Initial nutritional management during noninvasive ventilation and outcomes: a retrospective cohort study
Terzi et al. Critical Care
Initial nutritional management during noninvasive ventilation and outcomes: a retrospective cohort study
Nicolas Terzi 0 1
Carole Schwebel 0
for the OUTCOMEREA study group
0 Service de Réanimation Médicale, Centre Hospitalier Universitaire Grenoble - Alpes , CS10217 Grenoble, cedex 09 , France
1 INSERM, U1042, Université Grenoble-Alpes , HP2, F-38000 Grenoble , France
Background: Patients starting noninvasive ventilation (NIV) to treat acute respiratory failure are often unable to eat and therefore remain in the fasting state or receive nutritional support. Maintaining a good nutritional status has been reported to improve patient outcomes. In the present study, our primary objective was to describe the nutritional management of patients starting first-line NIV, and our secondary objectives were to assess potential associations between nutritional management and outcomes. Methods: Observational retrospective cohort study of a prospective database fed by 20 French intensive care units. Adult medical patients receiving NIV for more than 2 consecutive days were included and divided into four groups on the basis of nutritional support received during the first 2 days of NIV: no nutrition, enteral nutrition, parenteral nutrition only, and oral nutrition only. Results: Of the 16,594 patients admitted during the study period, 1075 met the inclusion criteria; of these, 622 (57.9%) received no nutrition, 28 (2.6%) received enteral nutrition, 74 (6.9%) received parenteral nutrition only, and 351 (32.7%) received oral nutrition only. After adjustment for confounders, enteral nutrition (vs. no nutrition) was associated with higher 28-day mortality (adjusted HR, 2.3; 95% CI, 1.2-4.4) and invasive mechanical ventilation needs (adjusted HR, 2.1; 95% CI, 1.1-4.2), as well as with fewer ventilator-free days by day 28 (adjusted relative risk, 0.7; 95% CI, 0.5-0.9). Conclusions: Nearly three-fifths of patients receiving NIV fasted for the first 2 days. Lack of feeding or underfeeding was not associated with mortality. The optimal route of nutrition for these patients needs to be investigated.
Nutrition; Noninvasive mechanical ventilation; Intensive care unit; Acute respiratory failure; Pneumonia
Over the last two decades, noninvasive ventilation (NIV)
has become the cornerstone supportive treatment for
acute respiratory failure requiring intensive care unit
(ICU) admission. NIV decreases the need for
endotracheal mechanical ventilation (MV), which is a major
source of complications. NIV has been proven to
decrease mortality, particularly in patients experiencing
acute exacerbations of chronic obstructive pulmonary
disease (COPD) or acute cardiogenic pulmonary edema
]. Both acute respiratory failure and COPD may
induce malnutrition, which may adversely affect patient
]. However, no recommendations about
nutritional support to patients receiving NIV are available.
Patients may be unable to remain off NIV for a
sufficient time to allow adequate food ingestion or may feel
too short of breath to eat. Either enteral nutrition via a
nasogastric tube or parenteral nutrition can be used in
this situation. Enteral nutrition has been associated with
a lower infection rate than parenteral nutrition in
patients with adequate gut function [
enteral nutrition via a nasogastric tube is associated with
adverse effects (e.g., nosocomial sinusitis and
tracheobronchial aspiration of gastric contents) [
], such as
mask leakage with decreased NIV efficiency [
]. In a
recent physiological study demonstrating improved
breathing-swallowing coordination and reduced
dyspnea with NIV during acute COPD exacerbations [
an off switch added to the ventilator for use during
swallowing proved effective. Such a device may allow
patients to eat sufficiently, including during NIV
sessions using a nasal mask, thus obviating the need for
nasogastric tube feeding.
Despite the considerable emphasis placed recently on
appropriate nutritional support in critically ill patients,
the accurate evaluation of malnutrition and provision of
adequate nutritional support remain major challenges in
ICU patients [
], especially those requiring NIV, for
the above-mentioned reasons. The considerable body of
evidence available on the nutritional management of
patients receiving MV contrasts with the paucity of data
on nutrition in patients started on NIV to treat acute
To begin filling this knowledge gap, we performed a
multicenter cohort study with the main objective of
describing the nutritional management of patients
admitted to the ICU and given first-line NIV. The
secondary objectives were to assess potential associations
between the type of nutritional management and patient
outcomes, including the need for MV, occurrence of
infection (i.e., bacteremia, urinary tract infection,
ventilatorassociated pneumonia [VAP], intensive care unit-acquired
pneumonia [ICU-AP], central line-associated bloodstream
infection), and death.
We used the multicenter OUTCOMEREA™ database
contributed to by physicians in 20 French ICUs with the
assistance of trained database monitors, as described
]. This study was approved by our
institutional review board (Clinical Investigation Center Ethics
Committee [CECIC] Clermont-Ferrand IRB number
5891, reference number 2007-16), which waived the
need for written informed consent of the participants,
in accordance with French legislation on
noninterventional studies. However, the patients and their next of
kin were informed about the inclusion of their
anonymized health data in the database, and none
We included adults admitted to medical ICUs between
2000 and 2015 who received NIV for more than 2
consecutive days. The 2-day period was selected as a
criterion for providing nutritional support [
Exclusion criteria were previous ICU admission during
the same hospital stay, postoperative period,
neuromuscular disease, NIV received after extubation, and
treatment limitation decisions within 24 h after starting NIV.
We separated the patients into four groups on the basis
of nutrition during the first 2 days of NIV: no nutrition
(NoN), enteral nutrition with or without parenteral
nutrition (EN), parenteral nutrition only (PN), and oral
nutrition only (ON).
We assessed associations between nutritional groups
and the need for MV, the occurrence of nosocomial
infection (i.e., bacteremia, urinary tract infection, VAP,
ICU-AP, central line-associated bloodstream infection), and
death. A patient was considered as a candidate for invasive
MV in case of loss of consciousness, hemodynamic
instability, inability to maintain the airway, worsening
respiratory distress, or persistently low peripheral
arterial oxygen saturation (<90%) despite 100%
fraction of inspired oxygen.
Nosocomial infection was defined as bacteremia,
urinary tract infection, pneumonia, or catheter-related
infection occurring after 72 h from admission. The
definition of nosocomial infection was taken from the
Hospital in Europe Link for Infection Control through
Surveillance (HELICS) project [
]. Bacteremia was
defined as the presence of pathogenic bacteria in blood
culture. Catheter-related infection was defined as a
positive quantitative catheter culture (≥ 103 colony-forming
units [CFU]/ml) treated by physicians in charge.
ICUAP was defined as a lower respiratory tract infection that
was not incubating at the time of hospital admission,
with symptom onset 2 or more days after NIV initiation.
ICU-AP was suspected on the basis of new or progressive
radiographic pulmonary infiltrates with at least two of the
following: temperature > 38 °C or < 36 °C, leukocytosis >
10,000/mm3 or leukopenia < 4000/mm3, and purulent
respiratory secretions [
]. The diagnosis was confirmed
by a quantitative sputum culture > 105 CFU/ml,
bronchoalveolar lavage (BAL) culture > 104 CFU/ml, or plugged
telescoping catheter culture > 103 CFU/ml. VAP was
defined as persistent pulmonary infiltrates seen on chest
radiographs combined with purulent tracheal secretions
and/or body temperature ≥ 38.5 °C or ≤ 36.5 °C and/or
peripheral blood leukocyte count ≥ 10,000/mm3 or ≤
4000/mm3. A definite diagnosis of VAP required
microbiological confirmation by quantitative culture from a
protected specimen brush (> 103 CFU/ml), plugged telescopic
catheter specimen (> 103 CFU/ml), BAL fluid specimen
(> 104 CFU/ml), or endotracheal aspirate (> 105 CFU/ml).
A urinary tract infection was defined as a quantitative
culture containing ≥ 105 CFU/ml of one or two organisms.
The baseline characteristics listed in Table 1 were collected
at ICU admission. The McCabe and Jackson classification
was used to estimate the prognosis of any preexisting
disease (rapidly fatal, ultimately fatal, or nonfatal).
Quality of the database
For most of the study variables, the data capture
software immediately ran an automatic check for internal
consistency, generating queries that were sent to the
ICUs for resolution before incorporation of the new data
into the database. In each participating ICU, data quality
was checked by having a senior physician from another
participating ICU review a 2% random sample of the
study data from alternate years. A 1-day-long data
capture training course held once annually was open to all
OUTCOMEREATM investigators and study monitors.
Characteristics of patients and outcomes were described
using frequency and percentage for qualitative variables
and median and interquartile range for quantitative
variables. A multivariable Cox model was built to evaluate
potential associations between nutrition group (NoN,
EN, PN, or ON) and day 28 mortality. To assess
potential associations linking nutrition group to the use of
MV and to the occurrence of nosocomial infection (i.e.,
bacteremia, urinary tract infection, VAP, ICU-AP, central
line-associated bloodstream infection) within 28 days,
we used a multivariable Fine and Gray model to allow
for discharge alive from the ICU as a competing event.
The adequacy of the models was checked using the
graphical and numerical methods of Lin et al. (1993).
We looked for associations between nutrition group and
ventilator-free days by day 28 using multivariable
negative binomial regression. Finally, an association between
nutrition group and the change in partial pressure of
carbon dioxide (PaCO2) from ICU admission to the
end of the second day (ΔPaCO2) was sought using
analysis of variance in the 772 patients with available
All models were adjusted on clinically relevant
variables. Choices among collinear variables were based
on clinical relevance, rate of missing variables, and
reproducibility of definitions. The variables selected for
adjustment were age, sex, Sequential Organ Failure
Assessment (SOFA) score on the first day of NIV,
chronic diseases, diabetes, obesity, main diagnosis at
ICU admission, respiratory and neurologic SOFA
subscores at ICU admission, and hospital length of stay
before ICU admission shorter than 2 days. Missing
values occurred for age (n = 1) and main diagnosis at
ICU admission (n = 19) and were imputed using the
median and mode, respectively.
P values less than 0.05 were considered significant.
Statistical analyses were performed using SAS version
9.4 software (SAS Institute, Cary, NC, USA).
During the study period, of the 16,594 patients
recorded in the database, 1075 (6.5%) required first-line
NIV for longer than 2 days. As shown in Table 1, NIV
was performed for COPD exacerbation in 201 patients
(19%), acute respiratory failure in 608 patients (57%),
and hypoventilation associated with coma in 35 patients
(3%). During the first 2 days of NIV, 622 patients
(57.8%) received no nutrition, 28 (2.6%) received EN,
74 (6.9%) received PN only, and 351 (32.7%) received
ON only (Fig. 1).
Table 1 reports the main patient characteristics.
Nutrition groups differed significantly regarding ICU
admission category, main symptom at ICU admission,
body weight, severity, and length of hospital stay
before ICU admission. Acute illness severity as
assessed by the Simplified Acute Physiology Score II
was lower in the ON group than in the NoN group.
The median ICU length of stay was 4 days
(interquartile range, 2–7).
Associations with type of nutrition
Overall, within the first 28 days, 145 patients (13.5%)
developed nosocomial infection (Additional file 1:
Table S1), 158 (14.7%) required MV, and 161 (15.0%)
died. Eighty-nine patients (8.3%) developed ICU-AP,
and 42 patients (3.9%) developed VAP. Table 2
reports the results of the multivariable analyses.
After adjustment for confounders (i.e., age, sex,
hospital stay length before ICU admission < 2 days, acute
illness severity at ICU admission [SOFA score], respiratory
and neurologic SOFA subscores at ICU admission,
obesity, chronic disease, and main diagnosis at ICU
admission), nutrition group was independently associated
with higher incidence of nosocomial infection (P = 0.02),
VAP (P = 0.002), and 28-day mortality (P = 0.02) (Fig. 2).
The incidence of infection was higher in the EN group
than in the NoN group (HR, 2.2; 95% CI, 1.1–4.5; P =
0.03). The occurrence of nosocomial infection was not
different in the PN or ON group compared with the NoN
group. The nutrition group was not associated with the
occurrence of ICU-AP (P = 0.18). The incidence of VAP
was higher in the EN and PN groups than in the NoN
group (HR, 6.9; 95% CI, 2.1–22.3; P = 0.001; and 2.9; 95%
95% CI, 1.1–7.4; P = 0.03, respectively).
Mortality was higher in the EN group than in the NoN
group (HR, 2.3; 95% CI, 1.2–4.4; P = 0.01). Mortality on
day 28 was not different in the PN or ON group
compared with the NoN group. The number of
ventilatorfree days by day 28 was significantly associated with
nutrition group (P = 0.006). Compared with NoN, EN
was associated with fewer ventilator-free days by day 28
(RR per day, 0.7; 95% CI, 0.5–0.9). ΔPaCO2 over the first
2 days was not associated with nutrition group.
In this large, multicenter database study, nearly
threefifths of patients fasted during the first 2 days of first-line
NIV used to treat acute respiratory failure in the ICU.
About one-third of patients received oral nutrition. EN
and PN were rarely used but were more often associated
with the need for invasive MV. EN, but not fasting, was
associated with higher 28-day mortality. EN was also
associated with a more days on ventilation. Type of nutrition
was not associated with the occurrence of ICU-AP.
In a previous observational study, patients with acute
respiratory failure requiring NIV often had inadequate
oral food intake, particularly early during admission and
as NIV duration increased [
]. Although nutritional
support is now recognized as an essential component of
the management of critically ill patients [
17, 21, 22
optimal intake and timing remain unclear. Positive
associations between protein intake and survival have been
reported in observational studies [
]. A major
weakness of these studies is the heterogeneity in acute illness
sHR (95% CI)
severity, which is a key potential confounder. Patients with
lower severity tolerate EN better, have caloric and protein
intake closer to the optimal values, and experience better
outcomes. Moreover, recent methodologically sound and
adequately powered randomized controlled trials have not
generated unequivocal evidence that full-replacement
nutrition early in the course of critical illness produces
clinical benefits [
In addition to timing of initiation, the delivery route is
viewed as an important determinant of the effect of
nutritional support. EN may produce nonnutritional
benefits, including maintenance of structural and
functional gut integrity and of the gut microbiome [
However, EN may fail to provide sufficient nutrition,
particularly at the acute phase of critical illness and in
patients with gastrointestinal dysfunction [
may be more effective in achieving nutritional targets
but is associated with infections, which are probably
related to overnutrition and hyperglycemia, as shown in
two meta-analyses [
]. These clinical data have
translated into a consensus, expressed in both
international recommendations [
] and expert opinions
], that EN should be preferred in critically ill patients
without contraindications to this route. CALORIE is a
large, randomized trial in which researchers recently
compared EN and PN started within 36 h after ICU admission
and continued for up to 5 days in unselected ICU patients
. In this pragmatic trial involving 2388 patients, neither
30-day mortality nor the frequency of infections differed
between the two groups. These results challenge the
previously held belief that EN produces better outcomes
than PN in ICU patients.
Enteral nutrition via nasogastric tube and parenteral
nutrition was rarely used in our study. As previously
described, enteral nutrition via a nasogastric tube is
associated with adverse effects [
], such as mask
leakage with decreased NIV efficiency . Furthermore,
Kogo et al. observed in a retrospective study that enteral
nutrition caused more airway complications in subjects
receiving NIV for acute respiratory failure than in those
receiving nutrition by other routes [
]. We can
hypothesize that physicians promote NIV efficiency
rather than nutrition during the first 2 days of NIV. These
results are in accordance with those of previous studies.
Indeed, Bendavid et al. showed, in a large prevalence study
of nutrition practice in intensive care, that enteral feeding
was prescribed to only 10% of the patients on the first day,
but this number increased to more than 40% of the
patients after 5 days [
Parenteral nutrition was used for only 7% of the
patients. As suggested earlier, some physicians could be
reluctant to use enteral nutrition via a nasogastric tube for
patients with NIV. Moreover, a fluid-restricted strategy
targeting patients with acute respiratory failure (more than
half of included patients) may explain few parenteral
nutrition prescriptions in the study population [
type of nutrition was not associated with the occurrence
of ICU-AP. However, occurrence of VAP was higher in
the PN and EN groups. This result is coherent with the
fact that the EN and PN groups were associated with a
higher need for invasive MV. Indeed, a protective effect
of NIV has been reported in single-center [
] studies and can be attributed both to
the absence of an endotracheal tube bypassing the upper
airways and to decreased invasiveness of the overall
management. Contrary to previous results, the reported
increase in infectious complications that have been associated
with the parenteral route was not observed [
absence of significance of this result is probably due to the
lack of power, and other contributory reasons may be
improvements in current management of vascular access [
In our study, fasting for 48 h after NIV initiation was
not associated with 28-day mortality. In contrast, EN
and PN during the first 2 days on NIV were associated
with higher need for invasive MV, and EN was
associated with higher 28-day mortality. The observational
design of this study could not prove causality. Critically ill
patients may be unable to tolerate EN, which may be
associated with a higher risk of respiratory complications
(e.g., mucus plug, aspiration pneumonia) [
]. EN may
increase the residual gastric volume, thereby promoting
bacterial colonization and the risk of aspiration
pneumonia, and VAP may increase [
]. Many risk factors
for aspiration pneumonia have been identified, including
intubation and difficult intubation, peri-intubation
vomiting, anesthesia, older age, gastroparesis, reflux,
impaired swallowing, mental state alteration, and cardiac
arrest . In our study, type of nutrition was not
associated with the occurrence of ICU-AP. However,
occurrence of VAP was higher in the PN and EN groups. This
result is coherent with the fact that the EN and PN
groups were associated with greater need for invasive
MV. Moreover, nosocomial infection was higher in the
EN group. We can hypothesize that the higher mortality
was due to higher occurrence of nosocomial infection.
We cannot exclude the negative impact of overfeeding.
As previously demonstrated, high protein intake may
lead to azotemia, hypertonic dehydration, and metabolic
]. Large amounts of intravenous glucose may
result in hyperglycemia, hypertriglyceridemia, and
hepatic steatosis [
], which can, however, be prevented to a
considerable extent by insulin therapy targeting
]. Moreover, NIV decreases the work and
therefore the energy needs of the diaphragm [
Previous data suggest that oversupply of energy relative to
needs may worsen diaphragmatic dysfunction [
Our study has several limitations. The patients were
identified retrospectively from the database, and we
cannot exclude selection bias. Choice of nutrition route was
made by clinicians without a specific protocol. Moreover,
unfortunately, we cannot provide the amount of calories
and protein for each group. NIV practices may have
varied across the study centers. The indications to perform
NIV were heterogeneous but in accordance with
recommendations. Decisions of application (i.e.,
continuous session, intermittent) were made by attending
clinicians, and total duration of NIV session was not
assessed; thus, we cannot exclude the possibility that
these modalities influenced the choice of the route of
nutrition. However, our study was a multicenter study in
20 French ICUs, and our results are in accordance with
previous results. Reeves et al. demonstrated that patients
with acute respiratory failure requiring NIV often had
inadequate oral intake, particularly with increasing time
on NIV and earlier during their hospital admission [
Moreover, a retrospective study can detect associations
but cannot provide evidence of causality. Although we
adjusted for potential confounders, we cannot exclude
the possibility that the observed associations were
related to a clustering effect (i.e., to variables that were
not adjusted for and that were related both to the choice
of nutrition type and to outcomes).
Most patients received no nutrition at all during the
first 2 days of first-line NIV. Early EN in a
heterogeneous population was independently associated with
higher 28-day mortality and fewer ventilator-free days.
Additional studies are required to assess the need for,
as well as the best timing and route of, nutritional
support in this specific population.
Additional file 1: Table S1. Description of interface used for NIV and type
of exhibited complications according to nutritional groups. (DOCX 17 kb)
BAL: Bronchoalveolar lavage; BMI: Body mass index; CFU: Colony-forming
units; COPD: Chronic obstructive pulmonary disease; EN: Enteral nutrition;
ICU: Intensive care unit; ICU-AP: Intensive care unit-acquired pneumonia;
LOS: Length of stay; MV: Mechanical ventilation; NIV: Noninvasive ventilation;
NoN: No nutrition; ON: Oral nutrition; PaCO2: Partial pressure of carbon
dioxide; PN: Parenteral nutrition; RR: Relative risk; SAPS II: Simplified Acute
Physiology Score II; sHR: Subdistribution hazard ratio; SOFA: Sequential Organ
Failure Assessment; VAP: Ventilator-associated pneumonia
We thank A. Wolfe, MD, for revising the manuscript.
Members of the OUTCOMEREA Study Group
Scientific Committee: Jean-François Timsit (Medical and Infectious Diseases
ICU, Bichat-Claude Bernard Hospital, Paris; UMR 1137 Inserm, Paris Diderot
University Infection Antimicrobials Modelling Evolution [IAME], Paris); Elie
Azoulay (Medical ICU, Saint Louis Hospital, Paris); Maïté Garrouste-Orgeas
(ICU, Saint-Joseph Hospital, Paris); Jean-Ralph Zahar (Infection Control Unit,
Angers Hospital, Angers, France); Christophe Adrie (ICU, Delafontaine Hospital,
Saint Denis, and Physiology, Cochin Hospital, Paris); Michael Darmon (Medical
ICU, Saint Etienne University Hospital, Saint-Etienne, France); and Christophe
Clec’h (ICU, Avicenne Hospital, Bobigny, and UMR 1137 Inserm, Paris Diderot
University IAME, Paris).
Biostatistical and Information System Expertise: Jean-Francois Timsit (Medical
and Infectious Diseases ICU, Bichat-Claude Bernard Hospital, Paris; UMR 1137
Inserm, Paris Diderot University IAME, Paris); Corinne Alberti (Medical Computer
Sciences and Biostatistics Department, Robert Debré Hospital, Paris); Stephane
Ruckly (OUTCOMEREA Organization and Inserm UMR 1137 IAME, Paris);
Sébastien Bailly (Grenoble University Hospital, Inserm UMR 1137 IAME, Paris);
Lenka Styfalova (ICUREsearch, Paris); and Aurélien Vannieuwenhuyze
OUTCOMEREA Database Investigators: Christophe Adrie (ICU, Delafontaine
Hospital, Saint Denis, and Physiology, Cochin Hospital, Paris); Bernard
Allaouchiche (ICU, Pierre Benite Hospital, Lyon, France); Laurent Argaud
(Medical ICU, Hospices Civils de Lyon, Lyon, France); Claire Ara-Somohano
(Medical ICU, University Hospital, Grenoble, France); Elie Azoulay (Medical ICU,
Saint Louis Hospital, Paris); Francois Barbier (Medical-Surgical ICU, Orleans,
France), Jean-Pierre Bedos (ICU, Versailles Hospital, Versailles, France); Julien Bohé
(ICU, Hôpital Pierre Benite, Lyon France); Lila Bouadma (ICU, Bichat Hospital,
Paris); Christine Cheval (ICU, Hyeres Hospital, Hyeres, France); Christophe Clec’h
(ICU, Avicenne Hospital, Bobigny, France); Michael Darmon (ICU, Saint Etienne
Hospital, Saint Etienne, France); Anne-Sylvie Dumenil (Antoine Béclère Hospital,
Clamart, France); Claire Dupuis (Bichat Hospital and UMR 1137 Inserm, Paris
Diderot University IAME, Paris); Jean-Marie Forel (Assistance Publique – Hôpitaux
Marseille, Medical ICU, Hôpital Nord Marseille); Marc Gainier (la Timone Hospital,
Marseille, France); Akim Haouache (Surgical ICU, Henri Mondor Hospital, Creteil,
France); Samir Jamali (ICU, Dourdan Hospital, Dourdan, France); Hatem Khallel
(ICU, Cayenne General Hospital, Cayenne, France); Alexandre Lautrette (ICU,
Gabriel-Montpied Hospital, Clermont-Ferrand, France); Guillaume Marcotte
(Surgical ICU, Hospices Civils de Lyon, Lyon, France); Eric Le Miere (ICU, Louis
Mourier Hospital, Colombes, France); Maxime Lugosi (Medical ICU, University
Hospital Grenoble, Grenoble, France); Bruno Mourvillier (ICU, Bichat Hospital,
Paris); Benoît Misset (ICU, Saint-Joseph Hospital, Paris); Delphine Moreau (ICU,
Saint-Louis Hospital, Paris); Bruno Mourvillier (ICU, Bichat Hospital, Paris); Laurent
Papazian (Hopital Nord, Marseille, France); Benjamin Planquette (Pulmonology
ICU, George Pompidou Hospital, Versailles, France); Bertrand Souweine (ICU,
Gabriel-Montpied Hospital, Clermont-Ferrand, France); Carole Schwebel (ICU,
Albert Michallon Hospital, Grenoble, France); Nicolas Terzi (ICU, Albert Michallon
Hospital, Grenoble, France); Gilles Troché (ICU, Antoine Béclère Hospital, Clamart,
France); Marie Thuong (ICU, Delafontaine Hospital, Saint Denis, France); Guillaume
Thierry (ICU, Saint-Louis Hospital, Paris); Dany Toledano (ICU, Gonesse Hospital,
Gonesse, France); and Eric Vantalon (Surgical ICU, Saint-Joseph Hospital, Paris).
Study Monitors: Julien Fournier, Caroline Tournegros, Stéphanie Bagur,
Mireille Adda, Vanessa Vindrieux, Loic Ferrand, Nadira Kaddour, Boris Berthe,
Samir Bekkhouche, Kaouttar Mellouk, Sylvie Conrozier, Igor Theodose,
Veronique Deiler, and Sophie Letrou.
Availability of data and materials
The datasets used and analyzed during the present study are available from
the corresponding author on reasonable request.
NT, MD, SR, CS, and JFT conceived of the original protocol. NT, MD, JR, MGO,
AL, EA, BM, LA, LP, MG, DGT, SJ, ASD, CS, and JFT recorded the data. SR and
JFT performed statistical analysis. NT, MD, CS, and JFT analyzed the data and
drafted the manuscript. JR, MGO, AL, EA, BM, LA, LP, MG, DGT, SJ, and ASD
helped to conduct the study and to draft the final manuscript. NT had full
access to all the study data and takes responsibility for the content of the
manuscript, including the integrity of the data and accuracy of the analysis.
All authors read and approved the final manuscript.
Ethics approval and consent to participate
This study was approved by the Clermont-Ferrand Hospital institutional
review board (Clinical Investigation Center Ethics Committee [CECIC]
Clermont-Ferrand IRB number 5891, reference 2007-16), which waived
the need for written informed consent of the participants, in accordance
with French legislation on noninterventional studies.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1INSERM, U1042, Université Grenoble-Alpes, HP2, F-38000 Grenoble, France.
2Service de Réanimation Médicale, Centre Hospitalier Universitaire Grenoble
– Alpes, CS10217 Grenoble, cedex 09, France. 3Medical Intensive Care Unit,
Saint-Etienne University Hospital, Saint-Priest en Jarez, France. 4Medical
Intensive Care Unit, Nantes University Hospital Center, Nantes, France.
5Department of Biostatistics, OUTCOMEREA™, Bobigny, France. 6UMR 1137,
Infection Antimicrobials Modelling Evolution (IAME) Team 5, Decision
Sciences in Infectious Diseases (DeSCID), Control and Care, Sorbonne Paris
Cité, Inserm/Paris Diderot University, Paris, France. 7Polyvalent Intensive Care
Unit, Groupe Hospitalier Saint-Joseph, Paris, France. 8Medical Intensive Care
Unit, Gabriel Montpied University Hospital, Clermont-Ferrand, France. 9Service
de Réanimation Médicale, CHU Saint-Louis, Assistance Publique – Hôpitaux
de Paris, Paris, France. 10Réanimation Médicale et Infectieuse, Hôpital Bichat
Claude Bernard, Assistance Publique – Hôpitaux de Paris, Paris, France.
11Medical Intensive Care Unit, Lyon University Hospital, Lyon, France.
12Réanimation des Détresses Respiratoires et Infections Sévères, Hôpital Nord,
Aix-Marseille University, Assistance Publique – Hôpitaux de Marseille, Unité
de Recherche sur les Maladies Infectieuses et Tropicales Émergentes
(URMITE), UMR CNRS 7278, Marseille, France. 13Réanimation des Urgences et
Medicale, CHU la Timone 2 Marseille, Aix-Marseille Université, 13385 Marseille,
France. 14Medical-Surgical Intensive Care Unit, Gonesse Hospital, Gonesse,
France. 15Medical-Surgical Intensive Care Medicine Unit, Dourdan Hospital,
Dourdan, France. 16Medical-Surgical Intensive Care Unit, Assistance Publique
– Hôpitaux de Paris, Antoine Béclère University Hospital, Clamart, France.
17Integrated Research Center, Inserm U1039, Radiopharmaceutical Bioclinical
Mixed Research Unit, University Joseph Fourier, Grenoble, France.
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