Julie Diplôme D'état De Docteur

Aiguë Respiratoire

A Une Associe

Leptospirose : Une

Retrospective Etude

De

E N Cas

Française Polynesie

Entre

Monsieur BAZIN Jean Etienne

Leptospirose

Directeur De

Monsieur Futier Emmanuel

MM. BACIN Franck -Begue René-Jean -Boucher

Daniel -Bourges Michel

Jean -Chipponi Chazal

Philippe - Coudert Jacques -Chollet

Jean -Dastugue Bernard -Dauplat

Jacques -Dechelotte Pierre - Demeocq

François -De Riberolles

Charles -Escande Georges -Mme Fonck

Yvette -Mm Gentou

Claude -Glanddier Gérard

Mme Glanddier

Phyllis -M Jacquetin

Bernard -Mme Lavarenne

Jeanine -Mm Laveran

Henri -Lesourd Bruno -Levai

Gérard -Malpuech Georges -Marcheix

Jean-Claude -Michel Jean-Luc - Molina

Jean-Michel -Peri Georges -Petit

Georges -Philippe Pierre -Plagne

Robert -Planche Roger -Ponsonnaille

Jean -Rey Michel - Mme Rigal

Danièle -Mm Rozan

Raymond -Schoeffler Pierre -Sirot

Jacques -Souteyrand Pierre -Tanguy

Alain -Terver Sylvain -Thieblot

Philippe - Tournilhac Michel -Vanneuville Guy -Viallet

Jean-François -Mle Veyre

Annie Professeurs Emerites

Mm. -Beytout Jean -Boiteux

Jean-Paul -Bommelaer Gilles -Chamoux

Alain -Deteix Patrice -Dubray

Alain -Irthum Bernard - Kemeny

Jean-Louis -Labbe André -Mme Lafeuille

Hélène -Mm Lemery

Didier -Lusson Jean-René -Ribal

Jean-Pierre Professeurs Des Universites-Praticiens Hospitaliers

Professeurs De Classe

Exceptionnelle M Vago

Philippe Histologie-Embryologie

Cytogénétique M Aumaitre

Olivier Médecine

Interne M Labbe

André Pédiatrie

M Avan

Paul Biophysique

Traitement De L'image

M Durif

Franck Neurologie

M Boire

Jean-Yves Biostatistiques

M Pouly

Jean-Luc Gynécologie

Obstétrique M Canis

Michel Gynécologie-Obstétrique

Mme Penault-Llorca

Frédérique Anatomie

Cytologie Pathologiques

M Bazin

Jean-Etienne Anesthésiologie

Chirurgicale M Réanimation

Yves Jean Bignon

Cancérologie

Biologique M Boirie

Yves Nutrition

Humaine M Gilain

Laurent O R L M Lemaire

Jean-Jacques Neurochirurgie

M Camilleri

Lionel Chirurgie Thoracique

M Cardio-Vasculaire

Michel Dapoigny

M Gastro-Entérologie

Pierre-Michel Llorca

Adultes M Psychiatrie D'

Denis Pezet

Digestive M Chirurgie

Bertrand Souweine

Médicale M Réanimation

Stéphane Chirurgie Boisgard

Orthopédique

Mme Traumatologie

Martine Duclos

M Physiologie

Jeannot Schmidt

M Thérapeutique

Marc Berger

M Hématologie

Jean-Marc Garcier

M Rosset

Eugénio Chirurgie

Vasculaire M Soubrier

Martin Rhumatologie

Professeurs De

Classe M Caillaud

Denis Pneumo-Phtisiologie

M Verrelle

Pierre Radiothérapie

Clinique M Citron

Bernard Cardiologie

M. D'INCAN Maladies Vasculaires

Michel Dermatologie -Vénéréologie

Mme Jalenques

Isabelle Psychiatrie D'adultes

Mle Barthelemy

Isabelle Chirurgie Maxillo-Faciale

M Gerbaud

Laurent Epidémiologie

Igor Endocrinologie

Métaboliques M Maladies

Thierry Mom

M Oto-Rhino-Laryngologie

Ruddy Richard

Marc Ruivard

Interne M Médecine

Vincent Sapin

Biochimie

Moléculaire M Biologie

Jacques-Olivier Bay

M Cancérologie

Emmanuel Médecine Coudeyre

Physique

Mme De Réadaptation

Catherine Godfraind

Cytologie Anatomie

M Pathologiques

Armando Abergel

M Hépatologie

Henri Laurichesse

Infectieuses Maladies

Tropicales M Et

Olivier Tournilhac

Frédéric Chiambaretta

M Ophtalmologie

Marc Filaire

Anatomie

Chirurgie Thoracique

M Gallot

Denis Gynécologie-Obstétrique

M Guy

Laurent Urologie

M Traore

Ousmane Hygiène

Hospitalière M Andre

Marc Médecine

Interne M Bonnet

Richard Bactériologie

Virologie M Cachin

Florent Biophysique

Médecine Nucléaire

M Costes

Frédéric Physiologie

M Futier

Emmanuel Anesthésiologie-Réanimation

Mme Heng

Anne-Elisabeth Néphrologie

M Motreff

Pascal Cardiologie

Mme Pickering

Gisèle Pharmacologie

Clinique M Rabischong

Benoît Gynécologie

Obstétrique Professeurs De

Classe

Mme Creveaux

M Faict

Kanold Lastawiecka

Justyna Pédiatrie

M Tchirkov

Andréï Cytologie

Histologie M Cornelis

François Génétique

M Descamps

Stéphane Chirurgie Orthopédique

Traumatologique M Pomel

Christophe Cancérologie -Chirurgie

Générale M Canavese

Fédérico Chirurgie

Infantile M Lesens

Olivier Maladies

Infectieuses Et

Tropicales M Authier

Nicolas Pharmacologie

Médicale M Brousse

M Lautrette

Alexandre Néphrologie

Réanimation Médicale

M Azarnoush Kasra

Cécile Bactériologie

Virologie M Eschalier

Romain Cardiologie

M Merlin

Etienne Pédiatrie

Mme Tournadre

Anne Rhumatologie

M Durando

Xavier Cancérologie

M Dutheil

Frédéric Médecine

Santé Au Travail

Mme Fantini

Maria Livia

Neurologie M Sakka

Laurent Anatomie -Neurochirurgie

M Bourdel

Nicolas Gynécologie-Obstétrique

M Guieze

Romain Hématologie

M Poincloux

Laurent Gastroentérologie

M Souteyrand

Géraud Cardiologie

M Evrard

Bertrand Immunologie

M Poirier

Philippe Parasitologie

Professeurs Mycologie

Universites M Des

Gilles Médecine Clement

Mme Générale

Corinne Malpuech-Brugere

Humaine M Nutrition

Philippe Vorilhon

Mme Bottet-Mauloubier

Anne Médecine

Générale M Cambon Benoît

Maitres De Conferences

Hors Classe

Mme Chambon

Martine Bactériologie

Virologie Mme

Bouteloup Corinne

Classe M Morvan

Daniel Biophysique

Mle Goumy

Carole Cytologie

Histologie

Mme Cytogénétique

Anne Fogli

Biologie Biochimie

Mle Moléculaire

Laetitia Gouas

Cytologie

Cytogénétique M Histologie

Marceau Geoffroy

M Robin

Frédéric Bactériologie

Mle Veronese

Lauren Cytologie

Julien Delmas

Mle Bactériologie

Audrey Mirand

Virologie M Bactériologie

Lemlih Ouchchane

Biostatistiques

M Libert

Frédéric Pharmacologie

Médicale Mle Coste

Karen Pédiatrie

Mle Aumeran

Claire Hygiène

Hospitalière Mme

Cassagnes Lucie

M Lebreton

Aurélien Hématologie

M Buisson

Anthony Gastroentérologie

Maitres De Conferences De

Mme Pons Hanaë

Jabaudon-Gandet Matthieu

Anesthésiologie -Réanimation Chirurgicale

M Bouvier

M Coll

Guillaume Neurochirurgie

Mme Sarret

Catherine Pédiatrie

M Maqdasy

Salwan Endocrinologie

Maladies Diabète

Mme Métaboliques

Céline Nourrisson

Parasitologie -Mycologie

Mme Vaurs-Barriere

Catherine Biochimie

Biologie Moléculaire

M Bailly

Jean-Luc Bactériologie

Virologie Mle

Aubel Corinne

Oncologie Moléculaire

M Blanchon

Loïc Biochimie

Mle Guillet

Christelle Nutrition

Humaine M Bidet

Yannick Oncogénétique

M Marchand

Fabien Pharmacologie

Médicale M Dalmasso

Guillaume Bactériologie

M Soler

Cédric Biochimie

M Giraudet

Fabrice Biophysique

Traitement De L'

Image Mme

Vaillant-Roussel Hélène

Médecine Générale

Mme Laporte

Catherine Médecine

Générale M Lolignier

Stéphane Neurosciences

Neuropharmacologie Mme

Marteil Gaëlle

M Pinel

Alexandre Nutrition

Humaine M Pizon

M Bernard Pierre

Mme Eschalier Bénédicte

N° UNIVERSITÉ CLERMONT AUVERGNE UFR DE MÉDECINE ET DES PROFESSIONS PARAMÉDICALES THÈSE D'EXERCICE pour le

Characteristics, ventilatory management and outcome of acute respiratory distress syndrome caused by leptospirosis: retrospective cohort study of 107 admissions in French Polynesia

REMERCIEMENTS

A Monsieur le Professeur Jean-Etienne BAZIN, merci d'avoir accepté de présider cette thèse.

Je vous remercie également de m'avoir donné le gout de l'humanitaire à travers cette merveilleuse aventure marocaine et de m'avoir appris à piquer les caudales (littéralement) les yeux fermés ! A Monsieur le Professeur Emmanuel FUTIER, merci d'avoir accepté de diriger cette thèse, Merci pour vos conseils, vos relectures et votre patience.

A Monsieur le Professeur Samir JABER, merci d'avoir accepté de participer à ce jury de thèse. Je vous remercie également pour l'enthousiasme dont vous faites preuve à l'égard de ce beau sujet.

A Monsieur le Docteur Éric BONNIEUX, merci de m'avoir proposé ce sujet de thèse. Merci également pour tout ce que tu m'as appris sur la réanimation, tant au point de vu technique qu'humain. Et à bientôt je l'espère pour un capuccino/croissant aux amandes de sortie de garde sur le toit de l'hôpital ;)

A Madame le Docteur Magali VIDAL, merci d'avoir accepté de participer à ce jury de thèse et un grand merci pour tous tes précieux avis d'infectiologie donnés au cours de ces 5 ans pour les patients de réanimation.

A ma famille :

Merci à mon Papou pour ton soutien inconditionnel aux cours de ces 11 années de hauts et de bas, de fou rire et de pleurs (assez souvent en même temps non ?), tes conseils précieux et ceux qui nous énervent. On ne peut pas rêver de Papa plus parfait que toi ! Merci à ma Mamounette pour ton grain de folie qui me redonne toujours le sourire, pour m'avoir appris d'avoir la volonté d'aller au bout de ce que j'entreprenais (et tu as vu, j'ai enfin fini quelque chose que j'ai commencé !). Heureusement que tu viens vivre à côté de chez moi pour ta retraite, on ne va pas s'ennuyer ! Merci à ma Princesse D'amour. Tu es la plus belle chose qui me soit arrivé dans la vie, mon petit rayon de soleil ! Je n'aurais pas assez de 100 pages de thèse pour écrire à quel point tu es parfaite, donc je te dis juste que je t'aime ! Merci à mon Moche d'amour, mon premier confident, avec qui j'ai fait toutes mes bêtises d'enfance. Tu me manques, j'espère qu'un jour tu feras de nouveau partie de ma vie… Merci à mon Papy et ma Mamie, qui m'ont toujours soutenue.

Merci à mon Pépé, tes conseils de jardinage et ta bienveillance.

Merci à ma Tata et mon Tonton, sans qui je ne serais pas la personne que je suis aujourd'hui.

Merci à Sophie, qui a accepté de transformer son salon en studio d'étudiant pour me permettre d'écrire cette thèse ;)

A mes amis :

A mes copines de Toulouse, les 8), [START_REF] Urner | Time-varying intensity of mechanical ventilation and mortality in patients with acute respiratory failure: a registry-based, prospective cohort study[END_REF]. In this respect, a multisite prospective cohort study of 482 patients with ARDS receiving routine medical care found that an increase of 1 ml/kg PBW in initial tidal volume above 6.5 ml/kg predicted body weight was associated with a 23% increase in ICU mortality risk [START_REF] Needham | Timing of Low Tidal Volume Ventilation and Intensive Care Unit Mortality in Acute Respiratory Distress Syndrome. A Prospective Cohort Study[END_REF]. In observational studies, limiting driving pressure and mechanical power have also been proposed as important objectives to improve outcome of ARDS patients [START_REF] Amato | Driving pressure and survival in the acute respiratory distress syndrome[END_REF], [START_REF] Neto | Mechanical power of ventilation is associated with mortality in critically ill patients: an analysis of patients in two observational cohorts[END_REF].

LIST OF TABLES AND FIGURES

Following the initial description of ARDS, several definitions were proposed. In 1994, the American-European Consensus Conference (AECC) defined ARDS as the acute onset of hypoxemia (arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FIO2] ≤ 200 mmHg) with bilateral infiltrates on frontal chest radiograph, with no evidence of left atrial hypertension. Because of its limitations, the definition has been criticized and, in 2012, a revised definition of clinical criteria for ARDS, the Berlin Criteria, was established to classify patients according to their disease severity [START_REF] Ards Definition | Acute respiratory distress syndrome: the Berlin Definition[END_REF]. ARDS was now classified depending on oxygenation criteria as mild, moderate, or severe. Oxygenation criteria were found to correlate well with severity, with a respective mortality of 7, 32, and 45% in mild, moderate, and severe ARDS [START_REF] Ards Definition | Acute respiratory distress syndrome: the Berlin Definition[END_REF]. The influence of ARDS definition on the prognosis of leptospirosis-associated ARDS has never been evaluated.

The main objective of this retrospective study was to describe the clinical characteristics and ventilatory management of patients admitted to ICU with leptospirosis-associated ARDS. Our secondary aims were to estimate whether ventilatory management and mortality in these patients have changed over a 20-year period, especially in the era of the revised clinical criteria for ARDS with the current Berlin definition, and to determine the factors associated with a poor prognosis.

METHODS

We conducted a retrospective study from January 2000 to March 2020. According to French law, neither informed consent nor approval by an ethics committee is necessary for the extraction of anonymous data or for the analysis of patients' medical files. We nonetheless received an approval from the Ethics and Research committee of French Society of Anesthesiology and Intensive Care (SFAR) (IRB 00010254-2020-196).

All adult patients who had been admitted in the 24-bed ICU at the French Polynesia Hospital with documented leptospirosis were identified by searching the ICU electronic database for code A27 in the International Classification of Diseases-10th revision and with a diagnosis of ARDS were included. There were no exclusion criteria. Documented leptospirosis was defined according to the recommendations of the Haute Autorité de Santé (13) by at least one among the following: detection of immunoglobulin M (IgM) using enzyme-linked immunosorbent assay (ELISA), microscopic agglutination test (MAT) with a positivity threshold of 1:400 or the presence of positive blood or urine polymerase chain reaction (PCR). ARDS was defined using the 1994 American /European Consensus Conference criteria until 2012, and using the criteria from Berlin definition thereafter [START_REF] Ards Definition | Acute respiratory distress syndrome: the Berlin Definition[END_REF].

Data collection

Data were collected from patients' electronic medical records by physicians trained in intensive care according to a standardized protocol.

RESULTS

Between January 2000 and March 2020, 1341 patients were hospitalized with documented leptospirosis, among which 578 had severe disease and required ICU admission. Over the study period, 107 patients (18.5%) developed ARDS; 81 of them (75.7%) were discharged alive and 26 (24.3%) died (Figure 1).

Baseline characteristics on admission

The characteristics of leptospirosis-associated ARDS patients at ICU admission are detailed in The median length of stay was 7 (3-10) days. Length of stay was significantly longer in survivors than in non-survivors (1 [START_REF] Costa | Global Morbidity and Mortality of Leptospirosis: A Systematic Review[END_REF][START_REF] Abela-Ridder | Estimating the burden of human leptospirosis[END_REF][START_REF] Jiménez | Leptospirosis: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine[END_REF] days and 8 [START_REF] Gouveia | Leptospirosis-associated severe pulmonary hemorrhagic syndrome, Salvador, Brazil[END_REF][START_REF] Vandroux | Acute respiratory distress syndrome in leptospirosis[END_REF][START_REF] Needham | Timing of Low Tidal Volume Ventilation and Intensive Care Unit Mortality in Acute Respiratory Distress Syndrome. A Prospective Cohort Study[END_REF][START_REF] Urner | Time-varying intensity of mechanical ventilation and mortality in patients with acute respiratory failure: a registry-based, prospective cohort study[END_REF][START_REF] Amato | Driving pressure and survival in the acute respiratory distress syndrome[END_REF][START_REF] Neto | Mechanical power of ventilation is associated with mortality in critically ill patients: an analysis of patients in two observational cohorts[END_REF][START_REF] Ards Definition | Acute respiratory distress syndrome: the Berlin Definition[END_REF] days, p<0.001). The overall incidence of ventilator-associated pneumonia was 29% (35.8% in survivors and 7.7% in non-survivors, p=0.006) (Table 7). Mortality in in patients with leptospirosis-associated ARDS has been reported to be lower than that of ARDS of other etiologies [START_REF] Máca | Past and Present ARDS Mortality Rates: A Systematic Review[END_REF].

The pathophysiology of ARDS in leptospirosis is particular, compared than other etiology of ARDS. Alveolar involvement occurs by a mechanism that is not fully understood: it could be due to direct involvement of the leptospires at the alveolar level or by a toxin mechanism [START_REF] Fraga | Leptospirosis: Aspects of Innate Immunity, Immunopathogenesis and Immune Evasion From the Complement System[END_REF].

These mechanisms lead to endothelial activation, by activation of the Toll like 2 receptor [START_REF] Del | Immune receptors and adhesion molecules in human pulmonary leptospirosis[END_REF]. This endothelial activation leads to a significant production of nitric oxide and a significant release of cytokines takes place at the vascular level (26)(27) [START_REF] Maciel | High serum nitric oxide levels in patients with severe leptospirosis[END_REF]. This inflammatory discharge leads to activation of adhesion molecules, including E selectins and ICAM 1 (29)(30) [START_REF] Goeijenbier | Markers of endothelial cell activation and immune activation are increased in patients with severe leptospirosis and associated with disease severity[END_REF]. It then appears a widening of the intercellular junctions [START_REF] Croda | Leptospirosis pulmonary haemorrhage syndrome is associated with linear deposition of immunoglobulin and complement on the alveolar surface[END_REF]. This leads to deposition of IgG, IgA and IgM (32) [START_REF] Nally | Alveolar septal deposition of immunoglobulin and complement parallels pulmonary hemorrhage in a guinea pig model of severe pulmonary leptospirosis[END_REF], activating C3 fraction of complement, favoring macrophage migration in the alveolar lumen [START_REF] Croda | Leptospirosis pulmonary haemorrhage syndrome is associated with linear deposition of immunoglobulin and complement on the alveolar surface[END_REF]. These macrophages produce hemophagocytosis of type II pneumocytes [START_REF] Schuller | Immunohistochemical detection of IgM and IgG in lung tissue of dogs with leptospiral pulmonary haemorrhage syndrome (LPHS)[END_REF].

The intra-alveolar hemorrhage produced is favored by thrombocytopenia due to leptospirosis.

It is interesting to note that a platelet count of less than 30 G / L is found to be an independent factor of mortality in our study. However, we did not show a difference in the platelet pool transfused during the first three days.

Regarding the analysis according to the publication of the Berlin criteria, we observe an evolution of ventilatory management with a decrease in tidal volume in the AECC criteria cohort, over the first three days of treatment. It corresponds to the implementation of a protective ventilation strategy which has shown a benefit in numerous studies [START_REF] Villar | A high positive endexpiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial[END_REF], [START_REF] Amato | Driving pressure and survival in the acute respiratory distress syndrome[END_REF], and is recommended in the management of ARDS [START_REF]Recommandations pour la prise en charge du SDRA -La SFAR[END_REF]. These changes in management, in particular on the decrease in tidal volume over the time in patients with ARDS, are consistent with a study carried out on 18,302 patients under mechanical ventilation in ICU between 1998 and 2010 [START_REF] Esteban | Evolution of mortality over time in patients receiving mechanical ventilation[END_REF]. On the other hand, this international multicenter study also found an increase in PEEP over time which was not found in our study. In 2015, Needham and al showed an increase of 1 ml/kg PBW in initial tidal volume was associated with a 23% increase in ICU mortality risk (adjusted hazard ratio, 1.23; 95%CI:1.06-1.44; p = 0.008) and a 1 ml/kg PBW increase subsequent tidal volumes compared with the initial tidal volume. was associated with a 15% increase in mortality risk (adjusted hazard ratio, 1.15; 95% CI, 1.02-1.29; p = 0.019) [START_REF] Needham | Timing of Low Tidal Volume Ventilation and Intensive Care Unit Mortality in Acute Respiratory Distress Syndrome. A Prospective Cohort Study[END_REF].

However, there is no difference in our study in terms of mortality between the AECC criteria cohort and the Berlin criteria cohort, despite the significant decrease in tidal volume. This may be due to insufficient power considering the number of patients included. In 2015, Amato and al studied the impact of driving pressure on mortality in a cohort of 3562 patients with ARDS.

They showed an 1-SD increment in driving pressure (approximately 7 cmH2O ) was associated with increased mortality (relative risk, 1.41; 95% confidence interval [CI], 1.31 to 1.51; P<0.001) [START_REF] Amato | Driving pressure and survival in the acute respiratory distress syndrome[END_REF]. In our study, no evolution was demonstrated in terms of driving pressure according to the ARDS definition, this may be due to an insufficient number of data could be collected on this parameter (78/107 at D1).

Finally, this work raises questions about the place of more specific therapies in the management of ARDS in leptospirosis. There is no difference for prone positioning treatment and the use of neuromuscular blocking agents between "survivors" and "non survivors". The use of ECMO as a therapy appears interesting, because leptospirosis induces deep and very hypoxemic ARDS, but rapidly reversible and not leading, to our knowledge, to pulmonary fibrosis. A few studies with a small number of patients appear to show encouraging results in this direction [START_REF] Chavez | A case of leptospirosis with acute respiratory failure and acute kidney injury treated with simultaneous extracorporeal membrane oxygenation and haemoperfusion[END_REF] [START_REF] Chaikajornwat | Leptospirosis manifested with severe pulmonary haemorrhagic syndrome successfully treated with venovenous extracorporeal membrane oxygenation[END_REF] [START_REF] Fonseka | Role of Plasmapheresis and Extracorporeal Membrane Oxygenation in the Treatment of Leptospirosis Complicated with Pulmonary Hemorrhages[END_REF]. It is also the first study to examine the evolution of the ventilatory management of ARDS in leptospirosis over the time, thanks to the analysis according to the publication of the Berlin criteria.

This study has several limitations. First, this is a monocenter study. However, the results found are consistent with the existing literature. Second, the Berlin criteria changed the definition of ARDS, including patients with mild to moderate ARDS (PaO2/FiO2 = [200-300]. We performed a sub-group analysis excluding patients with mild to moderate ARDS, in order to have a more homogeneous group of patients over 20 years. The mortality found in this subgroup (26.7%) is similar to that found for all patients (24.3%). Third, this study does not make it possible to conclude on the benefit of ECMO therapy in patients with ARDS in leptospirosis due to the small number of patients [START_REF] Gouveia | Leptospirosis-associated severe pulmonary hemorrhagic syndrome, Salvador, Brazil[END_REF] who were able to benefit from this therapy in our cohort.

Finally, the characteristics on admission differ between the AECC criteria cohort and Berlin criteria cohort. This may be due to an intensification of the policy of prevention of the risks of infection by leptospirosis over time in French Polynesia, implying a more rapid diagnosis of cases of leptospirosis, and therefore an adapted antibiotic therapy introduced earlier (41)(42)

CONCLUSION

Acute Respiratory Distress Syndrome in leptospirosis is a pathology leading to significant mortality. It mainly affects young men with no comorbidities. In this retrospective study including 107 patients with leptospirosis and ARDS, we found that older age, severe hypoxemia, SAPS II higher than 61, and severe thrombopenia at ICU admission were associated with poor prognosis. Finally, although patients received lower tidal volume ventilation after the Berlin definition has been established, we found that ventilation practices have changed only slightly over time.

.

Figure 1 .

 1 Figure 1. Flow of patients through study

  knowledge, this study is the study of ARDS in leptospirosis including the largest cohort of patients. It allowed us to perform a multivariate analysis to highlight independent predictive factors of mortality.

  3 autres fantastiques, à nos innombrables soirées, nos confidences, nos fous rires, toutes ces petites choses qui ont fait de nous les médecins que nous SUMMARY INTRODUCTION ................................................................................................................ METHODS .......................................................................................................................... Ventilator settings according to ARDS definition ................................................................. DISCUSSION ...................................................................................................................... CONCLUSION ....................................................................................................................

sommes ! A William, Elodie et Gabychou, merci pour toutes ces journées BU grâce à mon amant chaste, merci de m'avoir accueilli en Gwada, vous êtes au top tous les trois ! A Jordann, mon plus vieil ami, merci d'être toujours présent malgré la distance, merci de tenir le coup ! A Amandine, une jolie rencontre clermontoise, merci pour ton soutien inconditionnel, ta positive attitude, ton féminisme acharné (!) et ta bonne humeur communicative ! A Luce, ma binome parapentiste ! Une chirurgien brillante, une femme battante et une amie précieuse, tu es un modèle ! A Julie et Remi, encore des belles rencontres auvergnates, vivement le mariage ! A Aurel, merci pour tes conseils pleins de bon sens, merci de m'avoir reboostée quand il fallait et consolée quand j'en avais besoin ! Tu es au top du top ! A Lyna, mon éternelle princesse Disney, merci pour toutes nos soirées potins, nos sorties, et nos séchages de larmes mutuels ;) A Crispin, je ne me suis jamais autant trompé sur quelqu'un au premier abord, tu es ma « tête de con » préféré, surtout ne change rien parce que tu es parfait comme ça ! Aux copains de la coloc, à Lulu et Henri toujours motivés pour une petite bière, à Karim l'éternel enfant, à Madeleine, ma bolivienne préférée ! Aux copains de CHS, ma famille de Clermont. C'est en grande partie pour vous que je veux rester en Auvergne, vous être incroyable, je vous aime tous très fort, il me tarde de vous mettre de nouveau des coups de crosse et de palmes au fond d'un bassin ;) A Louise, ma danseuse tahitienne préférée, toujours de bonne humeur et motivée pour partir en vadrouille, et Enrique, avec tes gouts musicaux si particuliers et ton dialecte improbable (« une mousse dans le museau, une tige et on dérape ? »). Merci pour ces 7 mois de bonheur, d'Hinano et de pates carbos !! A Axou, mon soutien inconditionnel ces 5 derniers mois. Tu es certainement ma plus belle rencontre de l'année. Merci d'avoir subvenu à mes besoins nutritionnels, alcooliques, de vie sociale. Merci d'être là au quotidien pour prendre soin de moi ! Data collection ..................................................................................................................... Statistical analysis ................................................................................................................ RESULTS ............................................................................................................................ Baseline characteristics on admission ................................................................................... REFERENCES .....................................................................................................................

TABLETable 1 .

 1 Baseline characteristics on ICU admission

Table 2 .

 2 Ventilator settings and gas exchange on ICU admission

Table 3 .

 3 Laboratory findings on ICU admission

Table 4 .

 4 Hemodynamic data on ICU admission

Table 5 .

 5 Evolution of ventilator settings over the first 72 hours

Table 6 .

 6 Adjuvant therapeutic measures in survivors and non-survivors

Table 7 .

 7 Patient outcomes

Table 8 .

 8 Risk factors associated with mortality in patients with leptospirosis

Table 9 .

 9 Ventilator settings according to ARDS definition criteria

Table 10 .

 10 Evolution of ventilator settings over the first 3 days according to the ARDS definition criteria

Table 11 :

 11 Adjuvant therapeutic measures according to the ARDS definition criteria

Table 12 :

 12 Patient outcome according to the ARDS definition criteria

	FIGURES
	Figure 1. Flow of patients through study

MAT: Microscopic agglutination test PaCO2: Partial Pressure of Arterial Carbon Dioxide PaO2: Partial Pressure of Arterial Oxygen PCR: Polymerase Chain Reaction

	INTRODUCTION
	Leptospirosis is a zoonotic bacterial disease with a broad geographical distribution and a global
	incidence of 1.03 million cases per year. Leptospirosis, which is responsible for 58,900 deaths
	per year worldwide (1), constitutes a public health problem according to the World Health
	Organization (2).
	Leptospirosis can cause a wide range of symptoms and, in patients with severe disease, can lead
	to multi-organ failure and intensive care unit (ICU) admission (3). A recent retrospective
	multicenter study of 160 patients with documented leptospirosis from 79 ICUs in metropolitan
	France reported an hospital mortality of 9% (4). The need for invasive mechanical ventilation
	within 48 hours after ICU admission due to acute respiratory failure was associated with
	increased hospital mortality (odds ratio 44.12 [95% confidence interval, 5.56-389.44] (4).
	Pulmonary manifestations in leptospirosis, first described by Moeschler in 1943, occur in 20-
	70% of the patients (5). Endothelial damage and intra-alveolar hemorrhage, also known as
	leptospirosis-associated severe pulmonary hemorrhagic syndrome with reported mortality rate
	rates up to 50-70% (6), may develop in patients with severe pulmonary leptospirosis leading to
	subsequent acute respiratory distress syndrome (ARDS).
	Although prior studies have provided important insights into clinical features of patients with
	PEEP: Positive End-Expiration Pressure
	severe leptospirosis, there is a gap in knowledge about the incidence, clinical management and
	PT: prothrombin time
	prognosis of patients requiring mechanical ventilation because of leptospirosis, especially those
	PTT: Partial Thromboplastin Time
	with leptospirosis-associated ARDS. This assessment could have obvious implications for
	RRT: Renal Replacement Therapy
	clinical practice given the prevalence of ARDS in this patient population. A recent multicenter
	SAPS II: Simplified Acute Physiology Score
	retrospective study in 160 ICU patients with proven leptospirosis reported an incidence of
	SOFA: Sepsis-related Organ Failure Assessment
	SpO2: Peripheral Oxygen Saturation

ARDS of 36%

[START_REF] Miailhe | Severe leptospirosis in non-tropical areas: a nationwide, multicentre, retrospective study in French ICUs[END_REF]

. A small retrospective cohort study, including data from 39 patients admitted in ICU with leptospirosis and presenting with a moderate to severe ARDS, reported better prognosis of leptospirosis-associated ARDS than that of other causes of ARDS, with an overall mortality rate of 23%

[START_REF] Vandroux | Acute respiratory distress syndrome in leptospirosis[END_REF]

. Understanding the factors associated with outcome of leptospirosisassociated ARDS could lead to effective interventions to improve care. Prior studies have evidenced that, in patients requiring invasive mechanical ventilation, timely recognition of ARDS and adherence to strategies aimed at preventing ventilator-induced lung injury (i.e. lungprotective mechanical ventilation) are important for improving outcome especially reducing mortality (

  Data were collected on admission, during the first 72 hours after ICU admission, and at ICU discharge. Gaussian distribution) was assessed using the Shapiro-Wilk test. Comparisons between groups were carried out, for the quantitative variables, with the use of the Student t test or the Mann-Whitney U test if the conditions for applying the t-test were not met.Homoscedasticity was studied with the use of the Fisher-Snedecor test. Categorical variables were compared using the Chi squared test or, where appropriate, using the Fisher exact test. The results are expressed as odds ratios with 95% confidence intervals. All tests were two-tailed and p < 0.05 was considered to indicate statistical significance. The Sidak correction was applied for multiple testing of pairwise comparisons.

	clinical manifestations (fever, myalgia, arthralgia, jaundice, abdominal pain, nausea and/or
	vomiting, hepatosplenomegaly, oligo-anuria, hemorrhagic syndrome, meningeal syndrome,
	dyspnea, cough, the requirement of vasoactive drugs, hemoptysis); delay from the onset of
	symptoms to ICU admission ; and the Simplified Acute Physiology Score (SAPS II) and Sepsis The use of adjunctive treatments was also recorded and included the use of prone position,
	Organ Failure Assessment (SOFA) score. neuromuscular blocking agent, nitric oxide, extra-corporeal membrane oxygenation (ECMO),
	and corticosteroids. The requirement for vasoactive drugs (norepinephrine or dobutamine),
	Clinical data were ventilation parameters (minute ventilation, tidal volume (VT), respiratory antibiotics, renal replacement therapy and the transfusion of blood products were recorded daily
	rate, maximum plateau pressure (Pplat), maximum peak pressure, positive end-expiratory for the first 72 hours.
	pressure (PEEP), maximum FiO2, minimum SpO2; data obtained from transthoracic
	Biological data collected during the first 72 hours included arterial blood gases, lactate level,
	C-reactive protein, serum albumin, brain natriuretic peptide (BNP), troponin white blood cell

Data collected on inclusion included age; gender; height; weight; comorbidities (diabetes, hypertension, cirrhosis, chronic respiratory failure, ischemic heart disease, chronic heart failure, immune deficiency, chronic kidney disease, brain damage, cancer, alcohol and tobacco use); echocardiography (especially left ventricle ejection fraction, subaortic velocity time index) and central venous oxygen saturation (mmHg). The clinical data were collected once daily during the first 72 hours.

Static driving pressure of the respiratory system was calculated as plateau pressure minus positive end-expiratory pressure. Compliance of the respiratory system (zero flow conditions) was calculated as tidal volume divided by driving pressure (Crs = VT/(Pplat-PEEP)). The ventilation ratio (VR), a simple bedside index which was shown to correlate well with pulmonary dead space fraction (VD/VT) in patients with ARDS was calculated as minute ventilation (L/min) × PaCO2 (mmHg) / (predicted body weight × 100 × 37.5), as previously described

[START_REF] Sinha | Physiologic Analysis and Clinical Performance of the Ventilatory Ratio in Acute Respiratory Distress Syndrome[END_REF]

. Dynamic mechanical power was calculated as 0.098 × VT × RR × (peak inspiratory pressure -(0.5×driving pressure)) as described previously

[START_REF] Gattinoni | Ventilator-related causes of lung injury: the mechanical power[END_REF]

. count, hemoglobin level, platelet count, protrombin time, ratio of activated partial thromboplastin time, total and direct bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, alkaline phosphatases, blood urea nitrogen, serum creatinine, serum potassium, and urine output.

The following were recorded at ICU discharge: ICU length of stay, duration of mechanical ventilation, ICU mortality, need for tracheal reintubation or tracheostomy, occurrence of ventilator-associated pneumonia (VAP), use of non-invasive ventilation (NIV) and/or high flow nasal oxygen therapy and the need for ECMO.

Statistical analysis

All statistical analyzes were performed with Stata software (version 15, StataCorp, College Station, US). Categorical data were presented as proportion (%), and quantitative data were presented as mean (SD) or median (IQR) depending of the type of variable distribution.

Normality (

Multiple logistic generalized linear regression models were considered to evaluate factors associated with mortality. Covariates were selected according to univariate results and their clinical relevance. Particular attention was paid to multicollinearity and interactions between covariates.

Table 1 .

 1 The mean age was 38±17 years. Patients who died were older than those who did not (47.9±18 yr vs 34.6±15 yr, p<0.001). The severity scores on admission, SAPS II and SOFA,

	were higher in non-survivors compared with survivors (84.5±16 vs 50.9±14, p<0.001 and
	15.6±3.5 vs 13.8±3.7, p<0.001; for SAPS II and SOFA score in non-survivors and survivors,
	respectively). Overall, there were no other statistically significant differences between non-
	survivors and survivors except for oligo-anuria which was more common in non-survivors
	(69% vs 43.7%, p=0.024).

Table 1 .

 1 Baseline characteristics on ICU admission

	All	Survivors	Non-survivors
	(n=107)	(n=81)	(n=26)	p value

Table 2 .

 2 Ventilator settings and gas exchange on ICU admission

	All (n=107)	Survivors (n=81)	Non survivors (n=26)	p value

Table 3 .

 3 Laboratory findings on ICU admission

		All (n=107)	Survivors (n=81)	Non survivors (n=26)	p value
	Arterial lactates, UI/L	381 (255-800) 328 (218-526) 1042 (401-1557) <0.0001
	BNP, pg/L	684 (397-1275) 879 (240-1246) 909 (671-1713) 0.1655
	Troponin, μg/L	0.5 (0.14-1.78) 0.42 (0.14-1.75) 0.7 (0.17-2.79) 0.4391
	CRP, mg/L	249 (111-315) 237 (111-315)	280 (111-318)	0.867
	Albumin, g/L	30 (26-34)	30 (26-33)	30 (26-35)	0.71
	WBC count, giga/L	17.5 (13.3-22) 18.3 (13.4-22.2) 15.8 (13.2 -19)	0.18
	Hemoglobin, g/dL	10.4 (8.4-11.9) 10.4 (8.4-11.5)	11 (7.6-13.4)	0.873
	Platelets, G/L	34 (23-57)	43 (27-69)	25 (20-41)	0.012
	Total bilirubin, mg/L	39.5 (21-75)	37.5 (17.5-74)	42 (26-88)	0.265
	Direct bilirubin, mg/L	48 (26-70)	47 (25-63)	52 (26-92)	0.536
	TGO, UI/L	72 (51-125)	78 (52-113)	70 (50-142)	0.925
	GPT, UI/L	42 (33-66)	41 (33-66)	43 (34-64)	1
	ALP, UI/L	114 (86-138)	116 (86-147)	96 (76-127)	0.51
	GGT, UI/L	70 (40-110)	74.5 (42-110)	45 (24-212)	0.477
	PT, %	68.5±15	69.5±13	65±20	0.276
	ACT	1.1±0.26	1.1±0.21	1.2±0.39	0.213
	Blood urea nitrogen, g/L	1.06±0.59	0.97±0.56	1.3±0.62	0.01
	Serum creatinine, mg/L	32 (20-51)	29 (19-46)	48 (27-64)	0.005
	Serum potassium, mmol/L	4.42±1.1	4.34±0.94	4.82±1.6	0.391
	ACT, activated partial thromboplastin time; ALP, alkaline phosphatase BNP, brain natruiretic
	peptide; CRP, C-reactive protein ; GGT: gamma-glutamyl transferase; TGO, Glutamate
	Oxaloacetate Transaminase; GTP, glutamate pyruvate transaminase; PT, prothrombin time;
	WBC, white blood cells

Table 4 .

 4 Hemodynamic data on ICU admission

	All (n=107)	Survivors (n=81)	Non survivors (n=26)	p value

Table 5 .

 5 Evolution of ventilator settings over the first 72 hours

	Crs, compliance of the respiratory system; FiO2, fraction of inspired oxygen; ND, not determined; PaO2, arterial partial pressure of oxygen; PaCO2,
	arterial partial pressure of carbon dioxide; PEEP, positive end-expiration pressure; PPlat, plateau pressure; SpO2, peripheral arterial oxygen
	saturation; VR,ventilation ratio.

Table 6 .

 6 Adjuvant therapeutic measures in survivors and non-survivors

		All	Survivors	Non-survivors
	Variables, n (%)	(n=107)	(n=81)	(n=26)	p value
	Neuromuscular blocking agents	79 (73.8)	57 (70.3)	22 (84.6)	0.233
	Prone position	27 (25.2)	20 (24.7)	7 (26.9)	0.82
	NO	14 (13.2)	9 (11.2)	5 (19.2)	0.296
	ECMO	6 (5.6)	3 (3.7)	3 (11.5)	0.025
	Use of NIV before intubation	4 (3.7)	3 (3.7)	1 (3.8)	1.00
	Use of HFNC before intubation	32 (29.9)	26 (32.1)	6 (23.1)	0.38
	Use of desmopressin	24 (23.1)	18 (23.1)	6 (23.1)	1
	Use of cortisteroids	64 (65.3)	49 (66.2)	15 (62.5)	0.74
	Use of dobutamine	33 (31)	26 (32.1)	7 (26.9)	0.62
	RRT	44 (42.7)	31 (40.3)	13 (50)	0.38
	ECMO, extracorporeal membrane oxygenation; HFNC, high flow nasal oxygen therapy; NIV, non-
	invasive ventilation; NO, nitrous oxide; RRT, renal replacement therapy

Table 7 .

 7 Patient outcomes

	All	Survivors	Non-survivors
	(n=107)	(n=81)	(n=26)	p value

Table 8 .

 8 Risk factors associated with mortality in patients with leptospirosis

	Variables	Odds ratio (95% CI)	p value
	Age >36 yr	8.96 (1.07 to 74.64)	0.043
	SAPS II score >61	90.77 (4.5 to 1809.5)	0.0003
	SOFA score >15	3.34 (0.39 to 28.26)	0.267
	Oligo-anuria	0.87 (0.1 to 7.75)	0.9
	PaO2/FiO2 <100	29.33 (1.45 to 591)	0.027
	PaCO2 >50 mmHg	3.73 (0.32 to 43.48)	0.292
	pH <7.1	0.65 (0.06 to 7.27)	0.73
	Base excess <-8	3.81 (0.42 to 34.28)	0.233
	Platelet count <30 G/L	43 (1.8 to 1010)	0.02
	Blood urea nitrogen >1 g/L	0.66 (0.06 to 6.63)	0.723
	Serum creatinine >30 mg/L	0.17 (0.01 to 2.56)	0.2

Table 9 .

 9 Ventilator settings according to ARDS definition criteria

		All (n=107)	AECC criteria (n=62)	Berlin criteria (n=45)	p value
	Minute volume, L/min	8.65±2.41	8.93±1.67	8.26±3.17	0.251
	Respiratory rate, breaths/min	24±8.16	20.8±5.2	29±9	<0.0001
	Tidal volume, mL	467±106	505±100	413±90	<0.0001
	PEEP, cmH2O	10.1±3.2	10.2±3.6	10±2.7	0.823
	Static Pplat, cmH2O	29.3±6.7	32.2±7.3	25.6±3.4	<0.0001
	Peak pressure, cmH2O	36.6±0.8	35.9±7.5	37.5±6.3	0.292
	Static Crs, mL/cmH2O	25.8±7.8	24.4 ±7.57	27.7±1.54	0.073
	Static driving pressure, cmH2O	19.1±2 6	21.9±6.1	15.4±0.56	<0.0001
	VR	1.96±0.74	2.13±0.58	1.89±0.79	0.371
	Dynamic mechanical power, J/min	23.9±8.37	23.4±7.9	24.4±9	0.619
	FiO2, %	89.3±17.4	93.6±14.3	83.4±19.6	0.0043
	PaO2, mmHg	85.4±35.5	84.1±38.6	87.5±31.1	0.679
	PaO2/FiO2	122±73.4	99 ±59.8	152±80	0.0005
	SpO2, %	88.2±16.8	86.6±18.7	90.7±13.2	0.2
	Arterial pH,	7.16±0.17	7.13±0.19	7.19±0.14	0.0701
	PaCO2, mmHg	57.4±18.1	60.26±20.8	53.6±12.6	0.0439
	Serum bicarbonate, mmol/L	18.9±5	19.±5.4	18.3±4.4	0.3019
	Base excess	-8.17±6.9	-8.14±7.5	-8.22±6	0.958
	Crs, compliance of the respiratory system; FiO2, fraction of inspired oxygen; PaCO2, arterial partial
	pressure of carbon dioxide; PaO2, arterial partial pressureof oxygen; PEEP, positive end-expiration
	pressure; PPlat, plateau pressure ; SpO2, peripheral oxygen saturation; VR, ventilation ratio.

Table 10 :

 10 Evolution of respiratory characteristics during the first 72 hours according to the ARDS definition criteria PaO2, arterial partial pressure of oxygen; PEEP, positive end-expiration pressure; PaCO2: arterial partial pressure of carbon dioxide; SpO2, peripheral oxygen saturation.

			Day 1			Day 2			Day 3
		AECC criteria	Berlin criteria		AECC criteria	Berlin criteria		AECC criteria	Berlin criteria
		(n=62)	(n=45)	p value	(n=62)	(n=45)	p value	(n=62)	(n=45)	p value
	Minute volume, L/min	8.93 (1.67)	8.26 (3.17)	0.251	9.34 (1.97)	9.21 (3.81)	0.486	9.70 (2.4)	8.9 (2.58)	0.671
	Respiratory rate, breaths/min	20.8 (5.2)	29 (9)	<0.0001	21.2 (5)	25.8 (6.4)	0.011	22.1 (3.9)	25 (7.2)	<0.0001
	Tidal volume, mL	505 (100)	413 (90)	<0.0001	506 (90)	435 (119)	0.452	498 (94)	450 (131)	0.045
	PEEP, cmH2	10.2 (3.6)	10 (2.7)	0.823	9.7 (2.9)	9.5 (2.3)	0.88	9.1 (2.7)	9.5 (2)	0.166
	Plateau pressure, cmH2O	32.2(7.3)	25.6(3.4)	<0.0001	31.4 (7.8)	25.7 (4.17)	0.784	30.1 (6.3)	24.8 (4.6)	0.263
	Peak pressure, cmH2O	35.9 (7.5)	37.5 (6.3)	0.292	36.1 (7.5)	33.6 (7.4)	0.069	34.6 (6.5)	34.1 (8.1)	0.504
	Compliance, mL/cmH2O	24.4 (7.57)	27.7 (1.54)	0.073	25.3 (8.2)	28.6 (8.1)	0.836	27.1 (15.2)	32.3 (17.6)	0.417
	Driving pressure, cmH2O	21.9 (6.1)	15.4 (0.56)	<0.0001	21.4 (6.15)	16.02. (3.94)	0.654	20.2 (5.58)	15.2. (4.17)	0.284
	Ventilation ratio	2.13 (0.58)	1.89 (0.79)	0.371	2.23 (0.85)	1.94 (1.2)	0.684	1.9 (0.81)	1.84 (0.8)	0.953
	Mechanical power, J/min	23.4 (7.9)	24.4 (9)	0.619	21.3 (9.69)	22.7 (9.2)	0.885	27.4 (9)	30 (12)	0.257
	FiO2, %	93.6 (14.3)	83.4 (19.6)	0.0043	80.8 (19.9)	57.5 (22.9)	0.005	68.1 (21.2)	50.1 (21.9)	0.158
	PaO2, mmHg	84.1 (38.6)	87.5 (31.1)	0.679	105 (50.1)	95.6 (26.1)	0.151	94 (30)	93.5 (26.5)	0.715
	PaO2/FiO2	99 (59.8)	152 (80)	0.0005	151 (92)	220 (92)	0.315	164 (91)	225 (98)	0.813
	SpO2, %	86.6 (18.7)	90.7 (13.2)	0.2	93.8 (7.4)	95.8 (3.4)	0.539	96.1 (4.04)	95.6 (4.4)	0.151
	Arterial pH, mmHg	7.13 (0.19)	7.19 (0.14)	0.0701	7.22(0.15)	7.28 (0.12)	0.466	7.29 (0.14)	7.36 (0.12)	0.309
	PaCO2, mmHg	60.26 (20.8)	53.6 (12.6)	0.0439	55.1 (16.7)	46.8 (8.6)	0.203	51.2 (14.1)	46 (12)	0.769
	Alkaline reserve, mmol/L	19. 3 (5.4)	18.3 (4.4)	0.3019	21.9 (5.1)	22.1 (13)	0.347	23.2 (5.1)	23.5 (5.1)	0.337
	Base excess	-8.14(7.5)	-8.22(6)	0.958	-4.91(7.1)	-4.39(7.8)	0.388	-1.2(7.8)	-0.18(6.6)	0.256
	FiO2, oxygen fraction inspired;

Table 11 :

 11 Adjuvant therapeutic measures according to the ARDS definition criteria

		Total	AECC criteria	Berlin criteria
	Variables, n (%)	(n=107)	(n=62)	(n=45)	p-value
	Neuromuscular blocking agents	79 (76)	48 (80)	31 (70)	0.26
	Prone position	27 (25.3)	19 (30.6)	8 (17.7)	0.13
	NO	14 (13.2)	13 (21)	1 (2.27)	0.005
	ECMO	6 (10.3)	2 (15.4)	4 (8.9)	0.498
	Use of NIV before intubation	32 (30)	15 (24.2)	17 (37.8)	0.13
	Use of HFNC before intubation	4 (3.74)	0 (0)	4 (8.9)	0.029
	Use of desmopressin	24 (23.08)	20 (32.3)	4 (9.52)	0.007
	Use of cortisteroids	64 (65)	30 (52.6)	34 (83)	0.002
	Use of dobutamine	27 (25.3)	19 (30.6)	8 (17.7)	0.13
	RRT	44 (42.7)	22 (37.9)	22 (49)	0.265
	ECMO, extracorporeal membrane oxygenation; HFNC, high flow nasal oxygen therapy; NIV, non-
	invasive ventilation; NO, nitrous oxide; RRT, renal replacement therapy

Table 12 :

 12 Patient outcome according to the ARDS definition criteria

	Variables	Total (n=107)	AECC criteria (n=62)	Berlin criteria (n=45)	p-value
	Mortality, n (%)	26 (24.3)	19 (30.6)	7 (15.6)	0.072
	Duration of mechanical ventilation, days	7.29 (3-10)	7.17 (3-10)	7.47 (4-10)	0.667
	Duration of ICU stay, days	9.4(4-13)	9 (4-12)	9.9 (7-14)	0.46
	VAP, n (%)	31 (29)	21 (33.9)	10 (22.2)	0.19
	Reintubation, n (%)	3 (2.8)	2 (3.23)	1 (2.22)	0.756
	Tracheostomy, n (%)	0	0	0	0
	VAP, Ventilation-associated Pneumonia

SvO2: Central Venous Oxygen Saturation

TNF: Tumor Necrosis Factor

VAP: Ventilator-Associated Pneumonia

WHO: World Health Organization

There were no statistically significant differences in hemodynamic variables between nonsurvivors and survivors (Table 4). Mean central SvO2 was higher in survivors than in nonsurvivors (75.8±9.8 % vs 58.5±11.1%, p=0.01).

The evolution of mechanical ventilation variables over the first 72 hours is shown in Table 5.

Compared with non-survivors, survivors had higher PaO2/FiO2 ratio over the first three days.

Compared to survivors, non-survivors received significantly lower tidal volume on both day 2 and day 3, without statistically significant difference in PEEP levels. There were no statistically significant differences in the main ventilation variables between survivors and non-survivors on day 2 and day 3.

Adjunctive treatments in patients who survived and in those who did not are summarized in Table 6. Neuromuscular blocking agents, corticosteroids, and renal replacement therapy were the most frequently used adjuncts. Neuromuscular blockade agents were used in 73% and 85% of survivors and non-survivors, without statistically significant between-group differences. The use of ECMO was relatively low in both survivors and non survivors. All patients required vasoactive support using norepinephrine.

The factors associated with ICU mortality are presented in Table 8.

A SAPS II score >61 on admission (odds ratio 8.96 [95%CI 4.5 to 1809]), a PaO2/FiO2 ratio of <100 on Day 1 (odds ratio 29.33 [95%CI 1.45 to 591]) and a platelet count <30 G/L on day 1 (odds ratio 43 [95%CI 1.8 to 1010]) were independently associated with mortality

Ventilator settings according to ARDS definition

The ventilator settings on ICU admission according to the ARDS definition are presented in Table 9. A total of 62 (58%) patients were hospitalized before 2012 (ARDS defined using the AECC criteria) and 45 (42%) patients after 2012 (ARDS defined using the Berlin criteria).

Compared with patients in the Berlin criteria cohort, patients in the AECC criteria cohort had higher plateau pressure (32.2±7.3 cmH2O vs 25.6±3.4 cmH2O, p<0.001), higher driving pressure (21.9±6.1 cmH2O vs 15.4 ±0.56 cmH2O, p <0.001), received higher FiO2 (93.6±14.3 % vs 83.4±19.6 %, p=0.0043), had lower PaO2/FiO2 ratio (99±60 mmHg vs 152±80 mmHg, p=0.0005), and had higher PaCO2 levels (60.3±20.8 mmHg vs 53.6±12.6 mmHg, p=0.044).

The evolution of ventilator settings over the first 3 days according to the ARDS definition criteria is shown in Table 10. Compared with the AECC criteria cohort, patients in the Berlin criteria cohort received significantly higher respiratory rate and lower tidal volume over the first three days. There were no significant differences in PEEP levels as in other ventilation variables.

Compared with patients in the Berlin criteria cohort, patients in the AECC criteria cohort more frequently received NO therapy (21% vs 2.3%, p=0.005), and desmopressin (32.3% vs 9.5%, p=0.007). In contrast, patients in the Berlin criteria cohort more frequently received corticosteroid therapy (52.6% vs 83%, p=0.002) (Table 11).

There was a higher ICU mortality rate in the AECC criteria cohort than in the Berlin criteria cohort (30.6% vs 15.6%, p=0.072). There was no significant difference in the duration of mechanical ventilation (7.2 [3-10] days vs 7.5 [START_REF] Miailhe | Severe leptospirosis in non-tropical areas: a nationwide, multicentre, retrospective study in French ICUs[END_REF][START_REF] O'neil | Pulmonary manifestations of leptospirosis[END_REF][START_REF] Gouveia | Leptospirosis-associated severe pulmonary hemorrhagic syndrome, Salvador, Brazil[END_REF][START_REF] Vandroux | Acute respiratory distress syndrome in leptospirosis[END_REF][START_REF] Needham | Timing of Low Tidal Volume Ventilation and Intensive Care Unit Mortality in Acute Respiratory Distress Syndrome. A Prospective Cohort Study[END_REF][START_REF] Urner | Time-varying intensity of mechanical ventilation and mortality in patients with acute respiratory failure: a registry-based, prospective cohort study[END_REF][START_REF] Amato | Driving pressure and survival in the acute respiratory distress syndrome[END_REF] days, p=0.667) or length of stay in the ICU (9 [14-12] days vs 9.9 [START_REF] Vandroux | Acute respiratory distress syndrome in leptospirosis[END_REF][START_REF] Needham | Timing of Low Tidal Volume Ventilation and Intensive Care Unit Mortality in Acute Respiratory Distress Syndrome. A Prospective Cohort Study[END_REF][START_REF] Urner | Time-varying intensity of mechanical ventilation and mortality in patients with acute respiratory failure: a registry-based, prospective cohort study[END_REF][START_REF] Amato | Driving pressure and survival in the acute respiratory distress syndrome[END_REF][START_REF] Neto | Mechanical power of ventilation is associated with mortality in critically ill patients: an analysis of patients in two observational cohorts[END_REF][START_REF] Ards Definition | Acute respiratory distress syndrome: the Berlin Definition[END_REF][13][START_REF] Sinha | Physiologic Analysis and Clinical Performance of the Ventilatory Ratio in Acute Respiratory Distress Syndrome[END_REF], p=0.46) (Table 12).

DISCUSSION

To our knowledge, this is the first study to evaluate the clinical features and the settings of mechanical ventilation in patients with leptospirosis-associated ARDS. One goal of this study was also to identify risk factors associated with mortality in patients with leptospirosisassociated ARDS. We found that older age and a SAPS II score greater than 61 were associated with increased mortality. These results are consistent with those identified in previous studies in patients with leptospirosis (7)(4)(16)(17) [START_REF] Haake | Leptospirosis in Humans[END_REF].

As in ARDS from other etiology, we found that severe hypoxemia, as defined by a PaO2/FiO2 ratio lower than 100 mmHg was associated with an increased risk factor of mortality. This is in agreement with the Berlin definition whose oxygenation criteria were found well correlated to severity, with a respective mortality of 27%, 32%, and 45% in mild (PaO2/FiO2 ratio between 201 and 300 mmHg), moderate (PaO2/FiO2 ratio between 101 and 200 mmHg) and severe (PaO2/FiO2 ratio ≤ 100 mmHg) ARDS [START_REF] Ards Definition | Acute respiratory distress syndrome: the Berlin Definition[END_REF].

Pulmonary manifestations in leptospirosis, especially intra-alveolar hemorrhage in relation to leptospirosis-associated severe pulmonary hemorrhagic syndrome, are known to be associated with an increased risk of mortality (19)(20)(21) [START_REF] Papa | Leptospirosis in Greece[END_REF]. In our cohort, including 107 patients with ARDS, we found an overall mortality rate of 24.3%. This is consistent with recent findings from a retrospective study of 39 patients with leptospirosis-associated ARDS in which the authors reported a mortality rate of 23% [START_REF] Vandroux | Acute respiratory distress syndrome in leptospirosis[END_REF]. In our study population, early mortality (within the first 24 hours after ICU admission) was found in 14 out of 26 patients (53.8%).

SERMENT D'HIPPOCRATE (Version longue) (Conseil national de l'ordre des médecins)

Au moment d'être admis(e) à exercer la médecine. je promets et je jure d'être fidèle aux lois de l'honneur et de la probité.

Mon premier souci sera de rétablir. de préserver ou de promouvoir la santé dans tous ses éléments. physiques et mentaux. individuels et sociaux.

Je respecterai toutes les personnes. leur autonomie et leur volonté. sans aucune discrimination selon leur état ou leurs convictions. J'interviendrai pour les protéger si elles sont affaiblies. vulnérables ou menacées dans leur intégrité ou leur dignité. Même sous la contrainte. je ne ferai pas usage de mes connaissances contre les lois de l'humanité. J'informerai les patients des décisions envisagées. de leurs raisons et de leurs conséquences. Je ne tromperai jamais leur confiance et n'exploiterai pas le pouvoir hérité des circonstances pour forcer les consciences.

Je donnerai mes soins à l'indigent et à quiconque me les demandera. Je ne me laisserai pas influencer par la soif du gain ou la recherche de la gloire.

Admis(e) dans l'intimité des personnes. je tairai les secrets qui me seront confiés. Reçu(e) à l'intérieur des maisons. je respecterai les secrets des foyers et ma conduite ne servira pas à corrompre les moeurs. Je ferai tout pour soulager les souffrances. Je ne prolongerai pas abusivement les agonies. Je ne provoquerai jamais la mort délibérément.

Je préserverai l'indépendance nécessaire à l'accomplissement de ma mission. Je n'entreprendrai rien qui dépasse mes compétences. Je les entretiendrai et les perfectionnerai pour assurer au mieux les services qui me seront demandés. J'apporterai mon aide à mes confrères ainsi qu'à leurs familles dans l'adversité.

Que les hommes et mes confrères m'accordent leur estime si je suis fidèle à mes promesses ; que je sois déshonoré(e) et méprisé(e) si j'y manque.

LEROUX Julie Signature

SERMENT D'HIPPOCRATE (Version courte)

En présence des Maîtres de cette FACULTE et de mes chers CONDISCIPLES. je promets et je jure d'être fidèle aux lois de l'Honneur et de la Probité dans l'exercice de la Médecine.

Je donnerai mes soins gratuits à l'indigent et je n'exigerai jamais un salaire au-dessus de mon travail. Admis dans l'intérieur des maisons. mes yeux ne verront pas ce qui s'y passe. ma langue taira les secrets qui me seront confiés et mon état ne servira pas à corrompre les moeurs ni à favoriser le crime.

Respectueux et reconnaissant envers mes MAÎTRES. je rendrai à leurs enfants l'instruction que j'ai reçue de leurs pères.

Que les HOMMES m'accordent leur estime si je suis fidèle à mes promesses. Que je sois couvert d'OPPROBRE et méprisé de mes confrères si j'y manque.

LEROUX Julie


Belen Haza
email: hazabelen@gmail.com

Charlotte Pinabiaux

Laurence Conty

Keywords: Belen Haza, Charlotte Pinabiaux, Laurence

come

Evaluating the ability to follow social cues in ADHD: calibration of a computerised tool (TooN) in children aged from 6 to 10 years

INTRODUCTION METHOD

COMPUTERIZED TOOL

TooN is based on the attentional orientation paradigm [3], but uses videos of real people gazing or pointing at everyday objects.

Children's task consists in pressing a button as soon as possible when an object appears on the screen, on the right or the left of an individual.

EFFECT OF SOCIAL CUES

Standard effect sizes for Gaze and Pointing (= reaction time in incongruent trials -reaction time in congruent trials):

• Followed a normal distribution (0.04 < all d < 0.16, all p > .05) • Were significantly higher than 0 (all t > 2.70, all p < .01). Children were faster in congruent than incongruent trials. Healthy children thus follow social cues.

RESULTS

Evaluating the ability to follow social cues in ADHD: calibration of a computerised tool (TooN) in children aged from 6 to 10 years

CONDITIONS

Gaze: the individual deviates her gaze toward the side of the object appareance (i.e., congruent trials) or the other side (i.e., incongruent trials).

Pointing: the individual orients her gaze, finger and head in the congruent or the incongruent direction.

EFFECT OF GENDER

The effect size of Gaze was higher for girls than for boys (F (1,331) = 8.38, p < .01). This may reflect better capacities of social cognition in girls. Norms must be calculated separately for girls and boys.

EFFECT OF AGE

The effect sizes for Gaze (B = -0.72, SE = 0.29, p < .05) and Pointing (B = -1.43, SE = 0.28, p < .001) decreased with age. This may be related to the development of executive functions. In any case, the calculation of the normative data must take this variable into account.

CONCLUSION

TooN is a sensitive tool that assesses the effects of social cues on attentional orientation. The calculation of normative data has to take into account age and gender. TooN will be tested on children with ADHD in order to verify the clinical validity of the tool.

  POPULATION 339 children without disorders • 169 girls and 170 boys • Aged from 6 to 10 years old • From 16 schools of Paris

Figure 3 :Figure 1 :Figure 2 :

 312 Figure 3: Standard effect sizes for Gaze and Pointing by age range

Figure 4 :

 4 Figure 4: Standard effect sizes for Gaze and Pointing by gender