Publications 2021

Impact of early corticosteroids on 60-day mortality in critically ill patients

with COVID-19: A multicenter cohort study of the OUTCOMEREA network.

Dupuis C(1)(2), de Montmollin E(2)(3), Buetti N(3), Goldgran-Toledano D(4),

Reignier J(5), Schwebel C(6), Domitile J(1), Neuville M(7), Ursino M(8)(9),

Siami S(10), Ruckly S(11), Alberti C(12), Mourvillier B(13), Bailly S(14),

Laurent V(15), Gainnier M(16), Souweine B(1), Timsit JF(2)(3); OutcomeReaTM

research network.

KEY Finding :

At the early phase of the pandemics, when ICU care was administered without any restriction, early corticosteroid therapy was not associated with an improved outcome. Overal patient’s prognosis was better that the one observed in the control group of the RECOVERY study. Heterogeneity of standard of care may explain the discrepancies of the CS effect between studies.

OBJECTIVES: In severe COVID-19 pneumonia, the appropriate timing and dosing of

corticosteroids (CS) is not known. Patient subgroups for which CS could be more

beneficial also need appraisal. The aim of this study was to assess the effect

of early CS in COVID-19 pneumonia patients admitted to the ICU on the occurrence

of 60-day mortality, ICU-acquired-bloodstream infections(ICU-BSI), and

hospital-acquired pneumonia and ventilator-associated pneumonia(HAP-VAP).

METHODS: We included patients with COVID-19 pneumonia admitted to 11 ICUs

belonging to the French OutcomeReaTM network from January to May 2020. We used

survival models with ponderation with inverse probability of treatment weighting

(IPTW).

RESULTS: The study population comprised 303 patients having a median age of 61.6

(53-70) years of whom 78.8% were male and 58.6% had at least one comorbidity.

The median SAPS II was 33 (25-44). Invasive mechanical ventilation was required

in 34.8% of the patients. Sixty-six (21.8%) patients were in the Early-C

subgroup. Overall, 60-day mortality was 29.4%. The risks of 60-day mortality

(IPTWHR = 0.86;95% CI 0.54 to 1.35, p = 0.51), ICU-BSI and HAP-VAP were similar

in the two groups. Importantly, early CS treatment was associated with a lower

mortality rate in patients aged 60 years or more (IPTWHR, 0.53;95% CI, 0.3-0.93;

p = 0.03). In contrast, CS was associated with an increased risk of death in

patients younger than 60 years without inflammation on admission (IPTWHR =

5.01;95% CI, 1.05, 23.88; p = 0.04).

CONCLUSION: For patients with COVID-19 pneumonia, early CS treatment was not

associated with patient survival. Interestingly, inflammation and age can

significantly influence the effect of CS.

DOI: 10.1371/journal.pone.0255644

PMCID: PMC8336847

PMID: 34347836 [Indexed for MEDLINE]

Conflict of interest statement: The authors have read the journal’s policy and

have the following competing interests: SR is a paid employee of ICUREsearch.

There are no patents, products in development or marketed products associated

with this research to declare. This does not alter our adherence to PLOS ONE

policies on sharing data and materials.

Clinical and biological clusters of sepsis patients using hierarchical

clustering.

Papin G(1)(2), Bailly S(3)(4), Dupuis C(1)(2), Ruckly S(5), Gainnier M(6),

Argaud L(7), Azoulay E(8), Adrie C(9), Souweine B(10), Goldgran-Toledano D(11),

Marcotte G(12), Gros A(13), Reignier J(14), Mourvillier B(15), Forel JM(16),

Sonneville R(2), Dumenil AS(17), Darmon M(8), Garrouste-Orgeas M(18), Schwebel

C(19), Timsit JF(1)(2); OUTCOMEREA study group.

KEY FINDINGS:

Unsupervised clustering is able to differentiate at least 6 clusters of sepsis and septic shock. The most important variables are nosocomial acquisition, age , comorbidities, source of infection nature and severity of organ failures. Clusters have very distinct prognosis and may benefit for very different therapeutic strategies.

BACKGROUND: Heterogeneity in sepsis expression is multidimensional, including

highly disparate data such as the underlying disorders, infection source,

causative micro-organisms and organ failures. The aim of the study is to identify

clusters of patients based on clinical and biological characteristic available

at patients' admission.

METHODS: All patients included in a national prospective multicenter ICU cohort

OUTCOMEREA and admitted for sepsis or septic shock (Sepsis 3.0 definition) were

retrospectively analyzed. A hierarchical clustering was performed in a training

set of patients to build clusters based on a comprehensive set of clinical and

biological characteristics available at ICU admission. Clusters were described,

and the 28-day, 90-day, and one-year mortality were compared with log-rank

rates. Risks of mortality were also compared after adjustment on SOFA score and

year of ICU admission.

RESULTS: Of the 6,046 patients with sepsis in the cohort, 4,050 (67%) were

randomly allocated to the training set. Six distinct clusters were identified:

young patients without any comorbidities, admitted in ICU for community-acquired

pneumonia (n = 1,603 (40%)); young patients without any comorbidities, admitted

in ICU for meningitis or encephalitis (n = 149 (4%)); elderly patients with

COPD, admitted in ICU for bronchial infection with few organ failures (n = 243

(6%)); elderly patients, with several comorbidities and organ failures (n =

1,094 (27%)); patients admitted after surgery, with a nosocomial infection (n =

623 (15%)); young patients with immunosuppressive conditions (e.g., AIDS,

chronic steroid therapy or hematological malignancy) (n = 338 (8%)). Clusters

differed significantly in early or late mortality (p < .001), even after

adjustment on severity of organ dysfunctions (SOFA) and year of ICU admission.

CONCLUSIONS: Clinical and biological features commonly available at ICU

admission of patients with sepsis or septic shock enabled to set up six clusters

of patients, with very distinct outcomes. Considering these clusters may improve

the care management and the homogeneity of patients in future studies.

DOI: 10.1371/journal.pone.0252793

PMCID: PMC8336799

PMID: 34347776 [Indexed for MEDLINE]

Conflict of interest statement: The authors have declared that no competing

interests exist.

Performance of Repeated Measures of (1-3)-β-D-Glucan, Mannan Antigen, and

Antimannan Antibodies for the Diagnosis of Invasive Candidiasis in ICU Patients:

A Preplanned Ancillary Analysis of the EMPIRICUS Randomized Clinical Trial.

Dupuis C(1)(2), Le Bihan C(3), Maubon D(4), Calvet L(1), Ruckly S(5), Schwebel

C(6), Bouadma L(2)(7), Azoulay E(8), Cornet M(4), Timsit JF(2)(7); Empiricus

Study Group.

Key finding:

A post hoc analysis of the Empiricus trial that was leaded by the OUTCOMEREA study group. Serial measurement B D glucan and mannane were not able to select patients with subsequent fungal infections in ICU

BACKGROUND: We aimed to assess the prognostic value of repeated measurements of

serum (1-3)-β-D-glucan (BDG), mannan-antigen (mannan-Ag), and antimannan

antibodies (antimannan-Ab) for the occurrence of invasive candidiasis (IC) in a

high-risk nonimmunocompromised population.

METHODS: This was a preplanned ancillary analysis of the EMPIRICUS Randomized

Clinical Trial, including nonimmunocompromised critically ill patients with

intensive care unit-acquired sepsis, multiple Candida colonization, and multiple

organ failure who were exposed to broad-spectrum antibacterial agents. BDG (>80

and >250 pg/mL), mannan-Ag (>125 pg/mL), and antimannan-Ab (>10 AU) were

collected repeatedly. We used cause-specific hazard models. Biomarkers were

assessed at baseline in the whole cohort (cohort 1). Baseline covariates and/or

repeated measurements and/or increased biomarkers were then studied in the

subgroup of patients who were still alive at day 3 and free of IC (cohort 2).

RESULTS: Two hundred thirty-four patients were included, and 215 were still

alive and free of IC at day 3. IC developed in 27 patients (11.5%), and day 28

mortality was 29.1%. Finally, BDG >80 pg/mL at inclusion was associated with an

increased risk of IC (CSHR[IC], 4.67; 95% CI, 1.61-13.5) but not death

(CSHR[death], 1.20; 95% CI, 0.71-2.02).

CONCLUSIONS: Among high-risk patients, a first measurement of BDG >80 pg/mL was

strongly associated with the occurrence of IC. Neither a cutoff of 250 pg/mL nor

repeated measurements of fungal biomarkers seemed to be useful to predict the

occurrence of IC. The cumulative risk of IC in the placebo group if BDG >80

pg/mL was 25.39%, which calls into question the efficacy of empirical therapy in

this subgroup.

Infectious Diseases Society of America.

DOI: 10.1093/ofid/ofab080

PMCID: PMC8002176

PMID: 33816643

Life Support Limitations in Mechanically Ventilated Stroke Patients.

de Montmollin E(1)(2), Schwebel C(3), Dupuis C(1)(2), Garrouste-Orgeas M(4), da

Silva D(5), Azoulay E(6), Laurent V(7), Thiéry G(8), Grinea A(2), Marcotte G(9),

Oziel J(10), Gainnier M(11), Siami S(12), Reignier J(13), Sztrymf B(14), Adrie

C(15)(16), Ruckly S(1), Sonneville R(2)(17), Timsit JF(1)(2).

MESSAGES:

Chez les patients neuro lésés, les LATA sont plus fréquentes que chez les patients non neuro lésés avec des différences supplémentaires entre AVC ischémiques et hémorragiques.

OBJECTIVES: The determinants of decisions to limit life support (withholding or

withdrawal) in ventilated stroke patients have been evaluated mainly for

patients with intracranial hemorrhages. We aimed to evaluate the frequency of

life support limitations in ventilated ischemic and hemorrhagic stroke patients

compared with a nonbrain-injured population and to determine factors associated

with such decisions.

DESIGN: Multicenter prospective French observational study.

SETTING: Fourteen ICUs of the French OutcomeRea network.

PATIENTS: From 2005 to 2016, we included stroke patients and nonbrain-injured

patients requiring invasive ventilation within 24 hours of ICU admission.

INTERVENTION: None.

MEASUREMENTS AND MAIN RESULTS: We identified 373 stroke patients (ischemic, n =

167 [45%]; hemorrhagic, n = 206 [55%]) and 5,683 nonbrain-injured patients.

Decisions to limit life support were taken in 41% of ischemic stroke cases (vs

nonbrain-injured patients, subdistribution hazard ratio, 3.59 [95% CI,

2.78-4.65]) and in 33% of hemorrhagic stroke cases (vs nonbrain-injured

patients, subdistribution hazard ratio, 3.9 [95% CI, 2.97-5.11]). Time from ICU

admission to the first limitation was longer in ischemic than in hemorrhagic

stroke (5 [3-9] vs 2 d [1-6] d; p < 0.01). Limitation of life support preceded

ICU death in 70% of ischemic strokes and 45% of hemorrhagic strokes (p < 0.01).

Life support limitations in ischemic stroke were increased by a vertebrobasilar

location (vs anterior circulation, subdistribution hazard ratio, 1.61 [95% CI,

1.01-2.59]) and a prestroke modified Rankin score greater than 2 (2.38

[1.27-4.55]). In hemorrhagic stroke, an age greater than 70 years (2.29

[1.43-3.69]) and a Glasgow Coma Scale score less than 8 (2.15 [1.08-4.3]) were

associated with an increased risk of limitation, whereas a higher nonneurologic

admission Sequential Organ Failure Assessment score was associated with a

reduced risk (per point, 0.89 [0.82-0.97]).

CONCLUSIONS: In ventilated stroke patients, decisions to limit life support are

more than three times more frequent than in nonbrain-injured patients, with

different timing and associated risk factors between ischemic and hemorrhagic

strokes.

of the Society of Critical Care Medicine.

DOI: 10.1097/CCE.0000000000000341

PMCID: PMC7901798

PMID: 33634264

Conflict of interest statement: Dr. Thiéry has received honoraria from

Gilead-Kite. The remaining authors have disclosed that they do not have any

conflicts of interest.

Multistate Modeling of COVID-19 Patients Using a Large Multicentric Prospective

Cohort of Critically Ill Patients.

Ursino M(1)(2), Dupuis C(3)(4), Buetti N(4), de Montmollin E(4)(5), Bouadma

L(4)(5), Golgran-Toledano D(6), Ruckly S(4)(7), Neuville M(8), Cohen

Y(9)(10)(11), Mourvillier B(12), Souweine B(3), Gainnier M(13), Laurent V(14),

Terzi N(15)(16), Shiami S(17), Reignier J(18), Alberti C(1)(19), Timsit

JF(4)(5), On Behalf Of The Outcomerea Study Group.

MESSAGES:

Grace à un modèle multi état cette étude donne des estimateurs du pronostic des pateints en fonction des thérapeutiques utilisées. Elle montre que la corticothérapie et les IL6-ra diminue le risque d’intubation invasive.

The mortality of COVID-19 patients in the intensive care unit (ICU) is

influenced by their state at admission. We aimed to model COVID-19 acute

respiratory distress syndrome state transitions from ICU admission to day 60

outcome and to evaluate possible prognostic factors. We analyzed a prospective

French database that includes critically ill COVID-19 patients. A six-state

multistate model was built and 17 transitions were analyzed either using a

non-parametric approach or a Cox proportional hazard model. Corticosteroids and

IL-antagonists (tocilizumab and anakinra) effects were evaluated using

G-computation. We included 382 patients in the analysis: 243 patients were

admitted to the ICU with non-invasive ventilation, 116 with invasive mechanical

ventilation, and 23 with extracorporeal membrane oxygenation. The predicted

60-day mortality was 25.9% (95% CI: 21.8%-30.0%), 44.7% (95% CI: 48.8%-50.6%),

and 59.2% (95% CI: 49.4%-69.0%) for a patient admitted in these three states,

respectively. Corticosteroids decreased the risk of being invasively ventilated

(hazard ratio (HR) 0.59, 95% CI: 0.39-0.90) and IL-antagonists increased the

probability of being successfully extubated (HR 1.8, 95% CI: 1.02-3.17).

Antiviral drugs did not impact any transition. In conclusion, we observed that

the day-60 outcome in COVID-19 patients is highly dependent on the first

ventilation state upon ICU admission. Moreover, we illustrated that

corticosteroid and IL-antagonists may influence the intubation duration.

DOI: 10.3390/jcm10030544

PMCID: PMC7867229

PMID: 33540733

Conflict of interest statement: The authors disclose that they do not have any

conflict of interest. Timsit received fees for lectures with 3M, Merck, Pfizer,

and Biomerieux; he received research grants from 3M, Merck, Pfizer, Biomerieux,

and Medimune; and he participated in advisory boards by 3M, Merck, Bayer Pharma,

Nabriva, Medimune, Pfizer, and Gilead. Souweine reports fees from MSD, SANOFI,

LABORATOIRE AGUETTANT, and non-financial support from TTM BARD outside the

submitted work. Terzi reports fees from Pfizer outside the submitted work.

Association Between Early Invasive Mechanical Ventilation and Day-60 Mortality

in Acute Hypoxemic Respiratory Failure Related to Coronavirus Disease-2019

Pneumonia.

Dupuis C(1)(2), Bouadma L(2)(3), de Montmollin E(2)(3), Goldgran-Toledano D(4),

Schwebel C(5), Reignier J(6), Neuville M(7), Ursino M(8)(9), Siami S(10), Ruckly

S(11), Alberti C(12), Mourvillier B(13), Bailly S(14), Grapin K(1), Laurent

V(15), Buetti N(2), Gainnier M(16), Souweine B(1), Timsit JF(2)(3).

MESSAGES:

Toutes choses égale par ailleurs une intubation précoce des malades avec un SDRA covid aggrave leur pronostic. La question est de définir quand l’intubation tardive n’est pas trop tardive…

OBJECTIVES: About 5% of patients with coronavirus disease-2019 are admitted to

the ICU for acute hypoxemic respiratory failure. Opinions differ on whether

invasive mechanical ventilation should be used as first-line therapy over

noninvasive oxygen support. The aim of the study was to assess the effect of

early invasive mechanical ventilation in coronavirus disease-2019 with acute

hypoxemic respiratory failure on day-60 mortality.

DESIGN: Multicenter prospective French observational study.

SETTING: Eleven ICUs of the French OutcomeRea network.

PATIENTS: Coronavirus disease-2019 patients with acute hypoxemic respiratory

failure (Pao2/Fio2 ≤ 300 mm Hg), without shock or neurologic failure on ICU

admission, and not referred from another ICU or intermediate care unit were

included.

INTERVENTION: We compared day-60 mortality in patients who were on invasive

mechanical ventilation within the first 2 calendar days of the ICU stay (early

invasive mechanical ventilation group) and those who were not (nonearly invasive

mechanical ventilation group). We used a Cox proportional-hazard model weighted

by inverse probability of early invasive mechanical ventilation to determine the

risk of death at day 60.

MEASUREMENT AND MAIN RESULTS: The 245 patients included had a median

(interquartile range) age of 61 years (52-69 yr), a Simplified Acute Physiology

Score II score of 34 mm Hg (26-44 mm Hg), and a Pao2/Fio2 of 121 mm Hg

(90-174 mm Hg). The rates of ICU-acquired pneumonia, bacteremia, and the ICU

length of stay were significantly higher in the early (n = 117 [48%]) than in

the nonearly invasive mechanical ventilation group (n = 128 [52%]), p < 0.01.

Day-60 mortality was 42.7% and 21.9% in the early and nonearly invasive

mechanical ventilation groups, respectively. The weighted model showed that

early invasive mechanical ventilation increased the risk for day-60 mortality

(weighted hazard ratio =1.74; 95% CI, 1.07-2.83, p=0.03).

CONCLUSIONS: In ICU patients admitted with coronavirus disease-2019-induced

acute hypoxemic respiratory failure, early invasive mechanical ventilation was

associated with an increased risk of day-60 mortality. This result needs to be

confirmed.

of the Society of Critical Care Medicine.

DOI: 10.1097/CCE.0000000000000329

PMCID: PMC7838010

PMID: 33521646

Conflict of interest statement: Dr. Timsit declares no conflict of interest

related to the submitted work. Outside the submitted work, he declares

participation in advisory boards for Merck, Pfizer, Gilead, Nabriva, and

Paratek, lecture fees from Biomerieux, Pfizer, and Merck, and research grants to

his research unit from Merck, 3M, Astelas, and Thermofisher. Dr. Buetti is

currently receiving a mobility grant from the Swiss National Science Foundation

(grant number: P400PM_183865) and a grant from the Bangerter-Rhyner Foundation.

These grants support his fellowship in Paris. The remaining authors have

disclosed that they do not have any potential conflicts of interest.

COVID-19 increased the risk of ICU-acquired bloodstream infections: a

case-cohort study from the multicentric OUTCOMEREA network.

Buetti N(#)(1)(2), Ruckly S(#)(1), de Montmollin E(1)(3), Reignier J(4), Terzi

N(5)(6), Cohen Y(7)(8)(9), Siami S(10), Dupuis C(1)(11), Timsit JF(12)(13).

KEY MESSAGE:

Using prospectively collected multicentric data, we showed that the

ICU-BSI risk was higher for COVID-19 than non-COVID-19 critically ill patients

after seven days of ICU stay. Clinicians should be particularly careful on late

ICU-BSIs in COVID-19 patients. Tocilizumab or anakinra may increase the ICU-BSI

risk.

PURPOSE: The primary objective of this study was to investigate the risk of ICU

bloodstream infection (BSI) in critically ill COVID-19 patients compared to

non-COVID-19 patients. Subsequently, we performed secondary analyses in order to

explain the observed results.

METHODS: We conducted a matched case-cohort study, based on prospectively

collected data from a large ICU cohort in France. Critically ill COVID-19

patients were matched with similar non-COVID-19 patients. ICU-BSI was defined by

an infection onset occurring > 48 h after ICU admission. We estimated the effect

of COVID-19 on the probability to develop an ICU-BSI using proportional

subdistribution hazards models.

RESULTS: We identified 321 COVID-19 patients and 1029 eligible controls in 6

ICUs. Finally, 235 COVID-19 patients were matched with 235 non-COVID-19

patients. We observed 43 ICU-BSIs, 35 (14.9%) in the COVID-19 group and 8 (3.4%)

in the non-COVID-19 group (p ≤ 0.0001), respectively. ICU-BSIs of COVID-19

patients were more frequently of unknown source (47.4%). COVID-19 patients had

an increased probability to develop ICU-BSI, especially after 7 days of ICU

admission. Using proportional subdistribution hazards models, COVID-19 increased

the daily risk to develop ICU-BSI (sHR 4.50, 95% CI 1.82-11.16, p = 0.0012).

Among COVID-19 patients (n = 235), a significantly increased risk for ICU-BSI

was detected in patients who received tocilizumab or anakinra (sHR 3.20, 95% CI

1.31-7.81, p = 0.011) but not corticosteroids.

CONCLUSIONS: Using prospectively collected multicentric data, we showed that the

ICU-BSI risk was higher for COVID-19 than non-COVID-19 critically ill patients

after seven days of ICU stay. Clinicians should be particularly careful on late

ICU-BSIs in COVID-19 patients. Tocilizumab or anakinra may increase the ICU-BSI

risk.

DOI: 10.1007/s00134-021-06346-w

PMCID: PMC7839935

PMID: 33506379 [Indexed for MEDLINE]

Conflict of interest statement: The authors have disclosed that they do not have

conflict of interest. NT reports fees from Pfizer outside the submitted work.

JFT reports, outside the submitted work, participations to advisory boards for

Pfizer, MSD, Nabriva, Medimune, Gilead, Becton–Dickinson, and lecture fees from

MSD, Pfizer, Biomerieux.

Factors associated with survival of patients with solid Cancer alive after

intensive care unit discharge between 2005 and 2013.

Gheerbrant H(1), Timsit JF(2)(3), Terzi N(4)(5), Ruckly S(3), Laramas M(6),

Levra MG(7), Jacquet E(6), Falque L(7), Moro-Sibilot D(7), Toffart AC(7)(8).

Message: Le performans status est un élément majeur de la possibilité de conduire un traitement anti cancereux optimal après un séjour en réanimation.

BACKGROUND: At intensive care unit (ICU) admission, the issue about prognosis of

critically ill cancer patients is of clinical interest, especially after ICU

discharge. Our objective was to assess the factors associated with 3- and

6-month survival of ICU cancer survivors.

METHODS: Based on the French OutcomeRea™ database, we included solid cancer

patients discharged alive, between December 2005 and November 2013, from the

medical ICU of the university hospital in Grenoble, France. Patient

characteristics and outcome at 3 and 6 months following ICU discharge were

extracted from available database.

RESULTS: Of the 361 cancer patients with unscheduled admissions, 253 (70%) were

discharged alive from ICU. The main primary cancer sites were digestive (31%)

and thoracic (26%). The 3- and 6-month mortality rates were 33 and 41%,

respectively. Factors independently associated with 6-month mortality included

ECOG performance status (ECOG-PS) of 3-4 (OR,3.74; 95%CI: 1.67-8.37), metastatic

disease (OR,2.56; 95%CI: 1.34-4.90), admission for cancer progression (OR,2.31;

95%CI: 1.14-4.68), SAPS II of 45 to 58 (OR,4.19; 95%CI: 1.76-9.97), and

treatment limitation decision at ICU admission (OR,4.00; 95%CI: 1.64-9.77).

Interestingly, previous cancer chemotherapy prior to ICU admission was

independently associated with lower 3-month mortality (OR, 0.38; 95%CI:

0.19-0.75). Among patients with an ECOG-PS 0-1 at admission, 70% (n = 66) and

61% (n = 57) displayed an ECOG-PS 0-2 at 3- and 6-months, respectively. At

3 months, 74 (55%) patients received anticancer treatment, 13 (8%) were given

exclusive palliative care.

CONCLUSIONS: Factors associated with 6-month mortality are almost the same as

those known to be associated with ICU mortality. We highlight that most patients

recovered an ECOG-PS of 0-2 at 3 and 6 months, in particular those with a good

ECOG-PS at ICU admission and could benefit from an anticancer treatment

following ICU discharge.

DOI: 10.1186/s12885-020-07706-3

PMCID: PMC7786972

PMID: 33402107 [Indexed for MEDLINE]