Evaluating the Sum of Eye and Motor Components of the Glasgow Coma Score As a Predictor of Extubation Failure in Patients With Acute Brain Injury.

OBJECTIVES: To evaluate the association between the pre-extubation sum of eye and motor components of the Glasgow Coma Score (GCS-EM) and odds of extubation failure in patients with acute brain injury being liberated from mechanical ventilation. DESIGN: Secondary analysis of a prospective, multicenter observational study (ClinicalTrials.gov identifier NCT03400904). SETTING: Sixty-three hospital sites worldwide, with patient recruitment from January 2018 to November 2020. PATIENTS: One thousand one hundred fifty-two critically ill patients with acute brain injury, with a median age of 54 years, of whom 783 (68.0%) were male, 559 (48.5%) had traumatic brain injury, and 905 (78.6%) had a GCS-EM greater than 8 before extubation (scores range from 2 to 10). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: GCS-EM was computed in intubated patients on the day of extubation. The main outcome was extubation failure, defined as unplanned reintubation within 5 days of extubation. Analyses used multilevel logistic regression with adjustment for patient characteristics and a random intercept for hospital site. In the primary analysis, GCS-EM was not associated with extubation failure (odds ratio, 1.07 per additional point; 95% CI, 0.87-1.31). Findings were consistent in sensitivity analyses that: 1) used different adjustment covariates, 2) included a verbal estimate to derive an overall GCS, 3) accounted for missing data, 4) considered a 2-day time interval to define extubation failure, 5) accounted for competing risks, and 6) used a propensity score-based model. There was no association between GCS-EM and extubation outcome in subgroups defined by brain injury diagnosis or age. CONCLUSIONS: In this large, contemporary, multicenter cohort of patients with acute brain injury, we found no association between the GCS-EM and odds of extubation failure. However, few patients had a pre-extubation GCS-EM less than or equal to 8, and the possibility of a true prognostic association in patients with low scores is not excluded.

Ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury: a multicentre, randomised, double-blind, placebo-controlled, assessor-masked superiority trial.

BACKGROUND: Patients with acute brain injury are at high risk of ventilator-associated pneumonia (VAP). The benefit of short-term antibiotic prophylaxis remains debated. We aimed to establish the effect of an early, single dose of the antibiotic ceftriaxone on the incidence of early VAP in patients with severe brain injury who required mechanical ventilation. METHODS: PROPHY-VAP was a multicentre, randomised, double-blind, placebo-controlled, assessor-masked, superiority trial conducted in nine intensive care units in eight French university hospitals. We randomly assigned comatose (Glasgow Coma Scale score [GCS] ≤12) adult patients (age ≥18 years) who required mechanical ventilation for at least 48 h after acute brain injury to receive intravenous ceftriaxone 2 g or placebo once within the 12 h following tracheal intubation. Participants did not receive selective oropharyngeal and digestive tract decontamination. The primary outcome was the proportion of patients developing early VAP from the 2nd to the 7th day of mechanical ventilation, confirmed by masked assessors. The analysis was reported in the modified intention-to-treat population, which comprised all randomly assigned patients except those who withdrew or did not give consent to continue and those who did not receive the allocated treatment because they met a criterion for non-eligibility. The trial is registered with ClinicalTrials.gov, NCT02265406. FINDINGS: From Oct 14, 2015, to May 27, 2020, 345 patients were randomly assigned (1:1) to receive ceftriaxone (n=171) or placebo (n=174); 330 received the allocated intervention and 319 were included in the analysis (162 in the ceftriaxone group and 157 in the placebo group). 166 (52%) participants in the analysis were men and 153 (48%) were women. 15 patients did not receive the allocated intervention after randomisation and 11 withdrew their consent. Adjudication confirmed 93 cases of VAP, including 74 early infections. The incidence of early VAP was lower in the ceftriaxone group than in the placebo group (23 [14%] vs 51 [32%]; hazard ratio 0·60 [95% CI 0·38-0·95], p=0·030), with no microbiological impact and no adverse effects attributable to ceftriaxone. INTERPRETATION: In patients with acute brain injury, a single ceftriaxone dose decreased the risk of early VAP. On the basis of our findings, we recommend that an early, single dose of ceftriaxone be included in all bundles for the prevention of VAP in patients with brain injury who require mechanical ventilation. FUNDING: French Ministry of Social Affairs and Health.

Clinical practice and effect of carbon dioxide on outcomes in mechanically ventilated acute brain-injured patients: a secondary analysis of the ENIO study.

PURPOSE: The use of arterial partial pressure of carbon dioxide (PaCO2) as a target intervention to manage elevated intracranial pressure (ICP) and its effect on clinical outcomes remain unclear. We aimed to describe targets for PaCO2 in acute brain injured (ABI) patients and assess the occurrence of abnormal PaCO2 values during the first week in the intensive care unit (ICU). The secondary aim was to assess the association of PaCO2 with in-hospital mortality. METHODS: We carried out a secondary analysis of a multicenter prospective observational study involving adult invasively ventilated patients with traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracranial hemorrhage (ICH), or ischemic stroke (IS). PaCO2 was collected on day 1, 3, and 7 from ICU admission. Normocapnia was defined as PaCO2 > 35 and to 45 mmHg; mild hypocapnia as 32-35 mmHg; severe hypocapnia as 26-31 mmHg, forced hypocapnia as < 26 mmHg, and hypercapnia as > 45 mmHg. RESULTS: 1476 patients (65.9% male, mean age 52 ± 18 years) were included. On ICU admission, 804 (54.5%) patients were normocapnic (incidence 1.37 episodes per person/day during ICU stay), and 125 (8.5%) and 334 (22.6%) were mild or severe hypocapnic (0.52 and 0.25 episodes/day). Forced hypocapnia and hypercapnia were used in 40 (2.7%) and 173 (11.7%) patients. PaCO2 had a U-shape relationship with in-hospital mortality with only severe hypocapnia and hypercapnia being associated with increased probability of in-hospital mortality (omnibus p value = 0.0009). Important differences were observed across different subgroups of ABI patients. CONCLUSIONS: Normocapnia and mild hypocapnia are common in ABI patients and do not affect patients' outcome. Extreme derangements of PaCO2 values were significantly associated with increased in-hospital mortality.

Incidence and Outcomes of Acute Respiratory Distress Syndrome in Brain-Injured Patients Receiving Invasive Ventilation: A Secondary Analysis of the ENIO Study.

Background: Acute respiratory distress syndrome (ARDS) is an important pulmonary complication in brain-injured patients receiving invasive mechanical ventilation (IMV). We aimed to evaluate the incidence and association between ARDS and clinical outcomes in patients with different forms of acute brain injury requiring IMV in the intensive care unit (ICU). Methods: This was a preplanned secondary analysis of a prospective, multicenter, international cohort study (NCT03400904). We included brain-injured patients receiving IMV for ≥ 24 h. ARDS was the main exposure of interest and was identified during index ICU admission using the Berlin definition. We examined the incidence and adjusted association of ARDS with ICU mortality, ICU length of stay, duration of IMV, and extubation failure. Outcomes were evaluated using mixed-effect logistic regression and cause-specific Cox proportional hazards models. Results: 1492 patients from 67 hospitals and 16 countries were included in the analysis, of whom 137 individuals developed ARDS (9.2% of overall cohort). Across countries, the median ARDS incidence was 5.1% (interquartile range [IQR] 0-10; range 0-27.3). ARDS was associated with increased ICU mortality (adjusted odds ratio (OR) 2.66; 95% confidence interval [CI], 1.29-5.48), longer ICU length of stay (adjusted hazard ratio [HR] 0.59; 95% CI, 0.48-0.73), and longer duration of IMV (adjusted HR 0.54; 95% CI, 0.44-0.67). The association between ARDS and extubation failure approached statistical significance (adjusted HR 1.48; 95% CI 0.99-2.21). Higher ARDS severity was associated with incrementally longer ICU length of stay and longer cumulative duration of IMV. Findings remained robust in a sensitivity analysis evaluating the magnitude of unmeasured confounding. Conclusions: In this cohort of acutely brain-injured patients, the incidence of ARDS was similar to that reported in other mixed cohorts of critically ill patients. Development of ARDS was associated with worse outcomes.

Individualized Thresholds of Hypoxemia and Hyperoxemia and their Effect on Outcome in Acute Brain Injured Patients: A Secondary Analysis of the ENIO Study.

BACKGROUND: In acute brain injury (ABI), the effects of hypoxemia as a potential cause of secondary brain damage and poor outcome are well documented, whereas the impact of hyperoxemia is unclear. The primary aim of this study was to assess the episodes of hypoxemia and hyperoxemia in patients with ABI during the intensive care unit (ICU) stay and to determine their association with in-hospital mortality. The secondary aim was to identify the optimal thresholds of arterial partial pressure of oxygen (PaO2) predicting in-hospital mortality. METHODS: We conducted a secondary analysis of a prospective multicenter observational cohort study. Adult patients with ABI (traumatic brain injury, subarachnoid aneurysmal hemorrhage, intracranial hemorrhage, ischemic stroke) with available data on PaO2 during the ICU stay were included. Hypoxemia was defined as PaO2 < 80 mm Hg, normoxemia was defined as PaO2 between 80 and 120 mm Hg, mild/moderate hyperoxemia was defined as PaO2 between 121 and 299 mm Hg, and severe hyperoxemia was defined as PaO2 levels ≥ 300 mm Hg. RESULTS: A total of 1,407 patients were included in this study. The mean age was 52 (±18) years, and 929 (66%) were male. Over the ICU stay, the fractions of patients in the study cohort who had at least one episode of hypoxemia, mild/moderate hyperoxemia, and severe hyperoxemia were 31.3%, 53.0%, and 1.7%, respectively. PaO2 values below 92 mm Hg and above 156 mm Hg were associated with an increased probability of in-hospital mortality. Differences were observed among subgroups of patients with ABI, with consistent effects only seen in patients without traumatic brain injury. CONCLUSIONS: In patients with ABI, hypoxemia and mild/moderate hyperoxemia were relatively frequent. Hypoxemia and hyperoxemia during ICU stay may influence in-hospital mortality. However, the small number of oxygen values collected represents a major limitation of the study.

Development of a core outcome set for ventilation trials in neurocritical care patients with acute brain injury: protocol for a Delphi consensus study of international stakeholders.

INTRODUCTION: There is little consensus and high heterogeneity on the optimal set of relevant clinical outcomes in research studies regarding extubation in neurocritical care patients with brain injury undergoing mechanical ventilation. The aims of this study are to: (1) develop a core outcome set (COS) and (2) reach consensus on a hierarchical composite endpoint for such studies. METHODS AND ANALYSIS: The study will include a broadly representative, international panel of stakeholders with research and clinical expertise in this field and will involve four stages: (1) a scoping review to generate an initial list of outcomes represented in the literature, (2) an investigator meeting to review the outcomes for inclusion in the Delphi surveys, (3) four rounds of online Delphi consensus-building surveys and (4) online consensus meetings to finalise the COS and hierarchical composite endpoint. ETHICS AND DISSEMINATION: This study received ethical approval from the French Society of Anesthesia and Critical Care Medicine Institutional Review Board (SFAR CERAR-IRB 00010254-2023-029). The study results will be disseminated through communication to stakeholders, publication in a peer-reviewed journal, and presentations at conferences. TRIAL REGISTRATION NUMBER: This study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) Initiative.

A network meta-analysis of therapeutic and prophylactic management of vasospasm on aneurysmal subarachnoid hemorrhage outcomes.

Background: Vasospasm and cerebral ischemia after aneurysmal subarachnoid hemorrhage are associated with mortality and poor neurological outcomes. We studied the efficacy of all available strategies targeting vasospasm and cerebral ischemia on outcomes in a network meta-analysis. Methods: We searched EMBASE and MEDLINE databases from 1 January 1990 and 28 November 2021 according to PRISMA guidelines. Randomized controlled trials and longitudinal studies were included. All curative or preventive strategies targeting vasospasm and/or cerebral ischemia were eligible. A network meta-analysis was performed to compare all interventions with one another in a primary (randomized controlled trials only) and a secondary analysis (both trials and longitudinal studies). Mortality by 3 months was the primary outcome. Secondary outcomes were vasospasm, neurological outcome by 3 months, and dichotomized as "good" or "poor" recovery according to each study definition. Results: A total of 2,382 studies were screened which resulted in the selection of 192 clinical trials (92 (47.9%) and 100 cohorts (52.1%) and the inclusion of 41,299 patients. In randomized controlled studies, no strategy decreased mortality by 3 months. Statins (0.79 [0.62-1]), tirilazad (0.82 [0.69-0.97]), CSF drainage (0.47 [0.29-0.77]), and clazosentan (0.51 [0.36-0.71]) significantly decreased the incidence of vasospasm. Cilostazol was the only treatment associated with improved neurological outcomes by 3 months in the primary (OR 1.16, 95% CI [1.05-1.28]) and secondary analyses (OR 2.97, 95% CI [1.39-6.32]). Discussion: In the modern era of subarachnoid hemorrhage, all strategies targeting vasospasm failed to decrease mortality. Cilostazol should be confirmed as a treatment to improve neurological outcomes. The link between vasospasm and neurological outcome appears questionable. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=116073, identifier: PROSPERO CRD42018116073.

Complications and risk factors on midline catheters' follow-up about non-ICU patients: study protocol for a multicentre observational study (the midDATA study).

INTRODUCTION: The midline catheter (MC) is an increasingly popular device used commonly for patients with difficult venous access or those who require infusion for more than 6 days. Little is known about complications such as infection, thrombosis or occlusion for inpatient and home care patient. This protocol presents the follow-up of non-intensive care unit patients with an MC. The aim is to identify complications and search for risk factors associated with these complications. METHOD AND ANALYSIS: A prospective observational design is used for the follow-up of 2000 patients from 13 centres in France. Each practitioner (inserting clinician, anaesthetist nurse, hospital nurse and home nurse) will fill out a logbook to report each care made (eg, number of saline flushes, dress maintenance) on the MC and if any complications occurred. The incidence of complications (ie, infections, thrombosis or occlusions) will be expressed by the total number of events per 1000 catheter days. The period of recruitment began in December 2019 for a duration of 2 years. An extension of the inclusion period of 1 year was obtained. ETHICS AND DISSEMINATION: This study received the approval of the Committee for the Protection of Persons of Nord Ouest IV (No EudraCT/ID-RCB : 2019-A02406-51). It was registered at clinical trials (NCT04131088). It is planned to communicate results at conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04131088.

Mechanical ventilation in patients with acute brain injury: a systematic review with meta-analysis.

OBJECTIVE: To describe the potential effects of ventilatory strategies on the outcome of acute brain-injured patients undergoing invasive mechanical ventilation. DESIGN: Systematic review with an individual data meta-analysis. SETTING: Observational and interventional (before/after) studies published up to August 22nd, 2022, were considered for inclusion. We investigated the effects of low tidal volume Vt < 8 ml/Kg of IBW versus Vt > = 8 ml/Kg of IBW, positive end-expiratory pressure (PEEP) < or > = 5 cmH2O and protective ventilation (association of both) on relevant clinical outcomes. POPULATION: Patients with acute brain injury (trauma or haemorrhagic stroke) with invasive mechanical ventilation for ≥ 24 h. MAIN OUTCOME MEASURES: The primary outcome was mortality at 28 days or in-hospital mortality. Secondary outcomes were the incidence of acute respiratory distress syndrome (ARDS), the duration of mechanical ventilation and the partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio. RESULTS: The meta-analysis included eight studies with a total of 5639 patients. There was no difference in mortality between low and high tidal volume [Odds Ratio, OR 0.88 (95%Confidence Interval, CI 0.74 to 1.05), p = 0.16, I2 = 20%], low and moderate to high PEEP [OR 0.8 (95% CI 0.59 to 1.07), p = 0.13, I2 = 80%] or protective and non-protective ventilation [OR 1.03 (95% CI 0.93 to 1.15), p = 0.6, I2 = 11]. Low tidal volume [OR 0.74 (95% CI 0.45 to 1.21, p = 0.23, I2 = 88%], moderate PEEP [OR 0.98 (95% CI 0.76 to 1.26), p = 0.9, I2 = 21%] or protective ventilation [OR 1.22 (95% CI 0.94 to 1.58), p = 0.13, I2 = 22%] did not affect the incidence of acute respiratory distress syndrome. Protective ventilation improved the PaO2/FiO2 ratio in the first five days of mechanical ventilation (p < 0.01). CONCLUSIONS: Low tidal volume, moderate to high PEEP, or protective ventilation were not associated with mortality and lower incidence of ARDS in patients with acute brain injury undergoing invasive mechanical ventilation. However, protective ventilation improved oxygenation and could be safely considered in this setting. The exact role of ventilatory management on the outcome of patients with a severe brain injury needs to be more accurately delineated.

Prevalence and risk factors of significant persistent pain symptoms after critical care illness: a prospective multicentric study.

BACKGROUND: Prevalence, risk factors and medical management of persistent pain symptoms after critical care illness have not been thoroughly investigated. METHODS: We performed a prospective multicentric study in patients with an intensive care unit (ICU) length of stay ≥ 48 h. The primary outcome was the prevalence of significant persistent pain, defined as a numeric rating scale (NRS) ≥ 3, 3 months after admission. Secondary outcomes were the prevalence of symptoms compatible with neuropathic pain (ID-pain score > 3) and the risk factors of persistent pain. RESULTS: Eight hundred fourteen patients were included over a 10-month period in 26 centers. Patients had a mean age of 57 (± 17) years with a SAPS 2 score of 32 (± 16) (mean ± SD). The median ICU length of stay was 6 [4-12] days (median [interquartile]). At 3 months, the median intensity of pain symptoms was 2 [1-5] in the entire population, and 388 (47.7%) patients had significant pain. In this group, 34 (8.7%) patients had symptoms compatible with neuropathic pain. Female (Odds Ratio 1.5 95% CI [1.1-2.1]), prior use of anti-depressive agents (OR 2.2 95% CI [1.3-4]), prone positioning (OR 3 95% CI [1.4-6.4]) and the presence of pain symptoms on ICU discharge (NRS ≥ 3) (OR 2.4 95% CI [1.7-3.4]) were risk factors of persistent pain. Compared with sepsis, patients admitted for trauma (non neuro) (OR 3.5 95% CI [2.1-6]) were particularly at risk of persistent pain. Only 35 (11.3%) patients had specialist pain management by 3 months. CONCLUSIONS: Persistent pain symptoms were frequent in critical illness survivors and specialized management remained infrequent. Innovative approaches must be developed in the ICU to minimize the consequences of pain. TRIAL REGISTRATION: NCT04817696. Registered March 26, 2021.

Association of Noninvasive Respiratory Support with Extubation Outcomes in Brain-injured Patients Receiving Mechanical Ventilation: A Secondary Analysis of the ENIO Prospective Observational Study.

Rationale: Noninvasive respiratory support using a high-flow nasal cannula (HFNC) or noninvasive positive pressure ventilation (NIPPV) can decrease the risk of reintubation in patients being liberated from mechanical ventilation, but effects in patients with acute brain injury (ABI) are unknown. Objectives: To evaluate the association between postextubation noninvasive respiratory support and reintubation in patients with ABI being liberated from mechanical ventilation. Methods: This was a secondary analysis of a prospective, observational study of mechanically ventilated patients with ABI (clinicaltrials.gov identifier NCT03400904). The primary endpoint was reintubation during ICU admission. We used mixed-effects logistic regression models with patient-level covariates and random intercepts for hospital and country to evaluate the association between prophylactic (i.e., planned) HFNC or NIPPV and reintubation. Measurements and Main Results: 1,115 patients were included from 62 hospitals and 19 countries, of whom 267 received HFNC or NIPPV following extubation (23.9%). Compared with conventional oxygen therapy, neither prophylactic HFNC nor NIPPV was associated with decreased odds of reintubation (respectively, odds ratios of 0.97 [95% confidence interval, 0.54-1.73] and 0.63 [0.30-1.32]). Findings remained consistent in sensitivity analyses accounting for alternate adjustment procedures, missing data, shorter time frames of the primary endpoint, and competing risks precluding reintubation. In a Bayesian analysis using skeptical and data-driven priors, the probabilities of reduced reintubation ranged from 17% to 34% for HFNC and from 46% to 74% for NIPPV. Conclusions: In a large cohort of brain-injured patients undergoing liberation from mechanical ventilation, prophylactic use of HFNC and NIPPV were not associated with reintubation. Prospective trials are needed to confirm treatment effects in this population. Primary study registered with www.clinicaltrials.gov (NCT03400904).

Ventilator-associated pneumonia in neurocritically ill patients: insights from the ENIO international prospective observational study.

BACKGROUND: Acute brain injured (ABI) patients are at high risk of developing ventilator-associated pneumonia (VAP). However, incidence, risk factors and effects on outcome of VAP are not completely elucidated in this population. The primary aim of this study was to determine the incidence of VAP in a cohort of ABI patients. The secondary objectives included the identification of risk factors for development of VAP, and the impact of VAP on clinical outcomes. Clinical outcomes were defined as intensive care unit length of stay (ICU-LOS), duration of invasive mechanical ventilation (IMV), and ICU mortality. METHODS: Pre-planned sub-analysis of the Extubation strategies in Neuro-Intensive care unit (ICU) patients and associations with Outcomes (ENIO) international multi-center prospective observational study. Patients with available data on VAP, who received at least 48 h of IMV and ICU-LOS ≥ 72 h were included. RESULTS: Out of 1512 patients included in the ENIO study, 1285 were eligible for this analysis. The prevalence of VAP was 39.5% (33.7 cases /1000 ventilator-days), with a high heterogeneity across countries and according to the type of brain injury. VAP was significantly more frequent in male patients, in those with smoke habits and when intraparenchymal probe (IP), external ventricular drain (EVD) or hypothermia (p < 0.001) were used. Independent risk factors for VAP occurrence were male gender, the use of IP, hypothermia, and the occurrence of tracheobronchitis during ICU stay. VAP was not an independent risk factor for ICU mortality (Hazard Ratio, HR = 0.71 95%CI 0.43-1.16, p = 0.168), but was independently associated with longer ICU stay (OR = 2.55 95%CI 2.01-3.23, p < 0.001). CONCLUSIONS: VAP is common in ABI patients. Male gender, IP and EVD insertion, tracheobronchitis, and the use of therapeutic hypothermia were significantly associated with VAP occurrence. VAP did not affect mortality but increased ICU-LOS.

A multifaceted strategy to optimize pharmacokinetics of antimicrobial therapy in patients with hospital-acquired infections-a monocentre quality improvement project.

OBJECTIVE: We assessed the efficacy of a quality improvement programme to optimize the delivery of antimicrobial therapy in critically ill patients with hospital-acquired infections (HAI). PATIENTS AND METHODS: Before-after trial in a university hospital in France. Consecutive adults receiving systemic antimicrobial therapy for HAI were included. Patients received standard care during the pre-intervention period (June 2017 to November 2017). The quality improvement programme was implemented in December 2017. During the intervention period (January 2018 to June 2019), clinicians were trained to dose adjustment based on therapeutic drug monitoring and continuous infusion of ß-lactam antibiotics. The primary endpoint was the mortality rate at day 90. RESULTS: A total of 198 patients were included (58 pre-intervention, 140 intervention). The compliance with the therapeutic drug monitoring-dose adaptation increased from 20.3% to 59.3% after the intervention (P < 0.0001). The 90-day mortality rate was 27.6% in the pre-intervention period and 17.3% in the intervention group (adjusted relative risk 0.53, 95%CI 0.27-1.07, P = 0.08). Treatment failures were observed in 22 (37.9%) patients before and 36 (25.7%) patients after the intervention (P = 0.07). CONCLUSIONS: Recommendations for therapeutic drug monitoring-dose adaptation and continuous infusion of ß-lactam antibiotics were not associated with a reduction in the 90-day mortality rate in patients with HAI.