Raymond Cesaire

Moustapha Dramé

Narcisse Elenga

Pédiatrie De Ch

Cayenne

Michel Carles Anesthésie

Réanimation Chu

Pauline Ophtalmologie Butori

Chu

Hugo Chaumont

Neurologie

Florent Henno

Anesthésie-Réanimation

Jean-Marc Jeremie

Psychiatrie

Benjamin Maladies Lefevre

Infectieuses

Monfort Astrid

Parsemain Aurélie

Emmanuel Perrot

Renard Guillaume

Rolle Amélie

Vincent Sainte-Rose

Andrée Parasitologie

" De Rosemon

Tél Cayenne

Sylvestre Emmanuelle

Tramier Ambre

Andrée Rosemon

REMERCIEMENTS

A Monsieur le Professeur Samir JABER

Je vous remercie pour le temps que vous passez au service de l'enseignement et de la recherche médicale, apportant une formation de qualité en Anesthésie Réanimation, je n'oublierai pas tous ces lundis et jeudis matin. Je vous remercie de m'avoir appris à rester humble dans l'exercice de ma profession, et j'espère ne jamais vous avoir réellement déçu.

A Monsieur le Professeur Pierre François PERRIGAULT

Vous me faites l'honneur d'apporter votre expérience à la critique de ce travail en siégeant dans mon jury. Je vous prie de bien vouloir accepter mes sentiments respectueux.

A Christine,pour m'avoir permise de travailler avec toi sur ce sujet qui te tient tant à coeur ; pour ces moments où tu as su écarter le doute en moi. Merci d'avoir toujours été franche, honnête et sans artifice.

A Océane,pour le sérieux, la rigueur et le tableur.

A toute l'équipe du DAR C,sans qui ce travail n'aurait pas vu le jour, merci pourvotre engagement et le temps que vous y avez consacré. Vous êtes au top ! A Julie, pour ta disponibilité, ta relecture et tes corrections qui nous ont été d'une grande valeur.

A ma famille, A mes grands-parents,pour leur gentillesse, leur générosité et leurs encouragements. Merci pour votre douceur et les valeurs que vous m'avez inculquées. Jamais je n'oublierai.

A ma mère, pour tous ces moments de complicité et de rires qui font que notre relation reste unique. Merci pour ta créativité qui immortalise les instants passés ensemble et pour toutes ces attentions qui ne me laissent jamais insensible. Je t'aime.

A mon père, pour son soutien et sa vision de la vie. Merci de m'avoir tant fait réciter il y a de ça quelques années, sans toi je n'en serai pas là. Merci d'être fière de moi. Je t'aime.

A mon frère, Virgile,pour son ouverture d'esprit et sa culture qui me donnent l'envie perpétuelle de m'élever. Je t'aime.

A mon frère, Julien,pour toutes ces pustules accumulées et pour toutes ces chamailleries sansfin. Je t'aime.

Et bien sûr, à Maelle la plus belle.

A mes ami(e)s, A Pauline, pour cette rencontre I-N-C-R-O-Y-A-B-L-E. Doudou, merci pour tout… Merci

d'être un démon et un ange à la fois. Merci d'être totalement folle, de me rendre tarée et de me pousser au-delà de mes limites. Merci pour tous ces retours de soirées à 6h du mat fluottés de la tête au pied ; pour tous ces ascenseurs aRHUMatisés à Casepilus,pour ces moments calmes qui restent rares et ces regards qui veulent tout dire.Tu es l'une des personnes les plus extraordinaires que je connaisse, ne changes surtout rien.

A Antoine, Pinpin, pour le rappel biquotidien de T4, les réveils si doux, ton vocabulaireet tesexpressions sans précédent. Merci d'être une grande gueule avec un grand coeur.

Coeur coeur love.

A la team « Antilles à Montpeul »:

-A Matthieu, pour toutes ces parties de squash/apéro (plutôt apéro que squash), pour ton A tous mes co-internes, pour avoir contribué à mon épanouissement professionnel et personnel.

Plus spécialement, à ceux qui ont su faire de cet internat un fleuve tranquille rempli de joie :

-A Ambre (une très belle personne, the first thesis), Matthieu (un fin éleveur de cochon), Thomas (un écrivainde CR de renommé), Remy (un diplomate), Pierre (la mascotte Miss Dior J'adore, pousseur de caddie), Arthur (la prestance lors de sa présence), Marjorie

TABLE DES MATIERES

LISTE DES ILLUSTRATIONS

METHODS:

Pain assessment was performed before, during, just after, and 5 minutes after 3 procedures: the reference non-nociceptive procedure (assessment of the Richmond Agitation Sedation Scale) and 2 nociceptive procedures (turning and tracheal suctioning). The primary endpoint was construct validity (discriminant and criterion validation), determined by comparing pain measurements between different times/procedures. Secondary endpoints were internal consistency, inter-rater reliability, and feasibility.

RESULTS/DISCUSSION: Fifty patients (54% women, median age 63 years [56-68]) were included 13 [START_REF] Chanques | Validation de l'échelle de vigilance-agitation de Richmond traduite en langue française[END_REF][START_REF] Chanques | Impact of systematic evaluation of pain and agitation in an intensive care unit: Critical Care Medicine[END_REF][START_REF] Chanques | Assessing pain in non-intubated critically ill patients unable to self report: an adaptation of the Behavioral Pain Scale[END_REF][START_REF] Chanques | Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report[END_REF][START_REF] Chanques | Analgesia nociception index for the assessment of pain in critically ill patients: a diagnostic accuracy study[END_REF][START_REF] Chanques | The measurement of pain in intensive care unit: Comparison of 5 self-report intensity scales[END_REF][START_REF] Chatelle | A sensitive scale to assess nociceptive pain in patients with disorders of consciousness[END_REF][START_REF] Cronbach | Coefficient alpha and the internal structure of tests[END_REF][START_REF] De Jong | Decreasing severe pain and serious adverse events while moving intensive care unit patients: a prospective interventional study (the NURSE-DO project)[END_REF][START_REF] Dehghani | Validity and Reliability of Behavioral Pain Scale in Patients With Low Level of Consciousness Due to Head Trauma Hospitalized in Intensive Care Unit[END_REF][START_REF] Delong | Comparing the Areas under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach[END_REF][START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF][START_REF] Feldt | A test of the hypothesis that Cronbach's alpha reliability coefficient is the same for two tests administered to the same sample[END_REF][START_REF] Gélinas | Behaviors Indicative of Pain in Brain-Injured Adult Patients With Different Levels of Consciousness in the Intensive Care Unit[END_REF][START_REF] Gélinas | A Validated Approach to Evaluating Psychometric Properties of Pain Assessment Tools for Use in Nonverbal Critically Ill Adults. Seminars in Respiratory and Critical Care Medicine[END_REF][START_REF] Jendoubi | Pain measurement in mechanically ventilated patients with traumatic brain injury: Behavioral pain tools versus analgesia nociception index[END_REF][START_REF] Joffe | Validation of the Critical-Care Pain Observation Tool in brain-injured critically ill adults[END_REF][START_REF] Kline | A psychometrics primer[END_REF] days after brain injury (76% hemorrhagic or ischemic strokes). All tools increased significantly more (p<0.001) during the nociceptive procedures vs the nonnociceptive procedure. The BPS was the only pain tool that did not increase significantly during the non-nociceptive procedure (p=0.41), suggesting that it was the most discriminant tool. The BPS, NCS-I, and NCS-R-I were good predictors of nociception with areas under the curves 0.96, contrary to videopupillometry (area under the curve = 0.67). The BPS, NCS-I, and NCS-R-I had high interrater reliabilities (weighted kappa = 0.86, 0.82 and 0.84, respectively). Internal consistency was moderate (>0.60) for all pain scales. Factor analysis represented a majority of information on a first dimension, with motor domains represented on a second dimension. Scale feasibility was better for the NCS-I and NCS-R-I than for the BPS.

CONCLUSION:

In conclusion, the BPS, NCS-I, and NCS-R-I are valid, reliable, and acceptable pain scales for use in intubated critically ill, brain-injured patients, unlike videopupillometry. Future research requires tool design centered on domains of observation adapted to this very specific population.

INTRODUCTION

Over the past decade, great efforts have been made to better manage pain in critically ill patients [START_REF] Puntillo | Next steps in ICU pain research[END_REF]. In addition to ethical concerns, pain management has been associated with lowersedative use and improved patient outcomes [START_REF] Chanques | Impact of systematic evaluation of pain and agitation in an intensive care unit: Critical Care Medicine[END_REF][START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF]. However, the literature on pain management in critically ill, brain-injured (CIBI) patients remains scarce [START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF][START_REF] Puntillo | Next steps in ICU pain research[END_REF] highlighted as an evidence gap and future direction of research that "pain scale revisions could enhance the validity of their use in ICU patients with brain injury and other neurologically critically-ill patients" [START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF]. The validation study of the Nociception Coma Scale (NCS) was published in PAIN in 2010 [START_REF] Schnakers | The Nociception Coma Scale: A new tool to assess nociception in disorders of consciousness[END_REF], then later revised to a simpler version (NCS-Revised or NCS-R) [START_REF] Chatelle | A sensitive scale to assess nociceptive pain in patients with disorders of consciousness[END_REF]. Based on behavioral observations taking into account 3 or 4 domains (facial expressions, visual, motor, and verbal responses), these scales were constructed for and validated in brain-injured patients. They demonstrated good psychometric properties and, considering that brain injury and neurological deficiencies significantly alter/diminish pain expression in this group, constituted a considerable step forward in this challenging branch of pain management [3]. However, the NCS(-R) includes a verbal observational domain and, thus, was not constructed for use in intubated patients, although invasive mechanical ventilation is the most critical period for pain/discomfort in ICU patients (regardless of brain injury) [START_REF] Oddo | Optimizing sedation in patients with acute brain injury[END_REF][START_REF] Payen | Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study[END_REF].

In this context, we obtained permission from Prof Schnakers to adapt the NCS to intubated patients, creating the NCS-I and NCS-R-I, and proceeded with their psychometric validation.Simultaneously, we also compared these new scales with theBehavioral Pain Scale (BPS) [START_REF] Chanques | Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report[END_REF][START_REF] Payen | Assessing pain in critically ill sedated patients by using a behavioral pain scale[END_REF]which is one of the mostvalidated and used pain scales in critically ill patients, but like the NCS(R)-I, still has some concerns for validity among CIBIpatients [START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF].Given that all the latter have subjective components,we also included videopupillometry as an objective measure ofpain in nonverbal patients. Videopupillometry has been reportedas more sensitivethan behavioral observation in a population ofcritically ill patients without brain injury [START_REF] Li | Evaluations of physiologic reactivity and reflexive behaviors during noxious procedures in sedated critically ill patients[END_REF].

To summarize, weconducted the present psychometric study to compare 3 clinicaltools (NCS-I, NCS-R-I, and BPS) and videopupillometry for painassessment in a specific population of intubated CIBI patients.

MATERIALS AND METHODS 1 Ethics approval

The study was approved by a scientific/ethics committee (Comité de Protection des Personnes Sud-Méditerranée-1 [ID-RCB: 2016-A00748-43]) according to French law [START_REF] Toulouse | French legal approach to clinical research[END_REF] and registered on ClinicalTrials (NCT02830256).

Patient population

A 16-bed, medical-surgical, neuro-ICU at the University Hospital of Gui de Chauliac participated in this observational study from November 2016 to November 2017. Because of the absence of guidelines regarding the use of pain tools in CIBI patients [START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF], no pain tool was routinely used in noncommunicating patients hospitalized in the neuro-ICU before the study. Consecutive patients aged older than 18 years admitted to the ICU after a brain injury were eligible if they (1) required invasive ventilatory support (endotracheal or tracheostomy tube), ( 2) showed signs of awakening after the initiation of sedation weaning, and (3) were unable to self-report their pain using a numeric rating scale [START_REF] Chanques | The measurement of pain in intensive care unit: Comparison of 5 self-report intensity scales[END_REF].Exclusion criteria were brainstem involvement, neurovegetative crisis, and ocular lesions that might alter the accuracy of videopupillometry (glaucoma, keratitis, conjunctivitis, cataract, and anisocoria); pregnant or lactating women; and vulnerable and protected persons. All patients were affiliated with the French Health Care System. According to French law concerning research based on routine care and entailing minimal risks and constraints [START_REF] Toulouse | French legal approach to clinical research[END_REF], the patient relatives' nonopposition to patient participation in the research was requested [START_REF] Toulouse | French legal approach to clinical research[END_REF], as well as the patient's approval as soon as he/she was able to communicate.

Conduct of the study

Patients were screened daily for eligibility by investigators and included in the study after consent from their relatives. When awakening signs appeared, defined in our study by increasing scores on the Richmond Agitation Sedation Scale (RASS), the start of spontaneous breathing or coughing during a tracheal suctioning, investigators were contacted by the bedside nurse to assess pain during 3 routine care procedures planned by the bedside nurse:

(1) evaluation of the sedation level following a standardized approach using the RASS method [START_REF] Chanques | Validation de l'échelle de vigilance-agitation de Richmond traduite en langue française[END_REF][START_REF] Sessler | The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients[END_REF], consisting of calling the patient's name or gently touching the shoulders, defined as the reference non-nociceptive procedure [START_REF] Chanques | Is there a single non-painful procedure in the intensive care unit? It depends! Intensive Care Medicine[END_REF], (2) tracheal suctioning, and (3) turning onto the side, the 2 latter procedures being the 2 most frequent and recognized nociceptive procedures in ICU mechanically ventilated patients [START_REF] De Jong | Decreasing severe pain and serious adverse events while moving intensive care unit patients: a prospective interventional study (the NURSE-DO project)[END_REF][START_REF] Payen | Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study[END_REF][START_REF] Puntillo | Pain behaviors observed during six common procedures: Results from Thunder Project II[END_REF][START_REF] Puntillo | Determinants of Procedural Pain Intensity in the Intensive Care Unit: The Europain Study[END_REF]. Pain was assessed 5 minutes before, during, just after, and 5 minutes after each of the 3 care procedures, which were spaced 20 minutes apart. after the clinical assessment of pain had been performed to avoid any interaction between the videopupillometry and the pain scales.

Pain Scale

Behavioral Pain Scale (BPS)

Widely used in ICUs to assess pain in noncommunicating patients, the BPS consists of 3 subdomains (facial expression, upper limb movement, and compliance with mechanical ventilation), each containing 4 items rated from 1 to 4 [START_REF] Payen | Assessing pain in critically ill sedated patients by using a behavioral pain scale[END_REF].The total BPS score ranges from 3 (no pain) to 12 (maximal pain). In the general population of ICU patients, a value higher than 4 is considered clinically significant [START_REF] Chanques | Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report[END_REF][START_REF] Chanques | Analgesia nociception index for the assessment of pain in critically ill patients: a diagnostic accuracy study[END_REF], and a value higher than 5 is considered as representing severe pain [5,[START_REF] De Jong | Decreasing severe pain and serious adverse events while moving intensive care unit patients: a prospective interventional study (the NURSE-DO project)[END_REF], (see Table 1 for descriptions) [START_REF] Chanques | Assessing pain in non-intubated critically ill patients unable to self report: an adaptation of the Behavioral Pain Scale[END_REF][START_REF] Chanques | Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report[END_REF].

Nociception Coma Scale (NCS), Revised Nociception Coma Scale (NCS-R) and Nociception Coma Scale for Intubated patients

The NCS was constructed to assess 4 behavioral domains in patients with disorders of consciousness who are not intubated (ie, facial expression, visual response, verbal response, and motor response) [START_REF] Schnakers | The Nociception Coma Scale: A new tool to assess nociception in disorders of consciousness[END_REF]. Each domain contains 4 items, rating from0 to 3.

The total NCS score ranges from 0 (no pain) to 12 (maximal pain). The visual response was subsequently removed from the original NCS because it rarely changes during nociceptive procedures [START_REF] Chatelle | A sensitive scale to assess nociceptive pain in patients with disorders of consciousness[END_REF]. Also, eye opening can be a sign of recovery from brain injury rather than a pain behavior. The NCS-R ranges from 0 (no pain) to 9 (maximal pain). Pain thresholds for both the revised NCS (NCS-R) and the originalNCS were between 4 and 5 [START_REF] Chatelle | A sensitive scale to assess nociceptive pain in patients with disorders of consciousness[END_REF][START_REF] Schnakers | The Nociception Coma Scale: A new tool to assess nociception in disorders of consciousness[END_REF].

To adapt the NCS and the NCS-R to intubated mechanically ventilated patients (NCS-I and NCS-R-I), we replaced the verbal domain that is unusable in these patients, with the mechanical ventilation domain from the BPS score, both domains having the same number of items (n = 4), from no pain to maximal pain.

Videopupillometry

The pupil size was measured using a handheld videopupillometer (Algiscan;

IDMed, Marseille, France) with an acquisition of 67 images per second with an accuracy of 0.01 mm. Pupil size measurements have been reported to change more substantially than behavioral signs in a study of 48 mechanically ventilated patients [START_REF] Li | Evaluations of physiologic reactivity and reflexive behaviors during noxious procedures in sedated critically ill patients[END_REF]. Also, pupillometry was the most discriminant electrophysiological tool regarding pain assessment, compared with heart rate monitoring and bispectral index measurements. As specifically concerns the CIBI patients included in this study, brain-stem injuries and clinical anisocoria were considered as exclusion criteria because of an expected inaccuracy of pupillometry in this specific context.

Demographic and medical data

Patient characteristics were recorded from medical files including age, sex, height, weight, body mass index (kg/m2), Simplified Acute Physiology Score II (SAPS II) calculated within 24 hours after ICU admission, type of ICU admission, and time between admission and inclusion. Sedation levels were measured using the RASS (performed by the investigator at baseline before enrollment). Physiological parameters (heart and respiratory rates, arterial blood pressure, and pulse oximetry) were measured through bedside monitoring and recorded by the second investigator.

Statistical analysis

The psychometric properties of the pain tools used were assessed using the recommended terminology and methods for the assessment of pain in critically ill, nonverbal patients [START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF][START_REF] Gélinas | A Validated Approach to Evaluating Psychometric Properties of Pain Assessment Tools for Use in Nonverbal Critically Ill Adults. Seminars in Respiratory and Critical Care Medicine[END_REF].

Construct validity (primary endpoint)

There is no existing gold standard for measuring pain in nonverbal, CIBI patients. The measurement of the psychometric properties of the 3 pain scales and the videopupillometry was consequently based on indirect validation.

Discriminant validation

A valid pain tool would be able to significantly change during a nociceptive procedure (tracheal suctioning and turning), but not during the non-nociceptive reference procedure (RASS measurement). The Mann-Whitney-Wilcoxon test for paired data was used to test the difference between 2 conditions (before and during a procedure) for each pain tool.

Criterion validation

Because validating a pain tool is very challenging in nonverbal patients, we used required procedures that were notoriously nociceptive in critically ill patients (ie, turning and tracheal suctioning) [START_REF] De Jong | Decreasing severe pain and serious adverse events while moving intensive care unit patients: a prospective interventional study (the NURSE-DO project)[END_REF][START_REF] Payen | Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study[END_REF][START_REF] Puntillo | Pain behaviors observed during six common procedures: Results from Thunder Project II[END_REF][START_REF] Puntillo | Determinants of Procedural Pain Intensity in the Intensive Care Unit: The Europain Study[END_REF] as the reference procedures for assessing the ability of the pain tools to detect pain [START_REF] Chanques | Analgesia nociception index for the assessment of pain in critically ill patients: a diagnostic accuracy study[END_REF]. This was conducted to show and compare the performance of the pain tools. Receiving operator characteristic (ROC) curves were constructed using the nociceptive procedures as the reference. Pain measurements obtained before and during the 2 nociceptive procedures (tracheal suctioning and turning) were included for analysis. DeLong, DeLong, and Clarke-Pearson method was used to compare ROC curves [START_REF] Delong | Comparing the Areas under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach[END_REF].

Reliability

Internal consistency

Internal consistency was measured for the pain scales using the Cronbach alpha method [START_REF] Cronbach | Coefficient alpha and the internal structure of tests[END_REF].A Cronbach alpha coefficient between 0.6 and 0.7 reflects a moderate internal consistency, while values over 0.7 reflect high internal consistency (ie, the inter-relation between each domain of the tool) [START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF][START_REF] Gélinas | A Validated Approach to Evaluating Psychometric Properties of Pain Assessment Tools for Use in Nonverbal Critically Ill Adults. Seminars in Respiratory and Critical Care Medicine[END_REF]. Cronbach alpha coefficients were compared among the 3 scales using the Feldt method [START_REF] Chanques | Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report[END_REF][START_REF] Feldt | A test of the hypothesis that Cronbach's alpha reliability coefficient is the same for two tests administered to the same sample[END_REF].Pairwise comparisons of Cronbach alpha coefficients were made between 2 pain scales using the same method. Furthermore, the factor structure of the pain scales was extracted by performing exploratory principal component analysis to determine the contribution of each item of the scales [START_REF] Kline | A psychometrics primer[END_REF].

Inter-rater reliability

Inter-rater reliability of the pain tools was tested by the Cichetti-Allison weighted kappa coefficient [START_REF] Landis | The measurement of observer agreement for categorical data[END_REF].Coefficients above 0.80, 0.60, and 0.40 are considered as measuring "near perfect", "important," and "moderate" agreement [START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF][START_REF] Gélinas | A Validated Approach to Evaluating Psychometric Properties of Pain Assessment Tools for Use in Nonverbal Critically Ill Adults. Seminars in Respiratory and Critical Care Medicine[END_REF][START_REF] Landis | The measurement of observer agreement for categorical data[END_REF], respectively.

Comparisons of kappa coefficients between scales were made using the z test [1,[START_REF] Chanques | Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report[END_REF].

Scale feasibility

After the completion of the study, a questionnaire was sent to all observers to rate how they appreciated the precision, usefulness, and feasibility of the pain scales. A 5-point Likert scale was used (ie, very positive, positive, moderately positive, negative, or very negative).

Number of patients necessary to include for analysis

The power calculation was based on the discriminant validation of the pain tools (primary endpoint). A sample of 50 patients was calculated as necessary to demonstrate a variation of the BPS from 3 to 5 (±2), of the NCS-I or NCS-R-I from 0 to 4 (±1), and of the pupil size from 3 to 5 mm (±2), with an α of 0.05 and a β of 0.20.

Presentation of data

Quantitative data are shown as medians and 25 th to 75 th percentiles. A p-value of 0.05

was considered statistically significant. Data were analyzed using SAS Enterprise Guide

RESULTS

Among the 401 patients admitted to the neuro-ICU during the study period, 84 patients were eligible, and 50 patients were included. Figure 1 shows the study flowchart. The median age was 63 (56-68) years, and SAPS II was 47 (37-56). There were 54% women. The main reasons for admission were subarachnoid hemorrhage (46%), intraparenchymal hematoma (16%), ischemic stroke (14%), traumatic brain injury (8%), postoperative brain tumor (6%), and recovery after cardiac arrest (6%). Table 2 shows the patients' medical and demographic characteristics. Each patient was assessed 4 times (before, during, just after, and 5 minutes after) relative to 3 different care procedures, accounting or 600 pain assessments. Quantitative data are shown as medians and 25 th to 75 th percentiles

Discriminant validation (primary endpoint)

Figure 2 shows the variation of the pain tools at the different times of measurement, for each of the 3 care procedures. Each of the 3 pain scales and the pupil size increased significantly (p<0.001) during both tracheal suctioning and turning (nociceptive procedures).

The increase in pain scales and pupil size was also significantly higher during the nociceptive procedures than during the reference non-nociceptive procedure. All pain evaluations except the BPS increased significantly during the reference non-nociceptive procedure (p<0.001 for the NCS -I and pupil size; p= 0.046 for the NCS-R-I). The BPS was therefore the only pain tool that increased significantly during the nociceptive procedures (p<0.001), but not during the non-nociceptive procedure (p=0.41). This demonstrated that all pain tools reached the discriminant validation, but the BPS could be the most discriminant tool.

Criterion validation

Figure 3 shows the ROC curves constructed according to the nociceptive procedures as the gold standard. The 3 pain scales (BPS, NCS-I, and NCS-R-I) had high areas under the curve (AUCs between 0.96 and 0.97) lacking detectable statistical differences among them, suggesting similar performances among the pain scales. The pupil size had a small AUC (=0.67), significantly lower than the pain scales (p<0.001 for each pairwise comparison between the pupil size and the pain scales). This suggests that measuring pupil size had a poor performance when assessing pain in this specific patient population. Analysis of monitored vital signs also showed small AUCs: 0.62 for heart rate, 0.75 for mean arterial blood pressure, and 0.76 for respiratory rate. Pulse oxymetry was very stable throughout the procedures: 98% (97%-99%). Measurements of the BPS, NCS-I, NCS-R-I, and videopupillometry obtained before and during the 2 nociceptive procedures (tracheal suctioning and turning) were included for analysis.

The 3 clinical pain scales (BPS, NCS-I, and NCS-R-I) were more predictive of pain (ie, the nociceptive procedures) than videopupillometry (p<0.001). No significant differences were found among the 3 clinical

DISCUSSION

The main finding of this psychometric study of pain assessment inmechanically ventilated brain-injured patients is that the BPS, theNCS-I, and the NCS-R-I are valid and reliable pain scales. TheBPS is the most discriminant tool (ie, the only one that did notchangesignificantly during the reference non-nociceptive procedure).However, it has the lowest internal consistency, althoughthe latter is only moderate for all the tested pain scales.

Inaddition, the BPS had the lowest user preference from among ourparticipating neurocriticalcare givers. Contrary to the clinical painscales, videopupillometry was not validated in this specificpopulation of patients and had poor discriminant and criterionvalidation properties.These findings support the use of the BPSand NCS-I/NCS-R-I in CIBI patients. As concerns the latterscales, a detailed analysis of internal properties (consistency andfactor analysis)suggests that there is room for future improvementin scale structure for this specific patientpopulation.

Pain assessment is challenging in critically ill, mechanicallyventilated patientsbecause these patients are often unable tocommunicate their pain, which is the gold standardof painassessment in human beings [START_REF] Chanques | The measurement of pain in intensive care unit: Comparison of 5 self-report intensity scales[END_REF]. Over the past decade, theimplementation of clinicalbehavioral pain scales in ICU settingshas been beneficial for pain recognition and patientoutcomes [START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF].However, a recent international, multicenter, neuro-ICU auditshowed thatalthough a majority of patients received analgesicsduring their ICU stay, pain assessmentswere almost neverprovided due to the absence of pain protocols in the studiedICUs [START_REF] Zeiler | Analgesia in Neurocritical Care: An International Survey and Practice Audit[END_REF].Subsequently, the applicability of pain scales for patientswithout brain injury to those withbrain injuries emerged asa knowledge gap of interest. To start answering this question, theinter-rater reliability of the BPS was measured in 151 intubatedpatients with diverse brain injuries and showed a similaragreement to that demonstrated in this study (kappa coefficientof 0.83) [START_REF] Yu | Evaluating pain, sedation, and delirium in the neurologically critically ill-feasibility and reliability of standardized tools: a multi-institutional study[END_REF]. More recently, the inter-rater reliability and discriminantvalidation were tested forthe BPS in 2 studies including 5016 and3736 traumatic brain-injured patients, respectively,and with goodpsychometric properties. However, the BPS increased significantlyduring thereference "non-nociceptive" procedure, ie, aneye-care procedure in both studies. By contrast,this study is theonly one that uses an absolutely nonnociceptive procedure, thusenabling arobust discriminant validation. This is due to recentdata that showed that even a priori nonnociceptive proceduressuch as dressing changes, that have been used as referencenon-nociceptiveprocedure in previous studies [START_REF] Chanques | Assessing pain in non-intubated critically ill patients unable to self report: an adaptation of the Behavioral Pain Scale[END_REF][START_REF] Chanques | Analgesia nociception index for the assessment of pain in critically ill patients: a diagnostic accuracy study[END_REF], could bepainful in some patients [START_REF] Ayasrah | Care-related Pain in Critically Ill Mechanically Ventilated Patients[END_REF][START_REF] Chanques | Is there a single non-painful procedure in the intensive care unit? It depends! Intensive Care Medicine[END_REF]. This leadto the decision to use theRASS procedure as the reference nonnociceptive procedurethatabsolutely prevents pain contamination [START_REF] Chanques | Is there a single non-painful procedure in the intensive care unit? It depends! Intensive Care Medicine[END_REF][START_REF] Puntillo | Procedural Pain in Intensive Care: Translating Awareness into Practice[END_REF].This study is alsothe first to assess the psychometric properties of the NCS andNCS-R specifically for intubated patients. Previous studies innonintubated, brain-injured patients with diverse brain injuriesincluded 48 patientsto test the NCS [START_REF] Schnakers | The Nociception Coma Scale: A new tool to assess nociception in disorders of consciousness[END_REF] and 64 patients to test theNCS-R [START_REF] Chatelle | A sensitive scale to assess nociceptive pain in patients with disorders of consciousness[END_REF]. The inter-rater reliability was tested only for the NCSand was moderate (kappa = 0.61), while the discriminantvalidationdemonstrated very good properties for both the NCSand the NCS-R.

Internal consistency wasnot tested for the NCSand NCS-R. Previous studies in traumatic brain injuries reportedagood internal consistency for the BPS (Cronbach alphasbetween 0.7 and 0.9) [START_REF] Dehghani | Validity and Reliability of Behavioral Pain Scale in Patients With Low Level of Consciousness Due to Head Trauma Hospitalized in Intensive Care Unit[END_REF][START_REF] Ribeiro | Psychometric Properties of the Behavioral Pain Scale in Traumatic Brain Injury[END_REF], betterthan in this study (Cronbachalpha between 0.6 and 0.7 for all pain scales). This might beexplained by the differences in patient populations, the presentstudy including diverse braininjuries with a majority of vasculardisease (76%) and a minority of trauma or surgeries (14%). Astudy of 80 noncommunicating ICU patients with nontraumaticbrain injuries [START_REF] Roulin | Behavioral changes in brain-injured critical care adults with different levels of consciousness during nociceptive stimulation: an observational study[END_REF]reported that the most frequent behaviors werefacial reactions (eg, brow lowering, orbittightening, and eyemovements), ventilator asynchrony, and muscle rigidity, but bodymovements were less present. The latter is consistent with thisstudy where the motor domain was less represented by the firstprincipal component, explaining a moderate internalconsistency.In traumatic brain-injured patients, pain behavior might bedifferent. A study of45 ICU patients with traumatic brain injuryreported that behaviors were mostly "untypical," includinguncommon responses such as flushing, sudden eye opening,eye weeping, andflexion of limb [2]. In any case, the BPSdemonstrated globally good psychometric properties(discriminantand criterion validation, and inter-rater reliability), allowing itsuse in bothtraumatic [START_REF] Dehghani | Validity and Reliability of Behavioral Pain Scale in Patients With Low Level of Consciousness Due to Head Trauma Hospitalized in Intensive Care Unit[END_REF][START_REF] Ribeiro | Psychometric Properties of the Behavioral Pain Scale in Traumatic Brain Injury[END_REF]and nontraumatic (this study) braininjuredpatients. In the same way, theCritical Care ObservationPain Tool (CPOT), that, along with the BPS, is the most validatedand used tool in ICU settings throughout the world, has also beenvalidated in ICU braininjured patients with diverse braininjuries [START_REF] Joffe | Validation of the Critical-Care Pain Observation Tool in brain-injured critically ill adults[END_REF][START_REF] Lee | Patterns and Clinical Correlates of Pain Among Brain Injury Patients in Critical Care Assessed with the Critical Care Pain Observation Tool[END_REF][START_REF] Shan | Use of the critical-care pain observation tool and the bispectral index for the detection of pain in brain-injured patients undergoing mechanical ventilation: A STROBE-compliant observational study[END_REF][START_REF] Topolovec-Vranic | Validation and evaluation of two observational pain assessment tools in a trauma and neurosurgical intensive care unit[END_REF]. The CPOT was not tested in this studyto makethe study more feasible for the bedside nurses, to avoid potentialbias related toperforming too many scales in contrast with routinecare, and because previous studies hadalready shown that theBPS and CPOT were very similar [START_REF] Chanques | Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report[END_REF][START_REF] Severgnini | Accuracy of Critical Care Pain Observation Tool and Behavioral Pain Scale to assess pain in critically ill conscious and unconscious patients: prospective, observational study[END_REF].

Our study has severallimitations. First, we were not able toperform a convergent validation of the pain scales (correlationcoefficients) because, contrary to previous reports in non-braininjuredICUpatients [START_REF] Li | Evaluations of physiologic reactivity and reflexive behaviors during noxious procedures in sedated critically ill patients[END_REF][START_REF] Lukaszewicz | The relevance of pupillometry for evaluation of analgesia before noxious procedures in the intensive care unit[END_REF], videopupillometry poorly performed inour patient population, even if injuriespotentially associated withpupillary response were considered as exclusion criteria(brainsteminjuries and clinical anisocoria). This is a major finding of thisstudy. Recently, theelectrophysiology of pain based on heart ratevariability has shown promising results in ICUpatients, regardlessof brain injury status [START_REF] Chanques | Analgesia nociception index for the assessment of pain in critically ill patients: a diagnostic accuracy study[END_REF][START_REF] Jendoubi | Pain measurement in mechanically ventilated patients with traumatic brain injury: Behavioral pain tools versus analgesia nociception index[END_REF]. Also, due to the study purpose, thepatientswere unable to self-report their pain intensity, and thus,the correlation between self-reportedpain intensity and thebehavioral pain scales could not be measured. However, this isalso part of the reason why behavioral pain scales have beendeveloped as surrogate markers of pain inthe first place. Whenpatients are able to selfreport their pain intensity, even ifsignificant, thecorrelation between self-reported pain scalesand behaviors is poor, making the use of behavioral pain toolspossibly inappropriate [START_REF] Chanques | The measurement of pain in intensive care unit: Comparison of 5 self-report intensity scales[END_REF].Second, the item selection and contentvalidation of the pain scales were not performed before this study.Rather, this study dealswith pre-existing pain scales adapted toa more-specific type of population (brain-injured patients).However, the modification of the NCS(-R) for intubated patientswas made byexpert clinicians in intensive and neurointensivecare. Moreover, the content validation issupported by recentdata in braininjured patients, as previously discussed [START_REF] Roulin | Behavioral changes in brain-injured critical care adults with different levels of consciousness during nociceptive stimulation: an observational study[END_REF]. Finally,thepsychometric properties of the pain scales assessed in thisstudy can be quoted within therange of well-validated pain scalesin the general ICU population, following the method used in therecent guidelines regarding pain management in ICU patients [START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF](see Appendix 1). However,the principalcomponent analysis of the pain scales highlighted that someitems could bemodified to better fit with this specific population,contrary to what has been reported fornon-brain-injured patients(for the BPS) [START_REF] Chanques | Assessing pain in non-intubated critically ill patients unable to self report: an adaptation of the Behavioral Pain Scale[END_REF][START_REF] Chanques | Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report[END_REF]. In the same way, a greater proportion ofneurocritical caregivers preferred the NCS-I/NCS-R-I over theBPS in this study. This may bebecause the NCS was specificallyconstructed for brain-injured patients. Recent data onbraininjuredpatients reported several different and new types ofbehavior when assessed byvideo recording [START_REF] Gélinas | Behaviors Indicative of Pain in Brain-Injured Adult Patients With Different Levels of Consciousness in the Intensive Care Unit[END_REF].New pain toolsspecifically designed forCIBI patients will be developed in thefuture. These tools will need to be assessed for psychometricvalidity and feasibility inregards to pre-existing, routinely usedtools such as the BPS, NCS, and CPOT. Finally, thenext step inpain research will be to assess the impact of analgesia protocolsusing specificallyvalidated pain scales for improving the painmanagement and related outcomes in CIBIpatients, asdemonstrated in non-brain-injured patients [START_REF] Chanques | Impact of systematic evaluation of pain and agitation in an intensive care unit: Critical Care Medicine[END_REF][START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF].

CONCLUSION

In contrast to videopupillometry, the BPS, NCS-I, and NCS-R-Iare valid, reliable, andacceptable pain tools for use inmechanically ventilated brain-injured patients. In ICU settingswhere the BPS is commonly used for assessing pain innonverbal patients, the BPS can alsobe used in the specificsubgroup of brain-injured patients. In neurological settingswhere theNCS or NCS-R are commonly used for assessingpain in brain-injured patients, the NCS-I orNCS-R-I can nowalso be used in the specific subgroup of intubated patients.Future painscales that will be constructed specifically for braininjuredICU patients should be testedagainst these widely usedtools.

  Aux membres de monJury, A mon Président du Jury, Monsieur le Professeur Michel CARLES Je suis reconnaissante de l'honneur que vous me faites de présider ce jury et de juger mon travail. Merci pour votre implication en tant que coordinateur du DES d'Anesthésie Réanimation aux Antilles. Je vous témoigne ma profonde et respectueuse reconnaissance. A mon Directeur de Thèse, Monsieur le Professeur Gérald CHANQUES Je vous remercie d'avoir accepté de me soutenir et de m'accompagner tout au long de ce travail. Cela a été un réel plaisir de travailler avec vous, vos conseils avisés ont toujours été très instructifs. Je vous remercie d'être à l'écoute de chacun, reflet de votre bienveillance, et de votre gentillesse.

  honnêteté et ton soutien, et les multiples « mais meuf » qui m'ouvrent les yeux, -A Audrey, pour ces fous rires et sans qui les paperasseries administratives n'auraient pas été si « chouette »,-A Kiki, pour ta joie de vivre et tes histoires rocambolesques, -A Clément pour ta sagesse.Aux Piquettes, pour toutes ces parties de contrées et soirées enflammées, pour ces gouters gargantuesques, mais surtout ces soirées, et tous ces débriefings à la coloc…Vous êtes chacune unique, différente mais toutes complémentaires…Merci de m'avoir fait grandir et devenir la personne que je suis aujourd'hui. Particulièrement, -A Mathilde, pour nos voyages, -A Alicia pour nos stages d'externat, -A Coline pour les scènes de théâtre quotidiennes, -A Léa pour lamaturité, -A Mathilde pour la simplicité. A Alizée et Déa,pour nos soiréesbachotages, sans ellesje n'en serai surement pas là, et puis particulièrement à Déa pour la MEP. A Mickael, Momo, Pierre-Michel et Colin, pour les rires et la vie du groupe.

(

  la chouchou), Severin, Yassir, Francesca, Dorian, Louise, Guillaume et nos externes préférés, Charles et Leilo, -A Morgane, Anaïs, Laurent, Nathan, Simon,Remy, Julien, Charline et Clément, -A Julie, Alizée, Antoine, Jules et Valérie, -A Adeline, Olivier (le double de Niney), Audrey, Arthur(ito) (coeur coeur love), Hugo, Helene, Ludo et Lorrain, -A Jennifer, Siham, Sarah, Hugues et Adrichou, -A Jacques, Timothée et Aurélien. A tous mes chefs de clinique/assistant(e)s et PH, pour avoir contribué à ma formation. Plus précisément, à ceux qui m'ont tant appris : Shazima, Pascal, Julien, Marc, Bertrand, Pr Thierry, Dr Valentino, Dr Medhaoui, Ronan,Dr Chabartier, Sergio,Hassan, Flora,Frédérique, Kevin, Maxime, Fabien, Thibault, Sonia, Caroline, Jérémy, Olivier, Thaïs, Julie, Marion, Audrey, Matthieu, Laurie, Béranger, Marc, Cindé, Norrdine, Jacob, Philippe, Marine, Marion. A Hassan, pour tes attentions, ta relecture et ta gentillesse. Signé « Calidoudou », bientôt « Calidocteur ».

  LISTE DES ENSEIGNANTS ............................................................................................ --REMERCIEMENTS ....................................................................................................... --TABLE DES MATIERES ............................................................................................... --LISTE DES ILLUSTRATIONS ...................................................................................... --LISTE DES ABREVIATIONS ........................................................................................ --RESUME ........................................................................................................................ --ABSTRACT .................................................................................................................... --INTRODUCTION ........................................................................................................... --MATERIALS AND METHODS ..................................................................................... --1 Ethics approval ........................................................................................................ --2 Patient population .................................................................................................... --

Figure 1 :Figure 2 :Figure 3 :

 123 Figure 1: Study flowchart………………………….………………………………………-29 -

  ischémique). La validité discriminativea été démontrée pour tous les outils par une augmentation significativement plus importante de l'intensité douloureuselors des procédures douloureusesque lors dela procédure non douloureuse(p <0,001). Le BPS était le seul outil ne variant pas significativement au cours de la procédure non nociceptive (p = 0.41), suggérant qu'il était l'outil le plus discriminant. Le BPS, la NCS-I et la NCS-R-I permettaient de prédire les procédures douloureuses de manière performante(aires sous les courbes  0.96), contrairement à la vidéopupillométrie (aire sous la courbe = 0.67). Le BPS, la NCS-I et laNCS-R-I avaient une reproductibilité inter-observateur importante (kappa pondéré = 0.86, 0.82 et 0.84, respectivement).Le BPS, la NCS-I et la NCS-R-I avaient une consistance interne modérée (Cronbach α> 0.60). L''analyse factorielle ducomposant principalmontrait deux dimensions pour chacun des 3 outils cliniques : la premièrecomprenant la majorité des informationset la deuxième représentant les items moteurs. La faisabilité de l'échelle paraissait meilleure pour l'équipe paramédicale pour la NCS-I et la NCS-R-I que pour le BPS. CONCLUSION: Le BPS, la NCS-I et la NCS-R-I sont des échelles comportementales d'évaluation de la douleur valides, fiables et acceptables pour une utilisation chez les patients intubés cérébro-lésés contrairement à la vidéopupillométrie.

ABSTRACTINTRODUCTION:

  Three clinical scales (the Nociception Coma Scale adapted for Intubated patients [NCS-I], its Revised version [NCS-R-I], and the Behavioral Pain Scale [BPS]) and videopupillometry were compared for measuring pain in intubated, noncommunicating, critically ill, brain-injured patients.

  . The recent American guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the intensive care unit (ICU)

  Pain was assessed with pain scales and a videopupillometer. Pain scale descriptors and instructions for use were explained to the bedside nurses by the same investigator (C.B.) before the first procedure for each patient. Pain scales were used by the investigator and the nurse at the same time. Data were reported on separate sheets, the 2 assessors being blinded to each other. The videopupillometer was used by a second investigator, blinded to the first one,

version 7 .

 7 12 (2016) (SAS Institute, Cary, NC) and R software version 3.4.3 (November 30, 2017).

Figure 1 :

 1 Figure 1: Study flowchart. ICU, intensive care unit.

Figure 3 :

 3 Figure 3: Receiver operating characteristic (ROC) curves of the three clinical pain scales and videopupillometry associated with pain (nociceptive procedures).

  Criterion validation ...................................................................................... --5.2 Reliability ........................................................................................................ --

	3	Conduct of the study ................................................................................................ --
	4	Data recording ......................................................................................................... --
		4.1	Pain .................................................................................................................. --
		4.1.1 Pain Scale .................................................................................................... --
			4.1.1.1 Behavioral Pain Scale (BPS) ................................................................. --
			4.1.1.2 Nociception Coma Scale (NCS), Revised Nociception Coma Scale (NCS-R)
			and Nociception Coma Scale for Intubated patients .............................................. --
		4.1.2 Videopupillometry ....................................................................................... --
		4.2	Demographic and medical data......................................................................... --
	5	Statistical analysis .................................................................................................... --
		5.1	Construct validity (primary endpoint) ............................................................... --
		5.1.1 Discriminant validation ................................................................................ --
		5.1.2

Table 1 :

 1 Description of the three clinical pain scales……………...………………………-25 -

Table 2

 2

	: Demographic and medical characteristics of the 50 patients included for
	analysis…………………………………………………………………………………..…-30
	-

étaient la consistance interne de l'échelle, la reproductibilité inter-observateur et la faisabilité pratique.

RÉSULTATS / DISCUSSION : Cinquante patients (54% de femmes, âgésde 63 [56-68] ans) ont été inclus, 13

[START_REF] Chanques | Validation de l'échelle de vigilance-agitation de Richmond traduite en langue française[END_REF][START_REF] Chanques | Impact of systematic evaluation of pain and agitation in an intensive care unit: Critical Care Medicine[END_REF][START_REF] Chanques | Assessing pain in non-intubated critically ill patients unable to self report: an adaptation of the Behavioral Pain Scale[END_REF][START_REF] Chanques | Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report[END_REF][START_REF] Chanques | Analgesia nociception index for the assessment of pain in critically ill patients: a diagnostic accuracy study[END_REF][START_REF] Chanques | The measurement of pain in intensive care unit: Comparison of 5 self-report intensity scales[END_REF][START_REF] Chatelle | A sensitive scale to assess nociceptive pain in patients with disorders of consciousness[END_REF][START_REF] Cronbach | Coefficient alpha and the internal structure of tests[END_REF][START_REF] De Jong | Decreasing severe pain and serious adverse events while moving intensive care unit patients: a prospective interventional study (the NURSE-DO project)[END_REF][START_REF] Dehghani | Validity and Reliability of Behavioral Pain Scale in Patients With Low Level of Consciousness Due to Head Trauma Hospitalized in Intensive Care Unit[END_REF][START_REF] Delong | Comparing the Areas under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach[END_REF][START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF][START_REF] Feldt | A test of the hypothesis that Cronbach's alpha reliability coefficient is the same for two tests administered to the same sample[END_REF][START_REF] Gélinas | Behaviors Indicative of Pain in Brain-Injured Adult Patients With Different Levels of Consciousness in the Intensive Care Unit[END_REF][START_REF] Gélinas | A Validated Approach to Evaluating Psychometric Properties of Pain Assessment Tools for Use in Nonverbal Critically Ill Adults. Seminars in Respiratory and Critical Care Medicine[END_REF][START_REF] Jendoubi | Pain measurement in mechanically ventilated patients with traumatic brain injury: Behavioral pain tools versus analgesia nociception index[END_REF][START_REF] Joffe | Validation of the Critical-Care Pain Observation Tool in brain-injured critically ill adults[END_REF][START_REF] Kline | A psychometrics primer[END_REF]

jours après une lésion cérébrale (76% d'AVC hémorragique ou

Table 1 : Description of the three clinical pain scales.

 1

	Behavioral Pain Scale	Nociception Coma Scale	Nociception Coma Scale
			-Revised version-
		adapted for	adapted for
		Intubated patients	Intubated patients
	(BPS)	(NCS-I)	(NCS-R-I)
	FACIAL EXPRESSION	FACIAL EXPRESSION	FACIAL EXPRESSION
	1 -Relaxed	0 -None	0 -None
	2 -Partially tightened (= brow	1 -Oral reflexive	1 -Oral reflexive
	lowering)	movement/Startle response	movement/Startle response
	3 -Fully tightened (= eyelid	2 -Grimace	2 -Grimace
	closing)	3 -Crying (tears)	3 -Crying (tears)
	4 -Grimacing (=folded cheek)
	UPPER LIMBS	MOTOR RESPONSE	MOTOR RESPONSE
	1 -No movement	0 -None	0 -None
	2 -Partially bent	1 -Abnormal posturing	1 -Abnormal posturing
	3 -Fully bent with finger flexion	2 -Flexion withdrawal	2 -Flexion withdrawal
	4 -Retracted, opposition to care	3 -Localization to noxious	3 -Localization to noxious
		stimulation	stimulation
	COMPLIANCE WITH	COMPLIANCE WITH	COMPLIANCE WITH
	VENTILATON	VENTILATON	VENTILATON
	1 -Tolerating ventilation	0 -Tolerating ventilation	0 -Tolerating ventilation
	2 -Coughing but tolerating	1 -Coughing but tolerating	1 -Coughing but tolerating
	ventilation most of the time	ventilation most of the time	ventilation most of the time
	3 -Fighting ventilator but	2 -Fighting ventilator but	2 -Fighting ventilator but
	ventilation possible sometimes	ventilation possible sometimes	ventilation possible sometimes
	4 -Unable to control ventilation	3 -Unable to control ventilation	3 -Unable to control ventilation
		VISUAL RESPONSE
	Not applicable	0 -None	Not applicable
		1 -Startle
		2 -Eyes movements

Table 2 : Demographic and medical characteristics of the 50 patients included for analysis.

 2

  Taking into account other studies assessing BPS psychometrics in brain-injured intubated patients.

	Q.2 Q.3	Question Question Scale Testing -Scale Testing: Construct Reliability Validity	Scoring Legend Scoring Legend 2: 0.70<alpha<0.90	BPS BPS	Score NCS-I Score NCS-I	NCS-NCS-R-I R-I
	2.1 3.1	Was internal consistency of the scale calculated? What is the total of participants for the purpose	1: 0.60<apha<0.70 or alpha>0.90 0: alpha<0.60 or no information 2: N>50 1: 20<N<50	1 2*	1 1	1 1
		of testing the scale?	provided 0: N<20
			2: kappa>0.60 or ICC>0.80
	2.2 2.3 3.2	Was interrater reliability calculated? Was interrater reliability tested with other raters besides research team? Criterion validation: Was the scale correlated with the 1: 0.60<kappa>0.40 or 0.60<ICC<0.80 0: kappa<0.40, ICC<0.60 or no information provided 1: Other raters then research staff members were involved 0: Only research staff members were involved 2: r>0.60 with the "gold standard" measure "gold standard" measure self-report of pain)? provided interest (e.g. the patient's 0: r<0.40 or no information renown in the field of 1: 0.40<r<0.60	2 1 2	2 1 2	2 1 2
	2.4 3.3 Subtotal -Scale development (0-5 or 0-7 if intrarater reliability testing Was intrarater reliability tested? Optional-to be examined if kappa<0.60 or ICC<0.80 for interrater reliability 2: kappa>0.60 or ICC>0.80 1: 0.60<kappa>0.40 or 0.60<ICC<0.80 0: kappa<0.40, ICC<0.60 or no 2: Sensitivity > or = 80% Criterion validation: Was the sensitivity of the scale 1: 60% < or = Sensitivity<80% 0: Sensitivity<60% or no calculated? information provided information provided required) Subtotal weighted score -Scale development (0-6) 3.4 2: Specificity > or = 80% Criterion validation: Was the specificity of the scale information provided calculated? 1: 60% < or = Specificity < 80% 0: Specificity < 60% or no	N/A 2 4/5 4.8 2	N/A 2 4/5 4.8 2	N/A 2 4/5 4.8 2
		Discriminant validation:
		Was the scale able to
		discriminate between	2: A clinically important difference
		different situations, e.g.	was found
	3.5	between pain and no pain (e.g. at rest and during a	1: A difference was found but was not considered clinically important	2	2	2
		nociceptive procedure,	0: No difference was found or no
		before and after the	information is provided
		administration of an
		analgesic)?
	Subtotal -Scale development (0-10)	10	9	9
	Subtotal weighted score -Scale development (0-8)	8	7.2	7.2

*

-Fixation

SERMENT D'HIPPOCRATE

Au moment d'être admis à exercer la médecine, en présence des maîtres de cette école et de mes condisciples, je promets et je jure d'être fidèle aux lois de l'honneur et de la probité qui la régissent.

Mon premier souci sera, de rétablir, de préserver ou de promouvoir la santé dans tous les éléments physiques et mentaux, individuels collectifs et sociaux. Je respecterai toutes les personnes, leur autonomie et leur volonté, sans aucune discrimination selon leur état ou leurs convictions.

J'interviendrai pour les protéger si elles sont affaiblies, vulnérables ou menacées dans leur intégrité ou dignité.

Même sous la contrainte, je ne ferai usage de mes connaissances contre les lois de l'humanité. J'informerai les patients de décisions envisagées, de leurs raisons et de leurs conséquences.

Je ne tromperai jamais leur confiance et n'exploiterai pas le pouvoir hérité des circonstances pour forcer leurs consciences.

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

Admis dans l'intimité des personnes, je tairai les secrets qui me sont confiés.

Reçu à l'intérieur des maisons, je respecterai les secrets des foyers.

Et ma conduite ne servira pas à corrompre les moeurs.

Je ferai tout pour soulager les souffrances, sans acharnement.

Je ne provoquerai jamais la mort délibérément.

Je préserverai l'indépendance nécessaire à l'accomplissement de ma mission.

Que je sois modéré en tout, mais insatiable de mon amour de la science.

Je n'entreprendrai rien qui ne dépasse mes compétences ; je les entretiendrai et les perfectionnerai pour assurer au mieux les services qui me seront demandés. J'apporterai mon aide à mes confrères ainsi qu'à leurs familles dans l'adversité.

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

A tous ceux présents dans cette salle aujourd'hui.

Et puis à tous ceux que j'ai oubliés et qui j'espère ne m'en tiendront pas rigueur.

Mots

Internal consistency

Cronbach alpha coefficients were significantly different among the 3 pain scales (p<0.001), from 0.61 (95% confidence interval 0.56-0.66) for the BPS, through 0.69 (0.64-0.73) for the NCS-R-I and up to 0.70 (0.66-0.74) for the NCS-I. Even if the Cronbach alpha coefficient was significantly higher for the NCS-R-I and the NCS-I vs that for the BPS (p<0.001 for each pairwise comparison), these results suggest that the internal consistency was only moderate for all 3 pain scales. The principal component analysis showed that all 3 pain scales were primarily two-dimensional with a principal dimension representing 56% of the variance for the BPS, 53% for the NCS-I, and 62% for the NCS-R-I. The motor domain for each of the 3 scales was poorly represented by the principal dimension and correctly represented by the second dimension.

Inter-rater reliability

The weighted kappa coefficient assessed the inter-rater reliability of the pain scales, with values between 0.82 (0.78-0.85) for the NCS-I, 0.84 (0.81-0.87) for the NCS-R-I, and 0.86 (0.83-0.89) for the BPS. These results suggest that the inter-rater reliability was high for all 3 pain scales. The weighted kappa coefficient was significantly higher for the BPS compared with the NCS-I (p=0.01), but not for the NCS-R-I (p=0.24).

Scale feasibility

Fifteen (71%) observers from among the 21 who participated in the study sent back the questionnaire. Regarding the proportion of ratings that were moderately to very positive, the BPS, NCS-I, and NCS-R-I were believed to be precise by 80%, 93%, and 93% of users, respectively. The usefulness of the scales was 87% for the BPS and 100% for the NCS-I/NCS-R-I. The easiness of learning was 67% for the BPS and 80% for the NCS-I/NCS-R-I.

The scale that was found the most frequently easy or very easy to learn was the NCS-R-I (57%), compared with the others (NCS-I= 47%; BPS= 27%). Was the process of item selection described?

APPENDICES

NCS-R-I Scale Feasibility

4.1

Was the feasibility (i.e. ease of usage with which clinicians can apply the instrument in the clinical setting) of the scale examined?

1: Scale is considered to be feasible to use by more than 80% of the clinicians 0: Scale is considered to be complex to use by more than 20% of the clinicians or no information is provided information is provided Was the relevance of the scale or impact of its implementation in ICU patient outcomes examined? 1: Scale is considered to be useful and relevant to practice by more than 80% of the clinicians; use of the scale yielded a significant change into practice (e.g. better use of medication, increase in patients' assessments) 0: Scale is not considered to be useful and relevant to practice by more than 20% of the clinicians; use of the scale did not yield to a significant change into practice or no information provided

Methods:

The method of psychometric scoring for behavioral pain scales constructed for assessing pain in critically ill non communicant adult patients was developed for the Pain, Agitation and Delirium guidelines from the American College of Critical Care Medicine (ACCM) in conjunction with the Society of Critical Care Medicine (SCCM) in 2013 [1,3], and updated in 2018 [2].

Among the 13 behavioral pain scales scored in the 2018 guidelines, the scores ranged from 6 to 21

METHODS:

Pain assessment was performed before, during, just after, and 5 minutes after 3 procedures: the reference non-nociceptive procedure (assessment of the Richmond Agitation Sedation Scale) and 2 nociceptive procedures (turning and tracheal suctioning). The primary endpoint was construct validity (discriminant and criterion validation), determined by comparing pain measurements between different times/procedures. Secondary endpoints were internal consistency, inter-rater reliability, and feasibility. RESULTS/DISCUSSION: Fifty patients (54% women, median age 63 years [56-68]) were included 13 [START_REF] Chanques | Validation de l'échelle de vigilance-agitation de Richmond traduite en langue française[END_REF][START_REF] Chanques | Impact of systematic evaluation of pain and agitation in an intensive care unit: Critical Care Medicine[END_REF][START_REF] Chanques | Assessing pain in non-intubated critically ill patients unable to self report: an adaptation of the Behavioral Pain Scale[END_REF][START_REF] Chanques | Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report[END_REF][START_REF] Chanques | Analgesia nociception index for the assessment of pain in critically ill patients: a diagnostic accuracy study[END_REF][START_REF] Chanques | The measurement of pain in intensive care unit: Comparison of 5 self-report intensity scales[END_REF][START_REF] Chatelle | A sensitive scale to assess nociceptive pain in patients with disorders of consciousness[END_REF][START_REF] Cronbach | Coefficient alpha and the internal structure of tests[END_REF][START_REF] De Jong | Decreasing severe pain and serious adverse events while moving intensive care unit patients: a prospective interventional study (the NURSE-DO project)[END_REF][START_REF] Dehghani | Validity and Reliability of Behavioral Pain Scale in Patients With Low Level of Consciousness Due to Head Trauma Hospitalized in Intensive Care Unit[END_REF][START_REF] Delong | Comparing the Areas under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach[END_REF][START_REF] Devlin | Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU[END_REF][START_REF] Feldt | A test of the hypothesis that Cronbach's alpha reliability coefficient is the same for two tests administered to the same sample[END_REF][START_REF] Gélinas | Behaviors Indicative of Pain in Brain-Injured Adult Patients With Different Levels of Consciousness in the Intensive Care Unit[END_REF][START_REF] Gélinas | A Validated Approach to Evaluating Psychometric Properties of Pain Assessment Tools for Use in Nonverbal Critically Ill Adults. Seminars in Respiratory and Critical Care Medicine[END_REF][START_REF] Jendoubi | Pain measurement in mechanically ventilated patients with traumatic brain injury: Behavioral pain tools versus analgesia nociception index[END_REF][START_REF] Joffe | Validation of the Critical-Care Pain Observation Tool in brain-injured critically ill adults[END_REF][START_REF] Kline | A psychometrics primer[END_REF] days after brain injury (76% hemorrhagic or ischemic strokes). All tools increased significantly more (p<0.001) during the nociceptive procedures vs the non-nociceptive procedure. The BPS was the only pain tool that did not increase significantly during the non-nociceptive procedure (p=0.41), suggesting that it was the most discriminant tool. The BPS, NCS-I, and NCS-R-I were good predictors of nociception with areas under the curves  0.96, contrary to videopupillometry (area under the curve = 0.67). The BPS, NCS-I, and NCS-R-I had high interrater reliabilities (weighted kappa 0.86, 0.82 and 0.84, respectively). Internal consistency was moderate (>0.60) for all pain scales. Factor analysis represented a majority of information on a first dimension, with motor domains represented on a second dimension. Scale feasibility was better for the NCS-I and NCS-R-I than for the BPS.

CONCLUSION:

In conclusion, the BPS, NCS-I, and NCS-R-I are valid, reliable, and acceptable pain scales for use in intubated critically ill, brain-injured patients, unlike videopupillometry. Future research requires tool design centered on domains of observation adapted to this very specific population.

JURY: Président: Pr CARLES Michel

Juges: Pr JABER Samir : Pr PERRIGAULT Pierre François : Pr CHANQUES Gérald