Does Differential Item Functioning Jeopardize the Comparability of Health-Related Quality of Life Assessment Between Patients and Proxies in Patients with Moderate-to-Severe Traumatic Brain Injury?

BACKGROUND: Health-related quality of life (HRQoL) is clearly recognized as a patient-important outcome in patients with traumatic brain injury (TBI). Patient-reported outcomes are therefore often used and supposed to be directly reported by the patients without interpretation of their responses by a physician or anyone else. However, patients with TBI are often unable to self-report because of physical and/or cognitive impairments. Thus, proxy-reported measures, e.g., family members, are often used on the patient's behalf. Yet, many studies have reported that proxy and patient ratings differ and are noncomparable. However, most studies usually do not account for other potential confounding factors that may be associated with HRQoL. In addition, patients and proxies can interpret some items of the patient-reported outcomes differently. As a result, item responses may not only reflect patients' HRQoL but also the respondent's (patient or proxy) own perception of the items. This phenomenon, called differential item functioning (DIF), can lead to substantial differences between patient-reported and proxy-reported measures and compromise their comparability, leading to highly biased HRQoL estimates. Using data from the prospective multicenter continuous hyperosmolar therapy in traumatic brain-injured patients study (240 patients with HRQoL measured with the Short Form-36 (SF-36)), we assessed the comparability of patients' and proxies' reports by evaluating the extent to which items perception differs (i.e., DIF) between patients and proxies after controlling for potential confounders. METHODS: Items at risk of DIF adjusting for confounders were examined on the items of the role physical and role emotional domains of the SF-36. RESULTS: Differential item functioning was evidenced in three out of the four items of the role physical domain measuring role limitations due to physical health problems and in one out of the three items of the role emotional domain measuring role limitations due to personal or emotional problems. Overall, despite an expected similar level of role limitations between patients who were able to respond and those for whom proxies responded, proxies tend to give more pessimistic responses than patients in the case of major role limitations and more optimistic responses than patients in the case of minor limitations. CONCLUSIONS: Patients with moderate-to-severe TBI and proxies seem to have different perceptions of the items measuring role limitations due to physical or emotional problems, questioning the comparability of patient and proxy data. Therefore, aggregating proxy and patient responses may bias HRQoL estimates and alter medical decision-making based on these patient-important outcomes.

Effect of Remifentanil vs Neuromuscular Blockers During Rapid Sequence Intubation on Successful Intubation Without Major Complications Among Patients at Risk of Aspiration: A Randomized Clinical Trial.

Importance: It is uncertain whether a rapid-onset opioid is noninferior to a rapid-onset neuromuscular blocker during rapid sequence intubation when used in conjunction with a hypnotic agent. Objective: To determine whether remifentanil is noninferior to rapid-onset neuromuscular blockers for rapid sequence intubation. Design, Setting, and Participants: Multicenter, randomized, open-label, noninferiority trial among 1150 adults at risk of aspiration (fasting for <6 hours, bowel occlusion, recent trauma, or severe gastroesophageal reflux) who underwent tracheal intubation in the operating room at 15 hospitals in France from October 2019 to April 2021. Follow-up was completed on May 15, 2021. Interventions: Patients were randomized to receive neuromuscular blockers (1 mg/kg of succinylcholine or rocuronium; n = 575) or remifentanil (3 to 4 µg/kg; n = 575) immediately after injection of a hypnotic. Main Outcomes and Measures: The primary outcome was assessed in all randomized patients (as-randomized population) and in all eligible patients who received assigned treatment (per-protocol population). The primary outcome was successful tracheal intubation on the first attempt without major complications, defined as lung aspiration of digestive content, oxygen desaturation, major hemodynamic instability, sustained arrhythmia, cardiac arrest, and severe anaphylactic reaction. The prespecified noninferiority margin was 7.0%. Results: Among 1150 randomized patients (mean age, 50.7 [SD, 17.4] years; 573 [50%] women), 1130 (98.3%) completed the trial. In the as-randomized population, tracheal intubation on the first attempt without major complications occurred in 374 of 575 patients (66.1%) in the remifentanil group and 408 of 575 (71.6%) in the neuromuscular blocker group (between-group difference adjusted for randomization strata and center, -6.1%; 95% CI, -11.6% to -0.5%; P = .37 for noninferiority), demonstrating inferiority. In the per-protocol population, 374 of 565 patients (66.2%) in the remifentanil group and 403 of 565 (71.3%) in the neuromuscular blocker group had successful intubation without major complications (adjusted difference, -5.7%; 2-sided 95% CI, -11.3% to -0.1%; P = .32 for noninferiority). An adverse event of hemodynamic instability was recorded in 19 of 575 patients (3.3%) with remifentanil and 3 of 575 (0.5%) with neuromuscular blockers (adjusted difference, 2.8%; 95% CI, 1.2%-4.4%). Conclusions and Relevance: Among adults at risk of aspiration during rapid sequence intubation in the operating room, remifentanil, compared with neuromuscular blockers, did not meet the criterion for noninferiority with regard to successful intubation on first attempt without major complications. Although remifentanil was statistically inferior to neuromuscular blockers, the wide confidence interval around the effect estimate remains compatible with noninferiority and limits conclusions about the clinical relevance of the difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03960801.

Implementation of French Recommendations for the Prevention and the Treatment of Hospital-acquired Pneumonia: A Cluster-randomized Trial.

BACKGROUND: We determined whether an audit on the adherence to guidelines for hospital-acquired pneumonia (HAP) can improve the outcomes of patients in intensive care units (ICUs). METHODS: This study was conducted at 35 ICUs in 30 hospitals. We included consecutive, adult patients hospitalized in ICUs for 3 days or more. After a 3-month baseline period followed by the dissemination of recommendations, an audit on the compliance to recommendations (audit period) was followed by a 3-month cluster-randomized trial. We randomly assigned ICUs to either receive audit and feedback (intervention group) or participate in a national registry (control group). The primary outcome was the duration of ICU stay. RESULTS: Among 1856 patients enrolled, 602, 669, and 585 were recruited in the baseline, audit, and intervention periods, respectively. The composite measures of compliance were 47% (interquartile range [IQR], 38-56%) in the intervention group and 42% (IQR, 25-53%) in the control group (P = .001). As compared to the baseline period, the ICU lengths of stay were reduced by 3.2 days in the intervention period (P = .07) and by 2.8 days in the control period (P = .02). The durations of ICU stay were 7 days (IQR, 5-14 days) in the control group and 9 days (IQR, 5-20 days) in the intervention group (P = .10). After adjustment for unbalanced baseline characteristics, the hazard ratio for being discharged alive from the ICU in the control group was 1.17 (95% confidence interval, .69-2.01; P = .10). CONCLUSIONS: The publication of French guidelines for HAP was associated with a reduction of the ICU length of stay. However, the realization of an audit to improve their application did not further improve outcomes. CLINICAL TRIALS REGISTRATION: NCT03348579.

Change in the regulatory framework for zolpidem: What is the impact on the landscape of the prescription of sedative medications? The French national ZORRO study.

AIMS: In recent years, zolpidem has been the subject of numerous reports of misuse, abuse and dependence. In view of these risks, the French drug agency (ANSM) decreed in April 2017 the implementation of secure prescription pads. The objective of this study was to evaluate the impact of this regulatory measure on the prescription of zolpidem and other sedative medications (zopiclone, benzodiazepines and antihistamines) in long-term users of zolpidem and associated factors. METHODS: We performed a historical cohort study using data from the Generalist Sample of Beneficiaries (EGB). All patients aged over 18 years old who were long-term users (at least 3 months) before the measure were enacted. We analysed the reimbursement trajectories of zolpidem, zopiclone, benzodiazepines and antihistamines (hydroxyzine and alimemazine) up to 2 years after the measure using a state sequence analysis. RESULTS: Overall, 2502 patients were analysed. A four-cluster typology was identified: continuation of zolpidem (n = 1044, 42%), discontinuation of sedative medications (n = 766, 31%), change to zopiclone (n = 537, 21%) and change to hypnotic benzodiazepines (n = 155, 6%). The most frequently prescribed hypnotic benzodiazepine was lormetazepam. We identified age, sex, treatment for psychiatric or addictive disorder and volume of zolpidem use before the measure as factors associated with different reimbursement trajectories after the regulatory change. CONCLUSION: The regulatory change for zolpidem prescriptions reduced exposure to zolpidem among long-term users and also had a broad impact on prescriptions of other sedative medications. Switching to other medications that also present a potential risk of abuse or dependence should be carefully monitored.

Benzodiazepine withdrawal in older people: what is the prevalence, what are the signs, and which patients?

PURPOSE: Benzodiazepines (BZDs) and related drugs (Z-drugs) are mainly taken chronically, and older people are much more likely to take them on a chronic basis despite recommendations. Withdrawal symptoms could be an obstacle to stopping BZD/Z-drug administration. The main objective of this study is to estimate the prevalence of withdrawal symptoms in patients aged 65 years and older who have experience a stop of BZD/Z-drug. The secondary objectives are to describe the withdrawal symptoms and identify factors associated. METHOD: This ancillary study was based on a national observational study in patients with chronic BZD/Z-drug consumption. Patients who made at least one BZD/Z-drug stop experience were selected. Withdrawal symptoms are described, and a logistic regression was carried out to identify the variables most associated with withdrawal symptoms. RESULTS: In total, 697 patients were selected: 78% experienced at least one withdrawal symptom after a stop administering BZDs or Z-drugs; most of the withdrawal symptoms were psychological disorders. CONCLUSION: Our study identifies a specific population experiencing withdrawal symptoms and who cannot stop administering BZD/Z-drug. We assume that withdrawal symptoms in patients with chronic use play an essential role in the nonstop use of BZD/Z-drugs.

Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Unhealthy alcohol use can lead to agitation in the intensive care unit (ICU). Objective: To assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients with unhealthy alcohol use receiving mechanical ventilation. Design, Settings, and Participants: This phase 3, double-blind, placebo-controlled, randomized clinical trial conducted in 18 ICUs in France recruited adults receiving mechanical ventilation who met criteria for unhealthy alcohol use. Patients were enrolled from June 2016 to February 2018; the last follow-up was in May 2019. Interventions: Baclofen (n = 159), adjusted from 50 to 150 mg per day based on estimated glomerular filtration rate, or placebo (n = 155) during mechanical ventilation up to a maximum of 15 days before gradual dose reduction over 3 to 6 days. Main Outcomes and Measures: The primary end point was the percentage of patients with at least 1 agitation-related event over the treatment period. Secondary outcomes included duration of mechanical ventilation, length of ICU stay, and 28-day mortality. Results: Among 314 patients who were randomized (mean age, 57 years; 60 [17.2%] women), 313 (99.7%) completed the trial. There was a statistically significant decrease in the percentage of patients who experienced at least 1 agitation-related event in the baclofen group vs the placebo group (31 [19.7%] vs 46 [29.7%]; difference, -9.93% [95% CI, -19.45% to -0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35-0.99]). Of 18 prespecified secondary end points, 14 were not significantly different. Compared with the placebo group, the baclofen group had a significantly longer median length of mechanical ventilation (9 vs 8 days; difference, 2.00 [95% CI, 0.00-3.00]; hazard ratio [HR] for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14 vs 11 days; difference, 2.00 [95% CI, 0.00-4.00]; HR for discharge, 0.70 [95% CI, 0.54-0.90]). At 28 days, there was no significant difference in mortality in the baclofen vs placebo group (25.3% vs 21.6%; adjusted odds ratio, 1.24 [95% CI, 0.72-2.13]). Delayed awakening (no eye opening at 72 hours after cessation of sedatives and analgesics) occurred in 14 patients (8.9%) in the baclofen group vs 3 (1.9%) in the placebo group. Conclusions and Relevance: Among patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events. However, considering the modest effect and the totality of findings for the secondary end points and adverse events, further research is needed to determine the possible role of baclofen in this setting and to potentially optimize dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT02723383.

Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury: The COBI Randomized Clinical Trial.

Importance: Fluid therapy is an important component of care for patients with traumatic brain injury, but whether it modulates clinical outcomes remains unclear. Objective: To determine whether continuous infusion of hypertonic saline solution improves neurological outcome at 6 months in patients with traumatic brain injury. Design, Setting, and Participants: Multicenter randomized clinical trial conducted in 9 intensive care units in France, including 370 patients with moderate to severe traumatic brain injury who were recruited from October 2017 to August 2019. Follow-up was completed in February 2020. Interventions: Adult patients with moderate to severe traumatic brain injury were randomly assigned to receive continuous infusion of 20% hypertonic saline solution plus standard care (n = 185) or standard care alone (controls; n = 185). The 20% hypertonic saline solution was administered for 48 hours or longer if patients remained at risk of intracranial hypertension. Main Outcomes and Measures: The primary outcome was Extended Glasgow Outcome Scale (GOS-E) score (range, 1-8, with lower scores indicating worse functional outcome) at 6 months, obtained centrally by blinded assessors and analyzed with ordinal logistic regression adjusted for prespecified prognostic factors (with a common odds ratio [OR] >1.0 favoring intervention). There were 12 secondary outcomes measured at multiple time points, including development of intracranial hypertension and 6-month mortality. Results: Among 370 patients who were randomized (median age, 44 [interquartile range, 27-59] years; 77 [20.2%] women), 359 (97%) completed the trial. The adjusted common OR for the GOS-E score at 6 months was 1.02 (95% CI, 0.71-1.47; P = .92). Of the 12 secondary outcomes, 10 were not significantly different. Intracranial hypertension developed in 62 (33.7%) patients in the intervention group and 66 (36.3%) patients in the control group (absolute difference, -2.6% [95% CI, -12.3% to 7.2%]; OR, 0.80 [95% CI, 0.51-1.26]). There was no significant difference in 6-month mortality (29 [15.9%] in the intervention group vs 37 [20.8%] in the control group; absolute difference, -4.9% [95% CI, -12.8% to 3.1%]; hazard ratio, 0.79 [95% CI, 0.48-1.28]). Conclusions and Relevance: Among patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care did not result in a significantly better neurological status at 6 months. However, confidence intervals for the findings were wide, and the study may have had limited power to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03143751.

Do older people know why they take benzodiazepines? A national French cross-sectional survey of long-term consumers.

OBJECTIVES: Benzodiazepines and non-benzodiazepine hypnotics (or Z-drugs) (BZD/Z) are widely prescribed for older patients despite major side effects and risks when chronically used. The patient's understanding of the treatment is one of the keys to good adherence. The purpose of the study was to assess the knowledge of BZD/Z treatment among older people who were taking BZD/Z for the long term by studying the concordance between the declared reason for taking BZD/Z and its indication. METHODS: This was a cross-sectional, pharmacoepidemiologic ancillary of a national study. Data were collected through a semi-structured interview. All patients from the main study were included. "Good knowledge" was considered when patients gave an indication for each BZD/Z that was similar to its marketing authorisation. Univariate and multivariate analyses were carried out to adequately determine profiles and characterise associations. RESULTS: More than half of the patients (61.6%) had a good knowledge regarding their treatment. The presence of a psychiatric disorder, a mean duration of BZD/Z use of less than 120 months, a desire to stop treatment, educational status and number and type of BZD/Z used were significantly associated (P < .05) with good knowledge. In the multivariate analysis, only a psychiatric disorder, educational status and taking at least one hypnotic drug were associated with good knowledge. CONCLUSIONS: At the time of shared medical decision, it appears essential to improve the knowledge of the treatment by the patient. The rate of patients with good knowledge of their BZD/Z treatment remains low and even lower than what was previously found in the literature for other drug classes. In contrast to patients with good knowledge, these data highlight the characteristics of patients with poor knowledge of their BZD/Z treatment, which may allow populations at risk to be targeted and enable education measures to be strengthened.

The MEOPAeDent trial protocol-an observational study of the Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) effects in paediatric dentistry.

BACKGROUND: Many studies were conducted to assess the benefit/risk ratio of EMONO (Equimolar Mixture of Oxygen and Nitrous Oxide) in France before it was authorized for use outside the hospital setting in 2009. The main objective of this project is to evaluate the effects sought and felt by children when EMONO is used in paediatric dentistry. The secondary objectives are to (i) evaluate the appreciation of EMONO by the children, (ii) characterize children who experience both analgesia and anxiolysis, (iii) evaluate children's appetite for EMONO and characterize children with a high appetite and (iv) evaluate the impact of the difference in practice among the French dental service university hospitals on anxiety. The maintenance of a framework for the safe use of this drug, whose place in dental care is fundamental, is essential. Twelve of the 16 French dental service university hospitals agreed to participate in this study. METHODS: MEOPAeDent is an observational, descriptive, transversal study that aims to evaluate the effects sought and felt by children when EMONO is used in paediatric dentistry. Subjects requiring dental care under EMONO are recruited by 12 French dental service university hospitals. Patients aged from 3 to 15 years are recruited for the study when they visit a dental service of a French university hospital requiring dental care under EMONO. The investigator collects the necessary data from the child's medical records, from his own observations and from questions posed to the child and his/her parents. A survey is completed at the first and final sessions of dental care under EMONO. DISCUSSION: This study will provide an evaluation of the effects of EMONO on the French paediatric population in need of dental care as well as evaluate the appetite for the use of this substance. The results will first be used to provide additional data that is essential to monitor the use of a product with an authorization to use it outside of hospitals from 2009 in France, confirm its safety for use and justify its framework of application. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03453411 registered 2 March 2018.

Ventilator-Free Day Outcomes Can Be Misleading.

INTRODUCTION: Acute respiratory distress syndrome often requires invasive mechanical ventilation, with both mortality and mechanical ventilation duration as outcomes of interest. The concept of ventilator-free days has been proposed as an outcome combining these two outcomes. Here we analyzed the construction of the ventilator-free day outcome and provided a hypothetical scenario to alert physicians that such an outcome can lead to misleading interpretations. METHODS: We proposed the isoventilator-free day curve concept and, using an analytical development, illustrated how a median ventilator-free day value can actually result from very different combinations of death rates and mechanical ventilation durations. We also used a hypothetical example to compare the Student t test, Wilcoxon rank-sum test, and Gray test (which accounts for death as a competing event with extubation) in comparing exposition to mechanical ventilation. RESULTS: A median ventilator-free day value of 10 days may mean that 10% of the patients died while survivors were ventilated during a median of 14 days or that 40% died while survivors were ventilated during a median of 5 days. Changing the time horizon affected the Student t test but not the Wilcoxon rank-sum result. The Gray test was more relevant than both the Student t test and Wilcoxon rank-sum test in identifying differences in groups showing highly different mechanical ventilation duration, despite equal median ventilator-free days. This approach was also illustrated using real data. CONCLUSIONS: Use of ventilator-free days as an outcome appears to have many drawbacks. Suitable methods of analyzing time to extubation should be preferred.

Prediction Score for Postoperative Neurologic Complications after Brain Tumor Craniotomy: A Multicenter Observational Study.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Craniotomy for brain tumor displays significant morbidity and mortality, and no score is available to discriminate high-risk patients. Our objective was to validate a prediction score for postoperative neurosurgical complications in this setting. METHODS: Creation of a score in a learning cohort from a prospective specific database of 1,094 patients undergoing elective brain tumor craniotomy in one center from 2008 to 2012. The validation cohort was validated in a prospective multicenter independent cohort of 830 patients from 2013 to 2015 in six university hospitals in France. The primary outcome variable was postoperative neurologic complications requiring in-intensive care unit management (intracranial hypertension, intracranial bleeding, status epilepticus, respiratory failure, impaired consciousness, unexpected motor deficit). The least absolute shrinkage and selection operator method was used for potential risk factor selection with logistic regression. RESULTS: Severe complications occurred in 125 (11.4%) and 90 (10.8%) patients in the learning and validation cohorts, respectively. The independent risk factors for severe complications were related to the patient (Glasgow Coma Score before surgery at or below 14, history of brain tumor surgery), tumor characteristics (greatest diameter, cerebral midline shift at least 3 mm), and perioperative management (transfusion of blood products, maximum and minimal systolic arterial pressure, duration of surgery). The positive predictive value of the score at or below 3% was 12.1%, and the negative predictive value was 100% in the learning cohort. In-intensive care unit mortality was observed in eight (0.7%) and six (0.7%) patients in the learning and validation cohorts, respectively. CONCLUSIONS: The validation of prediction scores is the first step toward on-demand intensive care unit admission. Further research is needed to improve the score's performance before routine use.

Patient factors and outcomes associated with the withdrawal or withholding of life-sustaining therapies in mechanically ventilated brain-injured patients: An observational multicentre study.

BACKGROUND: Knowledge of the factors associated with the decision to withdraw or withhold life support (WWLS) in brain-injured patients is limited. However, most deaths in these patients may involve such a decision. OBJECTIVES: To identify factors associated with the decision to WWLS in brain-injured patients requiring mechanical ventilation who survive the first 24 h in the ICU, and to analyse the outcomes and time to death. DESIGN: A retrospective observational multicentre study. SETTINGS: Twenty French ICUs in 18 university hospitals. PATIENTS: A total of 793 mechanically ventilated brain-injured adult patients. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Decision to WWLS within 3 months of ICU admission, and death or Glasgow Outcome Scale (GOS) score at day 90. RESULTS: A decision to WWLS was made in 171 patients (22%), of whom 89% were dead at day 90. Out of the 247 deaths recorded at day 90, 153 (62%) were observed after a decision to WWLS. The median time between admission and death when a decision to WWLS was made was 10 (5 to 20) days vs. 10 (5 to 26) days when no end-of-life decision was made (P < 0.924). Among the 18 patients with a decision to WWLS who were still alive at day 90, three patients (2%) had a GOS score of 2, nine patients (5%) had a GOS score of 3 and five patients (3%) a GOS score of 4. Older age, presence of one nonreactive and dilated pupil, Glasgow Coma Scale less than 7, barbiturate use, acute respiratory distress syndrome and worsening lesions on computed tomography scans were each independently associated with decisions to WWLS. CONCLUSION: Using a nationwide cohort of brain-injured patients, we observed a high proportion of deaths associated with an end-of-life decision. Older age and several disease severity factors were associated with the decision to WWLS.

Extubation Success Prediction in a Multicentric Cohort of Patients with Severe Brain Injury.

BACKGROUND: Patients with brain injury are at high risk of extubation failure. METHODS: We conducted a prospective observational cohort study in four intensive care units of three university hospitals. The aim of the study was to create a score that could predict extubation success in patients with brain injury. RESULTS: A total of 437 consecutive patients with brain injury were included, and 338 patients (77.3%) displayed successful extubation. In the multivariate analysis, four features were associated with success the day of extubation: age less than 40 yr, visual pursuit, swallowing attempts, and a Glasgow coma score greater than 10. In the score, each item counted as one. A score of 3 or greater was associated with 90% extubation success. The area under the receiver-operator curve was 0.75 (95% CI, 0.69 to 0.81). After internal validation by bootstrap, the area under the receiver-operator curve was 0.73 (95% CI, 0.68 to 0.79). Extubation success was significantly associated with shorter duration of mechanical ventilation (11 [95% CI, 5 to 17 days] vs. 22 days [95% CI, 13 to 29 days]; P < 0.0001), shorter intensive care unit length of stay (15 [95% CI, 9 to 23 days] vs. 27 days [95% CI, 21 to 36 days]; P < 0.0001), and lower in-intensive care unit mortality (4 [1.2%] vs. 11 [11.1%]; P < 0.0001). CONCLUSIONS: Our score exploring both airway functions and neurologic status may increase the probability of successful extubation in patients with severe brain injury.

Association between continuous hyperosmolar therapy and survival in patients with traumatic brain injury - a multicentre prospective cohort study and systematic review.

BACKGROUND: Intracranial hypertension (ICH) is a major cause of death after traumatic brain injury (TBI). Continuous hyperosmolar therapy (CHT) has been proposed for the treatment of ICH, but its effectiveness is controversial. We compared the mortality and outcomes in patients with TBI with ICH treated or not with CHT. METHODS: We included patients with TBI (Glasgow Coma Scale ≤ 12 and trauma-associated lesion on brain computed tomography (CT) scan) from the databases of the prospective multicentre trials Corti-TC, BI-VILI and ATLANREA. CHT consisted of an intravenous infusion of NaCl 20% for 24 hours or more. The primary outcome was the risk of survival at day 90, adjusted for predefined covariates and baseline differences, allowing us to reduce the bias resulting from confounding factors in observational studies. A systematic review was conducted including studies published from 1966 to December 2016. RESULTS: Among the 1086 included patients, 545 (51.7%) developed ICH (143 treated and 402 not treated with CHT). In patients with ICH, the relative risk of survival at day 90 with CHT was 1.43 (95% CI, 0.99-2.06, p = 0.05). The adjusted hazard ratio for survival was 1.74 (95% CI, 1.36-2.23, p < 0.001) in propensity-score-adjusted analysis. At day 90, favourable outcomes (Glasgow Outcome Scale 4-5) occurred in 45.2% of treated patients with ICH and in 35.8% of patients with ICH not treated with CHT (p = 0.06). A review of the literature including 1304 patients from eight studies suggests that CHT is associated with a reduction of in-ICU mortality (intervention, 112/474 deaths (23.6%) vs. control, 244/781 deaths (31.2%); OR 1.42 (95% CI, 1.04-1.95), p = 0.03, I 2 = 15%). CONCLUSIONS: CHT for the treatment of posttraumatic ICH was associated with improved adjusted 90-day survival. This result was strengthened by a review of the literature.

Validation of the French versions of the Hirschsprung's disease and Anorectal malformations Quality of Life (HAQL) questionnaires for adolescents and adults.

BACKGROUND: The Hirschsprung's disease Anorectal malformation QoL questionnaire (HAQL) is a disease-specific quality of life (QoL) questionnaire for patients with Hirschsprung's disease (HD) or anorectal malformations (ARM). It was originally proposed in Dutch and is currently being translated into other languages to obtain an internationally standardized instrument. In this work we validate a French adaptation of the HAQL for adolescents and adults. METHODS: The questionnaires were translated into French and sent to patients aged 12 years and older, followed for HD or ARM at three French university hospitals. Questionnaires were sent to 147 adolescents and 188 adults. The psychometric properties of the questionnaires were analyzed in terms of reliability and validity. RESULTS: The original HAQL structure was not satisfactory. A new structure was proposed, while aiming to remain close to the original structure. The proposed structure has acceptable reliability and validity properties and reflects both physical, as well as psychosocial aspects. CONCLUSIONS: A French version of the HAQL questionnaire for adults and adolescents is ready for use in France. In particular the score could discriminate between degrees of clinical status based on the Krickenbeck consensus, which can aid clinicians to inform patients about physical and psychosocial challenges they may expect.

Empiric antimicrobial therapy for ventilator-associated pneumonia after brain injury.

Issues regarding recommendations on empiric antimicrobial therapy for ventilator-associated pneumonia (VAP) have emerged in specific populations.To develop and validate a score to guide empiric therapy in brain-injured patients with VAP, we prospectively followed a cohort of 379 brain-injured patients in five intensive care units. The score was externally validated in an independent cohort of 252 brain-injured patients and its extrapolation was tested in 221 burn patients.The multivariate analysis for predicting resistance (incidence 16.4%) showed two independent factors: preceding antimicrobial therapy ≥48 h (p<0.001) and VAP onset ≥10 days (p<0.001); the area under the receiver operating characteristic curve (AUC) was 0.822 (95% CI 0.770-0.883) in the learning cohort and 0.805 (95% CI 0.732-0.877) in the validation cohort. The score built from the factors selected in multivariate analysis predicted resistance with a sensitivity of 83%, a specificity of 71%, a positive predictive value of 37% and a negative predictive value of 96% in the validation cohort. The AUC of the multivariate analysis was poor in burn patients (0.671, 95% CI 0.596-0.751).Limited-spectrum empirical antimicrobial therapy has low risk of failure in brain-injured patients presenting with VAP before day 10 and when prior antimicrobial therapy lasts <48 h.

Pharmacists' different profiles characterization about opioid substitution treatments.

INTRODUCTION: Delivering practices of opioid substitution treatment (OST) in community pharmacies are heterogeneous. This study aims at drawing up an inventory and at characterizing different populations of pharmacists, regarding their practices and perceptions. METHODS: We distributed a questionnaire to pharmacists, which was divided into two parts: socio-demographic questions, and 49 binary questions collecting pharmacists' perceptions. Statistical analyses were performed using SAS 9.3 and SPAD7 software. The categorical variables were expressed as numbers and percentages. We characterized the different profiles of pharmacists using a multivariate analysis method. RESULTS: We analyzed 303 questionnaires; 60.8% of our cross-section of pharmacists consider that OSTs are a treatment for chronic disease, a treatment in which they consider that they play a key role. Regarding OSTs, 89.3% felt "comfortable" with current regulations, while 77.3% have mastered possible interactions with other drugs. 16.8% of pharmacists equate the act of delivering OSTs as a "legal narcotic deal". Regarding the patients, 49.2% of pharmacists consider them as "different", and 39.1% fear that they cause relationship problems. Most pharmacists perceive the role they are meant to play, although a lack of training and the need for recommendations have been highlighted. PCA allowed us to characterize 4 different profiles of pharmacists. CONCLUSION: Continuous training adapted to the different profiles we drew up will be offered in order to allow pharmacists to deepen their knowledge about drug dependence and related care support.

PHEDRE trial protocol - observational study of the prevalence of problematic use of Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) and analgesics in the French sickle-cell disease population.

BACKGROUND: The use of analgesics can lead to cases of drug abuse and dependence. It can also cause pseudo-addiction in patients suffering from pain. What is the actual situation in patients suffering from severe sickle-cell disease, exposed to acute pain during vaso-occlusive crises? Evaluation of the use of analgesics, on the basis of Diagnostic and Statistical Manual of Mental Disorders criteria for substance abuse and dependence, makes it possible to differentiate the symptoms occurring only in a context of pain, in the aim of managing the pain, and thus describing pseudo-addiction, from symptoms also occurring when there is no pain, and more in favour of true addiction. Currently there is no data available in France on this problem, and no studies have been carried out in children or adolescents with sickle-cell disease. The purpose of the study is to evaluate the prevalence of problematic use of equimolar mixture of oxygen and nitrous oxide and other analgesic drugs in a population of subjects with severe sickle-cell disease in France. METHODS/DESIGN: PHEDRE (Pharmacodépendance Et DREpanocytose-drug dependence and sickle-cell disease) is an observational, descriptive and transversal study. Patients under the age of 26 with sickle-cell disease are included in the study by the doctors looking after them in sickle-cell disease centres. The patients are then contacted by a trained researcher for a telephone interview, including an evaluation of the Diagnostic and Statistical Manual of Mental Disorders criteria for abuse and dependence to equimolar mixture of oxygen and nitrous oxide and for each of the analgesic drugs taken by the patient. The data are also completed using the subject's medical record. DISCUSSION: This study will make it possible to provide an initial quantitative and qualitative evaluation of problematic use of equimolar mixture of oxygen and nitrous oxide and analgesic drugs in the sickle-cell disease population. The results will be used firstly to provide additional data essential for monitoring the risk of overdose, abuse, dependence and misuse of these products, and to begin awareness-raising and to provide information for health care professionals, in order to significantly improve the management of sickle-cell disease-related pain. TRIAL REGISTRATION: Clinical Trials.gov ID: NCT02580565 registered 16 October 2015 Unique Protocol ID: RC14_0344.

On Comparison of Clustering Methods for Pharmacoepidemiological Data.

The high consumption of psychotropic drugs is a public health problem. Rigorous statistical methods are needed to identify consumption characteristics in post-marketing phase. Agglomerative hierarchical clustering (AHC) and latent class analysis (LCA) can both provide clusters of subjects with similar characteristics. The objective of this study was to compare these two methods in pharmacoepidemiology, on several criteria: number of clusters, concordance, interpretation, and stability over time. From a dataset on bromazepam consumption, the two methods present a good concordance. AHC is a very stable method and it provides homogeneous classes. LCA is an inferential approach and seems to allow identifying more accurately extreme deviant behavior.

Dependence on prescription benzodiazepines and Z-drugs among young to middle-aged patients in France.

BACKGROUND: Benzodiazepines (BZD) and nonbenzodiazepines hypnotics (z-drugs) are recognized as one of the most widely prescribed medications in the world. OBJECTIVES: The purpose of the study was to assess the BZD and z-drugs dependence in young to middle-aged outpatients who were taking BZD/z-drugs on a chronic basis, and to characterize their profile. METHODS: This is a forward-looking cross-sectional epidemiological study. Data were collected through a semi-structured interview within a network of partner pharmacies from the Nantes area, in France. All data were obtained exclusively through patients' declarations. 212 patients (19-64 years old) were included: they were considered dependent when they answered positively to at least three items of the DSM IV. A multivariate logistic regression and a principal component analysis (PCA) were carried out to determine their profile. RESULTS: Almost half of the patients met criteria for BZD/z-drugs dependence. The risk to develop BZD/z-drugs dependence is significantly associated with psychiatric history and with the quantity of BZD/z-drugs that is taken. A two factor concept of dependence could be identified according to the PCA: one axis with items of "tolerance" and "long term administration or higher doses", and a second axis with "concerned by treatment" and "somatic consequences". Conclusions/Importance: Among this BZD/z-drug dependent population, the two axes identified in the PCA represent two profiles of dependence: being in positive conditioning or suffering from negative consequences. Clinicians need to know them: these two clinical profiles may have an influence in terms of decision-making, especially to manage discontinuation.