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Background: Sedation/analgesia is a daily challenge faced by intensivists managing patients with brain injury (BI) in intensive care units (ICUs). The optimization of sedation in patients with BI presents particular challenges. A choice must be made between the potential benefit of a rapid clinical evaluation and the potential exacerbation of intracranial hypertension in patients with impaired cerebral compliance. In the ICU, a pragmatic approach to the use of sedation/analgesia, including the optimal titration, management of multiple drugs, and use of any type of brain monitor, is needed. Our research question was as follows: the aim of the study is to identify what is the current daily practice regarding sedation/analgesia in the management of patients with BI in the ICU in France?, Methods: This study was composed of two parts. The first part was a descriptive survey of sedation practices and characteristics in 30 French ICUs and 27 academic hospitals specializing in care for patients with BI. This first step validates ICU participation in data collection regarding sedation-analgesia practices. The second part was a 1-day prospective cross-sectional snapshot of all characteristics and prescriptions of patients with BI., Results: On the study day, among the 246 patients with BI, 106 (43%) had a brain monitoring device and 74 patients (30%) were sedated. Thirty-nine of the sedated patients (53%) suffered from intracranial hypertension, 14 patients (19%) suffered from agitation and delirium, and 7 patients (9%) were sedated because of respiratory failure. Fourteen patients (19%) no longer had a formal indication for sedation. In 60% of the sedated patients, the sedatives were titrated by nurses based on sedation scales. The Richmond Agitation Sedation Scale was used in 80% of the patients, and the Behavioral Pain Scale was used in 92%. The common sedatives and opioids used were midazolam (58.1%), propofol (40.5%), and sufentanil (67.5%). The cerebral monitoring devices available in the participating ICUs were transcranial Doppler ultrasound (100%), intracranial and intraventricular pressure monitoring (93.3%), and brain tissue oxygenation (60%). Cerebral monitoring by one or more monitoring devices was performed in 62% of the sedated patients. This proportion increased to 74% in the subgroup of patients with intracranial hypertension, with multimodal cerebral monitoring in 43.6%. The doses of midazolam and sufentanil were lower in sedated patients managed based on a sedation/analgesia scale., Conclusions: Midazolam and sufentanil are frequently used, often in combination, in French ICUs instead of alternative drugs. In our study, cerebral monitoring was performed in more than 60% of the sedated patients, although that proportion is still insufficient. Future efforts should stress the use of multiple monitoring modes and adherence to the indications for sedation to improve care of patients with BI. Our study suggests that the use of sedation and analgesia scales by nurses involved in the management of patients with BI could decrease the dosages of midazolam and sufentanil administered. Updated guidelines are needed for the management of sedation/analgesia in patients with BI., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: The present study aims at identifying the risk factors for ventilator-associated pneumonia (VAP) Staphylococcus aureus (S. aureus) in patients with severe brain injury (SBI)., Methods: In this multicentre, retrospective, observational study, patients ≥ 18 year old who had SBI (Glasgow coma scale GCS score < 9) who received mechanical ventilation for at least 48 h were analysed. The main objective was to identify risk factors for S. aureus VAP vs VAP due to other pathogens and to identify risk factors for S. aureus VAP vs patients who did not experience VAP., Results: Eight hundred and forty-seven patients with SBI were admitted in ICU after severe traumatic brain injury (n = 489, 58%), aneurysmal SAH (n = 156, 18%), stroke (n = 27, 3%), spontaneous intracranial haemorrhage (n = 80, 9%), arteriovenous malformation rupture (n = 25, 3%), and other causes (n = 70, 8%). Three hundred fifty of 847 patients (41%) had VAP with S. aureus (n = 161) or other pathogens (n = 189). In patients with VAP, the multivariate analysis shows that age per 10 years of ageing (OR 0.80, 95% CI [0.70; 0.90]; p < 0.001) and tobacco use (OR 0.54, 95%CI [0.33;0.88]; p = 0.014) were protective factors against S. aureus. Age per 10 years of ageing remained a protective factor against S. aureus VAP vs no VAP (OR 0.80, 95%CI [0.73; 0.89], p < 0.001)., Conclusions: In this retrospective study involving patients with SBI and who experienced VAP, increased age and tobacco use were protective factors against VAP due to S. aureus. Increased age remained protective against S. aureus in VAP vs no VAP analysis., (Copyright © 2020 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

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.

Purpose: We assessed outcomes in brain-injured patients after implementation of a multi-faceted approach to reduce respiratory complications in intensive care units., Methods: Prospective nationwide before-after trial. Consecutive adults with acute brain injury requiring mechanical ventilation for ≥24 h in 20 French intensive care units (ICUs) were included. The management of invasive ventilation in brain-injured patients admitted between 1 July 2013 and 31 October 2013 (4 months) was monitored and analysed. After the baseline period (1 November 2013-31 December 2013), ventilator settings and decision to extubate were selected as targets to hasten weaning from invasive ventilation. During the intervention period, low tidal volume (≤7 ml/kg), moderate positive end-expiratory pressure (PEEP, 6-8 cm H 2 O) and an early extubation protocol were recommended. The primary endpoint was the number of days free of invasive ventilation at day 90. Comparisons were performed between the two periods and between the compliant and non-compliant groups., Results: A total of 744 patients from 20 ICUs were included (391 pre-intervention; 353 intervention). No difference in the number of invasive ventilation-free days at day 90 was observed between the two periods [71 (0-80) vs. 67 (0-80) days; P = 0.746]. Compliance with the complete set of recommendations increased from 8 (2%) to 52 (15%) patients after the intervention (P < 0.001). At day 90, the number of invasive ventilation-free days was higher in the 60 (8%) patients whose care complied with recommendations than in the 684 (92%) patients whose care deviated from recommendations [77 (66-82) and 71 (0-80) days, respectively; P = 0.03]. The mortality rate was 10% in the compliant group and 26% in the non-compliant group (P = 0.023). Both multivariate analysis [hazard ratio (HR) 1.78, 95% confidence interval (95% CI) 1.41-2.26; P < 0.001] and propensity score-adjusted analysis (HR 2.25, 95% CI 1.56-3.26, P < 0.001) revealed that compliance was an independent factor associated with the reduction in the duration of mechanical ventilation., Conclusions: Adherence to recommendations for low tidal volume, moderate PEEP and early extubation seemed to increase the number of ventilator-free days in brain-injured patients, but inconsistent adoption limited their impact. Trail registration number: NCT01885507.

Background: Hospital-acquired pneumonia is common after traumatic brain injury, and might be partly a result of traumatic brain injury-induced adrenal insufficiency. We tested the efficacy of low-dose hydrocortisone with fludrocortisone for the prevention of hospital-acquired pneumonia., Methods: We did this double-blind, phase 3, placebo-controlled trial in 19 intensive care units in France. We enrolled patients aged 15-65 years in the first 24 h after severe traumatic brain injury (Glasgow coma scale score ≤8 and trauma-associated lesion on brain CT scan). Patients were randomly assigned (1:1; fixed blocks of 12, stratified by centre and mechanism, Glasgow coma scale, age, and arterial pressure [MGAP] score) to receive either hydrocortisone (200 mg per day tapered) and fludrocortisone (50 μg tablet once per day) or matching placebo for 10 days. Before receiving study drug, adrenal function was assessed with a short corticotropin test. Treatment was stopped if patients had no adrenal insufficiency. The primary outcome was the occurrence of hospital-acquired pneumonia within 28 days after randomisation. We did an intention-to-treat analysis and a modified intention-to-treat analysis including only patients with adrenal insufficiency (adjusted for etomidate use). This study is registered with ClinicalTrials.gov, number NCT01093261., Findings: From Sept 1, 2010, to Nov 29, 2012, we enrolled 336 patients (168 assigned to each group). Eight patients withdrew consent. At day 28, 74 of 165 patients (45%) in the steroid group and 87 of 163 (53%) in the placebo group had developed one or more episodes of hospital-acquired pneumonia (hazard ratio [HR] 0.75; 95% CI 0.55-1.03, p=0.07). In intention-to-treat analysis, we recorded 86 episodes of hospital-acquired pneumonia in the steroid group versus 110 in the placebo group (median 0, IQR 0-1 vs median 1, IQR 0-1 cases per patient, p=0.07). In modified intention-to-treat analyses, the HR for hospital-acquired pneumonia with steroids versus placebo was 0.80 (95% CI 0.56-1.14, p=0.22) in patients with adrenal insufficiency, and, in an exploratory preplanned analysis, 0·48 (0·23-1·01; p=0·05) in patients with normal adrenal function. We recorded no adverse events related to treatment., Interpretation: Low-dose hydrocortisone with fludrocortisone did not improve the outcome of patients with traumatic brain injury. However, the study was underpowered because the proportion of patients with hospital-acquired pneumonia in the placebo group was lower than expected. The results were close to statistical significance for efficacy, meaning that further studies are therefore needed., Funding: Société Française d'Anesthésie Réanimation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: S100B protein measurement in blood is proposed to exclude the presence of computed tomography (CT) lesions after minor head injury (MHI). We aimed to validate S100B as an accurate and valuable screening tool for MHI diagnosis in a large multicenter study, as well as: 1) to evaluate whether a second S100B blood level determination 3 h after the first one would be informative; 2) to compare the bioclinical performances of the two commercially available automated methods of measurement of S100B for the screening of patients., Methods: Four thousand and thirty MHI subjects were enrolled in a prospective observational multicenter study; results for serum S100B measurement determined within 3 h after the clinical event (H0) then at H3 were compared to that of cranial CT scans performed with 6 h following the presentation to emergency department. Both the Diasorin and the Roche Diagnostics assays were systematically performed., Results: Cerebral lesions on CT scan were identified with sensitivity and negative-predictive value (NPV) of 96.3% and 99.4% (Diasorin, 1 dissonant case), and of 100% and 100% (Roche Diagnostics, no dissonant case). Sensitivity and NPV at H3 appeared lower than those at H0, due to the rapid decrease in S100B levels., Conclusions: Serum S100B level on admission of patients with MHI is an accurate and useful screening tool to exclude intracranial lesions. Performing a second late S100B level determination is not informative. The two automated immunoassays appear usable in a similar manner, although the two methods are not interchangeable.

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC0-τ ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC0-τ ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF.

The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0-τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml(-1). This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution.

Objective: To evaluate the efficacy and safety of oral care with povidone-iodine on the occurrence of ventilator-associated pneumonia in a high-risk population., Design: A multicenter, placebo-controlled, randomized, double-blind, two-parallel-group trial performed between May 2008 and May 2011., Setting: Six ICUs in France., Patients: One hundred seventy-nine severely brain-injured patients (Glasgow Coma Scale ≤ 8) or cerebral hemorrhage expected to be mechanically ventilated for more than 24 hours., Interventions: Participants were randomly assigned to receive oropharyngeal care with povidone-iodine (n = 91) or placebo (n = 88) six times daily until mechanical ventilation withdrawal., Measurements and Main Results: Primary endpoint was the rate of ventilator-associated pneumonia. Secondary endpoint included the rates of ventilator-associated tracheobronchitis and acute respiratory distress syndrome and patient's outcome. The number of patients evaluable for the primary endpoint (preplanned modified intention-to-treat population) was 150 (78 in the povidone-iodine group, 72 in the placebo group). Ventilator-associated pneumonia occurred in 24 patients (31%) in the povidone-iodine group and 20 (28%) in the placebo group (relative risk, 1.11 [95% CI, 0.67-1.82]; p = 0.69). There was no significant difference between the two groups for ventilator-associated tracheobronchitis: eight patients (10%) in the povidone-iodine group and five patients (7%) in the placebo group (relative risk, 1.48 [95% CI, 0.51-4.31]; p = 0.47). Acute respiratory distress syndrome occurred in five patients in the povidone-iodine group but not in the placebo group (p = 0.06). There was no difference between groups for ICU and hospital lengths of stay, as well as ICU and 90-day mortality., Conclusions: There is no evidence to recommend oral care with povidone-iodine to prevent ventilator-associated pneumonia in high-risk patients. Furthermore, this strategy seems to increase the rate of acute respiratory distress syndrome.

Central nervous system (CNS) antibiotic distribution was described mainly from cerebrospinal fluid data, and only few data exist on brain extracellular fluid concentrations. The aim of this study was to describe brain distribution of cefotaxime (2 g/8 h) by microdialysis in patients with acute brain injury who were treated for a lung infection. Microdialysis probes were inserted into healthy brain tissue of five critical care patients. Plasma and unbound brain concentrations were determined at steady state by high-performance liquid chromatography. In vivo recoveries were determined individually using retrodialysis by drug. Noncompartmental and compartmental pharmacokinetic analyses were performed. Unbound cefotaxime brain concentrations were much lower than corresponding plasma concentrations, with a mean cefotaxime unbound brain-to-plasma area under the curve ratio equal to 26.1 ± 12.1%. This result was in accordance with the brain input-to-brain output clearances ratio (CL(in,brain)/CL(out,brain)). Unbound brain concentrations were then simulated at two dosing regimens (4 g every 6 h or 8 h), and the time over the MICs (T>MIC) was estimated for breakpoints of susceptible and resistant Streptococcus pneumoniae strains. T>MIC was higher than 90% of the dosing interval for both dosing regimens for susceptible strains and only for 4 g every 6 h for resistant ones. In conclusion, brain distribution of cefotaxime was well described by microdialysis in patients and was limited.

Concentrations of unbound meropenem in the cerebral extracellular fluid (ECF) of two patients with acute brain injury were assessed by microdialysis. Brain ECF unbound-meropenem concentrations were lower than serum unbound-meropenem concentrations, with brain-to-serum area under the concentration-time curve ratios of 0.73 and 0.14. A pharmacokinetic model was developed to fit the experimental data adequately.

Unlabelled: The aim of this study was to evaluate the effect of ventriculostomy on intracranial pressure (ICP), and related parameters, including cerebrospinal compensation, cerebral oxygenation (PbtO2) and metabolism (microdialysis) in patients with traumatic brain injury (TBI)., Materials and Methods: Twenty-four patients with parenchymal ICP sensors were prospectively included in the study. Ventriculostomy was performed after failure to control ICP with initial measures. Monitoring parameters were digitally recorded before and after ventriculostomy and compared using appropriate tests., Results: In all patients ventriculostomy led to rapid reduction in ICP. Pooled mean daily values of ICP remained < 20mmHg for 72h after ventriculostomy and were lower than before (p < 0.001). In 11 out of 24 patients during the initial 24-h period following ventriculostomy an increase in ICP to values exceeding 20mmHg was observed. In the remaining 13 patients ICP remained stable, allowing reduction in the intensity of treatment. In this group ventriculostomy led to significant improvement in craniospinal compensation (RAP index), cerebral perfusion pressure and PbtO2. Improvement in lactate/pyruvate ratio, a marker of energy metabolism, was correlated with the increase in PbtO2., Conclusion: Ventriculostomy is a useful ICP-lowering manoeuvre, with sustained ICP reduction and related physiological improvements achieved in > 50% of patients.