Bernard Albat

Michel Brunel

Claude Humeau

Maurice Navarro

Yves Allieu

Bernard Canaud

Claude Jaffiol

Henri Navratil

Robert Alric

Paul-André Chaptal

Charles Janbon

Jacques Othoniel

Bernard Arnaud

Albert-Jean Ciurana

François Janbon

Michel Pages

Gérard Asencio

Jacques Clot

Daniel Jarry

Claude Peguret

Jacques Astruc

Pierre Costa

Jacques Jourdan

Jacques Pelissier

Charles Aussilloux

Françoise D'athis

Bernard Klein

Professeurs Emérites

Jean-Claude Artus

Paul Landais

Michel Zanca

Dominique Prat

Patrick Bastien

Dominique Larrey

Joseph Pujol

François Blanc

Alain Le Quellec

Alain Bonafe

Pierre Mares

Jean-Philippe Boulenger

Thierry Maudelonde

Gérard Bourrel

Michèle Maury

Jacques Bringer

Patrick Messner

Mireille Claustres

Bertrand Millat

Bernard Combe

Louis Monnier

Jean-Pierre Daures

Georges Mourad

Michel Dauzat

Christian Prefaut

Jean-Marc Davy

Rémy Pujol

Jean-Pierre Dedet

Jean Ribstein

Jean-Jacques Eledjam

Jean-François Schved

Robert Grolleau Raoux

Charles Sultan

Bernard Guerrier

Jacques Touchon

Bernard Guillot

Alain Uziel

Olivuer Jonquet

Michel Voisin

Stéfan Matecki

Moranne Physiologie

Néphrologie Olivier

Jacques Morel

Navarro Rhumatologie

Francis

Jean-Luc Pasquie

Perez Cardiologie

Antonia Martin

Perney Pascal

Michel Prudhomme

Pujol Anatomie

Louis Jeans

Pascal Pneumologie

Tu-Anh Anatomie

Pédiatrie

Céline Bourgier

Cancérologie

Delphine Capdevielle

Adultes Psychiatrie D'

Pierre-Géraud Médecine

Pierre-Emmanuel Colombo

Vincent Ophtalmologie Daien

Anne Dorandeu

Florent Fuchs

Deloustal Gynécologie-Obstétrique

Neurologie Audrey

Viala Gaujoux

Rhumatologie Cécile

Sylvain Godreuil

Bactériologie-Virologie ; Hygiène Hospitalière

Frédéric Oto-Rhino-Laryngologie Villain

Max Ophtalmologie

Vincent Denis

Vincent Thierry

Immunologie Professeurs

Des Universites

Laoudj Chenivesse

Lambert Philippe

Amouyal Michel

Clary Bernard

Garcia Marc

Bessis Didier

Pédiatrie Agathe Roubertie

PERSONNEL ENSEIGNANT Professeurs Honoraires

Remerciements

Au Professeur Samir JABER, pour me faire l'honneur de présider ce jury de thèse et de juger ce travail. Merci de votre disponibilité tout au long de mon internat. Soyez assuré de mon profond respect.

A ma directrice de thèse le Dr Audrey DE JONG, merci infiniment pour la patience, la disponibilité et l'enthousiasme dont tu as fait preuve tout au long de ce projet. C'était un grand plaisir de travailler avec toi.

Au Dr Thomas GODET , vous me faites l'honneur de juger ce travail. Veuillez accepter mes remerciements les plus sincères pour votre temps consacré. Je vous remercie également de m'avoir permis de réaliser ce travail en équipe avec l'hôpital de Clermont Ferrand.

A Charlotte W, merci pour ton temps investi dans le recueil clermontois et ta réactivité de ces derniers mois. Bon courage pour ta thèse à venir ! A tout le personnel médical et paramédical des CHU de Montpellier et Clermont Ferrand, merci à tous de vous êtes investis dans la collecte des données de l'étude.

A mes parents pour m'avoir donné le goût des études et du travail. Merci Papa de t'être investi aussi dans mon apprentissage de Word et Excel.

A Loïc, mon petit frère dont je suis très fière.

A ma famille qui me soutien depuis le début de mes études, et en particulier mon Papy Tino qui a grandement participé à ma réussite de la première année.

A mes amies de longues dates Fanny et Ophélie, pour avoir rythmer mes études de voyages et de fous rires depuis l'externat. Merci pour tous ces bons souvenirs à vos côtés ! Au groupe de nanas auvergnates : Fanny, Ophélie, Charlotte, Romane, Tanya, Manon, Myriam, Inès, Julie, Chloé, Clémence, Leila et Aurélie. Merci d'avoir égayer mes années Clermontoises par de nombreuses soirées et d 'avoir rendu les révisions à la BU plus douces.

A ma meilleure rencontre Montpelliéraine, ma petite Meeel, pour tous tes mots justes et ton oreille attentive. Tu m'as énormément apporté durant mon internat et j'espère te le rendre. Merci pour ces footings, ces randonnées de 20km, les grandes déclarations bien arrosées de 4h du matin et les tisanes/plaid sur le canapé.

A mon ami Fred, avec qui j'ai grandi depuis plus de 15 ans. J'espère t'avoir encore longtemps à mes côtés.

A mes derniers colocs :

-L'infatigable Antoine, on s'est plus vu au bar qu'a l'appart finalement.. Merci de m'avoir présenter la Florence, toujours dispo pour les soirées intelligentes ! -Kela et sa bonne humeur indéfectible , pour m'avoir rassuré et motivé ces derniers mois.

Merci d'être toujours partante pour toutes les activités, plus ou moins périlleuses ! Et à tous les autres colocs qui ont partagé ma vie montpelliéraine ces 4 dernières années.

A toutes les personnes chouettes que j'ai pu rencontrer durant mon internat, pour tous les moments partagés :

-Les copains de la promotion d'anesthésie réanimation 2018, pour toutes les pintes partagées après les journées de stages -Les internes de Béziers pour l'inoubliable 1 er semestre et les week-ends Ski ou Pool Party depuis ! -Les co internes du DAR A (Pierre, Luke, Marion, Romain, Thomas, Maxime, Thibault mon belge préféré … et Rim qui a squatté le bureau au moins autant que nous), merci pour l'ambiance. On aura pas beaucoup travaillé mais qu'est-ce qu'on aura rigolé ! Extubation is an essential procedure in anesthesia, when endotracheal intubation is required.

Summary

While safely performed in a large proportion of cases, it can present significant challenges and complications [START_REF] Parotto | Extubation of the Challenging or Difficult Airway[END_REF]. Complications associated with extubation can be severe, resulting in major morbidity and mortality [START_REF] Cavallone | Review article: Extubation of the difficult airway and extubation failure[END_REF].

Although the incidence of post-extubation desaturation is less frequent than during induction, the consequences can be dramatic [START_REF] Cook Nwacf | on behalf of the Fourth National Audit Project (2011) Major complications of airway management in the UK: results of the Fourth National Audit Project of the Royal College of Anaesthetists and the Difficult Airway Society. Part 1: Anaesthesia[END_REF]. In addition, nowadays most of the recommendations about airway management after surgery focus on intubation and difficult ventilation, and not on extubation procedure. Whereas Peterson and. Col [START_REF] Peterson | Management of the difficult airway: a closed claims analysis[END_REF] showed a decrease in mortality and brain damage over the years related to induction, this rate remained fixed during the other stages of anesthesia, including extubation [START_REF] Peterson | Management of the difficult airway: a closed claims analysis[END_REF].

The original papers focused on the extubation procedure are scarce, despite the challenges and risks associated with this procedure.

For a successful extubation, some standard safety rules must be respected [START_REF] Langeron | Difficult intubation and extubation in adult anaesthesia[END_REF]:

-Absence of a residual neuromuscular blockade monitored by a Quantitative Train of Four (TOF) of more than 90% [START_REF] Grabitz | The Effects of Postoperative Residual Neuromuscular Blockade on Hospital Costs and Intensive Care Unit Admission: A Population-Based Cohort Study[END_REF];

-Spontaneous breathing ensuring adequate gas exchange;

-Hemodynamic stability;

-Awake patient (eye opening, response to orders, no agitation) unless decision to extubate a patient under general anesthesia (to prevent coughing for example);

-Lack of immediate risk of surgical complications.

Despite the respect of these rules, the frequency of reintubation reported in anesthesia care varies between 0.03% [START_REF] Chen | Risk factors for unplanned reintubation caused by acute airway compromise after general anesthesia: a case-control study[END_REF] and 0.09% [START_REF] Banik | Incidence and Mortality Rate of Perioperative Reintubation: Case Series of 196 Patients[END_REF]. Upon extubation following surgery, patients are especially at risk of oxygen desaturation from sometimes preventable complications. These complications can be laryngospasm, negative-pressure pulmonary oedema and atelectases due to residual effects of neuromuscular-blocking agents (NMBA), opioids and inadequate analgesia [START_REF] Lee | Postoperative opioid-induced respiratory depression: a closed claims analysis[END_REF][START_REF] Ortega | Videos in clinical medicine. Endotracheal extubation[END_REF]. Cervical oedema after prolonged positioning in the Trendelenburg position can also occur and frequently result in hypoxemia [START_REF] Cook Nwacf | on behalf of the Fourth National Audit Project (2011) Major complications of airway management in the UK: results of the Fourth National Audit Project of the Royal College of Anaesthetists and the Difficult Airway Society. Part 1: Anaesthesia[END_REF]. The airway obstruction is also favored by general anesthesia with a posterior displacement of the soft palate, the base of the tongue and the epiglottis at the induction of the anesthesia as well as during the awakening of the patient leading to an inspiratory collapse of these structures [START_REF] Parotto | Extubation of the Challenging or Difficult Airway[END_REF].

Following surgery, the patient is transferred from the operating room to the recovery room ensuring adequate monitoring and support, in order to prevent and manage complications.

Following the transfer of the patient to the recovery room, good handover and clear instructions to the recovery staff responsible for the patient helps predict and avoid common problems encountered in the recovery room. The discharge of the patient from the recovery room is the prime responsibility of the anesthesiologist. The patient can then return to the ward after completion of an Aldrete score of 10, which means that the patient has a satisfactory respiratory, hemodynamic and neurological status [START_REF] Choudhary | Postoperative Recovery and Discharge[END_REF].

Abdominal surgery is particularly associated with postoperative respiratory complications [START_REF] Jaber | Non-invasive ventilation after surgery[END_REF].

Surgery close to the diaphragm favors restrictive syndrome and compression atelectases [START_REF] Jaber | Effect of noninvasive ventilation on tracheal reintubation among patients with hypoxemic respiratory failure following abdominal surgery: a randomized clinical trial[END_REF][START_REF] Khaled | Intraoperative protective mechanical ventilation in patients requiring emergency abdominal surgery: the multicentre prospective randomised IMPROVE-2 study protocol[END_REF][START_REF] Pensier | Hydroxyethyl Starch for Fluid Management in Patients Undergoing Major Abdominal Surgery: A Systematic Review With Meta-analysis and Trial Sequential Analysis[END_REF].

Perioperative positive ventilation is a concept that has been developed by Pr Jaber and Futier [START_REF] Futier | Perioperative positive pressure ventilation: an integrated approach to improve pulmonary care[END_REF]. However, during the transfer of a patient from the operating room to the recovery room, all the efforts made to avoid atelectases during preoxygenation [START_REF] Delay | The effectiveness of noninvasive positive pressure ventilation to enhance preoxygenation in morbidly obese patients: a randomized controlled study[END_REF][START_REF] Futier | Noninvasive ventilation and alveolar recruitment maneuver improve respiratory function during and after intubation of morbidly obese patients: a randomized controlled study[END_REF] and ventilation [START_REF] Futier | A trial of intraoperative low-tidal-volume ventilation in abdominal surgery[END_REF] during surgery can be largely undone by the use of bag-valve ventilation without PEEP.

Moreover, it might increase the need of opioids and neuromuscular blockers before extubation, to ensure a "safe transfer". All these potential changes may lead to an increase of the rate of hypoxemia following extubation, when performed in the recovery room in comparison to the operating room.

The recent COVID-19 pandemic has led some institutions to change their practice, by favoring extubation in the operating room instead of in the recovery room [START_REF] Jong | Airway management for COVID-19: a move towards universal videolaryngoscope?[END_REF][START_REF] Velly | Guidelines: Anaesthesia in the context of COVID-19 pandemic[END_REF]. Experts suggested performing extubation and supraglottic airway removal in the operating room, during the pandemic, to avoid contamination of the extubation provider. They pointed out that extubation in the recovery room should remain exceptional [START_REF] Jong | Airway management for COVID-19: a move towards universal videolaryngoscope?[END_REF][START_REF] Velly | Guidelines: Anaesthesia in the context of COVID-19 pandemic[END_REF][START_REF] Patwa | All India difficult airway association (AIDAA) consensus guidelines for airway management in the operating room during the COVID-19 pandemic[END_REF].

However, to date no study has compared the rate of complications of extubation according to the place of extubation after abdominal surgery. There are currently no recommendations regarding the location of extubation. The choice between the operating room or the recovery room to remove the endotracheal tube is left to the anesthesiologist appreciation. According to a practice study [START_REF] Larousse | Book Où extuber? au bloc opératoire ou en salle de surveillance post-interventionnelle[END_REF], only one-third of anesthesiologists in France wanted to extubate their patients in the operating room. High-risk cardiovascular surgery was associated with an increase proportion of patients extubated in the operating room. On the contrary, the administration of neuromuscular blockers was associated with an increased proportion of patients extubated in the recovery room.

The main hypothesis of this study was that the proportion of post-extubation hypoxemia would be decreased after extubation in the operating room when compared with extubation in the recovery room, after abdominal surgery.

II.

Materials and methods

1) Study design & setting

We conducted an observational comparative study, multicenter, prospective at the University Hospital of Saint-Eloi (Montpellier, France) and the University Hospital of Gabriel Montpied (Clermont Ferrand, France). The anesthesia protocol and location of extubation were led by the discretion of the attending anesthesiologist. Extubation in the recovery room was advised in case of body mass index (BMI) ≥ 40 kg/m², severe cardiorespiratory disease and American Society of Anesthesiologists (ASA) score of 4.

2) Patients selection

All adult patients who were intubated for abdominal surgery over the period from September 1th, 2020 to July 1th, 2021 at the Montpellier University Hospital, and over the period from January 4 to 28, 2022 at the Clermont Ferrand University Hospital, were evaluated for eligibility.

Patients extubated in intensive care units or during the week-end or between 8 PM and 7 AM were excluded.

3) Data collection & Patient characteristics

Data were prospectively collected through an observational cohort and retrospectively analyzed.

We obtained approval from the Montpellier University Hospital ethics committee Institutional Review Board, agreement number: IRB-MTP_2022_04_202201100. The need for informed consent was waived by the ethics committee.

Data on patients characteristics were collected during the pre-surgical anesthesia assessment.

Intra-operative data were collected through the operating room and recovery room report files: length of surgery (from incision to closure), Cormack score (direct when using a direct laryngoscope and indirect when using an indirect laryngoscope [START_REF] Jong | Macintosh videolaryngoscope for intubation in the operating room: a comparative quality improvement project[END_REF][START_REF] Jong | A Videolaryngoscope as a First-intention Device for Tracheal Intubation in Unselected Patients in the Operating Room[END_REF]), difficulty of mask ventilation, material used for intubation, type of induction (rapid sequence induction or standard), use and amount of NMBA, opioids and hypnotics, use of adjuvant analgesics (lidocaine and ketamine), use of locoregional anesthesia, time from the end of the surgical procedure to extubation, and time from the end of surgical procedure to the operating room exit.

Immediate postoperative data were collected by anesthesiologists and nurse anesthetists, through a questionnaire: post extubation hypoxemia (defined as at least one episode of SpO2 <96% [START_REF] Crapo | Arterial blood gas reference values for sea level and an altitude of 1,400 meters[END_REF] within 5 minutes following extubation), use of rescue oxygen therapy after extubation (defined as the need to introduce oxygen or increase oxygen flow), bradycardia occurrence (defined as heart rate lower than 60/min) [START_REF] Tanriverdi | Comparison of sedation with dexmedetomidine vs propofol during hysteroscopic surgery: Single-centre randomized controlled trial[END_REF], hypotension occurrence (defined as mean arterial pressure lower than 60 mm Hg) [START_REF] Tanriverdi | Comparison of sedation with dexmedetomidine vs propofol during hysteroscopic surgery: Single-centre randomized controlled trial[END_REF], presence of residual neuromuscular blockade (defined as TOF <90% before extubation) [START_REF] Plaud | Guidelines on muscle relaxants and reversal in anaesthesia[END_REF], extubation failure before transfer to the ward, and time from the end of the surgical procedure to patient able to be transferred to the ward (Aldrete score of 10) [START_REF] Gulia | Comparison of two forced air warming systems for prevention of intraoperative hypothermia in carcinoma colon patients: a prospective randomized study[END_REF][START_REF] Jouybar | Comparison of the effects of remifentanil and dexmedetomidine on surgeon satisfaction with surgical field visualization and intraoperative bleeding during rhinoplasty[END_REF].

Data on the wards (oxygen requirement at Day-1, respiratory complications within Day-7 after surgery) were collected on the medical software (DxCare, Dedalus S.A., France).

The final database was de-identified.

4) Definitions & Outcomes

The primary endpoint was immediate post-extubation hypoxemia, defined as at least one episode of SpO2 <96% [START_REF] Crapo | Arterial blood gas reference values for sea level and an altitude of 1,400 meters[END_REF] within 5 minutes following extubation. Standard practices after extubation usually include the immediate application after extubation of low-flow nasal cannula oxygen (flow of 2L/minutes) during 10 to 15 minutes.

The prespecified secondary endpoints were:

-Use and amount of neuromuscular blockers/opioids/hypnotics; -Use of adjuvant analgesics (lidocaine and ketamine);

-Pharmacologic reversal of NMBA;

-Time from the end of the surgical procedure to extubation;

-Time from the end of the surgical procedure to exit of operating room;

-Use of rescue oxygen therapy after extubation;

-Bradycardia occurrence;

-Hypotension occurrence;

-Presence of residual neuromuscular blockade;

-Extubation failure before transfer to the ward;

-Time from the end of the surgical procedure to patient able to be transferred to the ward (Aldrete score of 10);

-Oxygen requirement at Day-1;

-Respiratory complications within Day-7 after surgery.

5) Statistical analysis

Expecting a difference on the primary outcome of 10% between extubation in the operating room and in the recovery room (from 5% to 15%), we calculated the sample size as 132 per group, using a χ2 test, with an α level of 0.05 and a power of 0.80.

All quantitative variables were described with median and interquartile range (25 th -75th percentile) and compared using the student t test or the Wilcoxon test as appropriate.

Qualitative variables were described with percentage (%) and compared with Chi-Square or exact Fisher test as appropriate.

In case of missing values, the number of available values was clearly stated for each variable. No imputation was made.

A first analysis was performed in the overall cohort. For the main outcome, a chi square test was used. Odds ratio (OR) with corresponding 95% confidence interval (CI) were computed.

For the other outcomes, a chi-square test, exact Fisher test, student t test or the Wilcoxon test were used according to the type of outcome (qualitative or quantitative).

A second analysis was performed on the overall cohort after adjustment on confounding factors between the 2 groups (defined by a p-value<0.20 after univariate analysis), using a multivariate logistic mixed regression [START_REF] Nikolla | Impact of video laryngoscope shape on first-attempt success during non-supine emergency department intubations[END_REF], taking the center effect in account (random effect), with a backward method to select the final model, including only significant variables (p<0.05).

Finally, a matching procedure was performed between patients extubated in the operating room and patients extubated in the recovery room, using a propensity score method [START_REF] Jong | Medical versus surgical ICU obese patient outcome: a propensity-matched analysis to resolve clinical trial controversies[END_REF], to further limit selection biases between the two groups.

Statistical analysis was performed using SAS software version 9.4 (SAS Institute, Cary, NC) and R software (version 3.0.2). P value <0.05 was considered statistically significant.

III. Results

1) Patients characteristics at admission

Over the period from September 1th, 2020 to July 1th, 2021, 410 patients were included at the Montpellier University Hospital, while over the period from January 4 to 28, 2022, 176 patients were included at the Clermont Ferrand University Hospital. A total of 366 patients were extubated in the operating room while 220 patients were extubated in the recovery room. The flow chart of the study participants is presented in Figure 1.

Baseline characteristics of the overall cohort are presented in Table 1.

Patients included in the study were both female (49%) and male (51 %), with a median age of 61 (47-72) years old, and a median BMI of 25 [START_REF] Patwa | All India difficult airway association (AIDAA) consensus guidelines for airway management in the operating room during the COVID-19 pandemic[END_REF][START_REF] Larousse | Book Où extuber? au bloc opératoire ou en salle de surveillance post-interventionnelle[END_REF][START_REF] Jong | Macintosh videolaryngoscope for intubation in the operating room: a comparative quality improvement project[END_REF][START_REF] Jong | A Videolaryngoscope as a First-intention Device for Tracheal Intubation in Unselected Patients in the Operating Room[END_REF][START_REF] Crapo | Arterial blood gas reference values for sea level and an altitude of 1,400 meters[END_REF][START_REF] Tanriverdi | Comparison of sedation with dexmedetomidine vs propofol during hysteroscopic surgery: Single-centre randomized controlled trial[END_REF][START_REF] Plaud | Guidelines on muscle relaxants and reversal in anaesthesia[END_REF][START_REF] Gulia | Comparison of two forced air warming systems for prevention of intraoperative hypothermia in carcinoma colon patients: a prospective randomized study[END_REF][START_REF] Jouybar | Comparison of the effects of remifentanil and dexmedetomidine on surgeon satisfaction with surgical field visualization and intraoperative bleeding during rhinoplasty[END_REF] kg/m².

The most frequent comorbidities in the whole population were arterial hypertension (36% of patients), followed by smoking (23%), diabetes (16%), obstructive sleep apnea syndrome (OSA, 10%) and chronic renal failure (10 %).

The two groups differed in terms of characteristics since patients extubated in the recovery room were more frequently female, had a higher BMI, an higher ASA score and had more frequently OSA than patients extubated in the operating room (Table 1).

With regards to the perioperative characteristics, patients extubated in the recovery room had more predicted and proven difficult ventilation than patients extubated in the operating room.

The surgeries performed in the two groups were not similar in terms of type, scheduling, and length (Table 1).

2) Main primary outcome

Post-extubation hypoxemia occurred in 52/344 (15 %) of patients extubated in the operating room versus 64/214 (30 %) of patients extubated in the recovery room (Figure 2, Table 2, p<0.001, OR 0.42 95%CI (0.28-0.63)).

After adjustment on gender, BMI, presence of OSA, difficult ventilation, ASA score, length of surgery, type of surgery, and center, post-extubation hypoxemia was still less frequent in patients extubated in the operating room in comparison to patients extubated in the recovery room (p<0.001, odds ratio OR 0.31 95%CI (0.18-0.52)).

3) Secondary outcomes

The secondary outcomes are presented in Table 2.

Importantly, the use of rescue oxygen therapy was lower in patients extubated in the operating room than in patients extubated in the recovery room (Figure 3, 10% vs 22%, p<0.001).

There was only one case of reintubation of a patient extubated in the recovery room. He presented an alveolar hypoventilation related to accidental morphine overdose after spinal anesthesia.

Use of sufentanil and cisatracurium were less frequent and sufentanil doses were lower in patients extubated in the operating room than in patients extubated in the recovery room (Table 2).

The time from the end of surgical procedure to the operating room exit was higher in patients extubated in the operating room than in patients extubated in the recovery room. On the contrary, the time from the end of surgical procedure to extubation and the time from the end of the surgical procedure to patient able to be transferred to the ward were lower in patients extubated in the operating room than in patients extubated in the recovery room (Table 2).

Patients extubated in the operating room had a lower residual neuromuscular blockade rate than patients extubated in the recovery room (Table 2, 0.8% vs 3.5%, p=0.042).

At Day-1 after surgery, need of oxygen was less frequent in patients extubated in the operating room than in patients extubated in the recovery room (Table 2, 14 % vs 30 %, p<0.001).

However, the rate of respiratory complications within Day-7 after surgery did not differ between patients extubated in the operating room and patients extubated in the recovery room (Table 2, 4% vs 6%, p=0.224).

4) Results of the matched cohort

One hundred and seventy-seven patients extubated in the operating room were matched with 177 patients extubated in the recovery room. The matching procedure was performed on gender, BMI, presence of OSA, difficult ventilation, ASA score, length of surgery, type of surgery and center.

Baseline characteristics of the matched cohort are reported in Table 3. Baseline characteristics were similar after matching.

Main and secondary outcomes of the matched cohort are shown in Table 4. After matching, post-extubation hypoxemia occurred in 16% (28/170) of patients extubated in the operating room compared to 32% (55/171) of patients extubated in the recovery room (Figure 2, Table 4, p<0.001, OR 0.42, 95%CI (0.25-0.70)).

The use of rescue oxygen therapy was lower in patients extubated in the operating room than in patients extubated in the recovery room (Figure 3, Table 4, 11% vs 23%, p < 0.001).

The time from the end of surgical procedure to the operating room exit was higher in patients extubated in the operating room than in patients extubated in the recovery room group (Table 4, Figure 4). On the contrary, the time from the end of surgical procedure to extubation and the time from the end of the surgical procedure to patient able to be transferred to the ward were lower in patients extubated in the operating room than in patients extubated in the recovery room (Table 4, Figure 4).

Need of oxygen at Day-1 after surgery in the matched cohort, and the rate of respiratory complications within Day-7 after surgery did not differ between patients extubated in the operating room and patients extubated in the recovery room (Table 4).

IV. DISCUSSION

In this study assessing the location of extubation after abdominal surgery, we reported that the proportion of post-extubation hypoxemia was decreased after extubation in the operating room when compared with extubation in the recovery room, in the overall cohort, after adjustment by multivariate analysis, and after propensity score matching (Figure 2).

Need for rescue oxygen therapy rescue was also less frequent after extubation in the operating room than extubation in the recovery room, before and after matching (Figure 3).

In both cohorts, before and after matching, the time from the end of surgical procedure to the operating room exit was higher in patients extubated in the operating room than in patients extubated in the recovery room group (Table 4, Figure 4). On the contrary, the time from the end of surgical procedure to extubation and the time from the end of the surgical procedure to patient able to be transferred to the ward were lower in patients extubated in the operating room than in patients extubated in the recovery room (Table 4, Figure 4).

To our knowledge, this is the first study aiming to assess the proportion of complications of extubation according to the place of extubation after abdominal surgery. In non-complex cardiac surgery patients, an operating room extubation protocol was investigated [START_REF] Totonchi | Feasibility of On-table Extubation After Cardiac Surgery with Cardiopulmonary Bypass: A Randomized Clinical Trial[END_REF]. Anesthesia protocols in the patients extubated in the operating room included a lower dose of induction and maintenance, short-acting drugs (especially opioids, sufentanil in this study), early reversal techniques (removing muscle relaxation and fast awakening), and maintenance of adequate anesthesia depth (using BIS monitoring). They found that early extubation in the operating room reduced the length of stay in the intensive care unit, when compared with extubation in the recovery room.

Studies have documented around 5% incidence of severe desaturation (SpO2<92%) in the period immediately following extubation after surgery [START_REF] Rostin | The association of early postoperative desaturation in the operating theatre with hospital discharge to a skilled nursing or long-term care facility[END_REF]. In our study, we chose a threshold of desaturation of 96% as most healthy patients physiologically have a baseline saturation of more than 96% [START_REF] Crapo | Arterial blood gas reference values for sea level and an altitude of 1,400 meters[END_REF]. Moreover, the patients systematically received prophylactic low flow nasal cannula oxygen therapy during 10 to 15 minutes after extubation.

The risks of transfer from operating room to recovery room were described more than thirty years ago [START_REF] Blair | Oxygen saturation during transfer from operating room to recovery after anaesthesia[END_REF]. Among 101 transferred patients included in this study [START_REF] Blair | Oxygen saturation during transfer from operating room to recovery after anaesthesia[END_REF], 29 experienced a lowest oxygen saturation < 91%. However, the patients were breathing room air during the transfer. Nowadays, patients transferred under invasive mechanical ventilation often receive oxygen through bag-valve ventilation. If no PEEP is applied, pulmonary atelectasis can occur, despite all the efforts made to prevent atelectases during surgery. The basic strategy is to allow the patient to breathe spontaneously and only help respiration if necessary, with intermittent manual assistance [START_REF] Jeong | Pressure Support versus Spontaneous Ventilation during Anesthetic Emergence-Effect on Postoperative Atelectasis: A Randomized Controlled Trial[END_REF]. It was reported that the incidence of post-operative atelectasis was lower in patients undergoing either laparoscopic colectomy or robot-assisted prostatectomy who received pressure support ventilation during emergence from general anesthesia compared to those receiving intermittent manual assistance [START_REF] Jeong | Pressure Support versus Spontaneous Ventilation during Anesthetic Emergence-Effect on Postoperative Atelectasis: A Randomized Controlled Trial[END_REF]. There is substantial evidence that atelectasis, in combination with alveolar hypoventilation and ventilation-perfusion mismatch, is the core mechanism responsible for postoperative hypoxemic events in the majority of patients [START_REF] Futier | Perioperative positive pressure ventilation: an integrated approach to improve pulmonary care[END_REF]. Many concomitant factors also must be considered, such as respiratory depression from the type and anatomical site of surgery altering lung mechanics, the consequences of hemodynamic impairment and the residual effects of anesthetic drugs, most notably residual neuromuscular blockade. The appropriate use of anesthetic and analgesic techniques, when combined with meticulous postoperative care, clearly influences pulmonary outcomes after surgery. It is worth noting that in the current study, sufentanil was more used in case of extubation in the recovery room than in the operating room (Tables 2 and4), which might also participate to the increased rate of post-extubation hypoxemia in the recovery room.

Another explanation of the differences observed between the two locations of extubation could be the availability of the medical team. In the operating room, the nurse anesthetist and/or the anesthesiologist have only one patient under their supervision. In the recovery room, on average in France, the nurse or nurse anesthetist have often more than 3 patients under their supervision [START_REF] Fletcher | A patient-based national survey on postoperative pain management in France reveals significant achievements and persistent challenges[END_REF]. This could lead to an extubation sometimes either too delayed, or too anticipated, explaining the higher rate of complications observed in recovery room (Figures 2 and3, Tables 2 and4).

As expected, patients extubated in the operating room were discharged less quickly from the operating room than patients extubated in the recovery room. On the contrary, patients extubated in the operating room were extubated faster after surgery and also ready to be discharged from the recovery room sooner. Their total stay in the anesthesia unit was therefore shortened. All these results were confirmed after propensity score matching analysis (Figure 4).

Noteworthily, the lower rate of postextubation hypoxemia and use of rescue oxygen therapy translated into lower need of oxygen at Day-1. However, this result has to be taken with caution as it was not confirmed in the matched cohort.

The current study has several strengths. First, it was adequately powered to find a difference between patients extubated in the operating room and patients extubated in the recovery room.

Moreover, it was a pragmatic study, performed in real-life setting. Results can therefore easily be transposed to daily clinical practice.

The current study has also several limitations. The observational design of the study can be considered as a limitation, as the baseline characteristics of patients extubated in the operating room differed from those of patients extubated in the recovery room. To limit this selection bias, we performed a multivariate analysis, taking into account potential known confounders, and also performed a propensity score matching, in order to perform a randomization a posteriori and obtain comparable groups at baseline. However, we cannot eliminate the presence of residual confounding.

V. Conclusion

After abdominal surgery, extubation in the operating room was associated with fewer postextubation hypoxemia and need of rescue oxygen therapy than extubation in the recovery room, after careful adjustment, in a prospective bicenter study. Further multicenter randomized controlled trials are needed to confirm these results.

  a major issue in anesthesia, and is one of the main factors of morbidity and mortality after surgery[START_REF] Langeron | Difficult intubation and extubation in adult anaesthesia[END_REF].

Figure 1 .Figure 2 .

 12 Figure 1. Flow chart of the study

Figure 3 .

 3 Figure 3. Percentage of rescue oxygen therapy in patients extubated in the operating room and in patients extubated in the recovery room, before and after matching process.

Figure 4 .

 4 Figure 4. Time from the end of surgical procedure to extubation, exit of operating and patient able to be transferred to the ward in patients extubated in the operating room and in patients extubated in the recovery room, after matching process.

Professeurs des Universités -Praticiens Hospitaliers PU-PH de classe exceptionnelle

	IMMEDIATO DAIEN Claire	Rhumatologie
	CAMU William JACOT William	Neurologie Cancérologie ; Radiothérapie
	CAPTIER Guillaume JEZIORSKI Eric	Anatomie Pédiatrie
	CARTRON Guillaume LALLEMANT Benjamin	Hématologie ; transfusion Oto-rhino-laryngologie
	ALRIC Pierre CAYLA Guillaume LATTUCA Benoît	Chirurgie vasculaire ; médecine vasculaire (option chirurgie vasculaire) Cardiologie Cardiologie
	BACCINO Eric CHANQUES Gérard LE QUINTREC DONNETTE	Médecine légale et droit de la santé Anesthésiologie-réanimation et médecine péri-opératoire Nephrologie
	CORBEAU Pierre Moglie	Immunologie
	COULET Bertrand LETOUZEY Vincent	Chirurgie orthopédique et traumatologique Gynécologie-obstétrique ; gynécologie médicale
	CUVILLON Philippe LONJON Nicolas	Anesthésiologie-réanimation et médecine péri-opératoire Neurochirurgie
	DADURE Christophe LOPEZ CASTROMAN Jorge Psychiatrie d'Adultes ; addictologie Anesthésiologie-réanimation et médecine péri-opératoire
	DAUVILLIERS Yves LUKAS Cédric	Physiologie Rhumatologie
	DE TAYRAC Renaud MENJOT de CHAMPFLEUR. Radiologie et imagerie médicale Gynécologie-obstétrique, gynécologie médicale
	DE VOS John Nicolas	Histologie, embryologie et cytogénétique
	DEMARIA Roland MILLET Ingrid	Chirurgie thoracique et cardio-vasculaire Radiologie et imagerie médicale
	DEREURE Olivier MURA Thibault	Dermatologie -vénéréologie Biostatistiques, informatique médicale et technologies de la communication
	DROUPY Stéphane NAGOT Nicolas	Urologie Biostatistiques, informatique médicale et technologies de la communication
	DUCROS Anne OLIE Emilie	Neurologie Psychiatrie d'adultes; addictologie
	DUPEYRON Arnaud PARIS Françoise	Médecine physique et de réadaptation Biologie et médecine du développement et de la reproduction ; gynécologie médicale
	FESLER Pierre PELLESTOR Franck	Médecine interne ; gériatrie et biologie du vieillissement, médecine générale, addictologie Histologie, embryologie et cytogénétique
	GARREL Renaud POUDEROUX Philippe	Oto-rhino-laryngologie Gastroentérologie ; hépatologie ; addictologie
	GENEVIEVE David RIGAU Valérie	Génétique Anatomie et cytologie pathologiques
	GUILLAUME Sébastien RIVIER François	Psychiatrie d'adultes ; addictologie Pédiatrie
	GUIU Boris ROGER Claire	Radiologie et imagerie médicale Anesthésiologie-réanimation et médecine péri-opératoire
	HAYOT Maurice ROSSI Jean François	Physiologie Hématologie ; transfusion
	HOUEDE Nadine ROUBILLE François	Cancérologie ; radiothérapie Cardiologie
	JUNG Boris SEBBANE Mustapha	Médecine intensive-réanimation Médecine d'urgence
	KALFA Nicolas SIRVENT Nicolas	Chirurgie infantile Pédiatrie
	KLOUCHE Kada SOLASSOL Jérôme	Médecine intensive-réanimation Biologie cellulaire
	KOUYOUMDJIAN Pascal STERKERS Yvon	Chirurgie orthopédique et traumatologique Parasitologie et mycologie
	LACHAUD Laurence STOEBNER Pierre	Parasitologie et mycologie Dermato-vénéréologie
	LAVABRE-BERTRAND Thierry Histologie, embryologie et cytogénétique SULTAN Ariane Nutrition
	LAVIGNE Jean-Philippe THURET Rodolphe	Bactériologie-virologie ; hygiène hospitalière Urologie
	LE MOING Vincent TUAILLON Edouard	Maladies infectieuses ; maladies tropicales Bactériologie-virologie ; hygiène hospitalière
	LECLERCQ Florence	Cardiologie

Maitres des Conférences des Universités -Practiciens Hospitaliers MCU-PH Hors classe -Echelon Exceptionnel

	MCU-
	MARTRILLE Laurent	Médecine légale et droit de la santé
	RICHARD Bruno	Médecine palliative
	MCU-PH Hors classe
	BADIOU Stéphanie	Biochimie et biologie moléculaire
	BOULLE Nathalie	Biologie cellulaire
	CACHEUX-RATABOUL Valère Génétique
	CARRIERE Christian	Bactériologie-virologie ; hygiène hospitalière
	CHARACHON Sylvie	Bactériologie-virologie ; hygiène hospitalière
	FABBRO-PERAY Pascale	Epidémiologie, économie de la santé et prévention
	GIANSILY-BLAIZOT Muriel	Hématologie ; transfusion
	MCU-PH de 1	re classe
	BERTRAND Martin	Anatomie
	BOUDOUSQ Vincent	Biophysique et médecine nucléaire
	BRET Caroline		Hématologie biologique
	BROUILLET Sophie	Biologie et médecine du développement et de la reproduction ; gynécologie médicale
	COSSEE Mireille	Génétique
	GIRARDET-BESSIS Anne	Biochimie et biologie moléculaire
	HERRERO Astrid	Chirurgie viscérale et digestive
	LAVIGNE Géraldine	Hématologie ; transfusion
	LESAGE François-Xavier	Médecine et Santé au Travail
	MATHIEU Olivier	Pharmacologie fondamentale ; pharmacologie clinique ; addictologie
	MOUZAT Kévin		Biochimie et biologie moléculaire
	PANABIERES Catherine	Biologie cellulaire
	RAVEL Christophe	Parasitologie et mycologie
	SCHUSTER-BECK Iris	Physiologie
	THEVENIN-RENE Céline	Immunologie

PH de 2 éme classe

	BARATEAU Lucie	Physiologie
	BERGOUGNOUX Anne	Génétique
	BOETTO Julien	Neurochirurgie
	CHIRIAC Anca	Immunologie
	DE JONG Audrey	Anesthésiologie-réanimation et médecine péri-opératoire
	DESHAYES Emmanuel	Biophysique et médecine nucléaire
	DU THANH Aurélie	Dermato-vénéréologie
	FITENI Frédéric	Cancérologie ; radiothérapie
	GATINOIS Vincent	Histologie, embryologie et cytogénétique
	GOUZI Farès	Physiologie
	HERBAUX Charles	Hématologie, transfusion
	HUBERLANT Stéphanie	Gynécologie-obstétrique ; Gynécologie médicale
	LEVEQUE Maude	Parasitologie et mycologie
	MAKINSON Alain	Maladies infectieuses, Maladies tropicales
	MARIA Alexandre	Médecine interne ; gériatrie et biologie du vieillissement ; addictologie
	PANTEL Alix	Bactérologie-virologie ; hygiène hospitalière
	PERS Yves-Marie	Thérapeutique; addictologie
	ROUBILLE Camille	Médecine interne ; gériatrie et biologie du vieillissement ; addictologie
	SZABLEWSKY	Anatomie et cytologie pathologiques

Maitres de Conférences des Universités Maîtres de Conférences hors classe

		Neurosciences
	LADRET Veronique	Mathématiques appliquées et applications des mathématiques
	LAINE Sébastien	Sciences du Médicament et autres produits de santé
	LE GALLIC Lionel	Sciences du médicament et autres produits de santé
	LOZZA Catherine	Sciences physico-chimiques et technologies pharmaceutiques
	MAIMOUN Laurent	Sciences physico-chimiques et ingénierie appliquée à la santé
	MOREAUX Jérôme	Science biologiques, fondamentales et cliniques
	MORITZ-GASSER Sylvie	Neurosciences
	MOUTOT Gilles	Philosophie
	PASSERIEUX Emilie	Physiologie
	RAMIREZ Jean-Marie	Histologie
	RAYNAUD Fabrice	Sciences du Médicament et autres produits de santé
	TAULAN Magali	Biologie Cellulaire
	BERNEX Florence	Physiologie
	CHAZAL Nathalie	Biologie cellulaire

Maîtres de Conférences de classe normale

BECAMEL Carine Neurosciences CHAUMONT-DUBEL Severine Sciences du médicament et des autres produits de santé DELABY Constance Biochimie et biologie moléculaire GUGLIEMI Laurence Sciences biologiques fondamentales et cliniques HENRY Laurent Sciences biologiques fondamentales et cliniques HERBET Guillaume

Maîtres de Conférences des Universités -Médecine Générale MCU-MG de 1 re classe COSTA David OUDE ENGBERINK Agnès MCU-MG de 2 éme classe FOLCO-LOGNOS Béatrice CARBONNEL François Maîtres de Conférences associés -Médecine Générale

	PAVAGEAU Sylvain
	REBOUL Marie Catherine
	SERAYET Philippe
		Praticiens Hospitaliers Universitaires
	CAZAUBON Yoann	Pharmacologie fondamentale ; pharmacologie clinique ; addictologie
	DAGNEAUX Louis	Chirurgie orthopédique et traumatologique
	DUFLOS Claire	Biostatistiques, informatique médicale et technologies de la communication
	GOULABCHAND Radjiv	Médecine interne ; gériatrie et biologie du vieillissement ; addictologie
	MIOT Stéphanie	Médecine interne ; gériatrie et biologie du vieillissement ; addictologie
	ROCH Benoît	Pneumologie, addictologie
	SARRABAY Guillaume	Génétique
	SOUCHE François-Régis	Chirurgie viscérale et digestive
	CAMPAGNAC Jérôme
	LOPEZ Antonio
	MILLION Elodie
	MINET Mathilde

PH chargés d'enseignements

	BOBBIA Xavier	DELPONT Marion	LANG Philippe	RAFFARD Laurence
	ABOUKRAT Patrick	BRINGER-DEUTSCH Sop	DJANIKIAN Flora	LE MOINE DONY Marie-	RIDOLFO Jérôme
	BOGE Gudrun	DENIS Hélène	LAZERGES Cyril	Christine RAPIDO Francesca
	AGUILHON Sylvain BOURRAIN Jean Luc	BRINGUIER BRANCHERE DEVILLE de PERIERE Gill LE GUILLOU Cédric DONNADIEU-RIGOLE Hélène	LETERTRE Simon RIBRAULT Alice	RIPART Sylvie
	AKKARI Mohamed BOUYABRINE Hassan	BRISOT Dominique DI CASTRI Alberto	FAIDHERBE Jacques LEGLISE Marie Suzanne	LOPEZ Régis RICHAUD-MOREL Brigitte	RONGIERES Michel
	ALRIC Jérôme	BRONER Jonathan	FATTON Brigitte	LUQUIENS Amandine	ROULET Agnès
	AMEDRO Pascal	CADE Stéphane	FAUCHERRE Vincent	MANZANERA Cyril	RUBENOVITCH Josh
	AMOUROUX Cyril	CAIMMI Davide Paolo	FAURE Elsa	MARGUERITTE Emmanuel	SANTONI Fannie
	ANTOINE Valéry	CARR Julie	FILLERON Anne	MARTIN Lucille	SASSO Milène
	ARQUIZAN Caroline	CARTIER César	FILLOLS Mélanie	MATTATIA Laurent	SCHULDINER Sophie
	ATTALIN Vincent	CASPER Thierry	FITENI Frédéric	MEROUEH Fadi	SEGURET Fabienne
	AYRIGNAC Xavier	CASSINOTTO Christophe FOURNIER Philippe	MEYER Pierre	SENESSE Pierre
	BADR Maliha	CATHALA Philippe	GAILLARD Nicolas	MICHEL Moïse	SERRE Jean-Emmanuel
	BAIS Céline	CAZABAN Michel	GALMICHE Sophie	MILESI Christophe	SKALLI El Medhi
	BARBAR Saber Davide	CHARBIT Jonathan	GENY Christian	MORAU Estelle	SOLA Christelle
	BASSET Didier	CHEVALLIER Thierry	GERONIMI Laetitia	MORQUIN David	SOULLIER Camille
	BATIFOL Dominique	CHEVALLIER-MICHAUD J GINIES Patrick	MOSER Camille	SOUKSI MEDIONI Isabelle
	BATTISTELLA Pascal	COLIN Olivier	GRECO Frédéric	MOUSTY Eve	STOEBNER DELBARRE Anne
	BAUCHET Luc	CONEJERO Ismael	GUEDJ Anne Marie	MOUTERDE Gaël	TEOT Luc
	BELL Ariane	CONSEIL Mathieu	GROSSIN Delphine	PANSARD Nicole	THIRION Marina
	BENEZECH Jean-Pierre	CORBEAU Catherine	GUYON Gaël	PERNIN Vincent	TUNEZ Virginie
	BENNYS Karim	COROIAN Flavia-Oana HEDON Christophe	PERRIGAULT Pierre François VACHIERY-LAHAYE Florence
	BERNARD Nathalie	COUDRAY Sarah	HENRY Vincent	PEYRON Pierre-Antoine	VERNES Eric
	BERTCHANSKY Ivan	CRANSAC Fréderic	JAMMET Patrick	PICARD Eric	VIALA Maurice
	BIBOULET Philippe	CUNTZ Danielle	JEDRYKA François	PICOT Marie Christine	VINCENT Laure
	BIRON-ANDREANI Christine DARDALHON Brigitte	JREIGE Riad	PIERONI Laurence	WAGNER Laurent
	BLANC Brigitte	DAVID Aurore	KINNE Mélanie	POQUET Hélène	WALTHER LOUVIER Ulrike
	BLANCHARD Sylvie	DE BOUTRAY Marie	LABARIAS Coralie	PUJOL Sarah-Lise	ZERKOWSKI Laetitia
	BLANCHET Catherine	DE LA TRIBONNIÈRE Xav LABORDE Caroline	PUPIER Florence
	BLATIERE Véronique	DEBIEN Blaise	LACAMBRE Mathieu	QUANTIN Xavier

Abstract

Introduction : Airway control and especially extubation are important issues after surgery.

Abdominal surgery is at risk of atelectases and postoperative hypoxemia. The recent COVID-19 pandemic has led some institutions to change their practice, by favoring extubation in the operating room instead of in the recovery room. However, to date no study has compared the rate of complications of extubation according to the place of extubation after abdominal surgery.

The main hypothesis of this study was that the rate of post-extubation hypoxemia would be decreased after extubation in the operating room when compared with extubation in the recovery room, after abdominal surgery.

Methods : In this prospective observational study, patients were included after abdominal surgery in the University Hospitals of Montpellier and Clermont-Ferrand. The primary endpoint was immediate post-extubation hypoxemia, defined as a peripheral oxygen saturation (SpO2)<96%. Secondary endpoints included time from the end of the surgical procedure to patient able to be transferred to the ward. Patients extubated in the operating room were compared with patients extubated in the recovery room, before and after matching using a propensity score. Results : A total of 586 patients were included and analyzed. After extubation in the operating room, 52/344 patients (15%) experienced post-extubation hypoxemia, when compared with 64/214 patients (30%) after extubation in the recovery room (p<0.001, odds ratio OR 0.42 95%confidence interval(CI) 0.28-0.63)). After matching, the rate of post-extubation hypoxemia was still lower in the operating room group (28/170 (16%)) when compared with recovery room (55/171 (32%), p<0.001, OR 0.42 95%CI (0.25-0.70). Before and after matching, time from the end of the surgical procedure to patient able to be transferred to the ward was significantly lower in patients extubated in the operating room when compared with patients extubated in the recovery room.

Conclusion: After abdominal surgery, extubation in the operating room was associated with fewer post-extubation hypoxemia than extubation in the recovery room, after careful adjustment.

Tables & Figures


I Buttinoni

L Caprini

L Alvarez

F J Schwarzendahl

H Löwen

Active colloids in harmonic optical potentials (a)

We study the motion of active Janus colloids in an optical trap using experiments, theory and numerical simulations. To achieve isotropic and harmonic confinement, we prototype microparticles with a nearly uniform refractive index and verify that, in the absence of activity, the confined motion is identical to that of optically homogeneous Brownian particles. If the activity is turned on by means of vertical AC fields, the density distributions are described by Boltzmann-like statistics (Gaussian with effective temperature) only for strongly confining traps, whereas weaker potentials give rise to non-Gaussian distributions with a bimodal shape. Our results showcase a simple way to study active soft matter in optical potential landscapes eliminating the optical torque.

Optical tweezers, i.e., tightly focused laser beams, are widely used in soft condensed matter to confine and manipulate micro-and nanospheres that have a refractive index larger than the one of the surrounding medium [1][START_REF] Jones | Optical Tweezers: Principles and Applications[END_REF][START_REF] Gieseler | [END_REF]. Their success is partly due to the fact that, in a very good approximation, the sum of the forces exerted by the trap in the focal plane normal to the beam's propagation gives rise to a harmonic potential well. Because the confining forces behave as springs of stiffness k, the equilibrium spatial probability distribution of a trapped particle is a Gaussian curve centred around the midpoint, and any external force F can be quantified from the average displacement of the particle from the trap's centre. This simple behaviour prompted a plethora of fundamental and applied studies (a) Contribution to the Focus Issue Statistical Physics of Self-Propelled Colloids edited by Hartmut Löwen, Sabine Klapp and Holger Stark.

(b) E-mail: Ivo.Buttinoni@hhu.de (corresponding author) (c) E-mail: lorenzo.caprini@hhu.de including the measurement of interaction forces with sub-piconewton accuracy (photonicforcesmicroscopic) [4][5][6][7][8][9], the investigation of resonance and stochastic phenomena [10][11][12][13][14], and the development of microscopic heat engines [15,16] and information machines [17]. The harmonic approximation is valid so long as the trapped object is homogenous in shape and composition [START_REF] Jones | Optical Tweezers: Principles and Applications[END_REF]18] -a condition that does not usually apply to microswimmers since symmetry breaking is a key ingredient to achieving locomotion at the micro-and nanoscale [19]. Synthetic active colloids, i.e., microparticles that undergo self-propulsion rather than being in thermal equilibrium with the fluid [20], are often fabricated by depositing onto one hemisphere of bare polymer or silica particles a second material (e.g., a layer of metal). The "cap" interacts with the surrounding liquid to generate local slip flows, and thus self-propulsion [21], but at the same time introduces refractive-index mismatches so that, in combination with optical tweezers, the particles can no longer be assumed as confined in a spring-like potential [22][23][24][25]. Because of this, the state of the art of light fields applied to active colloids is, so far, mostly limited to optical landscapes that reorient the particles or tune their velocities [26][27][28][29], but do not provide a confining harmonic potential (except for the experiments in ref. [30], done with nanoparticles). In contrast, the latter situation has been studied theoretically [31][32][33][34][35][36], in granular active systems [37] and in acoustic confinements [38].

In this work, we fabricate Janus colloidal particles with a nearly homogeneous refractive index, confine them in a tightly focused laser beam, and activate them by means of AC electric fields applied in the direction perpendicular to the plane of motion. We demonstrate that, despite the asymmetric material composition of the particles, the optical trap is harmonic. Within a range of swimming velocities and laser intensities, the active motion in the optical tweezer agrees well with theoretical predictions and numerical simulations of active Brownian particles in harmonic wells, showing non-Boltzmann properties.

The remainder of the manuscript is structured as follows. As a preliminary study, firstly, we consider the active motion of optically homogenous -yet Janus-particles without confinements (swimming velocity V 0 > 0, trap's stiffness k = 0). Secondly, we introduce and characterise the confinement, considering optically trapped particles that are "passive", i.e., there without activity (V 0 = 0, k > 0). Finally, we focus on active Brownian particles in optical traps (V 0 > 0, k > 0), interpreting the main result in a final discussion.

Unconfined active colloids (V 0 > 0, k = 0). -We prepare Janus colloids by coating one hemisphere of polymethyl methacrylate PMMA microparticles (radius R 1 μm, refractive index n PMMA =1.48, Microparticles GmbH) with a thin layer of silicon dioxide (SiO 2 , thickness λ = 10 nm, n SiO2 =1.46-1.48 [39,40]) using a magnetron sputter coater (PVD Inc.). A scanning electron microscope (SEM) snapshot of the resulting Janus particle is shown in the inset of fig. 1(a) (note that the "wrinkles" are due to partial buckling of PMMA in high vacuum, i.e., during SiO 2 deposition). The PMMA-SiO 2 colloidal particles are dispersed in deionised water and pipetted in a thin sample cell (thickness 120 μm) made of two planar negatively charged electrodes (indium tin oxide coated glasses functionalised with poly-sodium-4-styrenesulfonate, surface resistivity 8-12 Ω/sq, Merck KGaA). We apply vertical AC electric fields at frequency f = 4 kHz and use an inverted light microscope (Olympus IX73) to look at the two-dimensional motion of the particles onto the bottom electrode, where they sink due to gravity.

The PMMA-SiO 2 microspheres are active because of induced-charge electro-osmosis (ICEO, see the sketch in fig. 1(a)). The electric field, E, applied in the vertical direction sets in motion the electrical double layer of the substrate, polarises the particle and, ultimately, produces recirculating hydrodynamic flows [41]. If the particle is Janus, the magnitude (or even the direction) of the rolls near the two faces is different, causing net motion of the particles in the plane parallel to the electrode. This type of self-propulsion was demonstrated for both hybrid dimers [42][43][44] and Janus colloids [45] swimming onto conductive surfaces; remarkably, it does not require a metallic coating, in contrast to other self-propulsion mechanisms such as induced-charge electrophoresis (ICEP) [46]. Figure 1(b) shows a typical active trajectory; the PMMA-SiO 2 particle swims at constant velocity V 0 along the axis linking the poles of the two hemispheres and reorients according to its rotational diffusion time τ

R = D -1 R = (8πηR 3 )/(k B T) (fig. 1(c), horizontal line)
, where η is the water viscosity and k B T is the thermal energy at room temperature. Despite the fact that our spherical colloidal particles obey the Stokes-Einstein relation in three dimensions, rotational diffusion takes place only in 2D [45,46], leading to a fully two-dimensional active motion just above the bottom electrode (fig. 1(b)). τ R and V 0 are extracted by fitting the mean squared displacement (MSD) [20]; τ R does not depend on the activity, V 0 (fig. 1(c)), whereas V 0 increases linearly with the electric field squared, E 2 (fig. 1(d)) [42,43]. Due to the lack of optical contrast between the two hemispheres, which is paramount for optical tweezing, we are unable to resolve the local orientation. Nonetheless we speculate that the particles swim with the SiO 2 hemisphere heading, in analogy with polystyrenesilica dumbbells [43].

Confined passive colloids (V 0 = 0, k > 0). -We now consider the scenario in which the Janus particles are not active (E = 0, V 0 = 0) and confine them in two-dimensional optical trap, imposed by a focused laser beam propagating from above (wavelength, λ = 532 nm, note that out-of-plane motion due to optical scattering force is hindered by the underlying surface). We measure their MSD (fig. 2(a), orange curve) and spatial probability distribution (p(x), fig. 2(d)), and compare them to those of homogeneous (see blue data in fig. 2(a) and fig. 2(b)) and Pt-coated (see red data in fig. 2(a) and fig. 2(c)) SiO 2 colloids of similar size. The latter particle is chosen as model common synthetic microswimmer since the majority of active microspheres available to date are equipped with metallic caps. Notwithstanding, note that in this section none of the particles are active.

The dynamics of an optically homogeneous microsphere in an optical trap centred on the origin is described by a simple overdamped (diffusive) equation of motion in two dimensions for the particle position x,

γ ẋ = F(x) + γ √ 2DW, ( 1
)
where W is δ-correlated white noise with unit variance and zero average. The constants γ = 6πηR and D = K B T /γ are the friction and diffusion coefficients, respectively. The term F(x) describes the confinement force due to the optical trap; in first approximation, it can be recast onto a linear force,

F(x) ≈ -kx, ( 2
)
where k is the trap's stiffness (or spring constant) which determines the curvature of the harmonic potential. As a result, the density distribution projected onto the xaxis, p(x), is described by a Gaussian curve of variance

σ 2 = (k B T ) /k (black lines in figs. 2(b)-(d)
-we use this formula to calibrate experimentally the optical traps) and the MSD for the x-coordinates has the following form:

MSD(t) = 2 k B T k 1 -e -k γ t . (3)
It is diffusive for t → 0 and reaches a plateau at 2k B T /k when t γ/k, as usual for passive Brownian particles. Note, however, that the optical trap has a finite size and the harmonic approximation breaks down at the boundary where the shape of potential bends to a maximum.

The dynamics described above is observed for both bare SiO 2 colloids (blue data in fig. 2 and supplementary video Video S1.mp4 (S1)) and PMMA-SiO 2 Janus microspheres (orange data in fig. 2 and supplementary video Video S2.mp4 (S2)). In contrast, microparticles with metallic caps behave differently (supplementary video Video S3.mp4 (S3)): the red data in fig. 2 indicate that at short timescales (up to t ≈ 1 s) the motion of Pt-SiO 2 colloids in the trap is superdiffusive, possibly due to additional optical "kicks" as well as self-thermophoretic effects similar to those observed in ref. [25]. As such, the corresponding Gaussian density distribution (fig. 2(c)) has a width that is remarkably larger than what is expected in a harmonic confinement of curvature k, consequently departing from a Boltzmann distribution (even if Gaussian). Before saturation, the MSD of Pt-SiO 2 particles also exhibits a clear oscillatory behaviour (fig. 2, red data for t > 1 s). These oscillations confirm the presence of optical torques, stemming from the fact that the optical gradient force acts more on the Pt cap than the uncoated hemisphere [22][23][24][25].

A comprehensive study of the motion of optically inhomogeneous particles in laser traps is beyond the scope of this manuscript because it involves effects we want to avoid. Nonetheless, we expect that the behaviour shown by the red data in fig. 2 affects all active systems where self-propulsion is achieved by breaking the symmetric optical composition of the particles. This is not the case of PMMA-SiO 2 colloids, which are optically identical to their homogeneous counterparts; they are therefore a suitable choice to study active motion in combination with harmonic optical potentials.

Confined active colloids (V 0 > 0, k > 0). -Confined active Brownian particles display different properties with respect to their "passive" counterparts. While the dynamics of a "passive" colloid in a harmonic trap is fully determined by the competition between thermal fluctuations and the confining force (see eq. ( 1)), active microbeads have an additional effective swimming (selfpropulsion) force of magnitude F S = 6πηRV 0 . If the force due to activity is smaller than the confining force, the swimmer remains confined in the harmonic potential; otherwise, the optical trap is too weak to hold back the active colloid, which will escape when F S exceeds the optical force exerted on the particles at the boundary, where the optical potential reaches a maximum. This behaviour is illustrated in the supplementary videos Video S4.mp4 (S4) and Video S5.mp4 (S5). In S4, a colloid swimming at V 0 = 1.7 μm/s (E = 40 V/mm) is confined in an optical trap of stiffness k = 0.085 pN/μm. Assuming a displacement x = 1 μm (along the x-direction) with respect to the trap's centre, the optical restoring force, F(x) = -kx = -85 fN, is approximately twice the effective swimming force. The particle immediately leaves the trap if the laser is turned off (video S4) or the selfpropulsion velocity is increased in situ to V 0 = 5 μm/s (E = 66 V/mm, F S = 100 fN, video S5), while keeping the stiffness of the laser trap constant.

We consider the case of fully trapped active particles and model their dynamics through a popular model in the field of active matter, known as active Brownian particles (ABP) [47][48][49][50][51][52]. The position of the colloid, x, is described by an overdamped equation of motion in two dimensions,

γ ẋ = γ √ 2DW + F(x) + γV 0 n, (4)
which resembles eq. ( 1) except for the additional force, γV 0 n, accounting for the self-propulsion mechanism. The swim velocity, V 0 , is directed onto the orientational vector n = (cosθ, sinθ), where θ corresponds to the orientational angle of the active particle. According to the ABP model,

θ evolves as θ = 2 τ R ξ, ( 5
)
where ξ is another Gaussian random variable with zero mean and unit variance, statistically independent of W.

We identify two dimensionless parameters that control the dynamics in the harmonic confinement: the first can be interpreted as a reduced spring constant k = τ R k/γ, given by the ratio between the rotational diffusion time and the time due to the external optical force; the second corresponds to a reduced swim velocity, V 0 = V 0 τ R /D, which quantifies the strength of active and passive fluctuations (note that V 2 0 τ R is the diffusion of potential-free active particles). In practice, k and V 0 are experimentally modified through k (i.e., by tuning the laser power) and V 0 (i.e., by tuning the electric field), as τ R , γ and D are constant.

Following ref. [31] (see also sect. 4 of ref. [53]), we can also obtain an analytical approximation for the radial density distribution ρ(r), holding for k 1 (experimentally satisfied for all the values of k) and for self-propulsion velocities that are large enough (so that V 0 1):

ρ(r) ∼ r 1/2 exp - 1 2D k+ 1 2τ R r- V 0 k + (2τ R ) -1 2 . (6)
The integration of eq. ( 6) over one of the two Cartesian components provides a prediction for p(x) (a simple explicit expression for this integral is unknown in the literature to the best of our knowledge).

In fig. 3, we investigate the reduced distribution in Cartesian coordinates projected onto the x-axis, p(x), and the radial distribution, ρ(r), for different values of k and V 0 . The histograms are experimental data, whereas the solid lines correspond to numerical or theoretical predictions. When applicable, the analytical result of eq. ( 6) is used and marked in red to distinguish it from ABP simulations. Curves from simulations (black) are consistent with the theoretical predictions (red). Grey panels are inserted in correspondence of the values of k and V 0 for which the active particles escape the harmonic trap. The shape of p(x) reveals a transition from a unimodal (Gaussian) to a bimodal (non-Gaussian) distribution, when the reduced swim velocity V 0 increases (faster particles) at fixed k (see fig. 3(h) → (e) and (c) → (a)), or when k is decreased (weaker traps) at fixed V 0 (see fig. 3(a) → (b);(c) → (d) and (e) → (f)). In correspondence with this transition, the peak of ρ(r) shifts towards a larger value of r compared to the Gaussian cases, and even much larger as V 0 is increased (fig. 3(k),(m),(o)). In the bimodal regime (fig. 3(a), (c), (e)), p(x) shows two symmetric peaks far from the minimum of the potential trap, where p(x) is depleted: an active particle persistently moves against the potential force (i.e., it climbs up the potential barrier) until its self-propulsion is balanced by the optical force.

Equation ( 6) reflects the bimodality of the density distribution, shown in simulations of ABP confined in a harmonic trap [32,[54][55][56][57][58], and provides a distinct (and needed) feature compared to the results obtained through other popular models in active matter [33,[59][60][61][62]. As shown in fig. 3(k),(m) and (o), formula (6) is also in good agreement with experiments: the expression for ρ(r) (red curve) is roughly centred around

V 0 /[k/γ + 1/(2τ R )] ∼ V 0 γ/k (for kτ R /γ
1) and accounts for the shift of the main peak observed in fig. 3. Remarkably, the best Gaussian fits reported in the same panels (dashed blue lines) confirm the non-Gaussian effects occurring in ρ(r). A fair agreement between theory and experiments (less good than for ρ(r) because of worse statistics) is also obtained for p(x), where the bimodality and the positions of the peaks are correctly predicted by the integral form of eq. ( 6). In the Gaussian cases (all the other panels in fig. 3), experiments are reproduced through numerical simulations of the dynamics (eq. ( 4)).

Discussion. -We investigated active colloids that break symmetry to achieve self-propulsion, while conserving the uniform optical properties needed to confine them in harmonic laser potentials. After verifying independently that the Janus microspheres 1) undergo free active Brownian motion in the absence of confinements and 2) are laser-tweezed just as homogenous colloids in the absence of activity, we studied the active motion in harmonic traps as a function of the curvature of the optical potential, k, and swimming velocity, V 0 . The histograms and solid lines are obtained from experiments (each trajectory is measured for approximately 10 minutes) and theoretical predictions (or simulations), respectively. In particular, the red lines in panels (a), (c) and (e) are calculated from eq. ( 6), while the red lines in panels (k), (m) and (o) are obtained by integrating eq. ( 6) along one of the two spatial coordinates. The dashed blue lines in panels (k), (m), (o) are the results of best (radial) Gaussian fits, f (r) = b r exp -ar 2 where a and b are two fitting parameters. Finally, the solid black curves have been obtained through numerical simulations of the dynamics (eq. ( 4)).

The active dynamics in the trap strongly differs from the one of "passive" Brownian colloids; the Gaussian behaviour breaks down when the swimmers are fast or when the harmonic potential is weak. Nonetheless, a remarkable observation is that the Boltzmann-like statistics (Gaussian with effective temperature) is retained in strongly confining potential wells. At first glance, our result qualitatively disagrees with ref. [38], where Janus particles (platinum/polystyrene), swimming in hydrogen peroxide solution and harmonically confined in acoustic traps, show non-Boltzmann distributions for stiff traps (large values of k) and Gaussian distributions for weak traps (small values of k). In ref. [38], the transition is induced by the increase of the reduced spring constant, k (in particular, when k crosses one), interpreted in terms of the competition between persistence length, V 0 τ R , and the effective width of the potential, V 0 k/γ. On the contrary, our study focuses on the regime k 1 for all the values of the trap stiffness considered. In this regime, the transition (Gaussian → non-Gaussian shape of p(x)) is induced by the increase of the reduced swim velocity, V 0 , and the decrease of the potential stiffness, k . This occurs because stronger traps reduce the ability of active particles to climb up the potential barrier so that they are only responsible for a reduction of the variance of p(x) without affecting its Gaussian shape (see fig. 3(g) → (f); (j) → (i) → (h)). This effect is qualitatively in agreement with our intuition coming from the passive scenario. However, unlike the case of passive particles, the variance of p(x) does not scale as ∼ 1/k (not shown). This observation implies the occurrence of non-Boltzmann distributions also in the regime of parameters where p(x) is characterised by a Gaussian shape. Similarly, the increase of V 0 (for low V 0 and large values of k ) leads to the variance increase of the distribution, showing a phenomenology qualitatively consistent with the increase of the effective active temperature (see fig. 3(i) → (f); (j) → (g) → (d)). Moreover, its dependence on the model parameters goes beyond the simple scaling ∼ V 2 0 /D R (not shown), i.e., the effective diffusion typical of an unconfined active particle. The breaking of these scalings of the variance (∼ 1/k and ∼ V 2 0 τ R ) occurs because the system is far from the equilibrium for all the combinations of parameters of k and V 0 experimentally investigated.

Finally, we highlight the advantages of our experimental system. Firstly, the confining and swimming force (F = -kx and F S = γV 0 n) have similar magnitude and can be both tuned in situ -by changing the laser power and the strength of the AC electric field, respectively-to optically trap or release on demand the microswimmers. Secondly, the optical traps have a size comparable to the particle's diameter, as opposed to existing experimental works of active colloids in harmonic wells [37,38], where the confinements are much larger. Lastly, unlike many experiments in which active particles are used in combination with laser fields [26][27][28], here the optical beam does not alter the self-propulsion mechanism, but only provides a confining potential. All in all, these features are paramount to confine two particles in distinct traps and measure the pair interaction as a function of the relative distance, or study active Brownian motion in complex potential landscapes (e.g., periodic or random substrate potentials, time-modulated traps, etc.).

Fig. 1 :

 1 Fig. 1: Unconfined active colloids. (a) Schematic illustration of self-propulsion due to induced-charge electroosmotic flows (ICEO) under AC electric fields applied in the vertical direction. Inset: scanning electron microscopy image of a PMMA-SiO2 colloidal particle. (b) Two-dimensional trajectory of a PMMA-SiO2 particle swimming just above the bottom electrode (E = 66 V/mm). (c) Characteristic reorientation time, τR, in the 2D plane of motion as a function of the swimming velocity, V0. (d) V0 plotted against the electric field squared. The line is a linear fit. In (c) and (d) each data point is an average of 15-20 particles.

Fig. 2 :

 2 Fig. 2: Confined passive colloids. (a) MSD of colloidal particles (see legend) in an optical trap of stiffness k = 0.18 pN/μm. (b)-(d) Corresponding density distributions evaluated for approximately N = 10 4 coordinates. The histograms are normalized: the number of elements in the bin is divided by the number of elements in the input data. The solid black lines represent the Gaussian distributions expected in a harmonic confinement of curvature k, as described in the main text.

Fig. 3 :

 3 Fig. 3: Confined active colloids. (a)-(j) Normalized density distribution p(x) (along a single axis x) and (k)-(t) radial density distribution ρ(r) (along the radial axis r) for different values of reduced potential strength k = τRk/γ and reduced swim velocity V 0 = V0 τR/D. The grey panels (top, left) are drawn for the regimes of parameters where active particles escape from the trap. The two red solid lines between panels qualitatively mark the transition between bimodal and unimodal p(x).The histograms and solid lines are obtained from experiments (each trajectory is measured for approximately 10 minutes) and theoretical predictions (or simulations), respectively. In particular, the red lines in panels (a), (c) and (e) are calculated from eq. (6), while the red lines in panels (k), (m) and (o) are obtained by integrating eq. (6) along one of the two spatial coordinates. The dashed blue lines in panels (k), (m), (o) are the results of best (radial) Gaussian fits, f (r) = b r exp -ar 2 where a and b are two fitting parameters. Finally, the solid black curves have been obtained through numerical simulations of the dynamics (eq. (4)).

We thank Stefan Egelhaaf for access to his opticaltweezing setup, which has been used for some experiments presented in this manuscript. LC acknowledges support from the Alexander Von Humboldt foundation. LA acknowledges financial support from the Swiss National Foundation (SNF) Spark grant, No. 172913, and is grateful to Jose-Luis Pujol for assistance with the deposition of silicon dioxide.

Data availability statement: The data that support the findings of this study are available upon reasonable request from the authors.