Effect of changes in the use of noninvasive ventilation and high flow oxygen therapy on reintubation in a surgical intensive care unit. A retrospective cohort study

Membres du jury

Monsieur le Pr BEYDON Laurent | Président Monsieur le Pr LASOCKI Sigismond | Directeur Monsieur le Dr RINEAU Emmanuel | Membre Monsieur le Dr DUMARTINET Benjamin | Membre

Soutenue publiquement le :

2019-2020

THÈSE

pour le

DIPLÔME D’ÉTAT DE DOCTEUR EN MÉDECINE Qualification en ANESTHESIE – REANIMATION.

Effect of changes in the use of noninvasive ventilation and high flow oxygen therapy on reintubation in a surgical intensive care unit.

A retrospective cohort study.

Evolution des pratiques d’utilisation de la ventilation non invasive et de l’oxygénothérapie à haut débit et effet sur la

réintubation en réanimation.

Etude de cohorte rétrospective.

indiquer ici le titre en anglais et en français)

JEAN Lorine

Né le 13 août 1990 à Chartres (28)

Sous la direction de M. le Pr LASOCKI Sigismond

ENGAGEMENT DE NON PLAGIAT

Je, soussigné(e) Mme Lorine JEAN

déclare être pleinement conscient(e) que le plagiat de documents ou d’une partie d’un document publiée sur toutes formes de support, y compris l’internet, constitue une violation des droits d’auteur ainsi qu’une fraude caractérisée.

En conséquence, je m’engage à citer toutes les sources que j’ai utilisées pour écrire ce rapport ou mémoire.

signé par l'étudiant(e) le 20/09/2020

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Laurence Pharmacie Clinique et Education

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CHIKH Yamina Économie-Gestion Médecine

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O’SULLIVAN Kayleigh Anglais Médecine

Mise à jour au 09/12/2019

REME RC IEM ENTS

A Monsieur le Professeur Sigismond Lasocki,

Merci d’avoir accepté la direction de cette thèse. Merci pour votre aide précieuse dans ce projet, pour le temps que vous y avait consacré, et les multiples relectures du manuscrit. Merci également pour votre encadrement durant ces cinq dernières années.

A Monsieur le Professeur Laurent Beydon,

Vous m’avez fait l’honneur d’accepter de présider ce jury de thèse. Je vous remercie pour l’intérêt porté à ma thèse et merci pour votre enseignement durant l’internat.

A Monsieur le Docteur Emmanuel Rineau,

Je te remercie pour l’intérêt porté à ma thèse et de l'honneur que tu me fais de participer à mon jury de thèse. Au plaisir de travailler à tes côtés l’année prochaine.

A Monsieur le Docteur Benjamin Dumartinet

Merci de me faire l’honneur de te compter parmi les membres du jury et de juger mon travail. C’est un plaisir pour moi de travailler à tes cotés et plus encore de te retrouver à nos réunions intellectuelles hebdomadaires.

Merci à Stan d’avoir partagé ce travail avec moi, ça a été un plaisir pour moi de travailler à tes cotés. Bonne continuation à Lyon.

Un grand merci à mes parents, à mon frère et ma sœur et à l’ensemble de ma famille pour son soutien durant ces longues années.

Merci à mes co-internes rencontrés de semestre en semestre et aux autres merveilleuses rencontres angevines, aux Intellectuels : Charlotte, Claire, Léa, Benjamin, aux aventuriers corses : Jean et Charlotte, à mes copains de promo : Juliette, Apolline, Sarah, Olivier, Brice, Alice, Corentin, Paul, Charlotte et à mes co-internes de réa : Jade, Anna, Jean, Benjamin, William, Flore, Floriane, Valentin, Julien, Marion, Charline et Pauline qui m’ont offert de très bons moments ces 5 dernières années.

A tous les anesthésistes-réanimateurs et les équipes rencontrées au cours de mon internat pour votre bienveillance, vos enseignements et encouragements.

Merci pour tout ce que j’ai pu apprendre à vos côtés.

Merci à mes amis d’enfance chartrains et à mes copains d’externat tourangeaux.

LISTE DES ABREVIATIONS

Ce document contient des abréviations en Anglais et en Français.

ARDS Acute Respiratory Distress Syndrome ARF Acute Respiratory Failure

BMI Body Mass Index

COPD Chronic Obstructive Pulmonary Disease FiO2 Fraction of Inspired Oxygen

HFO High-Flow Oxygen HR Hazard ratio ICU Intensive Care Unit IQR Interquartile range NIV Noninavsive Ventilation

OHD Oxygénation nasale à Haut Débit OR Odds ratio

OSA Obstructive Sleep Apnea

P/F Arterial Partial Pressure of Oxygen / Fraction Inspired of Oxygen

P1 Phase 1

P2 Phase 2

PaO2 Arterial Partial Pressure of Oxygen PEEP Positive End Expiratory Pressure SAPSII Simplified Acute Physiologic Score VNI Ventilation Non Invasive

Plan

LISTE DES ABREVIATIONS PRE REQUIS

ABSTRACT INTRODUCTION METHODS

1. Study design and setting

2. Participants

3. Variables

4. Statistical analysis RESULTS

1. Study participants

2. Primary outcome

3. Secondary outcomes

DISCUSSION CONCLUSION REFERENCES CONCLUSION

REFERENCES PRE REQUIS LISTE DES FIGURES

LISTE DES TABLEAUX TABLE DES MATIERES ANNEXES

PRE REQUIS

En réanimation, l’échec de sevrage ventilatoire est courant, avec un risque non négligeable de détresse respiratoire chez les patients venant d’être extubés pouvant conduire à une réintubation (1). En effet, 10 à 15% de ces patients sont réintubés dans les 48h après leur extubation (1–3). Cette réintubation est associée à une durée de ventilation mécanique et une durée de séjour en réanimation prolongées entrainant une morbidité et une mortalité plus importante (2,4). La physiopathologie de cette détresse respiratoire aiguë est complexe.

Elle associe une obstruction des voies aériennes supérieures, une absence de toux efficace, des sécrétions respiratoires abondantes, des atélectasies, ainsi que des facteurs non respiratoires tels que l’encéphalopathie et l’insuffisance cardiaque (1,4–6). Dans la littérature, l’échec d’extubation est couramment défini comme le besoin de réintubation à 48h (1,7,8).

Actuellement, 3 différents types de méthodes non invasives sont disponibles pour prévenir ou traiter la détresse respiratoire en post-extubation : l’oxygénothérapie conventionnelle aux lunettes ou au masque haute concentration, couramment utilisée pour corriger l’hypoxémie après l’extubation, la ventilation non invasive (VNI) et plus récemment l’oxygénothérapie nasale à haut débit (OHD) via le système Optiflow.

La VNI est un traitement reconnu de la détresse respiratoire aiguë hypoxémique et hypercapnique (9). Son utilisation en post-extubation favorise le recrutement alvéolaire (10,11), permet de diminuer le travail respiratoire (1,12) et améliore l’oxygénation (11). Si parmi les patients présentant une détresse respiratoire aiguë en post-extubation, la VNI ne permet pas dans 10 à 50% des cas d’éviter la réintubation (13,14), 2 méta-analyses concluent cependant à l’intérêt de son utilisation précoce en post-extubation pour diminuer le taux de

réintubation (15,16). Malgré tout, la VNI reste un acte thérapeutique complexe et n’est pas toujours bien tolérée par les patients.

L’Optiflow est une méthode introduite plus récemment délivrant de l’oxygène à haut débit permettant une fraction inspirée en oxygène élevée. Cette technique améliore l’oxygénation, elle génère également une pression positive continue dans les voies respiratoires (17) permettant de réduire le travail respiratoire et permet un lavage de l’espace mort des voies aériennes supérieures (18). Les gaz inspirés sont humidifiés et réchauffés, améliorant ainsi le confort du patient et le drainage des sécrétions respiratoires, diminuant alors les obstructions des voies aériennes (17,18). Comparé à l’oxygénothérapie conventionnelle, en réanimation, l’Optiflow améliore l’oxygénation, le confort après l’extubation et prévient la détresse respiratoire post-extubation ainsi que le recours à une réintubation (19,20). De surcroit, Hernandez et al. a démontré que comparé à la VNI, l’Optiflow a le même effet sur la prévention de la réintubation et de la détresse respiratoire aiguë post extubation chez les populations les plus à risque de réintubation (3). Les données concernant la combinaison de l’Optiflow et de la VNI sont peu nombreuses. Il n’y a pas de données sur l’utilisation en association de la VNI et l’Optiflow pour traiter de manière curative la détresse respiratoire aigüe en post-extubation.

L’utilisation de ces techniques a soulevé des questions de sécurité pour le patient (13).

En effet, celles-ci peuvent retarder la réintubation dans certains cas, notamment en améliorant transitoirement le confort du patient et l’oxygénation, cela pouvant masquer temporairement une détresse respiratoire, et engendrer par la suite des conséquences défavorables en termes de morbi-mortalité.

Dans notre service de réanimation chirurgicale, l’introduction et l’utilisation de plus en plus fréquente de l’Optiflow a conduit à un changement de nos pratiques, celui-ci étant de plus

en plus utilisé en post-extubation. Ainsi l’objectif principal de notre étude est de comparer le taux de réintubation à 48h de l’extubation en réanimation entre 2 périodes, avant et après l’introduction de l’Optiflow en post-extubation. L’étude est présentée sous forme d’un article en Anglais.

Effect of changes in the use of noninvasive ventilation and high flow oxygen therapy on reintubation in a

surgical intensive care unit.

A Retrospective Cohort Study

Stanislas, ABRARD MD ^1,2 * stanislas.abrard@chu-angers.fr Lorine, JEAN MD ¹

lorinejean@hotmail.fr

Emmanuel RINEAU MD ^1,2 Emmanuel.Rineau@chu-angers.fr Pauline, DUPRE MD ¹

Pauline.dupre@chu-angers.fr Maxime LEGER, MD^{1, 3} Maxime.leger@chu-angers.Fr Sigismond, LASOCKI MD, PhD ^1,2 SiLasocki@chu-angers.fr

1 Department of Anesthesiology and Intensive Care, University Hospital of Angers, 4 Rue Larrey, 49100 Angers, FRANCE

2 MITOVASC Institut, INSERM 1083 - CNRS 6015, University of Angers, 3 rue Roger Amsler, 49100 Angers, FRANCE

3 INSERM UMR 1246 - SPHERE, Nantes University, Tours University, Nantes, France.

ABSTRACT

Rationale: Reintubation after weaning from mechanical ventilation is relatively frequent and associated with poorer outcomes. Different methods, including noninvasive ventilation (NIV) and more recently high-flow oxygen (HFO), have been proposed after extubation to decrease the reintubation rate.

Objective: To compare the rate of reintubation between two periods, before and after the introduction of HFO in the postextubation period.

Method: Single-center cohort in a surgical ICU, during 2 phases (before, phase P1 from April 2015 to April 2016 and after the introduction of HFO, Phase P2 from April 2017 to April 2018). Adult patients hospitalized in ICU and mechanically ventilated for more than one day were included if they were extubated alive.

Main outcomes: The primary endpoint was the reintubation rate within 48 hours of extubation.

Results: 290 patients (median age 65 [50-74] years; 190 (65.5%) men) were included in the analysis (181 and 109 in P1 and P2 respectively). Postextubation use of noninvasive methods (NIV and/or HFO) was similar between the two phases (41 (22.7%) vs 29 (26.6%) patients, p=0.480), but was earlier in P2 (0h vs 4h, p=0.009) and HFO was significantly more used (24 (83%) vs 25 (61%), p=0.039). The need for reintubation within 48 hours after

extubation was significantly lower in P2 (4 (3.7%) vs 20 (11.0%), RR 0.30, 95%CI [0.08- 0.92], p=0.034) but was similar at 7 days (10 (9.2%) vs 30 (16.6%), RR 0.47 [0.18-1.09], p=0.093).

Conclusion: The earlier implementation of noninvasive methods and the increased use of HFO between the 2 phases was accompanied by a lower extubation failure rate at 48 hours.

However, this effect was not persistent at 7 days.

INTRODUCTION

In intensive care units (ICUs), patients weaned from invasive mechanical ventilation are at risk of postextubation respiratory failure (ARF) and tracheal reintubation for mechanical ventilation^1,2. Around 10 to 15% of patients are reintubated within 48 hours following extubation³, with an associated increase in morbidity, mortality and length of hospital stay⁴. The pathophysiology of respiratory failure after extubation includes upper airway obstruction, inadequate cough, atelectasis, encephalopathy, cardiac dysfunction^2,5–7. Extubation failure is currently defined as the need for reintubation within 48h after extubation^8,9. Three

“noninvasive methods” are available to avoid and/or treat post-extubation ARF: conventional oxygen therapy, high-flow conditioned oxygen therapy (HFO), and noninvasive ventilation (NIV). NIV is a recommended treatment for acute hypercapnic and hypoxemic ARF¹⁰. NIV administered in the postextubation period can recruit zones of alveolar collapse^11,12, improve oxygenation¹³ and minimize the work of breathing^1,14. Although the use of curative NIV is ineffective in 10 to 50% of patients with postextubation ARF to avoid tracheal reintubation, two meta-analyses concluded that early use of NIV could decrease reintubation rates^15,16. HFO, a more recent method that delivers a high flow of high oxygen fraction, is able to generate a continuous positive airway pressure¹⁷, to reduce the work of breathing and to provide a washout of dead space in upper airways¹⁸. Compared with conventional oxygen therapy, high- flow conditioned oxygen therapy improves oxygenation and patients’ comfort after extubation and prevents postextubation ARF and reintubation in general populations of critically ill patients^3,19. In comparison with NIV, HFO was not inferior to prevent reintubation and postextubation respiratory failure in high-risk adult patients who were extubated²⁰. Currently, there is no known data on the comparison or combination of HFO and NIV to treat postextubation ARF (curative use). Moreover, the use of noninvasive methods has raised safety

concerns²¹. These therapies might increase the risk of worse outcomes by delaying reintubation because of the apparent improvements of patient comfort and oxygenation.

In our surgical ICU, the introduction of HFO has led to a change in practices, with a more frequent use of HFO in the postextubation period. The primary objective of this study was to compare the rate of reintubation 48 hours after extubation between two periods, before and after the introduction of HFO in this context.

METHODS

1. Study design and setting

The retrospective ARVENiO cohort study (Analyse Rétrospective de l’utilisation de la Ventilation Non-invasive et de l’Oxygénothérapie) was approved by the institutional review board of the French Anesthesiology and Critical Care Society (SFAR; 74 rue Raynouard; 75016 Paris France) (Chairperson Pr JE. Bazin) on 27 May 2019 (Ethical Committee N°IRB 00010254-2019‐094) and was registered at National Commission for Information Technology and Civil Liberties (DRCI-CGDE-FO-005), according to the French law²². The study is reported according to the STROBE statement.

This single-center, historical cohort was conducted in our 12-beds surgical ICU. We used data from 2 periods: from April 2015 to April 2016 (first phase, P1) and from April 2017 to April 2018 (second phase, P2). Between the two phases, physicians of the unit have gained experience and training on the benefits and use of HFO. No other changes in the respiratory management of patients was implemented.

2. Participants

All adult patients (age≥18 years) hospitalized in the intensive care unit, intubated, mechanically ventilated for a duration of more than one day and extubated alive during the two studied phases were included in our cohort.

3. Variables

Patient characteristics including age, body mass index, medical history (chronic obstructive pulmonary disease, arterial hypertension, sleep apnea syndrome, coronary artery disease), type of admission (medical, elective or emergency surgery), PaO2 / FiO2 ratio and reason for mechanical ventilation on admission if applicable, shock on admission (defined as the use of norepinephrine) and SAPS II score²³ were recorded. The day of the first extubation was recorded, as well as the PaO2 (in mmHg) / FiO2 ratio immediately before extubation. The use of noninvasive methods, the time of implementation, the indication mentioned by the physician (preventive or curative), the duration of use and the settings (NIV: inspiratory pressure support, positive end expiratory pressure (PEEP), fraction of inspired oxygen (FiO2); HFO: flow and FiO2) were recorded during the first 7 days following extubation.

The primary endpoint was the reintubation rate within the first 48 hours after extubation (excluding reintubation for surgery). Secondary endpoints included the reintubation rate at 7th post-extubation day, reintubation delay, length of ICU stay, 28-day mortality and days without mechanical ventilation on day 28 (a value of 0 was assigned if the patient died).

4. Statistical analysis

Quantitative data are expressed as medians IQR and compared using the Mann–Whitney U test. Qualitative data are described using numbers (%) and compared using Fisher's exact test or Chi-2 if more than 1 degree of freedom.

For the primary endpoint, patients were separated into two groups, according to the phase (P1 or P2). A multivariable analysis of the occurrence of reintubation within the 48 hours after extubation (excluding reintubation for surgery) was compared by the Fisher’s exact test. The use of noninvasive methods described by frequency, indication and combination of methods were compared by the Fisher’s exact test. The survival analysis of the reintubation delays used a univariate log-rank test. A Kaplan Meier-type graphical representation was used to show the survival curves for each group. For the others endpoints, reintubation delay, length of ICU stay, 28-day mortality and days without mechanical ventilation during the first 28 days were compared using the Mann–Whitney U test.

For some outcomes (i.e., reintubation rate at 48 hours, reintubation rate at 7 days, and survival analysis of the probability of reintubation censored at seven days), multivariable analyses were performed. Reintubation rates were analyzed using a logistic regression, while the survival analysis of the probability of reintubation used a multivariable Cox cause specific model.

Association between primary endpoint and risk factor was expressed by Hazard Ratio cause specific (HR) taking into account the competitive risks of censoring reintubation by death or leaving the service prior to the need for reintubation. For all models, we applied a selection process to choose among candidate predictor variables that had univariable p-value < 0.15.

Analyses were performed using R version 3.6.3 and SPSS version 24.

RESULTS

1. Study participants

Figure 1 – Flow-chart.

NIV: Noninvasive ventilation. HFO: High-flow oxygenation. P1: Phase 1. P2: Phase 2.

The patient flow chart is presented in Figure 1. Among the 302 patients included in the two cohorts, 290 were included in the analysis (181 in P1 and 109 in P2). There was a majority of men, with a median age of 65 [50-74] years (Table 1). The Simplified Acute Physiologic Score was 48 [37-59] (Table 1). One hundred ninety-six patients (67.6%) were admitted after recent surgery. The clinical characteristics of the patients were similar in the two phases except for a

higher proportion of patients with coronary artery disease in P1 and a higher incidence of ARDS and shock on admission in P2 (Table 1).

Characteristics All (n = 290) P1 (n = 181) P2 (n = 109) P

Male sex 190 (65.5) 121 (66.9) 69 (63.3) 0.610

Age, years 65 50-74 65 51-75 63 47-72 0.218

BMI 26.8 22.5-30.5 26.8 22.3-29.9 26.8 22.7-31.0 0.680

SAPS II 48 37-59 48 37-59 48 39-59 0.836

Medical history COPD

OSA

Arterial Hypertension Coronary artery disease

20 (6.9) 19 (6.6) 130 (44.8) 26 (9.0)

10 (5.5) 12 (6.6) 84 (46.4) 22 (12.5)

10 (9.2) 7 (6.4) 46 (42.2) 4 (3.7)

0.242 1.000 0.543 0.018 Type of ICU admission

Emergent surgery Elective surgery Medical

171 (59.0) 25 (8.6) 94 (32.4)

108 (59.7) 16 (8.8) 57 (31.5)

63 (57.8) 9 (8.3) 37 (33.9)

0.908

Reason for ICU admission Pneumonia

Acute pulmonary edema ARDS

Coma Shock

Recent surgery

34 (11.7) 3 (1.0) 13 (4.5) 96 (33.1) 95 (32.8) 196 (67.6)

19 (10.5) 3 (1.7) 4 (2.2) 60 (33.1) 43 (23.8) 124 (68.5)

15 (13.8) 0 9 (8.3) 36 (33.0) 52 (47.7) 72 (66.1)

0.453 0.294 0.020 1.000

< 0.001 0.699

Extubation day 2 1-8 3 1-8 2 1-8 0.488

P/F at extubation 287 217-359 288 216-366 283 220-348 0.778

Use of a noninvasive method 70 (24.1) 41 (22.7) 29 (26.6) 0.480

Time between extubation and noninvasive method implementation, hours

1 0-12 4 0-23 0 0-7 0.009

NIV used 33 (11.4) 23 (12.7) 10 (9.2) 0.146

Indication of NIV Preventive Curative

Other/not available

10 (30.3) 15 (45.5) 8 (24.2)

8 (34.8) 9 (39.1) 6 (26.1)

2 (20) 6 (60) 2 (20)

0.402

HFO used 49 (16.9) 25 (13.8) 24 (22.0) 0.039

Indication of HFO Preventive Curative

20 (40.8) 29 (59.2)

7 (28) 18 (72)

13 (54,2) 11 (45.8)

0.085

Combination of NIV and HFO 12 (4.1) 7 (3.9) 5 (4.6) 0.768

Table 1 – Patients baseline characteristics

n (% of phase). BMI: Body mass index. COPD: Chronic obstructive pulmonary disease. OSA:

Obstructive sleep apnea. ICU: Intensive care unit. ARDS: Acute respiratory distress syndrome. P/F:

Arterial partial pressure of oxygen (PaO2 in mmHg) / Fraction inspired of oxygen (FiO2). NIV:

Noninvasive ventilation. HFO: High-flow oxygenation.

The rate of patients receiving a noninvasive ventilation method was similar between the two

method was preventive in 4.5% of patients in P1 and 5.2% in P2 (p = 0.099). However, the noninvasive method was implemented significantly earlier in the P2 (0 [0-7] vs 4 [0-23] hours, p = 0.009). HFO was significantly more used in P2 (83% of patients with noninvasive method) vs 61% in P1 (p = 0.039) (Table 1). NIV was preferentially prescribed for few hour sessions, several times a day, whereas HFO was used almost continuously with an increase in daily HFO time performed between the two phases (13.5 [7.0-18.7] vs 20.9 17.7-22.5 hours per day per treated patient, p = 0.001) (Supplement Table 1).

2. Primary outcome

In total, 24 (8.3%) patients were reintubated within the first 48 hours after extubation.

Reintubation rate was significantly lower at 48 hours in the second phase of our cohort (20 (11.0%) vs 4 (3.7%) reintubations in P1 and P2 respectively, p = 0.028) (Table 2).

Outcomes All (n = 290) P1 (n = 181) P2 (n = 109) p

Reintubation within 48 hours^a, % 24 (8.3) 20 (11.0) 4 (3.7) 0.028

cause at 48 hours ^a Acute respiratory failure

Shock / cardiac arrest Neurologic failure

17 (70.8) 2 (8.3) 5 (20.8)

13 (65.0) 2 (10.0) 5 (25.0)

4 (100.0) 0 0

0.372

Reintubation within 7 days ^b 40 (13.8) 30 (16.6) 10 (9.2) 0.082

cause at 7 days ^b Acute respiratory failure Shock / cardiac arrest Neurologic failure

28 (70.0) 3 (7.5) 9 (22.5)

21 (70.0) 2 (6.7) 7 (23.3)

7 (70.0) 1 (10.0) 2 (20.0)

0.929

Reintubation delay, days 1 0-3 1 0-3 3 1-5 0.089

Days without ventilation on day 28 ^c 24.0 17.0-26.0 24.0 17.0-26.0 24.0 18.0-26.0 0.231 ICU length of stay, days 8.0 4.0-17.0 8.0 4.0-18.0 8.0 4.0-17.0 0.766

28-days mortality, % 16 (5.5) 11 (6.1) 5 (4.6) 0.792

Table 2 – Patients outcomes.

n (% of phase).

a Reintubation within 48 hours after extubation (excluding reintubation for surgery)

b Reintubation within 7 days after extubation (excluding reintubation for surgery)

c Value of 0 was affected if patient died during the 28 days after extubation.

ICU: Intensive care unit.

Multivariable analysis

We conducted a multivariate analysis to explore the factors associated with extubation success at 48 hours (Table 3). Phase 2 was independently associated with less reintubations at 48 hours (OR [95%CI] = 0.30 [0.08-0.92], p = 0.034), whereas the combined use of NIV and HFO was associated with an increased risk of reintubation (OR of 15.18 [2.78-83.16]).

Characteristics Reintubation at 48h

a (n=24)

Extubation success (n=266)

Univariate p

Multivariate regression OR[95%CI], p

Male sex 16 (66.7) 174 (65.4) 1.000 -

Age, years 64 54-73 65 50-74 0.949 -

BMI 26.9 24.4-33.2 26.7 22.5-30.3 0.519 -

SAPS II 45 36-55 48 38-59 0.218 -

Medical history COPD

OSA

Arterial Hypertension Coronary artery disease

3 (12.5) 1 (4.2) 12 (50.0)

1 (4.2)

17 (6.4) 18 (6.8) 118 (44.4)

25 (9.4)

0.223 1.000 0.670 0.708

- - - - Reason for ICU admission

Pneumonia

Acute pulmonary edema ARDS

Coma Shock

1 (4.2) 0 0 12 (50.0)

3 (12.5)

33 (12.4) 3 (1.1) 13 (4.9) 84 (31.6) 92 (34.6)

0.331 1.000 0.610 0.074 0.039

- - - 2.36 0.88-6.56

0.47 [0.10-1.61]

0.086 0.240 Postoperative admission

Postoperative day

21 (52.5)

0 0-0 170 (70.0)

0 0-0 0.044

0.518

0.76 [0.30-2.00]

-

0.577

P/F at admission 269 [184-377] 293 [169-401] 0.571 -

Extubation day 3 1-17 2 1-8 0.262 -

P/F at extubation 275 206-337 288 218-366 0.346 -

Phase 2 4 (16.7) 105 (39.5) 0.028 0.30 0.08-0.92 0.034

Preventive strategy 4 (16.7) 24 (9.0) 0.268

Use of a noninvasive method None

NIV used alone HFO used alone Combination

22 (55.0) 5 (12.5) 6 (15.0) 7 (17.5)

198 (82.5) 16 (6.7) 31 (12.9)

5 (2.0)

<0.001 Reference

0.065 0.750

<0.001

- 1.46 [0.20-6.73]

0.90 [0.13-3.85]

15.18 [2.78-83.16]

0.013 - 0.663 0.897 0.001

Table 3 – Multivariate analysis of factors associated with a reintubation within 48 hours, integrating study phase.

n (% of group). Odds ratio [95 % Confidence Interval]: OR [95%IC]

a Reintubation during 48 postextubation hours (excluding reintubation for surgery)

BMI: Body mass index. COPD: Chronic obstructive pulmonary disease. OSA: Obstructive sleep apnea.

ICU: Intensive care unit. ARDS: Acute respiratory distress syndrome. P/F: Arterial partial pressure of oxygen (PaO2) / Fraction inspired of oxygen (FiO2).

3. Secondary outcomes

Forty (13.8%) patients were reintubated within the first 7 days after extubation. The main cause of reintubation was occurrence of ARF in the 2 phases (70% vs 70%). The median reintubation delay was not significantly earlier in P1 (1[0-3] vs 3[1-5] days, for P1 and P2, p

= 0.089). The reintubation rate at 7 days was not significantly different between the two phases (30 (16.6%) vs 10 (9.2%) in respectively P1 and P2, p = 0.082) (Table 2). We conducted a multivariate analysis to explore the factors associated with extubation success at 7th day. It showed that the study period was not independently associated with extubation failure during the first 7 days (OR 0.47 [0.18-1.09], p = 0.093) (Supplement Table 2). Survival analysis of the probability of reintubation censored at 7 days, calculated by adjusted multivariable Cox model (Supplement Table 3), was not different between the two periods (adjusted HR of extubation failure in phase 2 was 0.47 [0.22-1.04], p = 0.061) (Figure 2).

Figure 2 – Kaplan-Meier curves showing extubation success within 7 days according to study phase. P-value obtained with the log-rank test.

The use of noninvasive methods was independently associated with reintubation during the first 48 hours but not during the 7 days following the extubation (p = 0.013 and p = 0.104 respectively) (Table 3 and Supplement Table 2). The reintubation was not significantly associated with the use of HFO or NIV alone at 48 hours as at 7 days after extubation. However, after multivariable analysis and adjustment, combined use of NIV and HFO in the same patient was independently associated with extubation failure during the first 48 hours (OR 15.18 [2.78-

83.16], p = 0.001) (Table 3). This association between combined use of NIV and HFO and extubation failure was also found during the first 7 days (OR 6.70 1.46-31.43, p = 0.013) (Supplement Table 2).

Finally, none of the other main clinical outcomes (day-28 mortality, ICU length of stay and ventilation-free days) were different the 2 phases (Table 2).

DISCUSSION

In this single-center retrospective cohort study, we confirmed an earlier and more extended postextubation use of HFO in the second period (P2). This was accompanied by a decrease by 70% of the reintubation rate at 48 hours but not at 7 days after extubation. We also observed that the combined use of NIV and HFO in the postextubation period was independently associated with extubation failure at 48 hours and 7 days.

We choose to assess reintubation rate at 48 hours because extubation failure is currently defined as the need to reintubate within 48 hours after extubation^8,9. In our study, the overall postextubation ARF rate within 48 hours was about 8%, which is similar to the overall rate reported at 48-72 hours in previous randomized trials assessing noninvasive methods^3,19. The rate of reintubation due to a non-respiratory cause is greater than 30% in our study. This finding is probably related to the high proportion of neurocritical patients in our ICU population (33.1 % of comatose patients at the admission). In these patients, reintubation for neurological failure is obviously more frequent⁷. Furthermore, in the context of neurological failure, the use of a noninvasive method is unlikely to avoid reintubation (22.5 % of reintubation for neurologic failure). This may have reduced the benefit of noninvasive methods in this study.

In our cohort, HFO therapy lasted longer than NIV (daily therapy duration and number of days). This may be related to a poorer tolerance of NIV, while comfort is improved under HFO³. Few data comparing NIV and HFO are available. They are inconclusive about oxygenation, work of breathing and need of intubation²⁴. Hernandez et al.²⁰ showed that in high-risk extubated patients, HFO was not inferior to NIV to prevent reintubation and postextubation respiratory failure. In line with previous published study, the reintubation was not associated specifically with one or the other methods in our study.

Combination of NIV and HFO has been proposed in order to prevent postextubation ARF. Thille et al.²⁵ showed that combination of NIV and HFO after extubation significantly decreased the risk of reintubation compared with HFO alone. We observed that the reintubation rate was independently increased in the subgroup of patients treated with a combination of NIV and HFO (OR 15.18 [2.78-83.16], p = 0.001) (Table 3). The proportion of surgical patients was higher in our cohort. Difference in pathophysiology of ARF between surgical and medical patients could explained in part this discrepancy. In our cohort, the combined use of NIV and HFO was low (4.1%) without evolution over the phases. We can assume that combination of therapy was proposed to the more severe patients, explaining the increase in extubation failure in this sub-group.

Use of noninvasive methods has traditionally raised safety concerns²¹, notably on a potential increased risk of worse outcomes by delaying reintubation. Our results do not seem to support these concerns. The median reintubation delay tended to be earlier in P1 (1 [0-3] vs 3 [1-5]

days in P1 and P2, p = 0.089), without difference of 28-day mortality (p = 0.792), ICU length of stay (p = 0.766) and days without ventilation (p = 0.231).

Recently, Thille et al. proposed to extend to 7 days after extubation the delay to define extubation failure when using noninvasive methods²⁶. Based on our results, it seems that an evaluation of extubation failure at 7 days is more clinically appropriate than at 48 hours.

Indeed, the reintubation rate we observed at 7 days (13.8% overall) was similar to those reported in previous studies²⁵. We observed a non-significant lower rate of reintubation at 7 days in the second period, with an absolute difference of 7.4 %, which would be considered clinically significant and in the range of previous large multicenter RCTs assessing reintubation as the main outcome^19,25. It is possible that our study did not have the power to detect statistical significance regarding this outcome.

This study has several limitations. First, given the retrospective and observational design of this study, we cannot establish any causal relationship. Second, missing data about the use of noninvasive ventilation or reintubation status could influence the results of the study. Third, the lack of statistical power did not allow to conclude about our second judgement criteria (reintubation at 7 days). Lastly, single-center design may have exacerbated the selection bias.

CONCLUSION

In this single-center retrospective cohort study, the rate of reintubation within the first 48 hours has significantly decreased between the 2 phases, with an earlier implementation of noninvasive method and an increased use of HFO.

REFERENCES

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2. Jaber S, Quintard H, Cinotti R, et al. Risk factors and outcomes for airway failure versus non-airway failure in the intensive care unit: a multicenter observational study of 1514 extubation procedures. Crit Care. 2018;22(1):236. doi:10.1186/s13054-018-2150-6

3. Maggiore SM, Idone FA, Vaschetto R, et al. Nasal high-flow versus Venturi mask oxygen therapy after extubation. Effects on oxygenation, comfort, and clinical outcome. Am J Respir Crit Care Med. 2014;190(3):282-288. doi:10.1164/rccm.201402-0364OC

4. Epstein SK, Ciubotaru RL, Wong JB. Effect of failed extubation on the outcome of mechanical ventilation. Chest. 1997;112(1):186-192.

5. Epstein S. Decision to extubate. Intensive Care Med. 2002;28(5):535-546.

doi:10.1007/s00134-002-1268-8

6. Khamiees M, Raju P, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Predictors of Extubation Outcome in Patients Who Have Successfully Completed a Spontaneous Breathing Trial. Chest. 2001;120(4):1262-1270. doi:10.1378/chest.120.4.1262

7. Salam A, Tilluckdharry L, Amoateng-Adjepong Y, Manthous ConstantineA. Neurologic status, cough, secretions and extubation outcomes. Intensive Care Med. 2004;30(7).

doi:10.1007/s00134-004-2231-7

8. Boles J-M, Bion J, Connors A, et al. Weaning from mechanical ventilation. Eur Respir J.

2007;29(5):1033-1056. doi:10.1183/09031936.00010206

9. Thille AW, Richard J-CM, Brochard L. The Decision to Extubate in the Intensive Care Unit. Am J Respir Crit Care Med. 2013;187(12):1294-1302. doi:10.1164/rccm.201208-1523CI 10. Organized jointly by the American Thoracic Society the ERS the European Society of

Intensive Care Medicine, and the Société de Réanimation de Langue Française, and approved by ATS Board of Directors, D cember 2000. International Consensus Conferences in Intensive Care Medicine: noninvasive positive pressure ventilation in acute Respiratory failure. Am J Respir Crit Care Med. 2001;163(1):283-291. doi:10.1164/ajrccm.163.1.ats1000

11. Tokics L, Hedenstierna G, Strandberg A, Brismar B, Lundquist H. Lung collapse and gas exchange during general anesthesia: effects of spontaneous breathing, muscle paralysis, and positive end-expiratory pressure. Anesthesiology. 1987;66(2):157-167.

12. Al-Saady N, Bennett ED. Decelerating inspiratory flow waveform improves lung mechanics and gas exchange in patients on intermittent positive-pressure ventilation.

Intensive Care Med. 1985;11(2):68-75.

13. Gust R, Gottschalk A, Schmidt H, Böttiger BW, Böhrer H, Martin E. Effects of continuous (CPAP) and bi-level positive airway pressure (BiPAP) on extravascular lung water after extubation of the trachea in patients following coronary artery bypass grafting. Intensive Care Med. 1996;22(12):1345-1350.

14. Jaber S, Chanques G, Jung B. Postoperative Noninvasive Ventilation. Anesthesiol J Am Soc Anesthesiol. 2010;112(2):453-461. doi:10.1097/ALN.0b013e3181c5e5f2

15. Glossop AJ, Shephard N, Shepherd N, Bryden DC, Mills GH. Non-invasive ventilation for weaning, avoiding reintubation after extubation and in the postoperative period: a meta- analysis. Br J Anaesth. 2012;109(3):305-314. doi:10.1093/bja/aes270

16. Lin C, Yu H, Fan H, Li Z. The efficacy of noninvasive ventilation in managing postextubation respiratory failure: a meta-analysis. Heart Lung J Crit Care. 2014;43(2):99- 104. doi:10.1016/j.hrtlng.2014.01.002

17. Parke RL, McGuinness SP. Pressures delivered by nasal high flow oxygen during all phases of the respiratory cycle. Respir Care. 2013;58(10):1621-1624.

doi:10.4187/respcare.02358

18. Lee JH, Rehder KJ, Williford L, Cheifetz IM, Turner DA. Use of high flow nasal cannula in critically ill infants, children, and adults: a critical review of the literature. Intensive Care Med. 2013;39(2):247-257. doi:10.1007/s00134-012-2743-5

19. Hernández G, Vaquero C, González P, et al. Effect of Postextubation High-Flow Nasal Cannula vs Conventional Oxygen Therapy on Reintubation in Low-Risk Patients: A Randomized Clinical Trial. JAMA. Published online March 2016. doi:10.1001/jama.2016.2711

20. Hernández G, Vaquero C, Colinas L, et al. Effect of Postextubation High-Flow Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation Respiratory Failure in High-Risk Patients: A Randomized Clinical Trial. JAMA. 2016;316(15):1565.

doi:10.1001/jama.2016.14194

21. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med. 2004;350(24):2452-2460.

doi:10.1056/NEJMoa032736

22. Toulouse E, Masseguin C, Lafont B, et al. French legal approach to clinical research.

Anaesth Crit Care Pain Med. 2018;37(6):607-614. doi:10.1016/j.accpm.2018.10.013

23. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270(24):2957-2963.

24. Lee CC, Mankodi D, Shaharyar S, et al. High flow nasal cannula versus conventional oxygen therapy and non-invasive ventilation in adults with acute hypoxemic respiratory failure:

A systematic review. Respir Med. 2016;121:100-108. doi:10.1016/j.rmed.2016.11.004 25. Thille AW, Muller G, Gacouin A, et al. Effect of Postextubation High-Flow Nasal Oxygen With Noninvasive Ventilation vs High-Flow Nasal Oxygen Alone on Reintubation Among Patients at High Risk of Extubation Failure: A Randomized Clinical Trial. JAMA. 2019;322(15):1465.

doi:10.1001/jama.2019.14901

26. Thille AW, Boissier F, Ben-Ghezala H, et al. Easily identified at-risk patients for

extubation failure may benefit from noninvasive ventilation: a prospective before-after study.

Crit Care. 2016;20(1). doi:10.1186/s13054-016-1228-2

CONCLUSION

Dans cette étude rétrospective monocentrique, le taux de réintubation 48h après l’extubation était significativement réduit lors de la 2^ème phase. Cela était associé à un changement des pratiques concernant l’utilisation des méthodes de ventilation non invasives, notamment une utilisation plus fréquente de l’Optiflow en post-extubation et une introduction plus précoce des différentes techniques de ventilation non invasives après l’extubation.

REFERENCES PRE REQUIS

1. Jaber S, Quintard H, Cinotti R, Asehnoune K, Arnal J-M, Guitton C, et al. Risk factors and outcomes for airway failure versus non-airway failure in the intensive care unit: a multicenter observational study of 1514 extubation procedures. Crit Care. déc 2018;22(1):236.

2. Epstein SK, Ciubotaru RL, Wong JB. Effect of Failed Extubation on the Outcome of Mechanical Ventilation. Chest. juill 1997;112(1):186‐92.

3. Hernández G, Vaquero C, Colinas L, Cuena R, González P, Canabal A, et al. Effect of Postextubation High-Flow Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation Respiratory Failure in High-Risk Patients: A Randomized Clinical Trial. JAMA.

18 oct 2016;316(15):1565.

4. Epstein S. Decision to extubate. Intensive Care Med. mai 2002;28(5):535‐46.

5. Khamiees M, Raju P, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Predictors of Extubation Outcome in Patients Who Have Successfully Completed a Spontaneous Breathing Trial. Chest. oct 2001;120(4):1262‐70.

6. Salam A, Tilluckdharry L, Amoateng-Adjepong Y, Manthous CA. Neurologic status, cough, secretions and extubation outcomes. Intensive Care Med. juill 2004;30(7):1334‐9.

7. Boles J-M, Bion J, Connors A, Herridge M, Marsh B, Melot C, et al. Weaning from mechanical ventilation. Eur Respir J. 1 mai 2007;29(5):1033‐56.

8. Thille AW, Richard J-CM, Brochard L. The Decision to Extubate in the Intensive Care Unit. Am J Respir Crit Care Med. 15 juin 2013;187(12):1294‐302.

9. International Consensus Conferences in Intensive Care Medicine: Noninvasive Positive Pressure Ventilation in Acute Respiratory Failure: Organized Jointly by the American Thoracic Society, the European Respiratory Society, the European Society of Intensive Care Medicine,

and the Société de Réanimation de Langue Française, and approved by the ATS Board of Directors, December 2000. Am J Respir Crit Care Med. janv 2001;163(1):283‐91.

10. Tokics L, Hedenstierna G, Strandberg Å, Brismar B, Lundquist H. Lung Collapse and Gas Exchange during General Anesthesia: Effects of Spontaneous Breathing, Muscle Paralysis, and Positive End-expiratory Pressure. Anesthesiology. févr 1987;66(2):157‐67.

11. Al-Saady N, Bennett ED. Decelerating inspiratory flow waveform improves lung mechanics and gas exchange in patients on intermittent positive-pressure ventilation.

Intensive Care Med. mars 1985;11(2):68‐75.

12. Jaber S, Chanques G, Jung B. Postoperative Noninvasive Ventilation: Anesthesiology.

févr 2010;112(2):453‐61.

13. Esteban A, Frutos-Vivar F, Ferguson ND, Arabi Y, Apezteguía C, González M, et al.

Noninvasive Positive-Pressure Ventilation for Respiratory Failure after Extubation. N Engl J Med. 10 juin 2004;350(24):2452‐60.

14. Keenan SP, Powers C, McCormack DG, Block G. Noninvasive Positive-Pressure Ventilation for Postextubation Respiratory Distress: A Randomized Controlled Trial. JAMA. 26 juin 2002;287(24):3238.

15. Glossop AJ, Shepherd N, Bryden DC, Mills GH. Non-invasive ventilation for weaning, avoiding reintubation after extubation and in the postoperative period: a meta-analysis. Br J Anaesth. sept 2012;109(3):305‐14.

16. Lin C, Yu H, Fan H, Li Z. The efficacy of noninvasive ventilation in managing postextubation respiratory failure: A meta-analysis. Heart Lung. mars 2014;43(2):99‐104.

17. Parke RL, McGuinness SP. Pressures Delivered By Nasal High Flow Oxygen During All Phases of the Respiratory Cycle. Respir Care. 1 oct 2013;58(10):1621‐4.

18. Lee JH, Rehder KJ, Williford L, Cheifetz IM, Turner DA. Use of high flow nasal cannula in critically ill infants, children, and adults: a critical review of the literature. Intensive Care Med. févr 2013;39(2):247‐57.

19. Hernández G, Vaquero C, González P, Subira C, Frutos-Vivar F, Rialp G, et al. Effect of Postextubation High-Flow Nasal Cannula vs Conventional Oxygen Therapy on Reintubation in Low-Risk Patients: A Randomized Clinical Trial. JAMA. 5 avr 2016;315(13):1354.

20. Maggiore SM, Idone FA, Vaschetto R, Festa R, Cataldo A, Antonicelli F, et al. Nasal High- Flow versus Venturi Mask Oxygen Therapy after Extubation. Effects on Oxygenation, Comfort, and Clinical Outcome. Am J Respir Crit Care Med. août 2014;190(3):282‐8.

LISTE DES FIGURES

Figure 1 – Flow-chart. ... 11 Figure 2 – Kaplan-Meier curves showing extubation success within 7 days according to study phase. ... 16

LISTE DES TABLEAUX

Table 1 – Patients baseline characteristics ... 12 Table 2 – Patients outcomes ... 13 Table 3 – Multivariate analysis of factors associated with a reintubation within 48 hours, integrating study phase ... 14

TABLE DES MATIERES

PRE REQUIS ... 1

ABSTRACT ... 5

INTRODUCTION ... 7

METHODS ... 8

1. Study design and setting ... 8

2. Participants ... 9

3. Variables ... 9

4. Statistical analysis ... 10

RESULTS ... 11

1. Study participants ... 11

2. Primary outcome ... 13

3. Secondary outcomes ... 15

DISCUSSION ... 17

CONCLUSION ... 19

REFERENCES ... 20

CONCLUSION ... 24

REFERENCES PRE REQUIS ... 25

LISTE DES FIGURES ... 28

LISTE DES TABLEAUX ... 29

TABLE DES MATIERES ... 30 ANNEXES ... I

ANNEXES

All P1 P2 p

NIV n=33

Days between extubation and NIV implementation

0.0 0.0-1.0 0.0 0.0-0.0 0.5 0.0-1.5 0.221 Initial prescription:

Session duration, h

Number of sessions per day Total time per day, h

3.0 2.0-5.7

1.5 1.0-4.7

7.5 4.0-12.0

2.0 2.0-5.2

1.5 1.0-4.2

7.0 4.5-13.0

3.5 2.7-8.0

1.5 1.0-6.0

8.0 4.0-10.5

0.235 0.857 0.704 Inspiratory pressure support,

cmH2O

10 8-11 8 8-12 10 8-10 0.784

Expiratory positive pressure, cmH2O

5 5-6 5 5-6 6 5-6 0.043

FiO2, % 40 30-45 40 30-45 37 30-47 0.775

Therapy really performed:

Number of days

Ratio Hours/Days therapy, h/d

1 1-3

7.0 4.0-10.0 1 1-3

7.0 3.2-11.7 1 1-2

8.0 4.0-9.2

0.603 0.787 Unplanned therapy termination

Death Reintubation Intolerance Switch for HFO

14 (42.4) 1 (3.0) 11 (33.3) 1 (3.0) 1 (3.0)

10 (43.5) 1 (4.3) 7 (30.4) 1 (4.3) 1 (4.3)

4 (40.0) 0 4 (40.0) 0 0

0.646

HFO n=49

Days between extubation and HFO implementation

0.0 0.0-1.0 0.0 0.0-2.0 0.0 0.0-0.0 0.018 Initial prescription:

Session duration, h Number session by day Total time by day, h

19.0 9.5-24.0

1.0 1.0-1.0

20.0 11.0-24.0

18.0 4.5-24.0

1.0 1.0-1.0

18.0 7.5-24.0

20.0 15.0-23.7

1.0 1.0-1.0

20.0 18.2-23.7

0.295 0.662 0.228

Debit, l/min 50 50-60 50 50-60 50 50-60 0.283

FiO2, % 50 40-50 50 42-60 45 32-50 0.071

Therapy really performed:

Number of days

Ratio Hours/Days therapy, h/d

2 1-4

18.0 12.0-21.3

2 1-4

13.5 7.0-18.7

2 1-4

20.9 17.7-22.5

0.769 0.001 Unplanned therapy termination

Death Reintubation Intolerance

14 (28.6) 0 14 (28.6) 0

9 (36.0) 0 9 (36.0) 0

5 (20.8) 0 5 (20.8) 0

0.094

Supplement Table 1 – Characteristics of use and setting of noninvasive methods FiO2: Fraction inspired of oxygen. NIV: Noninvasive ventilation. HFO: High-flow oxygenation.