Dr Martin Dres
email: martin.dres@aphp.fr

PhD Bruno-Pierre Dubé

MD, MSc Ewan Goligher

PhD Stefannie Vorona

MSc Suela Demiri

MD Elise Morawiec

MD Julien Mayaux

MD Laurent Brochard

MD Thomas Similowski

PhD Alexandre Demoule

Usefulness of Parasternal Intercostal Muscle Ultrasound during Weaning from Mechanical Ventilation

Keywords: Ultrasound, respiratory muscles, parasternal muscle, diaphragm, mechanical ventilation -! -

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Abstract

Background

The assessment of diaphragm function with diaphragm ultrasound seems to bring important clinical information to describe diaphragm work and weakness.

When the diaphragm is weak, extra-diaphragmatic muscles may play an important role but whether ultrasound can also assess their activity and function is unknown.

This study aimed 1) to evaluate the feasibility of measuring the thickening of the parasternal intercostal and investigate the responsiveness of this muscle to assisted ventilation, and 2) to evaluate whether a combined evaluation of the parasternal and the diaphragm could predict failure of a spontaneous breathing trial.

Methods

First, an exploratory evaluation of the parasternal in 23 healthy subjects.

Second, the responsiveness of parasternal to several pressure support levels were studied in 16 patients. Last, parasternal activity was compared in presence or absence of diaphragm dysfunction (assessed by magnetic stimulation of the phrenic nerves and ultrasound) and in case of success/failure of a spontaneous breathing trial in 54 patients.

Results

The parasternal was easily accessible in all patients. The inter-observer reproducibility was good (intra-class correlation coefficient 0.77 (95% confidence interval: 0.53 to 0.89). There was a progressive decrease in parasternal muscle thickening fraction with increasing levels of pressure -! -

Introduction

Critically ill patients frequently develop respiratory muscle dysfunction that may contribute to difficult and prolonged weaning from mechanical ventilation. Monitoring of the respiratory muscles function is therefore very useful during the weaning process. 1 Through several approaches that include the assessment of respiratory muscles pressure generating capacity 2 or the use of electromyogram 3 , the evaluation of the respiratory capacity/load balance is possible at the bedside. 1,4 To this end, there has been a growing interest in diaphragm ultrasound as it provides a direct visualization of the muscle and its functioning. 5,6 However, parasternal intercostal and neck muscles also contribute to the generation of tidal volume. 7 Their contribution is known to increase in case of diaphragm dysfunction or increased respiratory load. [START_REF] Parthasarathy | Sternomastoid, rib cage, and expiratory muscle activity during weaning failure[END_REF][START_REF] Hillman | Respiratory pressure partitioning during quiet inspiration in unilateral and bilateral diaphragmatic weakness[END_REF] As these situations are frequently encountered in the intensive care unit, parasternal intercostal muscle ultrasound could provide additional information in the assessment of the respiratory capacity/load balance. A study reported the feasibility and validity of parasternal intercostal muscle ultrasound in patients with stable chronic obstructive pulmonary disease (COPD). 10 This original approach echoes electromyographic findings where neural drive -as measured through surface electromyogram of the second intercostal space parasternal muscle -has been proven to predict the risk of clinical deterioration in chronic obstructive pulmonary disease inpatients. [START_REF] Suh | Neural respiratory drive predicts clinical deterioration and safe discharge in exacerbations of COPD[END_REF] Since limited research has focused on the use of parasternal intercostal muscle ultrasound, the present work aimed at evaluating the feasibility and -! -reproducibility of measuring the parasternal intercostal muscle thickening (TFic) and at investigating the responsiveness of TFic to respiratory unloading during assisted ventilation. Secondary objectives were to investigate the relationship between TFic and diaphragm function and to evaluate whether measuring TFic could be helpful during the weaning process.

-! -

Methods

The main study was divided into three sub-studies, all were conducted between January 2015 and December 2016 in two sites: at the outpatient clinic at the Toronto elsewhere. [START_REF] Dubé | Ultrasound evaluation of diaphragm function in mechanically ventilated patients: comparison to phrenic stimulation and prognostic implications[END_REF] Phrenic nerve stimulation. Diaphragm pressure generating capacity was assessed in terms of changes in endotracheal tube pressure induced by bilateral phrenic nerve stimulation during airway occlusion (Ptr,stim) in sub-study C. Phrenic nerve stimulation was performed by bilateral anterior magnetic stimulation as reported elsewhere 4,[START_REF] Dres | Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients[END_REF] (see the Supplemental Digital Content that displays a detailed description of the technique).

Subjects and studies design

-! -

The study was made of three sub-studies named A, B and C.

Study A was a physiological study dedicated to evaluate the reproducibility and values of parasternal intercostal muscle thickness and TFic in healthy subjects. Parasternal intercostal muscle ultrasound was performed at the following pressure support levels applied in a random sequence order: 5, 10, 15 and 20 cmH2O while positive end-expiratory pressure (PEEP) was set to 5 cm H2O. In addition, a last -! -condition was studied with a pressure support of 7 cmH2O and PEEP set to 0 cm H2O.

Inspired fraction of O2 was set to 30% in all cases and was not changed during the study. Investigators conducting ultrasound measurements were blinded to ventilator settings. Each condition was maintained for ten minutes and ultrasound measurements were performed during the last two minutes. Ultrasound measurements were performed by a physician with experience in respiratory muscle ultrasound. A fiveminute resting period during which the initial ventilator settings were reapplied was allowed between conditions.

Study C was part of a clinical study conducted in mechanically ventilated patients within the Respiratory and Critical Care Department, Hôpital Pitié Salpêtrière, Paris. 12 Some data from this cohort have been published elsewhere. [START_REF] Dubé | Ultrasound evaluation of diaphragm function in mechanically ventilated patients: comparison to phrenic stimulation and prognostic implications[END_REF][START_REF] Dres | Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients[END_REF][START_REF] Dres | Diaphragm function and weaning from mechanical ventilation: an ultrasound and phrenic nerve stimulation clinical study[END_REF] This primary study aimed to determine the prevalence and impact of diaphragm dysfunction at the time of weaning and to evaluate the potential interest of respiratory muscles ultrasound in mechanically ventilated patients. Study C aimed at investigating the relationship between TFic and diaphragm pressure-generating capacity as well as weaning outcome. Study C enrolled patients prospectively over an eight-months period. Patients were eligible if they had been mechanically ventilated through an endotracheal tube for >24 hours and were deemed ready to undergo a first spontaneous breathing trial as decided by their attending physician according to criteria derived from the International Conference on Weaning (see the Supplemental Digital Content for a full description of the weaning protocol). [START_REF] Boles | Weaning from mechanical ventilation[END_REF] Non-inclusion criteria for this study were mainly related to contraindication to magnetic stimulation of the phrenic nerves. Diaphragm function was assessed in term of change in Ptr,stim. 4 A -! -Ptr,stim <11 cmH2O was used to define diaphragm dysfunction. 4,[START_REF] Dres | Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients[END_REF] Following this, parasternal intercostal ultrasound and diaphragm ultrasound was performed while patients were ventilated under pressure support ventilation with PEEP of 5 cmH2O and pressure support set to reach a tidal volume of 6-8 ml/kg of predicted ideal body weight. Then, a 30-minutes spontaneous breathing trial performed under a pressure support of 7 cmH2O and PEEP set to zero was performed. The spontaneous breathing trial was defined as successful if patients had no sign of clinical intolerance during all the 30-minutes period. Otherwise, the spontaneous breathing trial was defined as a failure. In a subset of 15 patients from this sub-study, ultrasound measurement of end expiratory thickness and peak inspiratory thickness and TFic were assessed by two observers to assess inter-observer reliability.

Statistical analyses

Normality of the distribution of variables was assessed using the Kolmogorov-Smirnov test. Variables are presented as median (interquartile range) or number (%).

All three studies were conducted prospectively and index tests were planned before data collection. Two observers performed ultrasound to assess reproducibility of parasternal intercostal muscle measurements in healthy (study A) and in patients (study C). Reproducibility of diaphragm ultrasound has been reported elsewhere [START_REF] Goligher | Measuring diaphragm -! -thickness with ultrasound in mechanically ventilated patients: feasibility, reproducibility and validity[END_REF][START_REF] Vivier | Diaphragm ultrasonography to estimate the work of breathing during non-invasive ventilation[END_REF] .

For Study A, intra-and inter-rater reliability was analysed using intra-class correlation coefficient for parasternal intercostal end expiratory thickness, peak inspiratory thickness and TFic. Parasternal intercostal end expiratory thickness, peak inspiratory thickness and TFic between females and males were compared by Mann--! -Whitney test. As an exploratory study, sample size was estimated from previous publications [START_REF] Vivier | Diaphragm ultrasonography to estimate the work of breathing during non-invasive ventilation[END_REF][START_REF] Umbrello | Diaphragm ultrasound as indicator of respiratory effort in critically ill patients undergoing assisted mechanical ventilation: a pilot clinical study[END_REF][START_REF] Dinino | Diaphragm ultrasound as a predictor of successful extubation from mechanical ventilation[END_REF] and a convenience sample of 23 subjects was deemed necessary.

For study B, Friedman test and Dunn's multiple comparisons was used to compare the different values of TFic and TFdi across conditions. Sample size was estimated from previous publications [START_REF] Vivier | Diaphragm ultrasonography to estimate the work of breathing during non-invasive ventilation[END_REF][START_REF] Sklar | High-flow nasal oxygen versus noninvasive ventilation in adult patients with cystic fibrosis: a randomized crossover physiological study[END_REF] and a convenience sample of 16 patients was deemed necessary.

For study C, the relationship between Ptr,stim and TFic was evaluated using Spearman correlation. Differences between patients with and without diaphragm dysfunction and between those with spontaneous breathing trial failure or success were assessed using Mann-Whitney test or chi-square tests, where appropriate. The manuscript conforms to the "Essential Items for Reporting Diagnostic Accuracy

Studies" checklist for reporting of studies of diagnostic accuracy. [START_REF] Bossuyt | STARD 2015: updated reporting guidelines for all diagnostic accuracy studies[END_REF] The relationship between TFic and TFdi was assessed by computing the ratio TFic/TFdi. Receiver

Operating Characteristic curves were constructed to evaluate the performance of four indices to predict weaning failure: Ptr,stim, TFdi, TFic and TFic/TFdi ratio.

Sensitivities, specificities, positive and negative predictive values, positive and negative likelihood ratios and areas under the Receiver Operating Characteristic curves were calculated. Areas under the receiver operating characteristic curves were performed to identify optimal cut-off values in predicting failure, and these estimates were obtained using bootstrapping with 1000 replications. The best threshold value for each index was determined as the value associated with the best Youden index for the prediction of failure. Areas under the receiver operating characteristic curves were compared using the non-parametric approach of DeLong et al. [START_REF] Delong | Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach[END_REF] Inter-observer -! -reliability of the parasternal intercostal muscle ultrasound measurements was assessed using intra-class coefficient correlation in a subset of 15 patients. In this cohort, inter-observer reliability of the diaphragm ultrasound measurements has already been reported elsewhere. [START_REF] Dubé | Ultrasound evaluation of diaphragm function in mechanically ventilated patients: comparison to phrenic stimulation and prognostic implications[END_REF] There was no missing data nor loss of follow-up. In all cases, a p-value <0.05 was considered statistically significant and two-tailed testing was used to test hypothesis. All analyses were performed using SPSS, v.21 (IBM, Chicago, Illinois, USA) and MedCalc Software (bvba, Ostend, Belgium).

-! -

Results

Sub-study A: healthy subjects

Twenty-three subjects were recruited. Values of parasternal intercostal end expiratory thickness and peak inspiratory thickness were higher in men than in women, but values of TFic were similar between genders (Table 1). Intra-Class coefficient correlation between observers for the measurements of parasternal intercostal end expiratory thickness and peak inspiratory thickness were 0.92 (CI 95%: 0.82 to 0.96) and 0.92 (CI 95% 0.82 to 0.96) respectfully and only 0.77 (CI 95% 0.53 to 0.89) for TFic, but TFic values were very low in these healthy subjects at rest (median 3%, CI 95%: 2 to 5) (Figure 3). Table E1, Supplemental Digital Content 1, displays the intra-class correlation coefficients of parasternal intercostal muscle ultrasound measurements.

Study B: Parasternal intercostal muscle responsiveness to ventilatory support

Sixteen patients participated in the study B (see Figure 1 that shows the flow chart of the study). Their main characteristics are described in Table 2 2. Among them, 33 (61%) had diaphragm dysfunction and 21 (39%) did not. Pressure Support and PEEP level were similar in the two groups, but tidal volume was lower in patients with diaphragm dysfunction (Table 3). Table E1 in Supplemental Digital Content 1 displays the intra-class correlation coefficients of parasternal intercostal muscle ultrasound measurements.

Relationship between parasternal intercostal muscle and diaphragm function

Patients with diaphragm dysfunction had higher TFic compared to patients without diaphragm dysfunction (Table 3). There was a inverse curvilinear correlation between Ptr,stim and TFic (Spearman rho=-0.79 (CI 95%: -0.87 to -0.66), p<0.0001, see Figure 4).

Relationship between parasternal intercostal muscle, diaphragm function and weaning outcome

Among the 54 included patients, 22 (41%) failed the spontaneous breathing trial (Table 4). Patients who failed spontaneous breathing trial had lower Ptr,stim value, lower TFdi, higher TFic and lower TFic/TFdi ratio (Table 4). Predictive performances and best cut-offs of the four indices to predict failure are displayed in Table 5. No difference was found between areas under the receiver operating characteristic curves of the four indices (See Table E2 in Supplemental Digital Content 1, that shows the comparison of areas under the receiver operating characteristic curves of the four indices to predict spontaneous breathing trial failure).

-! -

Discussion

The main findings are summarized as follows: 1) measurement of TFic was feasible and reproducible, 2) TFic was responsive to respiratory load, 3) a greater TFic under pressure support ventilation was associated with diaphragm dysfunction and failure of a spontaneous breathing trial and 4) TFic in combination with TFdi gave similar information than TFic alone.

Anatomy and physiology of intercostal muscles

The intercostal muscles form two thin layers that span each of the intercostal spaces. Ventrally, between the sternum and the chondrocostal junctions, the external intercostal muscles are replaced by a fibrous aponeurosis conventionally called the "parasternal intercostal muscles". In dogs, parasternal intercostal denervation significantly decreases the expansion of the rib cage during inspiration. [START_REF] Troyer | Inspiratory elevation of the ribs in the dog: primary role of the parasternals[END_REF] In humans, electrophysiological data suggest that parasternal intercostal muscles have an inspiratory mechanical advantage and that this advantage decreases gradually from the second to the fifth interspace. 24 The parasternal intercostal muscles are active only during the inspiratory phase of the breathing cycle and interact together with the diaphragm and other extra-diaphragmatic inspiratory muscles. By contrast to other extra-diaphragmatic inspiratory muscles such as scalens or sternocleidomastoids located in the neck, the ultrasound window of parasternal intercostal has the advantage to be usually free of health care equipment (tracheostomy, intravascular lines). This study endeavored to investigate with ultrasound the parasternal intercostal activity.

TFic as a bedside indicator of the respiratory load -capacity balance

-! -Extra diaphragmatic inspiratory muscles are responsive to respiratory load. [START_REF] Raper | Scalene and sternomastoid muscle function[END_REF][START_REF] De Troyer | Neck muscle activity in patients with severe chronic obstructive pulmonary disease[END_REF] In the ICU, extra diaphragmatic inspiratory muscle electromyogram activity is a surrogate of respiratory drive. 3 As a matter of fact, increased extra diaphragmatic inspiratory muscle electromyogram activity is associated with insufficient level of inspiratory pressure support during weaning from mechanical ventilation [START_REF] Brochard | Inspiratory pressure support prevents diaphragmatic fatigue during weaning from mechanical ventilation[END_REF] , weaning failure 8 , and dyspnea. 3 In addition, the electromyographic activity of the parasternal intercostal muscle, is a marker of treatment response and predicts the outcome during acute exacerbation of COPD. [START_REF] Suh | Neural respiratory drive predicts clinical deterioration and safe discharge in exacerbations of COPD[END_REF][START_REF] Murphy | Neural respiratory drive as a physiological biomarker to monitor change during acute exacerbations of COPD[END_REF] Our results confirm these data as we report a dose response relationship between parasternal intercostal muscle thickening fraction and respiratory load (study B). This relationship suggests that the parasternal intercostal muscle thickening fraction is a relevant tool to assess the load/capacity balance in critically ill patients. Our approach was to use ultrasound, a non-invasive tool, widely available and that provides a real time assessment of muscle contraction. Data on parasternal intercostal muscle ultrasound are scarce. In an animal model, ultrasound morphometric assessment of the intercostal parasternal muscle was similar to measurement performed directly on the specimen, demonstrating the ability of ultrasound to accurately estimate the anatomical structure of the parasternal intercostal muscle. [START_REF] Diab | A method for morphometric study of the intercostal muscles by high-resolution ultrasound[END_REF] In addition, the good inter-observer repeatability of the ultrasound measurement of parasternal intercostal muscle thickness has also been reported in humans 10, [START_REF] Diab | A method for morphometric study of the intercostal muscles by high-resolution ultrasound[END_REF][START_REF] Cala | Respiratory ultrasonography of human parasternal intercostal muscle in vivo[END_REF] and are in line with our own reproducibility findings. It suggests that ultrasound measurement of parasternal intercostal thickness and thickening fraction is feasible and reproducible, and that the technique can reliably be employed. Remarkably, the parasternal intercostal muscle thickness was higher for -! -the ICU patients than for the healthy subjects but similar to what has been reported in COPD patients. 10 While the exact reasons of this increase in thickness is unclear (edema, inflammation, injury), it may reflect an over-recruitment of the extradiaphragmatic muscles that occurs in the intensive care unit patients. Further studies will have to specifically focus on this point.

Relationship between TFic and diaphragm function

The relationship between diaphragm function and the recruitment of extradiaphragmatic inspiratory muscles has been described in animal models and in humans, although few data are available in intensive care unit patients. [START_REF] Parthasarathy | Sternomastoid, rib cage, and expiratory muscle activity during weaning failure[END_REF][START_REF] Ninane | Mechanism of rib cage inspiratory muscle recruitment in diaphragmatic paralysis[END_REF][START_REF] Brichant | On the intercostal muscle compensation for diaphragmatic paralysis in the dog[END_REF][33][START_REF] Macklem | Partitioning of inspiratory pressure swings between diaphragm and intercostal/accessory muscles[END_REF] The diaphragm is the main inspiratory muscle and diaphragm dysfunction elicits a series of adaptive mechanisms that enable ventilation and pulmonary gas exchange to be maintained within reasonable limits. Patients with chronic diaphragm dysfunction exhibit an increase in extra-diaphragmatic inspiratory muscles contraction that is associated with respiratory discomfort. [START_REF] Similowski | Diaphragmatic dysfunction and dyspnoea in amyotrophic lateral sclerosis[END_REF][START_REF] Ward | Respiratory sensation and pattern of respiratory muscle activation during diaphragm fatigue[END_REF] Conversely, diaphragm paralysis results in a marked increase in parasternal intercostal muscle activity while minute ventilation is relatively unaffected. [START_REF] Ninane | Mechanism of rib cage inspiratory muscle recruitment in diaphragmatic paralysis[END_REF][START_REF] Nochomovitz | Respiratory responses in reversible diaphragm paralysis[END_REF] In situation of high respiratory drive, diaphragm dysfunction is associated with a significant increase in the contractile activity of the extradiaphragmatic respiratory muscles. [START_REF] Ninane | Mechanism of rib cage inspiratory muscle recruitment in diaphragmatic paralysis[END_REF][START_REF] Brichant | On the intercostal muscle compensation for diaphragmatic paralysis in the dog[END_REF] The extra diaphragmatic respiratory muscles recruitment is therefore a mechanism of compensation that can be activated in presence of diaphragm dysfunction. We evidenced this mechanism in our patients by showing a higher TFic in those who had a diaphragm dysfunction as compared to their counterparts. Difference between groups was very clear as the TFic value in patients with diaphragm dysfunction was on average three times higher than in patients -! -without diaphragm dysfunction. Moreover, we observed a negative curvilinear relationship between TFic and diaphragm function. It suggests an exponential increase in TFic under a critical value of Ptr,stim. In our patients, this value appeared lower than the Ptr,stim-threshold that classically defines diaphragm dysfunction. This finding suggests that the recruitment of parasternal intercostal muscle may start before diaphragm dysfunction -as it is classically defined [START_REF] Murphy | Neural respiratory drive as a physiological biomarker to monitor change during acute exacerbations of COPD[END_REF][START_REF] Diab | A method for morphometric study of the intercostal muscles by high-resolution ultrasound[END_REF] -is fully constituted.

Subsequently, documenting such recruitment by ultrasound may encourage clinicians to raise the hypothesis of a diaphragm dysfunction. Alternatively, it may also indicate underassistance and may encourage caregivers to optimize the ventilator settings.

TFic, diaphragm thickening fraction and weaning outcome

Diaphragm function is an important determinant of spontaneous breathing trial outcome. However, investigating diaphragm function at bedside in the intensive care unit setting may be a challenge. [START_REF] Dres | Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients[END_REF][START_REF] Mcconville | Weaning patients from the ventilator[END_REF] Diaphragm thickening fraction can be used as a surrogate of diaphragm function and is a reliable predictor of spontaneous breathing trial outcome. 5 However, a recent study highlighted that diaphragm ultrasound doesn't allow to predict extubation failure [START_REF] Vivier | Inability of diaphragm ultrasound to predict extubation failure: a multicenter study[END_REF] , justifying to explore extradiaphragmatic muscles. In the present study, we sought to examine whether either TFic or the addition of TFic to TFdi would improve the prediction of the trial outcome. Intercostal thickening fraction was higher in patients who failed the trial and appears to predict reasonably well the outcome of the spontaneous breathing trial, in the opposite fashion than TFdi (the higher the TFic, the worse the outcome). However, TFic did not perform better than TFdi, and neither did the combination of both indices.

Nevertheless, we believe our findings are of importance since diaphragm ultrasound is -! -not always feasible and TFic could be an interesting alternative. Documenting an increased TFic before starting the spontaneous breathing trial could be relevant insofar it may encourage caregivers to search for a reason susceptible to destabilize the respiratory load/capacity balance.

As per our results in healthy breathing at rest, TFic is expected to be as low as possible. Otherwise, it may be the sign of extra-diaphragmatic respiratory muscles recruitment suggesting inappropriate patient's inspiratory effort. This may be potentially relevant in context of increasing awareness of the adverse effects of both strong and weak respiratory efforts during mechanical ventilation on patient outcome [START_REF] Vaporidi | Respiratory Drive in Critically Ill Patients: Pathophysiology and Clinical Implications[END_REF] . Since monitoring patient inspiratory effort is rarely done in routine because it requires invasive procedure (esophageal catheter), performing parasternal intercostal ultrasound could be an alternative approach to provide a qualitative estimate of high inspiratory effort.

Limits

Our study has limitations. First, all ultrasound procedures were performed on the right side only in the study. This approach was chosen to facilitate the acquisition of ultrasound images. In addition, we assumed TFic of the right parasternal intercostal muscle to be a surrogate of the overall parasternal intercostal function since we did not assess all parasternal intercostal muscles separately. This approach is however usually taken in such physiological studies, in particular when using electromyogram. [START_REF] Murphy | Neural respiratory drive as a physiological biomarker to monitor change during acute exacerbations of COPD[END_REF] Second, TFic cut-off to predict spontaneous breathing trial outcome was determined while patients were receiving a standardized amount of ventilator support (i.e.

pressure-support level targeting a tidal volume of 6-8 ml/kg of ideal body weight).

-! -Therefore, this cut-off may be only valid in the ventilatory conditions under which measurements were performed. Such ventilatory settings, however, are in line with common practices and recommendations in the ICU setting and therefore are easily generalizable. Third, the causes of spontaneous breathing trial failure were not documented and it is likely that several reasons may explain the failure of the spontaneous breathing trial. However, the ultrasound measurements were made before conducting the spontaneous breathing trial while the patients were supposed to be adequately assisted. Therefore, the use of ultrasound to detect situations at high risk of spontaneous breathing trial failure remains clinically relevant whatever the causes of failure. Fourth, while the use of respiratory muscles ultrasound is growing in the intensive care unit, it remains challenging to generalize its use to nonexpert operators. Currently, there is no standard definition of adequate training. As a monocentric and pilot study, our findings warrant further confirmation with a larger number of patients and non-expert ultrasound observers.

Conclusion

Parasternal intercostal muscle ultrasound appears feasible and potentially helpful in mechanically ventilated patients to estimate inadequate inspiratory efforts in case of unbalanced load/capacity respiratory capacity. In the context of increasing awareness of the risk of overestimation and underestimation of patient's inspiratory effort, parasternal intercostal muscle and diaphragm ultrasound may constitute a valuable alternative to the classical invasive monitoring tools.

-! - -! -

METHODS

Study B

Decision to initiate pressure-support ventilation.

Patients were considered ready to be placed on pressure-support ventilation if they could sustain this mode for at least 1 hour with: 1 1) pressure support ≤24 cmH2O

2) positive end-expiratory pressure ≤12 cmH2O

3) total level of inspiratory pressure <30 cmH2O 4) respiratory rate ≤24/min 5) tidal volume ≥5 ml/kg ideal body weight, without signs of labored breathing, as defined by retractions or recessions -sucking in of the skin around the ribs and the top of the sternum, or prominent use of accessory respiratory muscles.

Study C

Readiness criteria to undergo a first spontaneous breathing trial

The criteria used to assess the readiness for weaning were derived from the International Conference on Weaning: 2 1) adequate oxygenation (SpO2 >90% on a fraction of inspired oxygen ≤40%

and positive end expiratory pressure ≤8 cmH2O)

2) respiratory rate ≤35/min 3) a cooperative cognitive state 4) stable cardiovascular status (systolic arterial blood pressure of 90-160 mmHg without or minimal vasopressors and heart rate ≤140/min) -! -Contraindications to magnetic stimulation of the phrenic nerves 1) cardiac pacemaker or defibrillator 2) cervical implants 3) cervical spine injury

4) pregnancy

Non-inclusion criteria for study C 1) suspicion of underlying hemi-diaphragm paralysis (defined as an elevation of >2.5 cm of one hemi-diaphragm compared to the other on chest radiograph),

2) pre-existing neuromuscular disorders,

3) age <18 years and 5) decision to withhold life-sustaining treatment.

Criteria defining failure of the spontaneous breathing trial

The criteria of failure of the spontaneous breathing trial were derived from the International Conference on Weaning. 2 The spontaneous breathing trial was considered to be a failure if at least one the following criteria was present:

1) blood oxygen saturation (SpO2) of < 90 % with a fraction of inspired oxygen (FiO2) ≥ 50 %;

2) acute respiratory distress (RR ≥ 40/min, agitation, cyanosis);

3) systolic arterial blood pressure of ≥ 180 mmHg;

-! - If none of these failure criteria was present, the spontaneous breathing trial was considered as successfully completed.

Measurements

Parasternal intercostal muscle ultrasound. Patients and subjects were studied in a semi-recumbent position. A 10-15 MHz linear array transducer (Sparq ultrasound system, Phillips, Philips Healthcare, Andover, MA, USA for patients and HFL-38xe, FUJIFILM Sonosite, Bothell, WA, USA for healthy subjects) was positioned perpendicular to the anterior thorax surface in the sagittal plane, at the level of the second right intercostal space, approximately 6-8 cm lateral to the sternal edge with a window visualising the 2 nd and 3 rd ribs. This intercostal space was chosen as the inspiratory effect of the external parasternal intercostal muscle is maximal at this location, compared to more caudal interspaces. 3 The second right parasternal intercostal muscle was identified as a three-layered biconcave structure: two linear hyperechoic membranes respectively running from the anterior and posterior aspects of the adjoining ribs, and a medial portion with muscle echotexture (Figure 1). Considering that during inspiration the muscle fibers of the parasternal intercostal contract, displacing the rib cage cranially and anteriorly 3 and that their mass remains constant, an increase in thickness of the muscular structure can be visualized -! -

  Hospital, Toronto, Canada and at the Respiratory and Medical Critical Care Department, Hôpital Pitié-Salpêtrière, Paris, France (Figure 1 which displays characteristics of each sub-study). Across three studies, parasternal intercostal ultrasound was performed in different conditions. All subjects, or their next of kin in the case of the critically ill patients, provided written informed consent. The study was approved by the Institutional Review Boards at both participating institutions (CPP6/84-14 -2014-A01168-39, CPP6/52-14 -2014-A00715-42 and Toronto University Health Network: 15-8998) and has been performed in accordance with the ethical standards laid down in the 2008 Declaration of Helsinki. Measurements Parasternal intercostal muscle ultrasound. The full detailed method for right parasternal intercostal ultrasound is reported in the Supplemental Digital Content. A 10-15 MHz linear array transducer was positioned perpendicular to the anterior thorax surface in the longitudinal scan, at the level of the second right intercostal space, approximately 6-8 cm lateral to the sternal edge with a window visualising the 2 nd and 3 rd ribs. The second right parasternal intercostal muscle was identified as a threelayered biconcave structure: two linear hyperechoic membranes respectively running from the anterior and posterior aspects of the adjoining ribs, and a medial portion with muscle echotexture (see Figure 2 and Video E1 in the Supplemental Digital Content which is a cine-loop of the parasternal intercostal ultrasound). Using M-mode, -! -the ultrasound beam was perpendicularly directed at the midsection of the muscle, where it is the thinnest at end-expiration. The thickness of the parasternal intercostal muscle was measured on frozen images at end-expiration and at peak inspiration. Change in thickness determined the thickening fraction of the parasternal intercostal muscle (TFic) as follows: TFic equals peak inspiration thickness minus end expiratory thickness divided by end expiratory thickness. All measurements were repeated on at least three separate breaths and their average was reported. For the sake of feasibility and convenience, ultrasound was performed on the right parasternal intercostal muscle only. Diaphragm ultrasound. Diaphragm ultrasound was conducted using a 4-12 MHz linear array transducer (Sparq ultrasound system, Phillips, Philips Healthcare, MA, USA). Diaphragm thickness was measured at end-expiration and at peak inspiration and thickening fraction (TFdi) was calculated offline as follows: TFdi equals peak inspiration thickness minus end expiratory thickness divided by end expiratory thickness. The full detailed method for diaphragm ultrasound has been reported

  . The highest TFic and TFdi were measured with Pressure Support level of 7 cmH2O and PEEP 0 cmH2O and the lowest TFic and TFdi were measured with Pressure Support level of 20 cmH2O and PEEP 5 cmH2O (Figure 2 and Figure E1 in Supplemental Digital Content 1 that displays the simultaneous changes in TFdi and TFic). There was a correlation between Pressure Support level and TFic (Spearman rho=-0.61 (CI 95%: -0.74 to -0.44), p<0.0001). Study C: Parasternal intercostal muscle, diaphragm function and weaning outcome -! -Of the 294 patients admitted during the study period, 54 were enrolled in study C (see Figure 1 that shows the flow chart of the study). Patients characteristics are displayed in Table

Figure 1 .Figure 2 .

 12 Figure 1. Characteristics and flow chart of each sub-study SBT: spontaneous breathing trial, PS: pressure support

Figure 3 .

 3 Figure 3. Parasternal intercostal muscle thickening fraction (TFic) (median, interquartile) at various levels of pressure support (PS) and positive end-expiratory pressure (PEEP), zero end-expiratory pressure (ZEEP) and in the 23 healthy subjects breathing at rest (grey bar). * p<0.05 as compared to PS 7 and ZEEP.

Figure 4 .-Figure SDC1 .- 1 *Figure SDC2 .

 4SDC11SDC2 Figure 4. Relationship between parasternal intercostal muscle thickening fraction (TFic) and diaphragm pressure generating capacity as assessed with bilateral anterior magnetic stimulation of the phrenic nerves (Ptr,stim). The dotted line represents the Ptr,stim-cut-off of 11 cmH2O under which diaphragm dysfunction is classically defined (2).

4) cardiac arrhythmias; 5 )

 5 respiratory acidosis [pH<7.32 with an arterial carbon dioxide tension (PaCO2) of ≥50 mmHg].

  using ultrasound. Using M-mode, the ultrasound beam was perpendicularly directed at the midsection of the muscle, where it is the thinnest at endexpiration. The thickness of the parasternal intercostal muscle was measured on frozen images at end-expiration (Tee) and at peak inspiration (Tei). TFic was defined as the percent change in muscle thickness between expiration and inspiration. This change in thickness determined the thickening fraction of the parasternal intercostal muscle (TFic = (Tei -Tee)/Tee). All measurements were repeated on at least three separate breaths and their average was reported.For the sack of feasibility, ultrasound was performed on the right parasternal intercostal muscle only. Ultrasound measurements were performed by MD, BPD and SV.Phrenic nerve stimulation methodDiaphragm pressure generating capacity was assessed in terms of changes in endotracheal tube pressure induced by bilateral phrenic nerve stimulation during airway occlusion (Ptr,stim). Phrenic nerve stimulation was performed by bilateral anterior magnetic stimulation. In brief, two figure-of-eight coils connected to a pair of Magstim® 200 stimulators (The Magstim Company, Dyfed, UK) were positioned immediately posterior to the sternomastoid muscles at the level of the cricoid cartilage. Stimulations were delivered at the maximum output intensity of the stimulator (100%) that is known to consistently result in supramaximal phrenic contraction.[4][5][6][7] Patients were studied in a standardized semi-recumbent position, as follows: end-expiratory pressure was set to zero and the patient was allowed to exhale during an end--! -expiratory pause. Intrinsic positive end expiratory pressure was found when at relaxed end-expiration, the endotracheal pressure could not reach the zero baseline while the endotracheal tube was disconnected from the ventilator, manually occluded and by checking the absence of respiratory effort. While the endotracheal tube was manually occluded, bilateral anterolateral magnetic stimulation was performed. The absence of active respiratory efforts in response to stimulation was determined by checking the stability of the airway pressure signal. Two operators were required to achieve both stimulation and measurements. After determining the optimal position of the coils, at least three stimulations were performed at 100% of maximal output allowed by the stimulator. Stimulations were separated by at least 60-sec to avoid superposition. The average of the three measures was taken into account for analysis. Ptr,stim was defined as the amplitude of the negative pressure wave following stimulation, taken from baseline to peak. It was measured at the proximal external end of the endotracheal tube, using a linear differential pressure transducer (MP45 ±100 cmH2O, Validyne, Northridge, Calif., USA). The pressure signal was sampled and digitized at 128 Hz (MP30, Biopac Systems, Santa Barbara, Calif., USA or Powerlab, AD Instruments, Bella Vista, Australia) for subsequent data analysis.-! -nerve stimulation in patients in the intensive care unit. Crit Care Med 2001; Intra-class correlation -intra-observer variations of parasternal intercostal muscle ultrasound measurements in healthy subjects (study A) and patients (study C) Tee: parasternal intercostal end-expiratory thickness; Tei: parasternal intercostal end-inspiratory thickness; TFic: parasternal intercostal muscle thickening fraction; ICC: intra-class correlation coefficient; CI: confidence interval

Table E2 .

 E2 Comparison of ROC curves of the four indices to predict spontaneous

			Intra-Observer #1	Intra-Observer #2	Inter-Observer
					IC		IC
			ICC	95% CI	C	95% CI	C	95% CI
	Stu	Tee	0.97 0.94 to 0.99	0.	0.94 to 0.99	0.	0.82 to 0.96
	dy				97		92
	A	Tei	0.97 0.94 to 0.99	0.	0.92 to 0.99	0.	0.82 to 0.96
					97		92
		TFic 0.86 0.68 to 0.94	0.	0.12 to 0.77	0.	0.53 to 0.89
					52		77
	Stu	Tee	0.79 0.48 to 0.92	0.	0.92 to 0.99	0.	0.60 to 0.94
	dy				97		84
	C	Tei	0.91 0.77 to 0.97	0.	0.93 to 0.99	0.	0.88 to 0.98
					97		95
		TFic 0.92 0.78 to 0.97	0.	0.77 to 0.97	0.	0.78 to 0.97
					92		92
	breathing trial failure
					Comparison with
					-! -

Table 1 .

 1 Characteristics and parasternal intercostal muscle measurements in healthy subjects (study A)Comparisons were made between Males and Females (Mann-Whitney test).

		All	Male	Female	p
	Characteristics, n	23	11	12
	Age, years	27 (25 to 36) 34 (26 to 36) 26 (24 to 29)	0.956
	Weight, kg	67 (59 to 75) 75 (72 to 82) 60 (57 to 65) <0.0001
	Height, cm	1.70 (1.62 to	1.81 (1.70 to	1.63 (1.60 to	0.001
		1.81)	1.85)	1.71)
	Body Mass index, kg/	23 (21 to 25) 24 (23 to 26) 22 (20 to 24)	0.087
	m 2
	Intercostal muscle
	ultrasound
	E n d -i n s p i r a t o r y	2.8 (2.2 to	3.3 (2.6 to	2.2 (2.0 to	<0.0001
	thickness, mm	3.4)	3.8)	2.8)
	E n d -e x p i r a t o r y	2.8 (2.1 to	3.3 (2.8 to	2.1 (1.9 to	<0.0001
	thickness, mm	3.3)	3.9)	2.8)
	Thickening fraction,	3 (2 to 5)	3 (2 to 5)	3 (0 to 5)	0.732
	%

Table 3 . Characteristics of patients (study C) according to the presence of diaphragm dysfunction

 3 Data presented as n (%) or median (interquartile). MV; mechanical ventilation; SBT; spontaneous breathing trial; PEEP, positive end-expiratory pressure; PBW, predicted body weight; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen; FiO2, inspired fraction of oxygen; Ptr,stim, airway opening pressure in response to bilateral phrenic nerve stimulation; TFdi, diaphragm thickening fraction, TFic, parasternal intercostal muscle thickening fraction

	Diaphragm	No diaphragm	p
	dysfunction	dysfunction
	(n=33)	(n=21)

Table 5 . Threshold, area under the receiver operating characteristics curves (AUC-ROC), sensitivity, specificity, positive and negative likelihood ratios and positive and negative predictive values of endotracheal pressure induced by a bilateral phrenic nerve stimulation (Ptr,stim), diaphragm thickening fraction (TFdi), parasternal intercostal muscle thickening fraction (TFic) and TFic/TFdi ratio to predict failure of the spontaneous breathing trial.

 5

		Thresh old	AUC-ROC (95% CI)	Sensitivity (%) (95% CI)	Specificity (%) (95% CI)	Likelihood ratios (95% CI) Positive Negative	Predictive Values (%) (95% CI) Positive Negative
	P t r, s t i	7.5	0.91 (0.80 to	91 (71 to	81 (64 to	4.85 (2.30 to	0.11 (0.03 to	77 (62 to	93 (77 to
	m	cmH2O	0.97)	99)	93)	10.10)	0.40)	87)	98)
	TFdi	28.7 % 0.88 (0.77 to	95 (77 to	72 (53 to	3.39 (1.90 to	0.06 (0.01 to	70 (57 to	96 (77 to
			0.95)	100)	86)	5.90)	0.40)	80)	99)
	TFic	9.5 % 0.88 (0.76 to	91 (71 to	72 (53 to	3.23 (1.80 to	0.13 (0.03 to	69 (56 to	92 (75 to
			0.95)	99)	86)	5.70)	0.50)	80)	98)
	T F i c /	0.35	0.92 (0.81 to	100 (85 to	78 (60 to	4.62 (2.40 to	0.02 (0.01 to	76 (62 to	100 (100 to
	TFdi		0.98)	100)	91)	8.80)	0.20)	86)	100)
	CI: Confidence interval.
					-! -1

Funding Statement MD was supported by The French Intensive Care Society (SRLF bourse de mobilité 2015); The 2015 Short Term Fellowship program of the European Respiratory Society; The 2015 Bernhard Dräger Award for advanced treatment of ARF of the European Society of Intensive Care Medicine; The Assistance Publique Hôpitaux de Paris; The Fondation pour la Recherche Médicale (FDM 20150734498) and by Mitacs Globalink Sorbonne Universités. BPD was supported by a research grant from the Réseau en Santé Respiratoire du Québec and by fellowship grant from the Centre Hospitalier de l'Université de Montréal. AD reports personal fees and non-financial support from Medtronic, grants, personal fees and non-financial support from Philips, personal fees from Baxter, personal fees from Hamilton, grants and non-financial support from Fisher & Paykel, grants from French Ministry of Health. MD received personal fees from Lungpacer Inc. BPD received personal fees from Grifols, Boehringer Ingelheim and Roche, and has signed clinical research contracts with Sanofi, Roche and Boehringer Ingelheim. Thomas Similowski has received personal fees from Lungpacer Inc. and is a member of the board of a research association that has received, over the past ten years, unrestricted research grants from Maquet, Hamilton, Covidien, and Philips; he is the head of a research unit (UMRS 1158) that has signed research contracts with Air Liquide Medical Systems, France; he is listed as inventor or co-inventor on several patents, granted or pending, describing a brain-ventilator interface. LB's Research Laboratory received research grants from Covidien, General Electric, Fisher Paykel, Maquet (with St Michael's Hospital) and Philips.

Conflict of interest Statements

-! -Ptr,stim: endotracheal pressure induced by a bilateral phrenic nerve stimulation, TFdi: diaphragm thickening fraction; TFic: parasternal intercostal muscle thickening fraction; AUC: area under the receiver operating characteristics curves; CI: confidence interval

P h y s i o l o g i c v a r i a b l e s a t inclusion

Heart rate, min -


Sloane Evariste

Ali Moustafa Khalil

Sebastien Kerneis

Chendong Xu

Guillaume Calvez

Karine Costuas

Christophe Lescop

Luminescent vapochromic single crystal to single crystal transition in onedimensional coordination polymer featuring the first Cu(I

Luminescent vapochromic single crystal to single crystal transition in one-dimensional coordination polymer featuring the first Cu(i) dimer bridged by an aqua ligand

Introduction

The design and the study of luminescent material based on coordination metal complexes attract a great attention due to the manifold fields of application that these derivatives can address.

1 In this field, Cu(I) coordination complexes supply a very fertile environment for impressive developments because of the fascinating and various photophysical properties they can exhibit. 1a,2 While these derivatives focus currently great attention for the preparation and study of innovative emitters in OLEDs, 2a they deserve also interest as new sources of stimuli responsive multifunctional luminescent materials. 2b Indeed, the large flexibility and lability of Cu(I) ion coordination sphere render the gross conformation of Cu(I) species potentially very sensitive to external stimuli, which concomitantly induces alteration of their photophysical properties. Therefore, Cu(I)based luminophors present multiple and original facets 3 (such as thermochromic and vapochromic luminescence) that are of great interest in various fields of applications such as sensoring and detection of volatile harmful chemical substances or nondestructive testing of materials.

Regarding specifically Cu(I)-based solid-state vapochromic luminescent luminophores, it is assumed that the origin of their vapochromic properties is due either to structural transitions occurring along desorption/adsorption processes of volatile molecules within porous Cu(I)-based materials, 3a,b or to reversible coordination/de-coordination of these molecules 3c on coordinatively-unsaturated Cu(I) metal centers.

In all cases, these events impact reversibly the electronic structure of the assemblies in their ground and photo-excited states, inducing the luminescence vapochromic effect. Among the manifold Cu(I) complexes reported so far, there are remarkably few stable Cu(I) complexes described in which the metal center is coordinated to a terminal aqua ligand. 4 Herein, Scheme 1 Synthesis of derivative C 1,2 [START_REF] Nohra | Coordination Polymers with -Stacked Metalloparacyclophane Motifs: F-Shaped Mixed-Coordination Dinuclear Connectors[END_REF] and D.

we report the preparation of a new luminescent onedimensional coordination polymer (1D-CP) D bearing the first semi-bridging aqua ligand coordinated to a Cu(I) ions bimetallic unit reported so far. This polymer presents vapochromic solid-state luminescence properties that are related to single crystal to single crystal (SC-SC) phase transition induced by the reversible incorporation of volatile solvent molecules within the crystalline network. The luminescence vapochromic effect is related to a molecular motion that takes place within the 1D-CP's backbone in the solid state, activated by the volatile molecule uptake. Its amplitude depends on both the temperature and the nature of the solvent molecules introduced.

Results and discussion

We have previously shown that the pre-assembled bimetallic [Cu2(2-dppm)2(CH3CN)4](PF6)2 complex A reacts at room temperature (RT) with homoditopic cyano-capped oligophenylvinylene-based linkers B 1,2 to afford in good yields single crystals of the 1D-CPs C 1,2 . [START_REF] Nohra | Coordination Polymers with -Stacked Metalloparacyclophane Motifs: F-Shaped Mixed-Coordination Dinuclear Connectors[END_REF] Their supramolecular backbones lies on the connection of tetrametallic -stacked compact metallacycles 6 by ditopic linkers B 1,2 (Scheme 1).

These reactions can be easily conducted either using anhydrous or non-distillated CH 2 Cl 2 as solvent without changes in the reaction outcomes. However, when a similar procedure is applied in anhydrous CH 2 Cl 2 using the shorter linker 1,4dicyanobenzene B 0 , no reaction product can be isolated and the mother solution stays clear upon pentane vapor diffusion for several months. Interestingly, when non-distillated CH 2 Cl 2 is used, crystallization experiments allow obtaining a few colorless single crystals after one week. [START_REF]For experimental details, spectroscopic, X-ray diffraction data and computational studies, see SI. 8 The void volumes were estimated using the PLATON SQUEEZE program[END_REF] Conversely to the crystals of C 1,2 that collapsed immediately once removed from the mother solution due to the loss of included CH 2 Cl 2 solvent molecules, 5 these colorless crystals keep their single crystal integrity after being collected, dried and stored at room with the phenyl rings of the dppm or B 0 ligands. As a result of these interchain interactions, imbrication of the neighboring 1D-CPs results in the formation of bi-dimensional (2D) layers (Fig. 2a) that stack perpendicularly to the a axis (Fig. 2b). Finally, between these sheets, no residual electronic density is observed revealing the absence of included solvent molecules in these single crystals. Nevertheless, it is important to note that small and isolated voids of 113 Å 3 (ca. 1.8 % of the unit cell volume) 8 are observed between these layers (Fig. 2b,d).

The 1D-CP D dry is the first derivative reported so far in which two Cu(I) metal centres are bridged by an aqua ligand. suggesting that the coordination of a water molecule on a Cu(I) center is not always detrimental regarding solid-state luminescence properties. In agreement with this assumption, we observed that the colorless polycrystalline samples of D dry emit, under UV-Vis light excitation ( ex = 365 nm), an eyeperceived blue-cyan luminescence. Interestingly, we also observed that, before being removed from their crystallization solution, the single crystals grown emit under the same UVlight excitation a markedly different eye-perceived greenyellow luminescence. In addition, single crystal of D dry exposed under air to CH 2 Cl 2 vapors (affording D CH2Cl2 single crystals) instantaneously switched their solid-state eye-perceived bluecyan emission to an eye-perceived green-yellow luminescence of a similar color than observed when crystals are maintained in the crystallization solution. ), mostly due to an increase of the a parameter value (D CH2Cl2 : 13.972(2) Å; D dry : 13.2578(6) Å), the other unit cell parameters being only very moderately altered (Table S1). X-ray single crystal structure resolution revealed that D CH2Cl2 composition is very similar of the one of D dry , being based on a zig-zag 1D-CP with a dicationic [Cu 2 ( 2 -dppm) 2 ( 2 -OH 2 )(B 0 )](PF 6 ) 2 repetition unit, but very importantly, two disordered included CH 2 Cl 2 solvent molecules are additionally found in the unit cell of D CH2Cl2 (Fig. Solid-state emission spectra of D dry at temperatures between 80 K and 300 K upon excitation at 370 nm; insert: plot of emission decay lifetime against temperature (80 K to 300 K); c) Solid-state emission spectra of D CH2Cl2 at temperatures between 80 K and 300 K upon excitation at 370 nm; insert: plot of emission decay lifetime against temperature (80 K to 300 K).

the case of D CH2Cl2 the 2D layers are separated by larger intermolecular distances corresponding to the increase of the value of the a parameter found for each unit cell. The CH 2 Cl 2 molecules found in D CH2Cl2 are located between these 2D layers (Fig. 2c), occupying formally at the same position than the voids found in the solid-state structure of D dry (Fig. 2b and2c). Yet, the volume occupied by these solvent molecules (Fig. 2e) describes in D CH2Cl2 infinite zig-zag 1D-channels (corresponding to ca. 2.7 % of the unit cell volume)

8 that propagate parallel to the c crystallography axis. It is important to stress that along these cavities, one phenyl ring of one of the two dppm ligands is found disordered over two positions (see Fig. S3) while no disorder is identified on any fragment of the 1D-CP backbone of the non-solvated structure D dry . This disordered phenyl ring is closely located to the included CH 2 Cl 2 solvent molecules. Finally, in order to allow conducting a comparative structure/photophysical behavior analysis of the thermal variation of the properties of D dry and D CH2Cl2 (vide infra), temperature dependent X-ray structural study of these two phases was performed. It revealed that both crystals D dry and D CH2Cl2 present only a very moderate and progressive shrinkage of the unit cell volume from 250 K to 150 K (ca. 1.5 % and 1.8 % volume contraction, respectively). This indicates that the solid state structural metric data of these 1D-CPs, established at 150 K, are kept mostly unchanged as temperature changes without occurrence of significant phase transition (vide infra).

A green-yellow luminescent single crystal freshly collected in the CH 2 Cl 2 /pentane crystallization solution was also submitted to X-ray diffraction analyses. It revealed that this compound is isostructural of those preliminary dried (D dry ) and subsequently submitted to CH 2 Cl 2 vapors (D CH2Cl2 ). Therefore, CH 2 Cl 2 solvent molecules are initially included in the single-crystals along the crystallization process. Once the single-crystals are removed from the mother solution, they release very rapidly their solvent molecules without loss of crystallinity, affording the blue-cyan luminophore D dry .

In the solid state at RT, D dry exhibits a strong and broad absorption band (Fig. S15) in the near UV region typical of -* transition centered on the aromatic rings of dppm and B 0 ligands. The TD-DFT calculations [START_REF]For experimental details, spectroscopic, X-ray diffraction data and computational studies, see SI. 8 The void volumes were estimated using the PLATON SQUEEZE program[END_REF] revealed that they are corresponding to [Cu 2 ( 2 -dppm) 2 ] fragment to *-dicyanobenzene charge transfer excitations. In its emission spectrum, D dry displays under excitation at 370 nm at 300 K a broad featureless band centered at  max = 486 nm (Fig. 3a). [START_REF]For experimental details, spectroscopic, X-ray diffraction data and computational studies, see SI. 8 The void volumes were estimated using the PLATON SQUEEZE program[END_REF]10 The average emissive lifetime  is 38 s and an emission RT quantum yield (EQY) is 20 %. Such band is in agreement with the solid-state eye-perceived blue-cyan luminescence observed arising from the single-crystals of D dry upon UV-light irradiation. The RT solid-state absorption spectrum of D CH2Cl2 is very similar to the one of D dry (Fig. S16) but its RT solid-state emission spectrum measured under excitation at 370 nm presents a broad featureless band centered at 502 nm (Fig. 3a), being significantly red-shifted regarding the band observed for D dry ( max = 486 nm). This bathochromic shift is accompanied by a decrease of both the RT emissive lifetime and the EQY, being respectively of 13 s and 7 %. The origin of red-shift observed in the emission spectra of D CH2Cl2 compared to D dry is unclear and difficult to be rationalized considering the close similarities of the solid-state parameters established for both derivatives. Therefore, to get more insights about the emission properties of D dry and D CH2Cl2 , temperature dependent photophysical characterizations were conducted for both phases upon temperature cooling from 300 K to 80 K.

In the emission spectra of D dry under excitation at 370 nm, 11 a gradual and very moderate blue-shift (Fig. 3b) of the large band observed at 300 K ( max = 486 nm) first occurs up to 260 K ( max = 482 nm), together with a slight increase of the signal intensity. From 260 K to 200 K, this intensity enhancement continues but is accompanied by a progressive structuration of the emission band. It yields at 200 K a large emission band bearing clearly two maxima centered at 443 and 474 nm and a shoulder at 490 nm, revealing the rise of a vibronic progression very likely assignable to ligand-centered transitions involving the 1,4-dicyanobenzene B 0 connecting ligand. Indeed, such a vibronic structuration has never been observed in the thermal variation of related luminescent polymetallic supramolecular assemblies based on the [Cu 2 ( 2 -dppm) 2 ] moiety and cyanobased inorganic ligands.

12 Upon cooling down to 140 K, this vibronic progression becomes more defined but, quite unexpectively, a decrease of the intensity of the whole spectrum is observed. Finally, between 140 K and 80 K, the intensity of the signal increases continuously while the band shape is not significantly altered. The thermal variation of the average emission decay lifetime  of D dry ( ex = 370 nm, Fig. 3b) displays a very unusual profile. [START_REF]This unusual behaviour recorded for the thermal variation of the average emission decay lifetime  of D dry was confirmed by several measurements performed on different and independent batches[END_REF] Indeed, a constant increase is first observed from 300 K ( = 38 s) to 200 K ( = 128 s) but then occurs a surprising decay until 150 K ( = 72 s). Finally, the value of  increases again as the temperature decreases and reaches 255 s at 80 K. By comparing these two thermal dependencies, it is possible to highlight a correlation between the unusual behaviors observed in the luminescence properties of D dry . Hence, the intensity decrease of the emission spectra upon cooling between 200 K and 140 K (coming together with the concomitant increase of the vibronic progression) occurs in the same temperature window than the drop of the average emission decay lifetime . Very likely, these features witness that competitive temperature-dependent relaxation pathways operate in the photophysical processes lying in D dry .

Concerning the temperature dependence of the photophysical properties of D CH2Cl2 , its emission spectra present upon cooling from 300 K ( max = 502 nm) to 260 K a significant hypsochromic shift (Fig. 3c) accompanied by a moderate increase in the intensity signal leading at 260 K to a large band centrered at  max = 485 nm. Below 260 K, while no spectral shift is observed, a continuous and progressive enhancement of the spectra intensity occurs together with a net structuration of the emission band. It results at 80 K in an emission spectrum bearing a signal with a clear vibronic progression associated with two maxima centered at 442 nm and 473 nm and a shoulder at 490 nm. Upon cooling the average emission decay lifetime  of D CH2Cl2 ( ex = 370 nm, Fig. 3c) is kept constant from 300 K to 180 K (, ca. 20 s) then it gradually increases until 80 K to reach the value of  = 625 s.

The solid-state emission behaviors of Cu(I)-based luminescent derivatives are characterized by the large diversity of the radiative relaxation processes involved, including for instance competitive temperature-dependant relaxation processes between different triplet states and Thermally Activated Delayed Fluorescence (TADF). 2,[START_REF]Highly Efficient OLEDs Materials Based on Thermally Activated Delayed Fluorescence[END_REF] In the latter case, the thermal population of the lowest energy excited singlet state from the lowest energy triplet excited state occurs, inducing fast and efficient radiative relaxation to the ground state and remarkable RT solid-state luminescence properties. Considering the overall temperature-dependent data collected for the photophysical properties of the two 1D-CPs phases D dry and D CH2Cl2 , it is very likely that several temperaturedependant relaxation pathways involving different low energy singlet and triplet states are operant, implying competitive effects. This account in particular for the unusual behaviour of the photophysical parameters of D dry between RT and 100 K (Fig. 3b). Indeed, this supports the hypothesis of a switch between at least two possible operating radiative relaxation processes. Tentatively, the photophysical behaviour of D dry can be associated with a high temperature regime typical of a 3 MLCT phosphorescence on the basis of its k r radiative rate constant value (Table 1) and a low temperature metalperturbed 3 -* phosphorescence relaxation process mainly centered on the 1,4-dicyanobenzene B 0 connecting ligands.

15

The high temperature large unresolved bands observed in the emission spectra for D dry and the high temperature thermal variation (between 300 K and 200 K) of its emission decay lifetime resemble significantly those previously reported for several luminescent Cu(I) polymetallic assemblies based on the [Cu 2 ( 2 -dppm) 2 ] unit and metallacyano ligands. 12a-c In these derivatives, the large emission bands observed at RT are typical of metal-to-ligand charge transfer (MLCT) involving electronic densities at the cyano-based building blocks and the dppm ligands. In the case of the RT photophysical beahevior of D dry , the k r radiative rate constant value is in favour of a purely 3 MLCT phosphorescence in which the high temperature large emission bands can be assigned radiative processes involving electronic densities located mostly on the 1,4-dicyanobenzene B 0 ligands (also supported by the S 0 → S 1 / and electronic density changes and their triplet counterpart S 0 → T 5 /T 6 shown in Fig. S18). Conversely, the low temperature emission spectra recorded for D dry (Fig. 3b) can be assigned to phosphorescence from metal-perturbed 3 -* transitions centered on the 1,4dicyanobenzene B 0 connecting ligands in agreement with the nature of the calculated lowest vertical triplet states (Fig. S18). The longer values of the decay lifetimes and the vibronic structuration of the band observed at low temperature support such assumption of B 0 ligand-centered 3 -* phosphorescence (Fig. 3b). Between ca. 250 K and ca. 100 K, both processes might be operant and compete, leading to the unusual thermal alteration of the photophysical parameters observed. It is worth noting that only a minor contribution of the semi-bridging aqua ligand is observed in the electronic excitation process on the basis of computational calculations (Fig. S18). [START_REF]For experimental details, spectroscopic, X-ray diffraction data and computational studies, see SI. 8 The void volumes were estimated using the PLATON SQUEEZE program[END_REF] Therefore, this bridging aqua ligand, while playing a fundamental structurating role by promoting the formation of this unique 1D-CP network, is almost not involved in the relaxation processes governing the original photophysical properties observed, avoiding consequently the communly observed luminescence quenching effect of coordinated water molecules. The low temperature photophysical data recorded for D dry and D CH2Cl2 (Fig. 3b and3c) are comparable, despite slight differences in relative intensities at the different maxima in the emission spectra and longer average emission decay lifetime for D CH2Cl2 . This suggests that the radiative relaxations rely on the similar 3 -* ligand-centered phosphorescence mechanism for both phases at these temperatures. The RT temperature k r radiative rate constant value (Table 1) supports at high temperature also a 3 MLCT phosphorescence. 15 The differences accounting for the vapochromic behaviour can be related with the significantly different RT k nr non-radiative rate constant values of D dry and D CH2Cl2 (Table 1). Yet, the thermal variation of the emission decay lifetime for D CH2Cl2 (Fig. 3c) does not present the unusual profile recorded for D dry (Fig. 3b), which likely is due to the largest difference in energy of 3 MLCT and 3

-* level in the less constrained D CH2Cl2 system. This is in spite of the fact that D dry and D CH2Cl2 present similar 1D-CPs supramolecular architectures. Importantly, we mentioned that the inclusion of CH 2 Cl 2 molecules in the single crystals of D CH2Cl2 is associated with the observation of a disorder at one phenyl ring of one dppm ligand in its low temperature X-ray single crystals structure. One can figure out that, in the high temperature regime, these included solvent molecules are mobile within the single crystals. This induces a molecular motion of the phenyl ring located in close vicinity of these mobile included solvent molecules and causes the disorder observed for this phenyl ring in the low temperature (150 K) Xray structure of D CH2Cl2 , a temperature at which this mobility is ''frozen'' at different positions. In turn, this molecular motion impacts the high temperature photophysical properties of D CH2Cl2 in the solid state. Likely, some atomic motions in the excited states and some vibrational modes that are hindered in D dry at RT due to its intrinsic rigidity can in this case be active and modify at high temperature the radiative and nonradiative des-excitation processes in D CH2Cl2 compared to D dry , resulting in significantly larger for RT k nr non-radiative rate constant values for D CH2Cl2 compared to D dry (Table 1). Notably, at high temperature, the red-shift of the D CH2Cl2 large emission band compared to D dry one supports this assumption of an impact of the solid-state mobility of the included solvent molecules in the photophysics of D CH2Cl2 . Indeed, such molecular motion in the solid state activates vibrational sublevels in the different energy states that operate in the radiative relaxation processes. Once the temperature decreases, the solvent's mobility within D CH2Cl2 progressively vanishes. It results in a lower accessibility of the higher energy vibrational states inducing the blue shift observed.

15 Consequently, D CH2Cl2 presents at low temperature an emission spectrum comparable to the low temperature emission spectrum of D dry in which these vibrational modes do not exist. The occurrence of a luminescent vapochromic behavior in D dry is a priori quite unexpected considering its solid-state crystal structure (Fig. 1 and 2) which presents only a very low porosity associated with voids (Fig. 2d) that are not interconnected. Nevertheless, single crystals of D dry can reversibly uptake CH 2 Cl 2 vapors in a SC-SC transformation leading to the formation of 1D channels (Fig. 2e) in D CH2Cl2 single crystals, concomitantly with a luminescence vapochromic response. Very likely, the voids observed in D dry are sufficient to allow the initiation of volatile molecules uptake process, activating a molecular motion within the single crystals. Concomitantly to this CH 2 Cl 2 inclusion, the photophysical properties of the solid are altered by this molecular motion, originating the vapochromic behavior via a unique temperature dependent dynamic process. In line with this assumption, the RT k nr value of D dry (2.1*10 4 s -1

, table 1) is the lowest among all the compounds measured in this study (vide infra), confirming that the non-radiative de-excitation processes present much larger amplitudes at RT in the solvated 1D-CP networks than in D dry . This observation supports the suggested mechanism of vapochromic luminescence. Interestingly, Perruchas et al. recently suggested that solid-state molecular motion induced by solvent adsorption can impact the photophysics of a Cu(I) discrete assembly within porous molecular solids.

3b This sets this 1D-CP derivative apart of the other Cu(I) based luminescent vapochromic derivatives for which intrinsic significant porosity was demonstrated to be a key preliminary factor allowing volatile molecule detection. 16 In a more general point of view, it reveals that solid-state luminescent molecular materials bearing very low porosity have to be considered as good candidates for such detection application. Importantly, this reversible luminescence vapochromic uptake process is not limited to CH 2 Cl 2 vapors but is also observed upon exposure of D dry to EtOH, CH 3 NO 2 and THF vapors, affording single crystals of D EtOH , D CH3NO2 and D THF , respectively. [START_REF]For experimental details, spectroscopic, X-ray diffraction data and computational studies, see SI. 8 The void volumes were estimated using the PLATON SQUEEZE program[END_REF] In each case, X-ray single crystal structure analyses revealed (Fig. 4), similarly to D CH2Cl2 , an uptake process associated with an increase of the unit cell volume. Within these new derivatives, included disordered solvent molecules (one and a half, one, and one molecule(s) per Cu(I) bimetallic unit in D EtOH , D CH3NO2 , and D THF respectively) are found formally located at the place of the void observed in D dry . [START_REF]For experimental details, spectroscopic, X-ray diffraction data and computational studies, see SI. 8 The void volumes were estimated using the PLATON SQUEEZE program[END_REF] Concomitantly, the solid-state emission properties of these new phases are also altered compared to those of D dry . Indeed, as in the case of D CH2Cl2 , their RT emission spectrum recorded with excitation at 370 nm are all red-shifted compared to D dry . They are characterized by a broad and featureless band having emission maximum  max at 512, 522, and 528 nm forD EtOH , D CH3NO2 , and D THF , respectively (Fig. 3), typical of green-yellow to yellow eye-perceived luminescences.

The RT EQY is 7 % for all these three new solvated phases.

Once the source of vapor of solvent molecules is removed, these single crystals returned rapidly to the initial pale bluecyan luminescent single crystals of D dry , revealing a general reversible luminescence vapochromic behaviour whose luminochromic signature is formally characteristic of the nature of the volatile solvent molecule used. The photophysical study 7 of these three new solvated phases reveals that D CH3NO2 and D THF present thermal variations of their emission spectra and average emission decay lifetime ( 80K = 430 s; 300K = 8 s for D CH3NO2 and ( 80K = 692 s; 300K = 13 s for D THF ) that are similar to those observed with D CH2Cl2 . [START_REF]For experimental details, spectroscopic, X-ray diffraction data and computational studies, see SI. 8 The void volumes were estimated using the PLATON SQUEEZE program[END_REF] Therefore, for these volatile molecules, the uptake process and its impact on the photophysical properties should proceed accordingly to the same mechanism. The slight but human-eye detectable differences observed in the emission spectra at room temperature must be related to subtle differences in the mobility of the included molecules and their interaction with the 1D-CPs backbones. Conversely, D EtOH presents temperature dependences of its photophysical data that are different of those of D CH2Cl2 , D CH3NO2 and D THF (Fig. 4d). Indeed, in the thermal variation of D EtOH emission spectra, upon cooling from 300 K to 150 K, a slight bathochromic shift of the large emission band is first displayed from  max = 512 nm (300 K) to  max = 531 nm (150 K). Concomitantly, a slight increase of the intensity of the signal is observed. Then, from 150 K to 80 K, the intensity of the spectrum increases significantly accompanied by the rise of the vibronic progression assignable to ligand-centered transitions. It leads at 80 K to a large band bearing three maxima at 442 nm, 471 nm and 488 nm presenting therefore a very similar energy pattern than the other low temperature emission spectra recorded in the series, yet having a clearly different maxima intensity distribution. In addition to the bathochromic shift of the large emission band observed from 300 K to 150 K, the discrepancy of photophysics of this phase compared to the other solvated phases is also confirmed by the temperature dependence of the average emission decay lifetime for D EtOH and its RT k nr value (Table 1). Indeed, the thermal variation observed for the average emission decay lifetime presents a much more moderated amplitude ( 80K = 62 s; 300K = 3 s for D EtOH ) while the RT k nr value of D EtOH is one order magnitude larger than those of the other solvates recorded in this study. The high temperature data are typical of a TADF from the 1 MLCT excited state while the low temperature regime would originate from low lying 3 MLCT excited state operating once the solvent mobility within the crystals has significantly vanished. Such a specific behaviour in the case of the luminescent vapochromic response of D dry in the presence of vapors of EtOH may be related to the possibility offered by this solvent to supply strong hydrogen bonds once uptake within single crystals in which semi-bridging aqua ligands are connected to Cu(I) metal centers. Yet, since the semi-bridging aqua ligands are not located in the crystal structures in the close vicinity of the voids (Fig. 2b), this effect can be mediated through indirect H-F interactions via the hexafluorophosphate anions that are closely connected to the semi-bridging aqua ligands (Fig. 1a) and might involve manifold mechanisms such as modification of the vibrational structure and reorganisation of the electronic structure in the excited states. Anyhow, the specific impact of the EtOH molecules inclusion on these 1D-CP single crystals photophysical properties reveals that the vapochromic behavior of the derivative D dry can be associated with different temperature dependent luminescence signatures considering the family of volatile molecules investigated.

Conclusions

With these results, the interest of the [Cu 2 ( 2 -dppm) 2 ] units for the preparation of new multifunctional luminescent Cu(I) assemblies is confirmed and the perspectives of applications of the resulting materials are enlarged. The conformational flexibility of such Cu(I) bimetallic precursors allows the preparation of the new solid-state luminescent 1D-CPs D dry in which a water molecule is trapped between the two Cu(I) metal centers, affording the first example of a bimetallic Cu(I) derivative bearing a semi-bridging aqua ligand. This reveals also that the conformational flexibility allowed in such bimetallic units can lead to original reactivity and new molecular materials. Importantly, in spite of their intrinsic very low porosity, single crystals of D dry can undergo CH 2 Cl 2 , EtOH, CH 3 NO 2 and THF vapor uptake along SC-SC transitions that display reversible luminescence vapochromic responses. Detailed temperature dependant photophysical studies conducted on the full series of solvated and non-solvated molecular solids reveal that such vapochromic behaviour are related to molecular motion of the solvent molecules occurring along 1D channels formed within the solvated crystalline solids. While a specific temperature dependant behaviour is observed with the samples submitted to EtOH vapors suggesting a special sensitivity toward hydrogen bond donors molecules, this survey also importantly highlights the complexity of the relaxation processes that may occur in such heteroleptic intricate Cu(I) supramolecular assemblies. This complexity contrasts with the simplicity of the syntheses conducted in one step under ambient conditions from cheap and easily available molecular precursors. By varying the nature of the diphosphane assembling ligands and of the polytopic cyano-capped linkers, a general and rational access to original Cu(I) supramolecular assemblies displaying original RT solid state photophysical properties can be therefore anticipated. fellowship for experienced researcher. Computations were performed using HPC resources from GENCI-CINES/IDRIS (Grants A0060800649 and A0080800649). The authors would like to greatly acknowledge the referees for their very valuable critical analysis of this article, in particular in relation with the interpretation of the intricate photophysical properties of the reported derivatives.

Notes and references

Fig. 1 .

 1 Fig. 1. a) Views of the molecular X-ray structures of derivative D dry : a) repetition unit b) fragment of the 1D-CP zig-zag chain, c) location of the PF 6 -anions and the H-F short contact interactions (black doted lines) between the PF 6 -and the aqua ligand.

  Fig. 3. a) Normalized solid-state emission spectra of D dry , D CH2Cl2 , D EtOH , D CH3NO2 and D THF at 300 K upon excitation at 370 nm; b)Solid-state emission spectra of D dry at temperatures between 80 K and 300 K upon excitation at 370 nm; insert: plot of emission decay lifetime against temperature (80 K to 300 K); c) Solid-state emission spectra of D CH2Cl2 at temperatures between 80 K and 300 K upon excitation at 370 nm; insert: plot of emission decay lifetime against temperature (80 K to 300 K).

Fig. 4 .

 4 Fig. 4. Views of the X-ray structures of the derivatives a) D EtOH , b) D CH3NO2 and c) D THF ; the backbones of the 1D-CP are shown in the stick and ball representation mode while the included solvent molecules are shown in the CPK representation mode; d) Solidstate emission spectra of D EtOH at temperatures between 80 K and 300 K upon excitation at 370 nm; insert: plot of emission decay lifetime against temperature (80 K to 300 K).

1

  (a) V. W.-W. Yam, V. K.-M. Au and S. Y.-L.Leung, Light-Emitting Self-Assembled Materials Based on d 8 and d 10 Transition Metal Complexes, Chem. Rev., 2015, 115, 7589-7728; (b) M.L. Saha, X. Yan and P.J. Stang, Photophysical Properties of Organoplatinum(II) Compounds and Derived Self-Assembled Metallacycles and Metallacages:

  The initial blue-cyan luminescence is recovered once the CH 2 Cl 2 vapor source is removed, indicating a reversible vapochromic luminescence response of D dry toward CH 2 Cl 2 vapors. In order to get structural insights about the origin of such luminescence vapochromism properties, single-crystals of D CH2Cl2 lying in an atmosphere saturated with CH 2 Cl

2 vapors were coated in paratone oil (in which they were still emitting an eyeperceived green-yellow luminescence upon UV-excitation) and submitted to X-ray diffraction single-crystal analysis at 150 K. It revealed that D CH2Cl2 kept single crystal integrity during the process, bearing as D dry , a P2 1 /c monoclinic unit cell. Yet, its unit cell volume is larger (D CH2Cl2 : ca. 6340 Å 3 , D dry : ca. 6082 Å 3

Table 1 .

 1 Photophysical

	-1 )	b	knr (s	-1 )	c

data ((ex = 370 nm) for derivatives Ddry, DCH2Cl2, DCH3NO2, DTHF and DEtOH at 298 K in the solid state. λem (nm) a Φem τobs (μs) a kr (s a Data recorded at 80 K are given in parentheses; b kr = Φem/τobs ; c knr = (1-Φem)/τobs.

Acknowledgements

This work was supported by the ANR (P-OPTOELECTR-MOLMAT), the French Research Ministry and the CNRS. C.L. thanks the Alexander von Humboldt Foundation for a

Conflicts of interest

There are no conflicts to declare.