Ventilator-Associated Events: Prevalence, Outcome,

and Relationship With Ventilator-Associated

Pneumonia
Lila Bouadma, MD, PhD1–3; Romain Sonneville, MD3; Maité Garrouste-Orgeas, MD, PhD1,4;
Michael Darmon, MD, PhD5,6; Bertrand Souweine, MD, PhD7; Guillaume Voiriot, MD2,3; Hatem Kallel, MD8;
Carole Schwebel, MD, PhD9; Dany Goldgran-Toledano, MD10; Anne-Sylvie Dumenil, MD11;
Laurent Argaud, MD, PhD12; Stéphane Ruckly, MSc13; Samir Jamali, MD14; Benjamin Planquette, MD15;
Christophe Adrie, MD, PhD16; Jean-Christophe Lucet, MD, PhD1,2,17; Elie Azoulay, MD, PhD2,18;
Jean-François Timsit, MD, PhD1–3; on behalf of the OUTCOMEREA Study Group

1
INSERM, IAME Team 5 DeScID: Decision Science in Infectious search and wrote the first draft. Dr. Timsit revised the first draft. All the
Diseases, Control and Care, UMR 1 137, Paris, France. authors criticized the article, saw, and approved the final report.
2
University Paris Diderot, Sorbonne Paris Cité, Paris, France. Dr. Darmon lectured for Merck Sharp and Dohme (MSD), Astellas, and
3
Medical and Infectious Diseases ICU, Bichat–Claude-Bernard Hospital, Bristoll Myers Squibb. His institution received grant support from MSD
Assistance Publique–Hôpitaux de Paris, Paris, France. (research grant) and Astutes (logistic support). Dr. Jamali received sup-
port for article research from the National Institutes of Health, Wellcome
4
Polyvalent ICU, Saint Joseph Hospital Network, Paris, France. Trust, Howard Hughes Medical Institute, Research Councils UK, and
5
Medical Surgical ICU, Saint-Etienne University Hospital, Avenue Albert other. Dr. Azoulay served as a board member for Gilead Sciences and
Raimond, Saint-Priest-en Jarez, France. lectured for MSD and Gilead Sciences. His institution received grant
6
Jacques Lisfranc Medical School, Jean Monnet University, Saint-Etienne, support from Pfizer, MSD, and Gilead Sciences; lectured for Astellas;
France. and received support for the development of educational presentations
from MSD. Dr. Timsit served as a board member for MSD and Bayer
7
Medical ICU, Gabriel Montpied University Hospital, Clermont-Ferrand and lectured for MSD, Pfizer, Astellas, Novartis, and Brahms. He and
Cedex 1, France. his institution served as a board member for 3M. His institution received
8
Medical Surgical ICU, General Hospital, Cayenne, France. grant support from Astellas, 3M, MSD, and Pfizer. The remaining authors
9
Medical Polyvalent ICU, Grenoble University Hospital, Grenoble, France. have disclosed that they do not have any potential conflicts of interest.
10
Polyvalent ICU, Gonesse General Hospital, Gonesse Cedex, France. Address requests for reprints to: Lila Bouadma, MD, PhD, Service de
Réanimation Médicale et des Maladies Infectieuses, Hôpital Bichat–
11
Surgical ICU, Antoine Beclère Hospital, Assistance Publique–Hôpitaux Claude-Bernard, 46 rue Henri-Huchard, 75877 Paris Cedex 18, France.
de Paris, Clamart Cedex, France. E-mail: lila.bouadma@bch.aphp.fr
12
Surgical ICU, Edouard Herriot Teaching Hospital, Lyon Cedex, France.
13
University Grenoble 1 Integrated Research Center U 823 “Epidemiology
of Cancers and Severe Diseases” Albert Bonniot Institute, La Tronche
Cedex, France. Objectives: Centers for Disease Control and Prevention built up
14
Polyvalent ICU, Dourdan Hospital, Dourdan, France. new surveillance paradigms for the patients on mechanical venti-
15
Polyvalent ICU, André Mignot Hospital, Le Chesnay, France. lation and the ventilator-associated events, comprising ventilator-
16
Polyvalent ICU, Saint-Denis Hospital, Saint-Denis, France. associated conditions and infection-related ventilator-associated
17
Infection Control Unit, Bichat–Claude-Bernard Hospital, Assistance
 complications. We assess 1) the current epidemiology of venti-
Publique–Hôpitaux de Paris, Paris, France. lator-associated event, 2) the relationship between ventilator-
18
Medical ICU, Saint Louis Hospital, Assistance Publique–Hôpitaux de associated event and ventilator-associated pneumonia, and 3) the
Paris, Paris, France.
impact of ventilator-associated event on antimicrobials consump-
Members of the OUTCOMEREA study group are listed in Appendix 1.
tion and mechanical ventilation duration.
Drs. Bouadma, Timsit, and Lucet designed the study. Drs. Timsit, Garrouste-
Orgeas, Darmon, Souweine, Voiriot, Kallel, Schwebel, Goldgran-Toledano, Design: Inception cohort study from the longitudinal prospective
Dumenil, Argaud, Jamali, Planquette, Adrie, Azoulay, and members of the French multicenter OUTCOMEREA database (1996-2012).
OUTCOMEREA study group collected the data. Dr. Timsit and Mr. Ruckly Patients: Patients on mechanical ventilation for greater than or
performed the data analysis. The interpretation of the results was done
by Drs. Timsit, Bouadma, and Sonneville. Dr. Bouadma did the references equal to 5 consecutive days were classified as to the presence
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer of a ventilator-associated event episode, using slightly modified
Health, Inc. All Rights Reserved. Centers for Disease Control and Prevention definitions.
DOI: 10.1097/CCM.0000000000001091 Intervention: None.

Critical Care Medicine www.ccmjournal.org 1

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Bouadma et al
Measurements and Main Results: Among the 3,028 patients,
2,331 patients (77%) had at least one ventilator-associated con-
dition, and 869 patients (29%) had one infection-related venti-
lator-associated complication episode. Multiple causes, or the
lack of identified cause, were frequent. The leading causes asso-
ciated with ventilator-associated condition and infection-related
ventilator-associated complication were nosocomial infections
(27.3% and 43.8%), including ventilator-associated pneumonia
(14.5% and 27.6%). Sensitivity and specificity of diagnosing
ventilator-associated pneumonia were 0.92 and 0.28 for ventila-
tor-associated condition and 0.67 and 0.75 for infection-related
ventilator-associated complication, respectively. A good correla-
tion was observed between ventilator-associated condition and
infection-related ventilator-associated complication episodes, and
ventilator-associated pneumonia occurrence: R2 = 0.69 and 0.82
(p < 0.0001). The median number of days alive without antibiotics
and mechanical ventilation at day 28 was significantly higher in
patients without any ventilator-associated event (p < 0.05). Venti-
lator-associated condition and infection-related ventilator-associ-
ated complication rates were closely correlated with antibiotic use
within each ICU: R2 = 0.987 and 0.99, respectively (p < 0.0001).
Conclusions: Ventilator-associated event is very common in a
population at risk and more importantly highly related to antimicro-
bial consumption and may serve as surrogate quality indicator for
improvement programs. (Crit Care Med 2015; XX:00–00)
Key Words: infection-related ventilator-associated complication;
nosocomial infections; surveillance; ventilator-associated condition;
ventilator-associated event; ventilator-associated pneumonia
V
entilator-associated pneumonia (VAP) is the most
common hospital-acquired infection in the ICU (1).
VAP surveillance is needed to measure prevalence and
to gauge the success of prevention efforts (2, 3). However, VAP
diagnosis is a complex issue for intensivists. Many of the diag-
nostic criteria are very subjective and poorly correlated with
histological pneumonia (4, 5).
The Centers for Disease Control and Prevention (CDC) has been
working in conjunction with Critical Care Societies Collaborative
and other professional groups to develop a new approach to VAP
surveillance (6). The result is an algorithm based on objective crite-
rion for the diagnosis of ventilator-associated events (VAE), that is,
ventilator-associated conditions (VAC) and infection-related ven-
tilator-associated complications (IVAC), instead of VAP episodes.
This new approach was scheduled to replace the VAP classical defi-
nition in 2013 in the CDC network surveillance (7).
Only few retrospective studies have explored the relation-
ships between VAEs and all potential events related to mechan-
ical ventilation (MV), for example, nosocomial infections
(including VAP), iatrogenic adverse events, and interventions
occurring in ICU, that is, the scope of this new approach (8–
12). The goals of this study were to evaluate 1) the VAE risk in
a large high-quality non-U.S. database, which recorded daily
VAP, other nosocomial infections, and adverse events in a rig-
orous manner; 2) the relationship between VAE and adverse
2 www.ccmjournal.org
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
events, nosocomial infections, and VAP; 3) the relationship
between VAE and other quality indicators, such as mortality,
length of MV, length of stay, and antimicrobials use (13, 14).
METHODS
This study used an inception cohort design. All data were
obtained from the OUTCOMEREA database (15). We included
all patients who are older than 18 years admitted between
November 1996 and October 2012 and who were on MV for
at least 5 consecutive days. Patients who met inclusion criteria
multiple times in multiple ICU stays were included only once.
The patients were studied until 2 days after a successful extuba-
tion (extubation followed by 2 d without MV). Day was defined
as the interval from admission to 8 am on the next day; all other
days were calendar days from 8 am to 8 am on the next day.
According to the French law, the OUTCOMEREA database
was declared to the Commission Nationale de l’Informatique
et des Libertés (15). This study did not require individual
patient consent because it involved research on a previously
developed and approved database. This study was approved by
the Institutional Review Board of the Rhône-Alpes-Auvergne
Clinical Investigation Centers.
OUTCOMEREA
OUTCOMEREA is an ongoing prospective observational col-
laborative study group that includes detailed clinical and out-
come data on patients admitted to participating French ICUs.
Details about the database have already been described (16, 17).
Study Protocol
Once all ICU admissions fulfilling enrollment criteria were iden-
tified, the following information was extracted for each patient:
●● Baseline characteristics on ICU admission: age and sex, body
mass index, admission category (medical, scheduled surgery,
or unscheduled surgery), admission diagnosis, Coma Glasgow
score, Pao2/Fio2 ratio, and severity of illness were evaluated
using the Simplified Acute Physiology Score II and Sequential
Organ Failure Assessment; Knaus scale definitions was used to
record preexisting chronic organ failures (including respira-
tory, cardiac, hepatic, renal replacement therapy, and use of
corticosteroids), and McCabe and Jackson classification was
used to record the estimated prognosis of any preexisting
underlying disease (rapidly fatal, ultimately fatal, or nonfatal).
●● At admission and subsequently on a daily basis: require-
ment for invasive MV, Fio2, and positive end-expiratory
pressure (PEEP) (≥ 6, ≥ 10, and ≥ 16 cm H2O). In addition,
data on daily interventions (i.e., transport and fluid resus-
citation), nosocomial infections and iatrogenic adverse
events, and change in antibiotic treatments were collected.
The nosocomial infections and iatrogenic adverse events were
predefined by the steering committee of the OUTCOMEREA
group when the database was started in 1997. Originally, these
adverse events, defined as any preventable or nonpreventable
event secondary to medical management and independent from
the patient’s underlying condition, were selected because they
XXX 2015 • Volume XX • Number XXX
 Clinical Investigation

were easy to collect and were considered the best candidates for
quality indicators. The definitions of the main adverse events
have been already published (13, 14) and are available at http://
www.outcomerea.org/ehtm/adverse-events-definitions.pdf.
In accordance with previous reports (18), VAP was defined
as persistent pulmonary infiltrates on chest radiographs com-
bined with purulent tracheal secretions and/or body tem-
perature greater than or equal to 38.5°C or less than or equal
to 36.5°C and/or peripheral blood leukocyte count greater
than or equal to 10 × 109/L or less than or equal to 4 × 109/L.
A definite diagnosis of VAP required microbiological confirma-
tion by quantitative culture from a protected specimen brush
(> 103 CFU/mL), plugged telescopic catheter specimen (> 103
CFU/mL), bronchoalveolar lavage (BAL) fluid specimen (> 104
CFU/mL), or endotracheal aspirate (> 105 CFU/mL).
Patients were classified as to the presence of at least one VAE
episode during their first session of MV (from intubation to
the first successful extubation) after the 5th day on MV. VAEs’
definition adapted from the CDC’s National Healthcare Safety
Network are presented in Table 1.
We reviewed each episode of VAE to identify episodes associ-
ated with nosocomial infections and iatrogenic adverse events
within 2 calendar days before or after the onset of worsen-
ing oxygenation. Transport and fluid resuscitation were only
screened from 2 days before the onset of worsening oxygenation.
Statistical Analysis
Quantitative variables are reported as median (interquartile
range, IQR) and qualitative variables as number (%). The pri-
mary outcome was hospital mortality. Secondary outcomes
were ICU mortality, MV duration, length of stay, and the num-
ber of days at 28 days after inclusion without broad-spectrum
antimicrobials and without MV. We also assessed the p ­ ercentage
of patients with at least one episode of VAE and VAP, the num-
ber of first event per 1,000 ventilator-days at risk (until diagno-
sis, extubation, or death), and the time from admission in ICU
to the first VAE and VAP.
For all the analyses, the date of origin (day 0) was the 5th
day of MV. Patients were censored at day 28.
Cumulative incidence curve for VAP, VAC, and IVAC were
plotted. Daily incidence rates were computed for the 5th, 10th,
15th, 20th, and 28th day.
We also tested the correlations between first VAC and
IVAC and first VAP prevalence and the correlations between
VAC and antimicrobial consumption according to center
using a multiple linear regression. The linear relationships
between number of VAP and number of VAEs per center-
year were described on scatter plots with the corresponding
linear regression line.
Statistical analyses were performed using SAS 9.3 software
(SAS Institute, Cary, NC).

Table 1. Definitions of Ventilator-Associated Conditions and Infection-Related

Ventilator-Associated Complications
Infection-Related Ventilator-Associated
Criteria Ventilator-Associated Condition Complication

Sustained respiratory Two successive sequences: Two successive sequences:

deterioration
 A ≥ 2 d stable or decreasing range of  A ≥ 2 d stable or decreasing range of PEEP
PEEP (≥ 6, ≥ 10, and ≥ 16 mm Hg) (≥ 6, ≥ 10, and ≥ 16 mm Hg) and a stable or
and a stable or improved Pao2/Fio2 improved Pao2/Fio2 ratio
ratio
 A ≥ 2 d rise in range of PEEP or a  A ≥ 2 d rise in range of PEEP or a decreasing
decreasing Pao2/Fio2 ratio by > Pao2/Fio2 ratio by > 50 mm Hg with the
50 mm Hg with the same level of same level of PEEP or by > 100 mm Hg
PEEP or by > 100 mm Hg whatever whatever the level of PEEP
the level of PEEP
Systemic inflammatory respiratory No At least 2 criteria within 2 calendar days before
syndrome or after the onset of respiratory deterioration:
 Body temperature < 36°C or > 38°C
 Heart rate > 90 beats/min
 WBC count > 12,000 or < 4,000 cells/mm3
Antimicrobial treatment No At least one new antimicrobial agent prescribed
within 2 calendar days before or after
the onset of respiratory deterioration and
continued for ≥ 4 d or less in case of death,
ICU discharge, or withholding or withdrawing
life-sustaining medical treatment
PEEP = positive end-expiratory pressure.
Adapted from the Centers for Disease Control and Prevention National Healthcare Safety Network (6). Adaptations are themselves works protected by
copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of
copyright in the translation or adaptation.

Critical Care Medicine www.ccmjournal.org 3

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Bouadma et al

RESULTS
Study Population
Of the 13,702 patients admitted to all OUTCOMEREA ICUs
during the study period, 3,028 patients were on MV for at least
5 consecutive days, corresponding to a total of 51,117 days
studied (study chart shown in Fig. 1). Population characteris-
tics are described in Table 2.
Prevalence of VAE
Among the 3,028 patients, a total of 2,331 patients (77%) expe-
rienced at least one episode of VAC. This episode was associ-
ated with a systemic inflammatory response syndrome in 2,117
patients (70%), 972 patients received a new antimicrobial
treatment from 2 days before to 2 days after the episode onset,
and 869 patients received a treatment for at least 4 consecutive
days (or were discharged or dead within 4 d or were under a
withholding or withdrawing life-sustaining medical treatment
in the meantime). Overall, 869 patients (29%) met the IVAC
definition.
The incidence densities of VAC and IVAC were 107 and 35
per 1,000 ventilator-days, respectively. The rate and incidence
densities did not vary significantly over units. The median
(IQR) number of VAC and IVAC episodes per patients was 2
(1–3) and 1 (1–2), respectively. The median (IQR) time from
ICU admission to the onset of the first VAC and IVAC episodes
was 6 days (5–8 d) and 6 days [5–8 d], respectively. Cumulative
incidences of VAP, VAC, and IVAC are shown in Figure 2.
Conditions Associated With VAE
Multiple causes were frequently observed. The median number
(IQR) of etiologies per first episode was 1 (0–2) and 1 (1–2) for
VAC and IVAC episodes, respectively. Nosocomial infections,
and mainly VAP, were the leading causes associated with VAEs,
followed by transport, iatrogenic adverse events, and fluid
resuscitation. Details are provided in Table 3.
Relationship of VAEs With VAP
Taking into account the occurrences of VAP, VAC and IVAC
during the stay, sensitivity, specificity, positive predictive value,
and negative predictive value for VAP were 0.92 (0.90–0.93),
0.28 (0.27–0.30), 0.32 (0.30–0.34), and 0.90 (0.88–0.92) for
VAC and 0.67 (0.64–0.70), 0.75 (0.73–0.77), 0.50 (0.47–0.53),
and 0.86 (0.84–0.87) for IVAC,
respectively.
When considering the
prevalence per center and year,
there was a good correlation
between VAC or IVAC episode
and VAP occurrences: R2 =
0.67 (p < 0.0001) and R2 = 0.82
(p < 0.0001), respectively.

Outcomes in Patients
With At Least One
Episode of VAE
The median number of days
alive without antimicrobials at
day 28 was significantly higher
in patients with no episode of
VAC (24 [2; 26]) than in patients
with at least one episode of VAC
(17 [4; 23]) (p < 0.05) or at least
one episode of IVAC (10 [4; 23])
(p < 0.05).
The median number of days
alive without MV at day 28 was
significantly higher in patients
with no episode of VAC (24 [0;
26]) than in patients with at least
one episode of VAC (14 [0; 23])
(p < 0.05) or at least one episode
of IVAC (5 [0; 18]) (p < 0.05).

Antibiotic Use Within

Each ICU
Figure 1. Flow chart of the patients included in the study and of the 3,028 patients with at least 5 consecutive days
on mechanical ventilation (MV) and presenting at least one or more episode of ventilator-associated conditions (VAC) When considering the preva-
during the study period. IVAC = infection-related VAC, SIRS = systemic inflammatory response syndrome. lence per center and year,

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 Clinical Investigation

Table 2. Characteristics and Crude Mortality Rates for Patients With and Without
Ventilator-Associated Events
Infection-Related
All No VAC VAC Ventilator-Associated
Variable (n = 3,028) (n = 697) (n = 2,331) Complication (n = 869)

Male sex, n (%) 1,931 (63.8) 435 (62.4) 1,496 (64.2) 564 (64.9)
Age, median (interquartile range) 65.4 (53.8–76.2) 65.9 (55.1–77) 65.3 (53.3–76) 62.4 (51.5–73.2)
Admission category, n (%)
 Medical 2,251 (74.5) 546 (78.4) 1,705 (73.3) 649 (74.8)
 Scheduled surgery 266 (8.8) 46 (6.6) 220 (9.5) 76 (8.8)
 Unscheduled surgery 504 (16.7) 104 (14.9) 400 (17.2) 143 (16.5)
Reason for ICU admission, n (%)
 Multiple organ failure 105 (3.5) 24 (3.4) 81 (3.5) 35 (4)
 Septic shock 555 (18.4) 101 (14.5) 454 (19.5) 191 (22)
 Hemorrhagic shock 103 (3.4) 27 (3.9) 76 (3.3) 24 (2.8)
 Cardiogenic shock 139 (4.6) 35 (5) 104 (4.5) 39 (4.5)
 Other shocks 85 (2.8) 28 (4) 57 (2.5) 17 (2)
 Acute respiratory failure 1,026 (34) 215 (30.9) 811 (34.9) 294 (33.9)
 Acute renal failure 64 (2.1) 10 (1.4) 54 (2.3) 22 (2.5)
 Chronic obstructive disease 98 (3.2) 20 (2.9) 78 (3.4) 27 (3.1)
 Coma 560 (18.5) 162 (23.3) 398 (17.1) 136 (15.7)
 Trauma 30 (1) 6 (0.9) 24 (1) 11 (1.3)
 Monitoring 177 (5.9) 50 (7.2) 127 (5.5) 50 (5.8)
 Scheduled surgery 80 (2.6) 18 (2.6) 62 (2.7) 22 (2.5)
Underlying disease (McCabe score), n (%)
 Nonfatal 1,721 (57.2) 378 (54.8) 1,343 (57.9) 525 (60.6)
 Ultimately fatal (< 5 yr) 1,055 (35.1) 243 (35.2) 812 (35) 279 (32.2)
 Rapidly fatal (< 1 yr) 233 (7.7) 69 (10) 164 (7.1) 62 (7.2)
Other chronic illness (Knaus definition), n (%)
 Hepatic 179 (5.9) 39 (5.6) 140 (6) 59 (6.8)
 Cardiovascular 427 (14.1) 109 (15.6) 318 (13.6) 120 (13.8)
 Pulmonary 572 (18.9) 138 (19.8) 434 (18.6) 141 (16.2)
 Renal 150 (5) 38 (5.5) 112 (4.8) 50 (5.8)
 Immunosuppression 464 (15.3) 110 (15.8) 354 (15.2) 165 (19)
Simplified Acute Physiology Score II, 44 (34–56) 47 (35–59) 44 (34–55) 44 (33–55)
median (Q1; Q3)
Sequential Organ Failure Assessment, 6 (4–9) 6 (4–9) 6 (4–9) 7 (4–9)
median (Q1; Q3)
Pao2/Fio2, median (Q1; Q3) 201 (121–308) 202 (114–314) 201 (122–306) 200 (120–300)
Coma Glasgow score (Q1; Q3) 7 (3–13) 6 (3–12) 7 (3–13) 7 (3–14)
Ventilation days, median (Q1; Q3) 10 (7–19) 6 (5–8) 13 (8–23) 17 (11–27)
ICU length of stay, median (Q1; Q3) 15 (10–26) 9 (7–13) 18 (11–29) 22 (14–34)

(Continued)

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Bouadma et al

Table 2. (Continued) Characteristics and Crude Mortality Rates for Patients With and
Without Ventilator-Associated Events
Infection-Related
All No VAC VAC Ventilator-Associated
Variable (n = 3,028) (n = 697) (n = 2,331) Complication (n = 869)

Hospital length of stay, median (Q1; Q3) 31 (18–54) 19 (11–34) 35 (21–60) 36.5 (22–64)
Crude ICU mortality, n (%)
 30-d ICU mortality 731 (24.1) 217 (31.1) 514 (22.1) 222 (25.6)
 Global ICU mortality 882 (29.1) 225 (32.3) 657 (28.2) 297 (34.2)
 Hospital mortality 1,134 (37.5) 278 (39.9) 856 (36.7) 386 (44.4)
VAC = ventilator-associated conditions.

there was a good correlation between VAC or IVAC episode
and number of antibiotic-days within each ICU: R2 = 0.987
(p < 0.0001) and R2 = 0.99 (p < 0.0001), respectively.
DISCUSSION
This large prospective, multicenter study showed that VAEs were
common (VAC, 77% and IVAC, 29%) in ICU patients at risk
(MV > 5 d). Multiple causes or the lack of identified cause were
frequent. IVAC episodes were strongly correlated to VAP; how-
ever, only 27.6% IVAC episodes were related to VAP and less than
half to a nosocomial infection. Importantly, VAC and IVAC were
clearly associated with a poor outcome and directly correlated
with an increase in the antimicrobial consumption. As such, they
may be useful quality indicators and guide continuous quality
improvement and antibiotic stewardship programs in ICUs.
Our VAE rate was higher than those reported in previous
retrospective studies (8–12). As opposed to previous studies,
we only took into account patients at risk according to CDC
Cumulative incidence curves
1.0
definitions (8). Patients on MV for less than 5 days contribute to
the denominator in the previous studies, although they were at
no risk of VAC (8, 9). Therefore, the 77% crude VAC rate in our
study is difficult to compare with the results of the other studies.
Indeed, critically ill patients are at high risk for respiratory state
worsening due to various processes (13, 19).
Difference could also be due to slight differences in defini-
tions of VAE as compared with CDC definition. According to the
definition used, large or more restrictive, VAC incidence has been
shown to vary from 0.5 to 26.3 per 1,000 ventilator-days (20).
We only recorded PEEP range in the OUTCOMEREA database.
However, compared with the CDC’s definition, our definition
took into account the change of Pao2/Fio2 with regard to the level
of PEEP as a more reliable criterion for worsening oxygenation
assessment. The lack of standard ventilator settings and oxygen-
ation objective in ICUs may limit the reliability of the ventilator
settings for the VAC definition.
CDC definitions using more objective criterion were
developed as a less restrictive way to monitor VAP. In return,
both VAC and IVAC surveillance captured a large set of com-
plications. Indeed, in our study, VAP accounted for only

14.5% of the VAC episodes and 27.6% of the IVAC episodes.

VAP Furthermore, all IVAC episodes were not related to a noso-
VAC
IVAC comial infection, although patients received antibiotics.
0.8

Nevertheless, giving antibiotics to patients who have a wors-

ening oxygenation period is an appropriate behavior. On one
hand, that “events”-driven definition might circumvent the
0.6
Probability

subjectivity and inaccuracy of the definition of VAP, facilitate

its electronic assessment, and make interfacilities comparisons
more meaningful (8). On the other hand, embedding VAP in
0.4

the larger concept of IVAC may dilute the attention to VAP

pathophysiology and prevention (1).
However, a striking result of our study is the association
0.2

between VAE and antibiotic consumption. Notably, we found

that VAC rates, easy to collect and less sensitive to interpretations
than VAP definition (and not only IVAC, it was expected consid-
0.0

ering the CDC definition), closely correlate with antibiotic use

0 5 10 15 20 25
within each ICU. This finding strongly argues for the use of VAC
Days rate as one of the process indicator of quality of care in the ICU
for antimicrobial stewardship programs (21). A decrease of VAC
Figure 2. Daily incidence rates for ventilator-associated pneumonia
(VAP), ventilator-associated conditions (VAC), and infection-related and antibiotic consumption together should be the right target
ventilator-associated complications (IVAC). for future interventions on VAP prevention (22).

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 Clinical Investigation

Table 3. Causes of Ventilator-Associated Events

Infection-Related
Ventilator-Associated Ventilator-Associated
Variablesa Condition (n = 2,331) Complication (n = 869)

Number of etiologies per patient

 0 818 (35.1) 189 (21.78)
 1 726 (31.2) 260 (29.9)
 2 445 (19.1) 213 (24.5)
 3 214 (9.2) 124 (14.3)
 ≥ 4 128 (5.5) 83 (9.6)
Nosocomial infections 637 (27.3) 381 (43.8)
 Ventilator-associated pneumonia 339 (14.5) 240 (27.6)
 Tracheobronchitis 23 (1) 12 (1.4)
 Bloodstream infection 173 (7.4) 95 (10.9)
 Catheter-related infection 81 (3.5) 44 (5.1)
 Urinary infection 102 (4.4) 42 (4.8)
 Sinusitis 5 (0.2) 4 (0.5)
 Viral infection 10 (0.4) 8 (0.9)
 Surgical site infections 41 (1.8) 30 (3.5)
Iatrogenic adverse events 322 (13.8) 137 (15.8)
 Pneumothorax 37 (1.6) 23 (2.6)
 Failure of planned extubation 11 (0.5) 1 (0.1)
 Accidental extubation 21 (0.9) 9 (1)
 Self-extubation 71 (3) 19 (2.2)
 Venous puncture accident 14 (0.6) 9 (1)
 Atelectasis 52 (2.2) 20 (2.3)
 Peripheral thrombosis 36 (1.5) 18 (2.1)
 Pulmonary embolism 9 (0.4) 1 (0.1)
 Myocardial infarction 10 (0.4) 4 (0.5)
 Cardiac arrest 43 (1.8) 24 (2.8)
 Cardioversion 29 (1.2) 17 (2)
 Gastrointestinal bleeding 26 (1.1) 11 (1.3)
 Acute mesenteric infarction 5 (0.2) 4 (0.5)
 Intestinal pseudo-obstruction 2 (0.1) 0
Transport 387 (16.6) 186 (21.4)
Fluid resuscitation 123 (5.3) 58 (6.7)
a
Expressed as number (%).

To what extent VAE can be prevented and the possible
impact of VAEs prevention program on antibiotic consump-
tion are key issues that can be used as surrogate quality indi-
cators. Given that VAE are related to many different causes,
VAE prevention needs a broader prevention strategy. Recent
studies have demonstrated that changes in system factors
(e.g., workload, work environment, and safety climate) can
result in a substantial risk reduction in VAE prevalence and
that many procedures are amenable to substantial improve-
ment (13). However, the contribution of patient-related fac-
tors to the occurrence of adverse events has been recently
highlighted (23). Furthermore, in an overview of published
reports, Harbarth et al (24) stated that if a potential exists to
decrease nosocomial infections rates, its effect ranged from

Critical Care Medicine www.ccmjournal.org 7

Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Bouadma et al
10% to 70%, depending on many factors. Overall, although
easy to measure and related to VAP, VAC/IVAC episode inci-
dence may be poorly sensitive to changes and accessible to
prevention program.
Strengths of our study include the use of a national mul-
ticenter database with prospective data collection methods
that include special attention to VAP documented by quanti-
tative cultures, a large sample size with all patients observed
until ICU or hospital discharge, and the examination of a
large panel of predefined adverse events (13, 14). Despite its
strengths, our study has potential limitations. First, there is a
potential for biases due to self-selection of ICUs joining the
OUTCOMEREA database. Second, although it is multicenter,
our database is not multinational. Thus, our population may
not be representative of ICU patients in other countries.
Nevertheless, the baseline characteristics and VAP prevalence
were similar to those reported in European previous studies.
Third, although all the study centers agreed to perform bacte-
riological samples in case of suspicion of VAP, the number of
negative BAL was not recorded.
In conclusion, this study is the first study that targets a
wide population of ICU patients at risk and the prospective
collection of data enabling to record the causes of VAE. VAEs
are common and associated with high morbidity, and the
VAE rate seems to be a good indicator for quality-improve-
ment purpose. However, given the number of different
causes involved in VACs, prevention strategies are not easy
to design. In ICU setting, we consider that VAE rate should
be important to monitor.
ACKNOWLEDGMENT
We thank Celine Feger, MD (EMIBiotech), for her editorial
support.
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XXX 2015 • Volume XX • Number XXX

APPENDIX 1. Members of the OUTCOMEREA
Study Group
Scientific committee: Jean-François Timsit (Hôpital Albert
Michallon and INSERM U823, Grenoble, France), Elie Azou-
lay (Medical ICU, Hôpital Saint Louis, Paris, France), Yves
Cohen (ICU, Hôpital Avicenne, Bobigny, France), Maïté Gar-
rouste-Orgeas (ICU, Hôpital Saint-Joseph, Paris, France), Lilia
Soufir (ICU, Hôpital Saint-Joseph, Paris, France), Alban Le
Monnier (Microbiology, Hôpital Saint-Joseph, Paris, France),
Jean-Ralph Zahar (Microbiology Department, CHU Angers,
France), Christophe Adrie (ICU, Hôpital Delafontaine, Saint
Denis, France), Michael Darmon (Medical ICU, University
Hospital Saint Etienne, France), Corinne Alberti (Robert
Debré Hospital, Paris, France), and Christophe Clec’h (ICU,
Hôpital Avicenne, Bobigny, France).
Biostatistical and informatics expertise: Jean-Francois Timsit
(Hôpital Albert Michallon and Integrated Research Center
U823, Grenoble, France), Corinne Alberti (Medical Computer
Sciences and Biostatistics Department, Robert Debré, Paris,
France), Sebastien Bailly (Integrated Research Center U823,
Grenoble, France), Stephane Ruckly Outcomerea (INSERM
UMR 1137, Paris, France), Christophe Clec’h (ICU, Hôpi-
tal Avicenne, Bobigny, France), Aurélien Vannieuwenhuyze
(Tourcoing, France).
Investigators of the OUTCOMEREA database: Christophe
Adrie (ICU, Hôpital Delafontaine, Saint Denis, France,
and Physiology, Hôpital Cochin, Paris, France), Bernard
Allaouchiche (Surgical ICU, Edouard Herriot Hospital, Lyon,
France), Claire Ara-Somohano (CHU A Michallon, Grenoble,
France), Laurent Argaud (Medical ICU, Edouard Herriot Hos-
pital, Lyon, France), Jean-Pierre Bedos (ICU, CH A Mignot,
Versailles, France), Agnès Bonadona (CHU A Michallon,
Grenoble, France), Anne Laure Borel (Nutrition, Grenoble,
Critical Care Medicine
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Clinical Investigation
France), Caroline Bornstain (ICU, Hôpital de Montfermeil,
France), Lila Bouadma (ICU, Bichat Claude Bernard Hospi-
tal, Paris, France), Alexandre Boyer (ICU, Hôpital Pellegrin,
Bordeaux, France), Yves Cohen (ICU, Hôpital Avicenne,
Bobigny, France), Jean-Pierre Colin (ICU, Hôpital de Dour-
dan, Dourdan, France), Michael Darmon (ICU, CHU Saint
Etienne, France), Anne-Sylvie Dumenil (Hôpital Antoine
Béclère, Clamart, France), Jean-Philippe Fosse (ICU, Hôpital
Avicenne, Bobigny, France), Rebecca Hamidfar-Roy (CHU
A Michallon, Grenoble, France), Hakim Haouache (Surg
ICU, CHU H Mondor, Creteil, France), Samir Jamali (ICU,
Hôpital de Dourdan, Dourdan, France), Hatem Kallel (ICU,
Cayenne General Hospital, France), Christian Laplace (ICU,
Hôpital Kremlin-Bicêtre, Bicêtre, France), Alexandre Lau-
trette (ICU, CHU G Montpied, Clermont-Ferrand, France),
Guillaume Marcotte (Surgical ICU, Edouard Herriot Hos-
pital, Lyon, France), Benoit Misset (ICU, St Joseph Hospital,
Paris, France), Laurent Montesino (ICU, Hôpital Bichat, Paris,
France), Bruno Mourvillier (ICU, Hôpital Bichat, France),
Benoît Misset (ICU, Hôpital Saint-Joseph, Paris, France),
Virgine Lemiale (ICU, Hôpital Saint-Louis, Paris, France),
Benjamin Planquette (ICU, CH A Mignot, Versailles,
France), Romain Sonneville (ICU, Bichat Claude Bernard
Hospital, Paris, France), Bertrand Souweine (ICU, CHU
G Montpied, Clermont-Ferrand, France), Carole Schwebel
(CHU A Michallon, Grenoble, France), Gilles Troché (ICU,
CH A Mignot, Versailles, France), Marie Thuong (ICU, Pon-
toise, France), Dany Goldgran-Toledano (CH Gonnesse,
France), and Eric Vantalon (Surgical ICU, Hôpital Saint-
Joseph, Paris, France).
Study monitors: Caroline Tournegros, Loïc Ferrand, Nadira
Kaddour, Boris Berthe, Kaouttar Mellouk, Sophie Letrou, Igor
Théodose, Julien Fournier, and Véronique Deiler.
www.ccmjournal.org 9