MD Bastien Genet
email: bastien.genet@aphp.fr

MD Tina Lamy

MD Judith Cohen-Bittan

MD Pauline Glasman

MD Marc Verny

MD Bruno Riou

MD Jacques Boddaert

MD Lorène Zerah

Lack of association between perioperative medication and postoperative delirium in hip fracture patients in an orthogeriatric care pathway Running title: Perioperative drugs and postoperative delirium

Keywords: postoperative delirium, hip surgery, perioperative drugs, orthogeriatric care, older person

depression, etc).

INTRODUCTION

In older people, a common but avoidable complication in the first postoperative days after hip fracture surgery is postoperative delirium, characterized by an acute onset and fluctuating course of inattention and either disorganized thinking or altered level of consciousness. A specialized geriatric intervention can lead to a 30% reduction in risk of postoperative delirium [START_REF] Aldecoa | European Society of Anaesthesiology evidencebased and consensus-based guideline on postoperative delirium[END_REF][START_REF] Inouye | Delirium in elderly people[END_REF][START_REF] Mohanty | Optimal perioperative management of the geriatric patient: a best practices guideline from the American College of Surgeons NSQIP and the American Geriatrics Society[END_REF][START_REF] Silva | Estimates of geriatric delirium frequency in noncardiac surgeries and its evaluation across the years: a systematic review and metaanalysis[END_REF] . Postoperative delirium, which is distressing to patients, family members and clinicians, is associated with poor cognitive and functional recovery, increased use of health care resources, and increased mortality [START_REF] Aldecoa | European Society of Anaesthesiology evidencebased and consensus-based guideline on postoperative delirium[END_REF][START_REF]American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. Postoperative delirium in older adults: best practice statement from the American Geriatrics Society[END_REF] . The UK National Institute for Health and Care Excellence, American Geriatric Society, American College of Surgeons, and American Society of Anesthesiologists have all identified the prevention of postoperative delirium as a public health priority [START_REF] Aldecoa | European Society of Anaesthesiology evidencebased and consensus-based guideline on postoperative delirium[END_REF][START_REF] Mohanty | Optimal perioperative management of the geriatric patient: a best practices guideline from the American College of Surgeons NSQIP and the American Geriatrics Society[END_REF][START_REF]American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. Postoperative delirium in older adults: best practice statement from the American Geriatrics Society[END_REF] .

Risk factors for postoperative delirium can be classified by the timing of their occurrence, as pre-, intra-, and postoperative [START_REF] Aldecoa | European Society of Anaesthesiology evidencebased and consensus-based guideline on postoperative delirium[END_REF] . Advanced age, preoperative cognitive impairment and comorbidities are the most frequent preoperative recognized risk factors [START_REF] Aldecoa | European Society of Anaesthesiology evidencebased and consensus-based guideline on postoperative delirium[END_REF][START_REF] Inouye | Delirium in elderly people[END_REF][START_REF] Mohanty | Optimal perioperative management of the geriatric patient: a best practices guideline from the American College of Surgeons NSQIP and the American Geriatrics Society[END_REF][START_REF]American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. Postoperative delirium in older adults: best practice statement from the American Geriatrics Society[END_REF][START_REF] Smith | Factors predicting incidence of post-operative delirium in older people following hip fracture surgery: a systematic review and meta-analysis[END_REF][START_REF] Dasgupta | Preoperative risk assessment for delirium after noncardiac surgery: a systematic review[END_REF] .

Postoperative risk factors include severe pain, chronic administration of benzodiazepine (or benzodiazepine withdrawal) and anticholinergic drugs, and several postoperative complications (i.e., atrial fibrillation, infectious diseases, and urinary retention) [START_REF] Aldecoa | European Society of Anaesthesiology evidencebased and consensus-based guideline on postoperative delirium[END_REF][START_REF]American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. Postoperative delirium in older adults: best practice statement from the American Geriatrics Society[END_REF] . Intraoperative risk factors are debated; whether different regimens of anesthesia may affect postoperative delirium occurrence is unclear [START_REF] Aldecoa | European Society of Anaesthesiology evidencebased and consensus-based guideline on postoperative delirium[END_REF] . Beyond anesthesia, all therapeutics received pre-and postoperatively may represent additional postoperative delirium risk factors. Because dedicated orthogeriatric care pathways, including units for perioperative geriatric care, are playing a growing role for patients with hip fracture, one cannot consider postoperative delirium occurrence restricted to geriatric factors without considering management in other settings. However, to the best of our knowledge, no study has assessed the impact of all drugs used before, during, and after hip fracture surgery on postoperative delirium occurrence.

Our main objective was to assess the association between all drugs used in emergency, operating, and recovery departments in older people with hip fracture and the occurrence of inhospital postoperative delirium during the acute stay in an unit for perioperative geriatric.

METHODS

The database was declared to the French National Commission on Computing and Liberty (CNIL) of the Assistance Publique-Hôpitaux de Paris (APHP) for this study (no.

20190822165316

). This report follows the STROBE recommendations [START_REF] Von Elm | The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies[END_REF] .

Study design, study setting and eligibility criteria

A retrospective cohort study was conducted in the unit for perioperative geriatric care of an academic hospital. The unit for perioperative geriatric care is part of a dedicated orthogeriatric care pathway including coordination between the department of emergency medicine and surgery, department of anesthesiology and critical care, department of orthopaedic surgery and the department of rehabilitation. This dedicated orthogeriatric care pathway is defined as 1) early alert from the emergency department (ED), 2) considering hip fracture as requiring surgery as soon as feasible (i.e., 24 hr/day), 3) rapid transfer to the unit for perioperative geriatric care after surgery, and 4) rapid transfer of stable patients to a dedicated rehabilitation unit [START_REF] Boddaert | Perioperative management of elderly patients with hip fracture[END_REF]10 .

The management strategy in this unit for perioperative geriatric care, previously described 10 , focused on early mobilization with the aim of chair-sitting and walking within 24 and 48 hours after arrival respectively, pain management, the provision of air-filled mattresses for patients with pressure sores or a high risk of pressure sores, swallowing disorders detected using a systematic medical survey, detection of stool impaction and urinary retention using bedside ultrasound, correction of anemia with transfusion of packed red blood cells (usually when the hemoglobin level was <8 g.L -1 ), detection of delirium and malnutrition.

From July 2009 to December 2019, all consecutive patients with hip fracture admitted to the unit for perioperative geriatric care were evaluated for eligibility. Patients were included if they were ≥70 years old and their primary presentation was due to hip fracture (first hospitalization after surgery in the unit for perioperative geriatric care). We excluded patients with multiple or metastatic or periprosthetic fractures, patients with missing data (missing anesthesia records, missing data from the ED), patients with surgery under exclusive locoregional anesthesia, and patients with delirium before surgery (in the ED). We excluded patients whose admission to the unit for perioperative geriatric care was > 24 hr after the operating room (due to in-hospital organizational reasons) because we could not to retrieve information about all the treatments they had received in orthopedics. Patients were followed until death or the end of hospitalization in the unit for perioperative geriatric care. Some patients had been included in previous studies [10][11][12][13][14][15][16][17] .F Outcomes Our main outcome measure was the occurrence of in-hospital postoperative delirium during the acute stay in the unit for perioperative geriatric care, identified by using the confusion assessment method scale [START_REF] Inouye | Delirium in elderly people[END_REF] , assessed on arrival in the unit for perioperative geriatric care and then once a day consistently by one of 2 physicians (JCB, JB). To prevent and manage the postoperative delirium occurrence, we used the recommendations proposed by Inouye et al.

(non-pharmacological and pharmacological acute treatment strategies) [START_REF] Inouye | Delirium in elderly people[END_REF] .

Data collection methods

Since the opening of unit for perioperative geriatric care in 2009, we have created a dedicated research database that is prospectively supplemented by 3 senior geriatricians (J.B., J.C.B., L.Z.), experts in orthogeriatric, and that integrates all the data from the orthogeriatric care pathway for each patient.

The following variables were collected prospectively by interviewing patients, their family members or their physicians and pharmacists during the hospital stay and were defined as baseline characteristics before hip fracture: age, sex, home or nursing home living conditions, walking ability, previous medical history including cognitive status and depression (with or without antidepressants), chronic medications, and type of fracture (radiological definition by an orthopedic surgeon). Co-morbidity severity was assessed with the Cumulative Illness Rating Scale [START_REF] Linn | Cumulative illness rating scale[END_REF] , because all comorbidity scores are equivalent in predicting mortality in this population 13 . Functional status was evaluated with an activities of daily living scale [START_REF] Katz | Index of ADL[END_REF] . Obesity was defined as body mass index > 30 kg.m 2 , repeated falls as ≥ 2 falls in the previous year, chronic renal failure as Cockcroft creatinine clearance < 60 ml/min, and anemia as haemoglobin level < 12 g.dL -1 for women and 13 g.dL -1 for men.

During the perioperative period, we prospectively recorded the surgical treatment, the delay and duration of surgery, and the anesthetic drugs used. All drugs and transfusions administered from the ED to the unit for perioperative geriatric care were recorded, including those administered in the operating room and recovery room.

After surgery, delays to first sitting and first walking, destination at discharge of unit for perioperative geriatric care (home or rehabilitation) and length of stay in acute care were recorded. All postoperative complications during the acute care period were prospectively recorded.

Delirium in the ED was the only variable that was classified retrospectively, before any statistical analysis (exclusion criteria). It was adjudicated by 2 geriatricians (BG, LZ) who independently reviewed medical charts (К = 0.88, 95% CI [0.70 to 0.99]). In case of disagreement, consensus was reached with a third independent senior expert (JB).

Statistical considerations

The statistical plan of the study was established before the statistical analysis. Because the database was prospectively supplemented, all authors were "blinded" to the research question at the time of data collection. The study is based on all available patients during the study period, and thus no a priori power calculation was conducted. Data are presented as mean Logistic regression analysis was used to assess variables independently associated with in-hospital postoperative delirium during the acute stay, and adjusted odds ratios (OR) with 95% confidence intervals (CIs) were calculated. To avoid overestimation, a conservative approach was used: [START_REF] Sun | Inappropriate use of bivariable analysis to screen risk factors for use in multivariable analysis[END_REF][START_REF] Harrell | Regression models for prognostic prediction: advantages, problems, and suggested solutions[END_REF] all variables with P <.20 on univariate analyses and all clinically relevant variables were included [START_REF] Aldecoa | European Society of Anaesthesiology evidencebased and consensus-based guideline on postoperative delirium[END_REF] . Correlation between continuous variables was considered significant with Spearman correlation coefficient >.50. The choice between 2 correlated variables was based on their respective clinical relevance.

We assessed missing data and their distribution between the 2 groups (with and without postoperative delirium). Because missing values represented < 3% of the data and were balanced between the 2 groups, no specific treatment strategy was necessary.

Statistical analyses were performed with R v4.0.0. All p-values were two-tailed and p ≤ .05 was considered statistically significant.

RESULTS

Demographic data and patients baseline characteristics of patients

We included 490 patients (Figure ); 215 (44%) had postoperative delirium (Table 1).

Patients excluded (N = 775, 61%) had similar characteristics (demographics, comorbidities, inhospital mortality, postoperative complications including delirium) as patients included (Appendix 1).

Baseline characteristics are reported in Table 1. The mean (SD) age was 87 (6) years, 383 (78%) patients were female; the median Cumulative Illness Rating Scale score was 9 [IQR 6-12], median number of drugs per day was 5 [3-8], and 15% were living in a nursing home before the hip fracture. Patients with postoperative delirium were older, had more comorbidities (especially dementia), were less autonomous and more frequently lived in a nursing home than patients without postoperative delirium. They were more likely to use neurological medication, beta-blockers and angiotensin-converting enzyme-angiotensin II receptor blockers before surgery than patients without postoperative delirium (Table 1).

Patients with and without postoperative delirium did not differ in type of hip fracture or surgery. The median time to surgery was 24 hr [IQR 16-46] and was higher in patients with than without postoperative delirium (Table 1).

Main outcome and post-operative complications

On univariate analysis, 2 anesthetic drugs, etomidate and droperidol, were significantly used differently between patients with and without postoperative delirium (Table 2). The groups did not significantly differ regarding drugs prescribed in the ED, recovery room, or unit for perioperative geriatric care, with the exception of transfusion (more prevalent in patients with than without postoperative delirium). Anemia, stool impaction, bladder retention and infection were more frequent in patients with than without postoperative delirium (Table 3).

On multivariable logistic regression analysis, after controlling for potential confounders (all variables detailed in Table 4, Appendix 2), no anesthetic drug use was associated with postoperative delirium. The factors associated with in-hospital postoperative delirium were advanced age, dementia, depression and preoperative use of beta-blockers (Table 4). Among the 145 patients with a medical history of depression, 76 (52%) were treated with antidepressant.

DISCUSSION

To the best of our knowledge, this is the first study considering the association between all therapeutics received during a dedicated orthogeriatric care pathway and in-hospital postoperative delirium after hip fracture surgery in a cohort of older patients. The incidence of postoperative delirium was high (44%), but no emergency or anesthetic drugs were significantly associated with postoperative delirium. Advanced age, dementia, depression and preoperative beta-blocker use were associated with postoperative delirium.

The wide variance in postoperative delirium incidence between our cohort and the literature [START_REF] Silva | Estimates of geriatric delirium frequency in noncardiac surgeries and its evaluation across the years: a systematic review and metaanalysis[END_REF][START_REF] Zhang | Strategies for prevention of postoperative delirium: a systematic review and meta-analysis of randomized trials[END_REF] is probably a result of the considerable heterogeneity in definitions and methods used to identify postoperative delirium, the study populations, and the settings. By selecting only studies specific to older patients with hip fracture surgery [START_REF] Harris | Clinical predictors of postoperative delirium, functional status, and mortality in geriatric patients undergoing non-elective surgery for hip fracture[END_REF][START_REF] Sharma | Recovery room delirium predicts postoperative delirium after hip-fracture repair[END_REF][START_REF] Sieber | Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair[END_REF] , the incidences were comparable (30% to 42%).

We found no association between anesthetic drugs used and postoperative delirium despite potential pathophysiological hypotheses (gamma-aminobutyric acid activation [START_REF] Ferrarelli | Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness[END_REF][START_REF] Sanders | Hypothesis for the pathophysiology of delirium: role of baseline brain network connectivity and changes in inhibitory tone[END_REF] , anticholinergic action [START_REF] Praticò | Drugs of anesthesia acting on central cholinergic system may cause post-operative cognitive dysfunction and delirium[END_REF] ). Only one prospective observational study, analysing the incidence of emergence delirium after anesthesia, reported an association between etomidate and postoperative delirium (12.6% of patients receiving etomidate vs 3.8% receiving propofol, p < .001), [START_REF] Radtke | Risk factors for inadequate emergence after anesthesia: emergence delirium and hypoactive emergence[END_REF] but patients were younger (mean age < 60 years) and were admitted for elective surgery. The most-described anesthetic predictor of postoperative delirium remains general anesthesia regarding local anesthesia but is still debated [START_REF] Aldecoa | European Society of Anaesthesiology evidencebased and consensus-based guideline on postoperative delirium[END_REF][START_REF] Chen | Perioperative outcomes in geriatric patients undergoing hip fracture surgery with different anesthesia techniques: A systematic review and meta-analysis[END_REF] . All patients in this cohort had general anesthesia.

The preoperative risk factors we found (advanced age, dementia, depression) agreed with factors described in the literature [START_REF] Aldecoa | European Society of Anaesthesiology evidencebased and consensus-based guideline on postoperative delirium[END_REF][START_REF] Ansaloni | Risk factors and incidence of postoperative delirium in elderly patients after elective and emergency surgery[END_REF][START_REF] Kotfis | Early delirium after cardiac surgery: an analysis of incidence and risk factors in elderly (≥ age;65 years) and very elderly (≥ age;80 years) patients[END_REF][START_REF] Wu | Different MMSE Score Is associated with postoperative delirium in young-old and old-old adults[END_REF] . Surprisingly, we found a significant association between preoperative use of beta-blockers and postoperative delirium. This association has never been observed in hip fracture surgery. Controversial data have been published for vascular and cardiologic surgeries [START_REF] Stransky | Hypoactive delirium after cardiac surgery as an independent risk factor for prolonged mechanical ventilation[END_REF] . In 582 patients (mean age 68 years) who underwent vascular surgical procedures, the postoperative delirium incidence was 26.5% in patients who received preoperative beta-blockers versus 17.4% in patients who did not (p = .032) [START_REF] Katznelson | Delirium following vascular surgery: increased incidence with preoperative beta-blocker administration[END_REF] . Patients who started and did not start beta-blocker therapy postoperatively did not differ in incidence of postoperative delirium [START_REF] Katznelson | Delirium following vascular surgery: increased incidence with preoperative beta-blocker administration[END_REF] . However, in 455 patients (mean age 66 years) undergoing cardiac surgery, the incidence of hypoactive presentation of postoperative delirium after cardiac surgery was decreased by > 3 times with preoperative beta-blockers (p < .01) [START_REF] Stransky | Hypoactive delirium after cardiac surgery as an independent risk factor for prolonged mechanical ventilation[END_REF] . This association could be due to 1) reduced cerebral perfusion pressure and potentially reduced cerebral oxygen supply [START_REF] Katznelson | Delirium following vascular surgery: increased incidence with preoperative beta-blocker administration[END_REF] , 2) an interaction with the beta-adrenoceptors and serotonin (5-HT) receptors [START_REF] Katznelson | Delirium following vascular surgery: increased incidence with preoperative beta-blocker administration[END_REF][START_REF] Costain | beta-Adrenoceptor antagonists inhibit the behavioural responses of rats to increased brain 5-hydroxytryptamine[END_REF] , and 3) the abolishment of nocturnal secretion of melatonin [START_REF] Stoschitzky | Influence of beta-blockers on melatonin release[END_REF] .

Median length of stay was only one day longer in the group with postoperative delirium compared to patients without. Discharge to home can alleviate postoperative delirium. In the group with postoperative delirium, 25% lived in an institution before surgery, often because of preexisting neurocognitive disorders, and could therefore return "home" despite the delirium because of the medical and paramedical staff in these structures. Similarly, if the home environment allowed it, discharge home was also organized. This could explain why the median length of stay was close between the 2 groups.

Our study has several strengths. We included all consecutive patients ≥ 70 years old with hip fracture and excluded only patients with complicated fractures, which suggests that our population was representative of most older patients with hip fracture. Second, outcomes were closely monitored by only 3 highly trained physicians who prospectively collected the data, which allowed for a homogeneous description of complications and particularly postoperative delirium. Lastly, we reported all treatments administered from the ED to discharge, which allowed for a precise analysis of the association between all therapeutics received during a dedicated orthogeriatric care pathway and the occurrence of postoperative delirium.

Our study has several limitations. First, it was an observational study, and causality cannot be demonstrated. Second, many patients had to be excluded because of missing anesthesia records or because of > 24 hr for transfer to the unit for perioperative geriatric care.

However, these patients had the same characteristics as included patients. We excluded all patients with a diagnosis of delirium established in the ED before surgery to ensure as much as possible a temporal link between drugs received and postoperative delirium. Nevertheless, some forms of hypoactive delirium may not have been diagnosed in the ED and some patients could have been wrongly included. Third, we did not differentiate subtypes of postoperative delirium or severity and duration of delirium. Fourth, we had no data on the dosage or depth of anesthesia nor on hemodynamics recordings during surgery. Finally, our study was conducted in a highly specialized environment (department of emergency medicine and surgery, department of anesthesiology and critical care, department of orthopaedic surgery, unit for perioperative geriatric care and department of rehabilitation) because each step of care pathway may represent a new risk of delirium and our results may not be extrapolated to conventional or other orthogeriatric models previously reported. However, in outside institutions without a geriatric perioperative unit in a dedicated care pathway, previous studies have shown the benefit of one-off geriatric interventions in non-surgical conditions and the intervention of the orthogeriatrician in perioperative hip fracture conditions [START_REF] Inouye | A multicomponent intervention to prevent delirium in hospitalized older patients[END_REF][START_REF] Neuburger | Increased orthogeriatrician involvement in hip fracture care and its impact on mortality in England[END_REF][START_REF] Middleton | Improving hip fracture outcomes with integrated orthogeriatric care: a comparison between two accepted orthogeriatric models[END_REF] . This is why we believe that multimorbid older patients with hip fracture should be hospitalized in a geriatric environment and that an interdisciplinarity and pathway should be encouraged.

Our study has revealed several perspectives. One is the need for external validation using another cohort of multimorbid older patients (in particular, the association between preoperative use of beta-blockers and in-hospital postoperative delirium). However, only a randomized control trial could provide a definite demonstration of a causality link. Also, according to this study and the literature, patient characteristics and geriatric management seem to be the main factors associated with postoperative delirium occurrence after hip fracture surgery in older patients. Physicians and health policy decision-makers should focus actions to minimize risk of postoperative delirium on patients at risk (advanced age, with dementia, depression, etc.) and ensure that hip fracture prevention strategies are applied (physiotherapy, nutrition, antiosteoporosis treatment, etc).

CONCLUSION AND IMPLICATIONS

In a cohort of older patients with hip fracture managed in a dedicated orthogeriatric care pathway, we evaluated the incidence of postoperative delirium according to all therapeutics received. The incidence of postoperative delirium was high (44%), with no significant difference between patients with and without postoperative delirium regarding emergency or anesthetic drugs used. In contrast, probability of postoperative delirium was increased after hip fracture surgery for patients with advanced age, dementia or depression and using preoperative beta-blockers. Further studies are needed to demonstrate a possible causal link between preoperative use of beta-blockers and postoperative delirium.

Tables and Figures

(

  SD) or median (interquartile range [IQR]) for continuous variables and number (percentage) for categorical variables. Comparison of quantitative variables involved unpaired Student t test or Mann-Whitney test depending on the normal distribution of data. Normality was assessed by graphical representation of the distribution. Comparison of categorical variables involved chisquare or Fisher's exact test, as appropriate.

Figure :

 : Figure: Flow of participants in the study.

Table 1 :

 1 Demographic data and baseline characteristics of older patients with and without postoperative delirium in the unit for perioperative geriatric care

Table 2 :

 2 Perioperative drugs of older patients with and without postoperative delirium in the unit for perioperative geriatric care

Table 3 :

 3 Postoperative complications of older patients with and without postoperative delirium in the unit for perioperative geriatric care

Table 4 :

 4 Logistic regression analysis of factors associated with probability of in-hospitalpostoperative delirium during hospitalization in the unit for perioperative geriatric care

	Appendices:
	Appendix 1: Comparison between included and excluded patients in the perioperative geriatric
	unit
	Appendix 2: Correlation matrices guiding variable selection for logistic regression
	Competing interests: No conflict of interest to declare

Table 1 :

 1 Demographic data and baseline characteristics of older patients with and without 396 postoperative delirium in the unit for perioperative geriatric care 397 398

	All patients	With	Without	p value
	N = 490	delirium	delirium
		N = 215	N = 275

Table 2 :

 2 Perioperative drugs of older patients with and without postoperative delirium in the 427 unit for perioperative geriatric care 428 429

			All patients	With	Without	p value Missing
			N = 490	delirium	delirium		data n (%)
				N = 215	N = 275
			EMERGENCY DEPARTMENT (ED)
		Paracetamol	197 (40)	85 (40)	112 (41)	.27	3 (0.6)
		Tramadol	245 (50)	102 (47)	143 (52)	.30	3 (0.6)
		Nefopam	45 (9)	23 (11)	22 (8)	.31	3 (0.6)
		Morphine	165 (34)	68 (32)	97 (35)	.38	3 (0.6)
		NSAIDs	2 (0)	1 (0)	1 (0)	.99	3 (0.6)
			ANAESTHESIA
		Sufentanil	430 (88)	186 (87)	244 (89)	.47	2 (0.4)
		Remifentanil	58 (12)	26 (12)	32 (12)	.87	2 (0.4)
		Propofol	439 (90)	186 (87)	253 (92)	.07	1 (0.2)
		Etomidate	103 (21)	54 (25)	49 (18)	.05	2 (0.4)
		Sevoflurane	239 (49)	102 (47)	137 (50)	.84	31 (6.3)
		Desflurane	83 (17)	32 (15)	51 (19)	.35	31 (6.3)
		Ketamine	88 (18)	33 (15)	55 (20)	.18	2 (0.4)
		Muscular relaxant	474 (97)	207 (96)	267 (97)	.95	2 (0.4)
		Prostigmine	26 (5)	12 (6)	14 (5)	.81	4 (0.8)
		Atropine	42 (9)	17 (8)	25 (9)	.66	3 (0.6)
		Corticoids	280 (57)	122 (57)	158 (57)	.93	3 (0.6)
		Droperidol	125 (26)	42 (20)	83 (30)	.008	3 (0.6)
		Ondansetron	20 (4)	8 (4)	12 (4)	.82	3 (0.6)
		All cardiovascular drugs	409 (83)	178 (83)	231 (84)	.90	8 (1.6)
		Phenylephrine	130 (27)	54 (25)	76 (28)	.54	4 (0.8)
		Ephedrine	327 (67)	141 (66)	186 (68)	.60	3 (0.6)
		Norepinephrine	64 (13)	33 (15)	31 (11)	.18	1 (0.2)
		Paracetamol	474 (97)	209 (97)	265 (96)	.34	3 (0.6)
		Tramadol	222 (45)	90 (42)	132 (48)	.18	2 (0.4)
		Nefopam	111 (23)	46 (21)	65 (24)	.56	2 (0.4)
		Morphine	276 (56)	125 (58)	151 (55)	.42	3 (0.6)
		NSAIDs	39 (8)	13 (6)	26 (9)	.18	3 (0.6)
		Local anesthetics (femoral block)	123 (25)	101 (47)	122 (44)	.59	1 (0.2)
			TRANSFUSION (ED + anaesthesia)
		RBC transfusion	63 (13)	40 (19)	23 (8)	<.001	1 (0.2)
			Unit for perioperative geriatric care
		Paracetamol	456 (93)	199 (93)	257 (93)	.24	17 (3.5)
		2 nd -level analgesics	10 (2)	3 (1)	7 (3)	.53	17 (3.5)
		Morphine	455 (93)	205 (95)	250 (91)	.06	0 (0)
		RBC transfusion	175 (36)	82 (38)	93 (34)	.35	2 (0.4)
		RBC transfusion (in all units)	238 (49)	121 (56)	117 (43)	.002	2 (0.4)
	430 431	Total packed RBC per patient transfused * Data are mean ± SD, median (interquartile range), or number (percentage). 2 [1-3] 2 [1-3] NSAIDs = non-steroidal anti-inflammatory drugs; RBC = red blood cell; ED = emergency department 2 [1-3] <.001	1 (0.2)
	432	* with at least one transfusion

Table 4 :

 4 Logistic regression analysis of factors associated with probability of in-hospitalpostoperative delirium during hospitalization in the unit for perioperative geriatric care

		Univariate analysis	P value	Multivariable analysis *	P value
		OR (95% CI)		OR (95% CI)
	ANAESTHESIA
	Propofol	0.58 (0.32 to 1.04)	.07	0.79 (0.34 to 1.81)	.58
	Etomidate	1.55 (1.01 to 2.40)	.05	1.23 (0.65 to 2.35)	.52
	Ketamine	0.73 (0.45 to 1.16)	.19	0.92 (0.50 to 1.66)	.78
	Droperidol	0.57 (0.37 to 0.86)	.008	0.82 (0.49 to 1.37)	.45
	Noradrenaline	1.44 (0.85 to 2.44)	.18	1.26 (0.66 to 2.40)	.48
	Tramadol	0.78 (0.54 to 1.12)	.18	0.87 (0.55 to 1.38)	.56
	NSAIDs	0.61 (0.30 to 1.21)	.17	0.78 (0.34 to 1.71)	.55
	Unit for perioperative geriatric care
	Morphine	2.05 (0.99 to 4.57)	.06	1.81 (0.71 to 4.99)	.23
	ALL UNITS
	Transfusion	1.75 (1.22 to 2.51)	.002	1.34 (0.85 to 2.12)	.21
	OTHER PREDICTORS
	Age <85 years	1
	85-90 years	1.78 (1.15 to 2.76)	.01	1.69 (0.96 to 2.99)	.07
	>90 years	2.52 (1.56 to 4.90)	<.001	2.03 (1.07 to 3.89)	.03
	Male	1.00 (0.65 to 1.54)	.99	1.27 (0.73 to 2.19)	.40
	Dementia	5.50 (3.72 to 8.24)	<.001	3.51 (2.14 to 5.82)	<.001
	Parkinson disease	2.22 (0.97 to 5.37)	.07	1.77 (0.66 to 4.95)	.26
	Depression	2.07 (1.40 to 3.08)	<.001	1.85 (1.14 to 3.01)	.01
	Chronic renal failure	1.71 (1.53 to 2.16)	.007	0.97 (0.58 to 1.62)	.91
	Beta-blockers	1.69 (1.14 to 2.53)	.009	1.75 (1.10 to 2.79)	.02
	Benzodiazepine	1.95 (1.22 to 3.13)	.005	1.06 (0.60 to 1.90)	.83
	Antipsychotic drugs	3.08 (1.29 to 8.14)	.02	1.63 (0.57 to 5.19)	.38
	ADL (per 1-point increase)	0.67 (0.59 to 0.76)	<.001	0.87 (0.75 to 1.02)	.09
	Albumin <30 g/L	1.33 (0.92 to 1.94)	.16	1.09 (0.71 to 1.69)	.68
	Time to surgery > 48 hr	1.67 (1.08 to 2.58)	.02	1.27 (0.74 to 2.19)	.38
	Duration of surgery (for 1 min) 1.00 (0.99 to 1.00)	.06	1.00 (0.71 to 4.99)	.82
	Infection in UPOG	1.76 (1.09 to 2.88)	.02	1.12 (0.62 to 2.03)	.71
	Bladder retention in UPOG	1.66 (1.10 to 2.50)	.02	1.56 (0.92 to 2.65)	.10
	Stool impaction in UPOG	1.96 (1.37 to 2.82)	<.001	1.37 (0.85 to 2.23)	.20
	Notes: N = 464
	NSAIDs = non-steroidal anti-inflammatory drugs; ADL = activities of daily living; UPOG: unit for perioperative geriatric
	care

* Only significant ORs in the multivariate analysis are provided.

LOS = length of hospital stay (in days)

⁎ defined as haemoglobin level < 12 g.dL -1 for women and 13 g.dL -1 for men † Institution was considered "home" in patients previously living in an institution


Serge Turcaud

Thierry Martens

Emma Sierecki

Joe ¨lle Pe ´rard-Viret

Jacques Royer
email: jacques.royer@univ-paris5.fr

Anodic oxidation of chiral sulfinylamines: a new route to highly diastereoselective a-alkylation of piperidine

Keywords: Sulfinylamine, Anodic oxidation, Diastereoselective alkylation, Pelletierine

The anodic oxidation of some chiral non-racemic N-arylsulfinyl piperidines was investigated and for the first time a methoxylated sulfinyl piperidines were obtained. The so-formed compounds are equivalent of chiral N-sulfinyliminiums and used as new intermediates for the preparation of chiral a-substituted piperidine derivatives in good yield and diastereoselectivity.

Stereoselective substitution at the a position of secondary amines offers opportunities for convenient and efficient syntheses of nitrogen containing derivatives. Nevertheless, this sequence remains challenging and, despite several attempts, very few reactions permitting this substitution have been described so far.

Both anionic and cationic routes were reported. Deprotonation a to the nitrogen was investigated 1 with some success and asymmetric versions [1][2][3] exist whilst confined to the alkylation of allylamines 2b and pyrrolidines. 2a,3 The cationic pathway has been extensively studied (Scheme 1). A secondary amine 1 is transformed to amethoxy derivative 3 (Z = COOR) via carbamate 2 (Z = COOR) using the ShonoÕs anodic oxidation. 4 The methoxy compound 3 reacts with a nucleophile in the presence of a Lewis acid to give the substituted derivative 5 via acyliminium 4. [START_REF] Suga | A variant was proposed allowing the direct substitution without isolation of methoxy derivative[END_REF] This anodic oxidation-amidoalkylation sequence is a very powerful method allowing the introduction of various nucleophiles. [START_REF] Overman | Comprehensive Organic Synthesis[END_REF] Moreover this process is very easy to perform and does not need any special technical knowledge. [START_REF] Moeller | [END_REF] Surprisingly, few asymmetric developments of this efficient methodology appeared in the literature. Use of chiral carbamates led to disappointing diastereoselectivities 8 (except if a chiral center is already present on the starting amine 1). 9 A recent example using a chiral Lewis acid and providing an encouraging 56% ee was also reported. 10 It thus appeared that improvement of the diastereoselectivity would call for the choice of another type of chiral activating Z group besides carbamates.

Several reports from the literature showed that diastereoselectivities for addition of nucleophiles to chiral sulfinylimines are consistently good to excellent. 11 Thus, we planned to study the use of sulfoxide as chiral auxiliary in the oxidation/alkylation sequence described in Scheme 1 (Z = S*(O)R).

To the best of our knowledge there is no report in the literature neither concerning the generation of N,O-acetal equivalent of N-sulfinyliminium by direct oxidation of sulfinylamine, nor their use in the alkylation step.

Tetrahedron Letters

Only one example of N-sulfinyliminium was described (as the expected intermediate in the Pictet-Spengler reaction of (R)-N-p-toluenesulfinyltryptamine). 12 We now report on the first successful electrochemical oxidation of chiral N-sulfinylamine to a-alkoxy-N-sulfinylamine and the diastereoselective addition of a nucleophile onto this potential sulfinyliminium. In this preliminary study, we investigated some chiral sulfoxide groups as N-activating group (Z, Scheme 1) of the piperidine ring chosen as a model substrate (Scheme 2). The sequence was applied to the asymmetric synthesis of pelletierine (10).

N-Sulfinyl piperidines 7 were prepared 13 according to the literature [START_REF] Garcia-Ruano | [END_REF] with some modifications. The enantioenriched N-arylsulfinyl piperidines 7a-d were obtained in high yields and ee (Table 1) by addition of piperidine magnesium bromide to the diastereomerically pure menthyl sulfinates. 15 Compound 7e was prepared in only 30% ee from unseparated mesityl menthyl sulfinate diastereoisomers and 7f was prepared in racemic form from t-BuSS(O)t-Bu 16 and piperidine lithium. 17 The oxidation step was particularly challenging and hypothetic since both nitrogen and sulfur atoms can be oxidized. Indeed, the anodic oxidation of sulfinylamines was reported by DÕOca et al. [START_REF] Dõoca | [END_REF] to give sulfur oxidation or N-S bond cleavage. [START_REF] Carreno | N-S cleavage was also observed in N-sulfinyl anilines[END_REF] However, fragmentary data from the literature suggested that the regioselective nitrogen oxidation is possible. 21 We reasoned that this electrochemical procedure should be quite sensitive to the reaction conditions. The anodic oxidation is known to generate protons, which can be a serious drawback for the integrity of N-S bond. 11a The first very simple idea was to perform the anodic oxidation in the presence of added base. Furthermore, it can help in the kinetic of deprotonation of the expectedly formed nitrogen centered cation-radical. After some trials, it was found that anodic oxidation, [START_REF]The electrolysis was conducted at 0 °C in an undivided glass cell equipped with two graphite plate electrodes (35 • 20 mm) and at a constant current (15 mA), under nitrogen on a 0.05 M methanolic solution of 7 containing Et 4 NBF 4 (0.5 equiv) and KHCO 3 (0.5 equiv). The course of the electrolysis was checked by HPLC[END_REF] at constant current with graphite plate electrodes, of sulfinylamine 7a (R = p-tolyl) in MeOH and in the presence of KHCO 3 occurred cleanly to furnish the desired amethoxylated derivative 8a in a good 69% yield as a mixture (75:25) of two diastereoisomers. The enantiomeric purity of each diastereoisomer was checked by chiral HPLC and no racemization was observed. The formation of methylsulfinate 11a corresponding to the N-S bond cleavage reported by DÕOca et al. [START_REF] Dõoca | [END_REF] (Scheme 2) could not be completely avoided. Under more basic conditions, the formation of 11a was minimized and 8a was formed in a nice 77% yield but each diastereoisomer of 8a was proved to be only 80% ee. This partial racemization under these specific conditions is not clearly understood.

As it can be seen in Table 1, compounds 7a-d gave the expected a-methoxylated sulfinylamines 8a-d 13 in acceptable to good yields. The N-S bond cleavage is still present in a small amount (about 15%) in all cases regardless of the structure. It is noteworthy that compound 11 were found to be racemic products.

In contrast to the oxidation of 7a-d, N-sulfinyl piperidines 7e (R = mesityl) and 7f (R = t-Bu) containing bulky groups led exclusively to cleavage products under several experimental conditions. This can be linked to their lower oxidation potential (Ep = 1.3 and 1.5 V sce for, respectively, 7f and 7e compared to 1.7-1.9 V sce for 7a-d).

The possibility to regenerate the sulfinyliminium from the a-methoxylated product 8 and the diastereoselectivity of the addition of a nucleophile were then investigated. When 8a was treated with trimethylsilyloxypropene at À78 °C in the presence of 0.4 equiv of TMSOTf, the N-sulfinyl amino ketone 9a was obtained in a fair 64 % yield and a nice 90:10 diastereoisomeric ratio (Scheme 3). This ratio was determined by HPLC and NMR analyses on the crude reaction mixture. The absence of racemization at sulfur atom was once again checked by chiral HPLC on each diastereoisomer. The methoxylated derivatives 8b-d proceeded as well with de ranging from 64% to 84% (Table 2). A by-product was systematically observed and identified as the S-alkylated derivative 12. [START_REF]The enantiomeric purity of 12 was not checked[END_REF] In each case the major isomer of 9 13 is obtained pure after simple flash chromatography.

Brief treatment (10 min) with 0.5 equiv of a 0. In conclusion, we showed for the first time that N-sulfinylamines can be transformed to the corresponding amethoxy N-sulfinylamines through anodic oxidation. This allowed us to prepare chiral non-racemic equivalent of sulfinyliminium on 0.5 g scale. The so-formed a-methoxylated N-sulfinylamines can react as potential sulfinyliminium allowing highly diastereoselective alkylation. The R group beared at the sulfoxide is important to the success of the anodic oxidation, while several substituents allow the alkylation reaction to occur in good yield and diastereoselectivity.

The overall sequence is a short (four steps) procedure to diastereomerically a-alkylate secondary amines. The generalization of this procedure to other amines and nucleophiles is under investigation.

  Scheme 1.

  Scheme 3.

Table 1 .

 1 Preparation and anodic oxidation of N-sulfinyl piperidines 7

						O	S	R
	H N	i)	O	N S	R	iii)	N		OMe
		or ii)				8a-d
				7a-f		O	S	R	+ piperidine
							OMe
							11a-f
	Scheme 2. Reagents and conditions: (i) MeMgBr, THF, 0 °C, then
	menthyl arylsulfinate, 1 equiv; (ii) for 7f: BuLi, THF, À78 °C, then
	t-BuSS(O)t-Bu; (iii) anodic oxidation. 18

5 M aqueous H 2 SO 4 solution in MeOH gave quantitatively the (S)-enantiomer of pelletierine sulfate

(10)

: ([a] D +28.9 (c 0.9, H 2 O))

[START_REF] Gilman | Reported values for the natural (R) isomer: [a] D À29[END_REF]

without epimerization. This very simple cleavage of the N-sulfoxide bond contrasts with the tedious cleavage of carbamates. The alkylation of a-methoxylated sulfinylamines 8a-d possessing a (S)-sulfoxide

Table 2 .

 2 Diastereoselective alkylation of methoxylated N-sulfinyl piperidines 8

		R	99 :12 ratio
			Isolated yield (%)	de
	a	p-Tol	64	80	92:8
	b	o-Tol	55	84	83:17
	c	Ph	60	80	82:18
	d	o-CF 3 -C 6 H 4	62	64	82:18

Acknowledgements

The authors thank the CNRS and the French Ministry of Education and Research for funding.


Bruno Ribeiro Baptista
email: bruno.baptista@hotmail.fr

Morgane Faure

Benny Gimbada

Mwenge

Capucine Morelot-Panzini

Thomas Similowski

Jésus Gonzalez-Bermejo

Feasibility of a hypoxic challenge test under non-invasive ventilation versus oxygen in neuromuscular patients with chronic respiratory insufficiency

Background: The British Thoracic Society recommendations suggest that all patients with an oxygen saturation < 85% during a hypoxic challenge test (HCT) should receive supplemental oxygen during air travel. However, neuromuscular patients already using ventilatory support are a specific population and non-invasive ventilation (NIV) during a flight could be an alternative to oxygen for hypoxemia correction, through the augmentation of ventilation.

Methods:

We conducted a comparative, observational study of neuromuscular patients with chronic respiratory failure, requiring nocturnal mechanical ventilation, who were planning to take a flight. HCT was performed with a ventilated canopy placed over the patient's head or the patient's home ventilator. The positive threshold value chosen for the HCT was < 90% SpO2.

Results: HCTs were performed on 13 adults with neuromuscular diseases using their home ventilator. Among them, 11 had a positive HCT. For all patients with a positive test, hypoxemia was corrected (SpO2 to > 90%) by oxygen therapy (+9 [6 to 12] %, p = 0.0029). Patient's home ventilator also significantly increased the SpO2 by 8 [7 to 12] % (p = 0.016). Correction of SpO2 during the HCT was not different between oxygen and NIV. NIV was associated with a significant decrease in PetCO2 (-10 [-16 to -7.5] mmHg, p = 0.04).

Conclusions:

The performance of an adapted HCT in home-ventilated patients with a neuromuscular pathology may be is useful in a personalized treatment plan for air travel. NIV can be a new alternative to oxygen therapy for neuromuscular patients planning to take a flight.

Keywords:

-Hypoxic challenge test -Non-invasive ventilation -Chronic respiratory insufficiency -Neuromuscular pathology -Oxygen

Introduction

In 2018, four billion passengers were carried by air transport according to the International Civil Aviation Organization (ICAO's Annual Report of the Council, 2018). Among passengers planning air travel, patients with respiratory diseases are at high risk of in-flight complications [START_REF] Noble | Cor pulmonale presenting in a patient with congenital kyphoscoliosis following intercontinental air travel[END_REF][START_REF] Ergan | Should I stay or should I go? COPD and air travel[END_REF]. Indeed, a commercial aircraft cabin is pressurized to a maximum altitude of 2,400 m and the oxygen pressure is equivalent to a FiO2 of 15.1%. In this condition, the partial pressure of arterial oxygen (PaO2) falls to 60-75 mmHg and the oxygen saturation (SpO2) measured by pulse oximetry is between 89 and 94% in healthy subjects. This results in moderate hyperventilation and moderate tachycardia. In 2011, the British Thoracic Society (BTS) recommended performing a hypoxic challenge test (HCT) for all patients planning air travel with severe restrictive lung disease (vital capacity < 1 litre), especially for those with hypoxemia and/or hypercapnia, as well as for those requiring ventilatory support [START_REF] Ahmedzai | Managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations[END_REF]. If the oxygen saturation at the end of the test remains > 85%, oxygen supplementation is not required. Below this value, it is recommended to add 2 to 4 l/min of oxygen via a nasal cannula. However, the correction of hypoxemia in patients with chronic respiratory failure due to advanced neuromuscular disease can be achieved by ventilatory support, which allows the patient to reach a level of ventilation equivalent to that of a normal subject [START_REF] Mestry | Hypoxic challenge flight assessments in patients with severe chest wall deformity or neuromuscular disease at risk for nocturnal hypoventilation[END_REF]. Few studies have investigated the use of a ventilator instead of oxygen to correct hypoxia during air travel in these particular patients. This study was designed to evaluate the feasibility of a HCT under non-invasive ventilation (NIV) and to compare the correction of hypoxemia by increasing ventilation with NIV to that by oxygen therapy during a HCT in patients with chronic respiratory failure due to neuromuscular diseases already treated with home ventilatory support.

Methods

We conducted a comparative, observational study in the respiratory medicine department of the Pitié Salpêtrière Hospital (Paris) over a six months period. We extracted retrospectively the data from the medical files from patients tested before air travelling. The study was approved by the ethics committee from the Institutional Review Board of the French Learned Society for Respiratory Medicine (CEPRO 2012-039). Written informed consent was obtained from all subjects. Patients were included if they suffered from chronic respiratory failure due to neuromuscular disorders and requiring nocturnal mechanical ventilation and if they were planning a flight. Patients with non-treated cardiovascular diseases, recent myocardial infarction, cardiac arrhythmia, pregnancy, FEV1 < 30% due to obstructive disease, pulmonary arterial hypertension, infectious tuberculosis, or ongoing pneumothorax with persistent air leak and major hemoptysis were excluded [START_REF] Ahmedzai | Managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations[END_REF]. Data collected were age, diagnosis, sitting and supine force vital capacity (FVC), oxygen saturation (SpO2), expired CO2 (PetCO2), room air blood gases and daily adherence to home mechanical ventilation.

The HCT was performed with a ventilated canopy placed over the patient's head or the patient's home ventilator (Figure 1A) and connected to a hypoxia generator (HYPOXICO Inc., Jalhay, Belgium). The extraction of O2 was adapted to obtain a stable FiO2 of 15% ± 0.2%. FiO2 was measured using a FiO2 sensor (MAXTEC Inc., Utah, USA) placed inside the canopy. The measurement of oxygen saturation, PetCO2, heart rate, and respiratory rate was performed using an integrated monitor (Capnocheck ® Plus, Smiths Medical PM, Inc. Wisconsin 53186 USA), including pulse oximetry and nasal cannula for measuring CO2. Oxygen was administered using another nasal cannula previously placed in superposition of the Capnocheck cannula. The HCT was performed with the patients seated at rest in four successive measurements (15 min each):

1) spontaneous ventilation, room air (baseline), 2) under the canopy, spontaneous ventilation, FiO2 of 15% and, if the test was positive (SpO2 < 90%), 3) under the canopy, spontaneous ventilation, FiO2 of 15%, with an oxygen flow of 2 l/min, and finally 4) under patient's home ventilator, FiO2 of 15% (Figure 1B). Dyspnea and headaches were measured at the end of each period by visual analog scales (VAS) rated from 0-10.

We chose a positive value for the HCT of < 90% SpO2, which is different from that of the BTS recommendation (positive < 85% of SaO2). Indeed, patients with neuromuscular disease or extrapulmonary restrictive chest wall deformity are more at risk of hypoxemia during a HCT, even with a resting saturation of > 95% [START_REF] Masa | Noninvasive positive pressure ventilation and not oxygen may prevent overt ventilatory failure in patients with chest wall diseases[END_REF]. Our choice of 90% was selected for two reasons. First, the related effect of hypoxemia, such as an increase in respiratory rate, was observed at < 90% of the SpO2, suggesting a lower respiratory tolerance. Second, the BTS threshold is common to all respiratory disease, broadly based on studies that include obstructive lung disease. Our patients had normal lung parenchyma associated with reduced ventilatory adaptation in a hypoxemia condition. Thus, a threshold of 90% appeared to be more clinically relevant for this neuromuscular population. It was a choice of caution; it is difficult to formally prove that a patient with severe diaphragmatic dysfunction can remain with a SpO2 between 85 and 90% for a long time.

A p-value of < 0.05 was considered statistically significant. Quantitative variables were compared using a Friedman's test and a post hoc Dunn test and the results expressed as their standard value (median and interquartile range). Qualitative variables were compared using Fisher's exact test and are expressed in terms of numbers and percentage. All statistical analyses were performed using GraphPad Prism software.

Results

Thirteen patients were included, of whom 7 had amyotrophic lateral sclerosis. Their characteristics are presented in Table 1.

At baseline, median blood gas measures were a PaO2 of 82 mmHg and a PaCO2 of 41 mmHg.

All patients performed the HCT. The median SpO2 was 95% at baseline. By the end of the test, the SpO2 of 11 patients had fallen to < 90% (Figure 2). Among these patients, the SpO2 of two had fallen to < 85%. The median fall of oxygen saturation was 7 [5.5 to 8.5] % relative to the baseline SpO2 (p < 0.001). There was no significant change in the PetCO2 during spontaneous ventilation at the end of the HCT.

An oxygen flow of 2 l/min allowed a correction of SpO2 to > 90% for all positive HCT patients (+9 [6 to 12] %, p = 0.0029). In comparison, patient's home ventilator significantly increased the SpO2 by 8 [7 to 12] % (p = 0.016). Oxygen was not more effective than NIV for SpO2 correction during the HCT (Figure 3). There was a significant decrease in PetCO2 only with NIV (-10 [-16 to -7.5] mmHg, p = 0.04). The HCT was not associated with a significant increase in the respiratory rate and the VAS score for dyspnea. Three tests were prematurely stopped: one because of dyspnea (at the end of HCT), one because of dyspnea and headache (at the end of HCT + O2 period), one at the request of the patient (at the end of HCT). No other patients reported a change in the VAS for dyspnea or headache.

Discussion

Our study shows that a pre-flight HCT is feasible under NIV in neuromuscular patients. The study also shows that SpO2 drops below 90% under a 15% FiO2 in the majority of such patients (11 out of 13 in this study) and that NIV correct hypoxemia in all cases.

HCT is achievable for patients using NIV under a canopy coupled to a hypoxia generator. In contrast to other already available methods using a Douglas bag or a Venturi mask, it is easily achievable directly at the patient's bedside, making it accessible to patients with motor disabilities or respiratory failure. Its speed of acquisition (45 minutes for a complete test) allows its routine use. Moreover, unlike conventional methods, it allows the evaluation of alternative therapies, such as mechanical ventilation. The order of the different periods of the test was planned to avoid the necessity of re-establishing a stable hypoxia multiple times which would have lengthened the experiment. However, a potential effect of the sequence cannot be excluded and the results could be different with another sequence.

NIV was always as effective as oxygen therapy in our group of patients. NIV appeared to be an acceptable alternative therapy, with physiological advantages like decreasing CO2 level. Furthermore, Winck et al. showed that a patient with a neuromuscular disease who is correctly ventilated, without supplemental oxygen, can maintain oxygen saturation throughout a flight [START_REF] Winck | Oxygen or ventilation during flight for patients with Baseline characteristics Median [interquartile range[END_REF]. In our study, the PetCO2 did not significantly decrease during the HCT because of a possible lack of ventilatory adaptation in this particular population. Indeed, hypoxemia normally induces a stimulation of the central respiratory drive leading to an augmentation of ventilation to maintain the oxygen level. In the case of normal respiratory mechanics, it should have led to a significant decrease in CO2 level. The interpretation of the PetCO2 is limited by the measurement method and should be considered with caution given the potential for washout of this signal by NIV flows. However, the evolution of this parameter is in favor of the absence of hypercapnia during an HCT with oxygen or NIV. We can assume that this favorable effect of NIV would be even more obvious for patient with more advanced respiratory failure. Even if not significant, probably because of the small number of subjects, the increase in respiratory rate at the initiation of hypoxia was well corrected by NIV.

Importantly, this respiratory frequency was always higher than the minimum frequency set on the ventilator and therefore corresponded to the patients' "voluntary" frequency. These results suggest that the respiratory effort under NIV is reduced, and therefore the risk of respiratory exhaustion during longer exposure to hypoxemia, such as during air travel prolonged several hours, may decrease with NIV.

Conclusion

We conclude that performing an adapted HCT for home-ventilated patients with a neuromuscular pathology is useful to choose a personalized treatment for air travel. NIV allows sufficient hypoxemia correction for certain patients and can be used instead of oxygen therapy during air travel for this population. NIV can therefore be a new alternative for patients planning to take a flight. neuromuscular disease? Thorax 65, 370-371.

Figure 1 .

 1 Figure 1. (A) Hypoxic challenge test with non-invasive ventilation (NIV). The NIV device is

Figure 2 .

 2 Figure 2. Oxygen saturation (SpO2) at baseline and at the end of the hypoxic challenge test.

Figure 3 .

 3 Figure 3. Comparison of SpO2 (A), PetCO2 (B), respiratory rate (C) of patients with a positive

Table 1 .

 1 Baseline characteristics (n = 13). The values shown are median and interquartile range, except for gender and disease. a Other: Central core disease, Steinert's disease, two diaphragmatic dysfunction and two Charcot Marie Tooth neuropathy.

Acknowledgement:

We thank Grégoire Justeau for proofreading this article.

Funding statement:

The study did not benefit from any private funding. Logistical support was provided by "Association pour le Développement et l'Organisation de la Recherche en Pneumologie et sur le Sommeil, ADOREPS", a non-profit organization devoted to the promotion of respiratory and sleep research. The study was supported by the program "Investissement d'Avenir ANR-10-AIHU 06" of the French Government.

Competing statement:

There is no financial and non-financial competing interests for any authors of this manuscript.

Authors' contributions:

Concepting and design: JG, TS, CMP, CS Analysis and interpretation: BRB, GM, TS, JG Drafting the manuscript for important intellectual content: BRB, MF, GM, CS, CMP, TS, JG All authors have reviewed and approved the manuscript prior to submission.


Feral-Pierssens Anne-Laure

Avondo Aurélie

De Stefano Carla

Deltour Sandrine

Frédéric Lapostolle
email: frederic.lapostolle@aphp.fr

Feral-Pierssens Anne- Laure

Stefano De

Carla

Samu

Pr Frédéric

Lapostolle Samu

Gender equity in medical publications: nurses have smashed the glass-ceiling

We included 20 recent consecutive papers from each journal. For each paper, the number of authors, their gender and rank were recorded. Primary endpoint: overall rate of women as authors. Secondary endpoints: rate of women as first, last, second and third authors.

Results

Sixty papers including 322 authors were analyzed. Overall rate of women authors: 74%. Overall rate of

Introduction

Gender equity has become a major concern in many professional fields. The rate of women as authors has to be interpreted according to the rate of women in the related professions. In this perspective, studying nurses' population should be of particular interest since, worldwide, nurses are mostly women.

Then, our aim was to study gender disparity in nurses' publications.

Methods

We selected the three main journals dedicated to nurse publications: International Journal of Nursing Studies, Journal of Nursing Scholarship and European Journal of Cardiovascular Nursing.

1

Gender equity in medical publications: nurses have smashed the glass-ceiling

Introduction

Gender equity has become a major concern in many professional fields [START_REF] Economist | Gender parity in science is an uphill struggle. The Economist[END_REF]UNESCO, 2014). Inequalities have been recently highlighted in science and in medicine. Many papers, in medical journals, have been recently dedicated to the exploration of the gap between men and women. Studies focusing on female authorship in medical publications, in reviewing process and editorial boards have been largely used as a tool to assess the place of women in medicine. Majors disparities have been reported. Women were first authors in 58% of psychiatry papers and in 12% of anaesthesiology papers (Feral-Pierssens, AL et al., 2020). Despite these disparities, authors unanimously concluded that women were underrepresented. The place of women in medical publications seems to give a reliable outline of their place in the society, particularly in sciences. Recent OECD analysis found 'considerable differences' across countries regarding the rate of women with PhDs as well as the rate of women as first author in publications (Feral-Pierssens, AL et al., 2020).

However, the rate of women as authors has to be interpreted according to the rate of women in the related professions. In this perspective, studying nurses' population should be of particular interest. Indeed, worldwide, nurses are mostly women. [START_REF] Gunn | Gender equality policies, nursing professionalization, and the nursing workforce: A cross-sectional, time-series analysis of 22 countries, 2000-2015[END_REF] The rate of men is close to zero in China or Iceland. In the best case, it reaches one third of the nurses in Saudi-Arabia and Africa. [START_REF] Boniol | Gender equity in the health workforce: Analysis of 104 countries[END_REF] In Europe and in the United-States the rate is close to 15%. Moreover, the recognition of nursing research as an independent and specific academic field is quite recent. This is why, our aim was to study nurses' publications as a way of investigating gender equity in academic leadership and publications of a predominantly female profession. To the best of our knowledge, such analysis has not been performed before.

Methods

Based on 2018 impact factor, we selected the three main journals dedicated to nurse publications: Then, We included 20 consecutive papers from each selected journal published before February 2020. For each paper, the number of authors, their gender and rank were recorded. When studied papers included four or less authors, second and third ranks were attributed after first and last authors were filled. Gender was established through first name analysis. When it was not provided in the paper's reference or for epicene name, the author's gender was searched for among the available information from the affiliation (other The selection of the three first nursing journals could be considered as a limitation to our study. However, focusing on these three main journals with the highest level of publications was relevant since they are the main aim of academic research in nursing studies. Thus, these journals should be involved and stir the leadership in academic publications ensuring and promoting gender equity or at least increasing women implication in scientific production. Knowing the rate of female nurse involved in academic careers would allow us to assess the depth of the gender equity gap between practice and academic research or between academic research and authorship.

Conclusion

Almost three quarters of the authors in the three main scientific journals of nursing studies were female.

It is the highest rate ever reported in studies investigating gender in scientific production in the medical field. It can be explained by the large rate of women working as nurses all around the world. However, this rate is still lower than the gender rate in the nursing profession. One should not forget that dealing with gender representativity and equity in authorship remains a major challenge in many scientific fields, including health studies.

Word count: 969

  the first three journals selected were International Journal of Nursing Studies (IJNS; IF = 3.6), Journal of Nursing Scholarship (JNS; IF = 2.5) and European Journal of Cardiovascular Nursing (EJCN; IF = 2.5).

published papers, institutional website, etc.). When it was not possible to determine the author's gender the paper was excluded.

Our primary endpoint was the overall rate of women as authors. Our secondary endpoints were the rate of women as first, last, second and third authors.

Results

The last 20 consecutive issues published by the three selected journals included 79 papers. Nineteen of them were excluded because gender could not be ascertained. Sixty papers including 322 authors were analyzed.

The overall rate of women authors was 74% (Table 1). The overall rate of women as first author was 82% (Table 1). The overall rate of women as last author was 72%. The overall rate of women as second and third authors were respectively 80% and 70% (Table 1). Total results and results for each journal are detailed in the tables.

Discussion

The rate of female authors reported in this study is the highest rate ever reported when investigating gender equity in medical fields' publications. (Feral-Pierssens, AL et al., 2020;[START_REF] Hafeez | Gender distribution in psychiatry journals' editorial boards worldwide[END_REF][START_REF] Li | Gender trends in emergency medicine publications[END_REF]The Lancet Infectious Diseases, 2019) Even though these results could be associated to the fact that the rate of women is especially high in the nursing field, the rate of women as authors remain inferior to the rate of women in the nursing profession. Indeed, the rate of men as nurses exceptionally reaches 25%, mostly in Africa countries according to a recent report issued by the WHO. [START_REF] Boniol | Gender equity in the health workforce: Analysis of 104 countries[END_REF] We found disparities according to the papers and the journals (from 60% to more than 80%). The rate of women was lower in the most specialized journal (cardiology). These results might also be explained by the fact that authors' rank and profession (nurse or physician) were not often specified and could not be ascertained in the studied journals. Since female authors rate is much lower in the medical academic field, physicians' implication in nursing papers could be one of the reasons that led to a lower female authors' rate compared to their rate as professionals. Women are constituting the majority of the authors of nursing scientific publications which is rare in the health field. As European Journal of Cardiovascular Nursing is an interdisciplinary journal, it publish also papers in psychology or physical therapy. Then the rate of female in these disciplines has to be taken into consideration. In Europe, psychology and physical therapy graduates are females in respectively 70 to 75% of the cases. Yet, fostering the involvement of nurses in academic research should be even more instigated.