6-5.5)
0.3 (1.5-2.1)
.65
0.7 (7.0-5.5)
0 (9.8-6.1)
0.5 (5.0-4.2)
.77
Pneumonia
5 (2.7)
1 (0.5)
2.2 (0.4-4.7)
.09
8 (4.3)
6 (3.1)
1.2 (2.6-5.0)
.41
Hypercapnic encephalopathy
14 (7.5)
16 (8.3)
0.8 (6.2-4.6)
.98
2 (1.1)
3 (1.6)
0.5 (2.8-1.8)
.99
Cardiorespiratory arrest
2 (1.1)
1 (0.5)
0.6 (1.2-2.3)
.60
Unspecified
9 (4.8)
8 (4.1)
0.7 (3.5-4.8)
.81
Variable
P Value
Abbreviations: ASAT, aspartate aminotransferase; CI, confidence interval; and IQR, interquartile range.
aLaboratory
parameter values were determined at least every 5 days from day 1 until the end of invasive ventilation or collected every day, when available.
9
bBetween-group
differences for quantitative variables are expressed as medians with the 95% CI around the median difference.
10
eTable 3: Per-protocol analysis: Study laboratory parametersa and causes of weaning failure
Acetazolamide Group
Placebo Group
Between-Group Differenceb
(n = 131)
(n = 149)
(95% CI)
0.04 (0.04-0.20)
0.04 (0.04-0.16)
0.0 (0.0-0.0)
.56
100 (730-830)
80 (850-510)
0.0 (0.3-0.4)
.53
2 (1-8)
2 (0.6-5.7)
0.8 (1.2-2.9)
.34
0.3 (6.5-5.5)
0 (7-6)
0.5 (4.6-3.8)
.78
Pneumonia
5 (3.8)
1 (0.7)
3.1 (0.4-6.7)
.09
6 (4.6)
3 (2)
2.6 (1.7-6.8)
.29
Hypercapnic encephalopathy
13 (9.9)
16 (10.7)
0.8 (8.0-6.3)
.93
2 (1.5)
3 (2)
0.5 (3.6-2.6)
.99
Cardiorespiratory arrest
2 (1.5)
1 (0.7)
0.9 (1.6-3.3)
.59
Unspecified
6 (4.6)
6 (4)
0.6 (4.2-5.3)
.81
Variable
P Value
Abbreviations: ASAT, aspartate aminotransferase; CI, confidence interval; and IQR, interquartile range.
aLaboratory
parameter values were determined at least every 5 days from day 1 until the end of invasive ventilation or collected every day, when available.
11
bBetween-group
differences for quantitative variables are expressed as medians with the 95% CI around the median difference.
12
eFigure 1
Randomization
Acetazolamide
Placebo
D0
NO
YES
NO
Temporary
withdrawal
Acetazolamide
or placebo
NO
YES
Possible tracheotomy
during weaning off
invasive ventilation
NO
Invasive
ventilation >28
days?
YES
End of
protocol
D1 to D28
eFigure 2
Panel A: Bicarbonate
60
7.6
50
7.5
mEq/L
40
30
7.4
7.3
20
7.2
10
7.1
Placebo
Acetazolamide
Panel B: pH
7.7
7.0
1
10
15
20
25
187
182
115
104
49
44
26
16
13
11
8
6
Days
Placebo
Acetazolamide
Panel C: PaCO2
120
10
15
20
25
188
182
115
104
49
44
26
16
13
11
8
6
Days
800
100
600
60
mm Hg
mm Hg
80
400
40
200
20
0
Placebo
Acetazolamide
0
1
10
15
20
25
188
182
115
104
49
44
26
16
13
11
8
5
Days
Placebo
Acetazolamide
60
10
15
20
25
188
181
112
102
49
43
26
16
13
11
8
6
1000
50
Days
800
600
30
20
mL
Cycle/min
40
10
15
20
25
190
182
114
106
49
44
26
16
13
10
8
6
Days
Placebo
Acetazolamide
10
15
20
25
188
182
114
106
49
44
26
16
13
10
7
6
Days
20
20
L/min
cm H2O
15
15
10
Placebo
Acetazolamide
25
10
200
10
Placebo
Acetazolamide
400
0
1
10
15
20
25
188
180
114
106
48
44
26
15
13
10
7
6
Days
Placebo
Acetazolamide
Placebo
10
15
20
25
189
181
116
105
50
44
26
16
13
11
7
6
Acetazolamide
Days
eFigure 3
Panel A: Bicarbonate
60
7.6
50
7.5
mEq/L
40
30
7.4
7.3
20
7.2
10
7.1
Placebo
Acetazolamide
Panel B: pH
7.7
7.0
1
10
15
20
25
148
130
104
86
44
38
24
16
13
11
8
6
Days
Placebo
Acetazolamide
Panel C: PaCO2
120
10
15
20
25
149
130
104
86
44
38
24
16
13
11
8
6
Days
800
100
600
60
mm Hg
mm Hg
80
400
40
200
20
0
Placebo
Acetazolamide
0
1
10
15
20
25
149
130
104
86
44
38
24
16
13
11
8
5
Days
Placebo
Acetazolamide
60
10
15
20
25
149
129
101
84
44
37
24
16
13
11
8
6
1000
50
Days
800
600
30
20
mL
Cycle/min
40
0
1
10
15
20
25
149
130
102
87
44
38
24
16
13
10
8
6
Days
Placebo
Acetazolamide
10
15
20
25
147
130
102
87
44
38
24
16
13
10
7
6
Days
20
20
L/min
cm H2O
15
15
10
Placebo
Acetazolamide
25
10
200
10
Placebo
Acetazolamide
400
0
1
10
15
20
25
148
129
102
87
43
38
24
15
13
10
7
6
Days
Placebo
Acetazolamide
Placebo
10
15
20
25
148
130
104
87
45
38
24
16
13
11
7
6
Acetazolamide
Days
eFigure 4A
Subgroup
Overall
Acetazolamide Group
Placebo Group
Eventsa, n Patients, n
Eventsa, n Patients, n
117
131
137
149
1.09 (0.851.40)
Yes
84
95
112
123
0.98 (0.741.30)
No
33
36
25
26
0.66 (0.381.14)
Yes
50
53
64
67
1.27 (0.871.85)
No
67
78
73
82
1.01 (0.721.41)
Yes
101
113
111
122
1.14 (0.871.49)
No
16
18
26
27
1.04 (0.532.10)
Yes
51
52
43
44
1.59 (1.042.42)
No
66
79
94
105
0.91 (0.661.24)
0.5
1.0
Placebo
better
1.5
2.0 2.5
Acetazolamide
better
eFigure 4B
Subgroup
Overall
Acetazolamide Group
Placebo Group
Eventsa, n Patients, n
Eventsa, n Patients, n
105
110
127
129
0.98 (0.751.27)
Yes
76
81
103
104
0.90 (0.661.21)
No
29
29
24
25
0.77 (0.431.39)
Yes
47
49
63
64
1.02 (0.701.50)
No
58
61
64
65
1.01 (0.701.45)
Yes
90
94
103
105
1.01 (0.761.34)
No
15
16
24
24
0.87 (0.451.66)
Yes
47
47
40
40
1.21 (0.791.85)
No
58
63
87
89
0.84 (0601.19)
0.5
1.0
Placebo
better
1.5
2.0
Acetazolamide
better
2.5